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Human Evolution is Leading to a Reduction in Alzheimer's Disease and Chronic Smoking
In order to understand the link between genetic variation and evolutionary fitness, scientists from Columbia University developed a new method of analysis which allowed them to quantitatively measure viability selection. Using their novel methodology, researchers were able to identify a significant reduction in the frequency of the genes APOE and CHRNA3, which are responsible for Alzheimer's Disease progression and chronic smoking, respectively. The study was conducted using two well established genetic cohorts, the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort and the parents of participants in the UK biobank. These groups allowed researchers to analyze genomes from about 200,000 people of varying genders and ages. Using their novel methodology, researchers were able to identify a significant reduction in the frequency of a limited number of genes, two of which were APOE and CHRNA3. APOE έ4 allele has been shown to be responsible for increased risk of both late onset Alzheimer's disease and cardiovascular disease. In this study, researchers were able to identify that the frequency of this gene significantly decreased in patients 70 years old or older, indicating the onset of purifying evolution. A similar pattern was identified for the nicotine receptor gene CHRNA3. In particular, the frequency of this gene is thought to significantly contribute to chronic or increased smoking. Interestingly, researchers noticed a linear decrease in the frequency of the A allele of this gene across all ages, once again indicating purifying evolution. Interestingly, the study also confirmed previous theory that higher levels of genetically predicted TC, LDL, BMI, and cardiovascular disease lead to reduced fitness as well as vitality. Cumulatively, the authors are hopeful that they can apply their novel methodology to analyze even more cohorts for genetic viability and new patterns of humane evolution.
Using IPSC Derived Dopaminergic Neurons to Cure Parkinson’s Disease in Monkeys
A hallmark of Parkinson’s disease is the degeneration of mid brain dopaminergic neurons. This loss is thought to be one of the main causes of the reduction of voluntary body movement; the key characteristic of Parkinson’s Disease (PD). In order to reverse the effects of this degeneration, investigators from Kyoto University grafted dopaminergic neurons produced from IPS cells directly onto the putamen of cynomolgus monkeys with PD phenotype. The researchers began this project by isolating skin cells from healthy and PD affected human individuals and reverting those cells into IPS cells. The 8 IPS cell lines were induced to develop into midbrain dopaminergic neurons via SMAD inhibition and floor plate induction. The resulting cells were analyzed for dopaminergic specific markers and expanded to create implantable grafts. The grafts were implanted into both sides of the putamen of MPTP (dopaminergic inhibitor) and immunosuppressant treated monkeys. In order to evaluate the efficacy of the graft the monkeys were subjected to a neurological rating scale and a video based analysis of spontaneous movements. The monkey’s which received grafts all showed improved neurological function with no signs of abnormal behavior, even if the IPSC donor had PD. The researchers were also interested in identifying if this treatment had similar efficacy to the known PD drug L-DOPA. Interestingly, PD monkeys with neuronal grafting responded similarly to those given L-DOPA in neurological rating, but lower in their analysis of spontaneous movement. However, efficacy of a new treatment means absolutely nothing if the drug is not safe, therefore the researchers analyzed each grafted monkey for cell survival and proliferation via MRI and PET for over 1 year. The resulting analysis revealed that the grafted tissue not only survived, but showed signs of neurite extension. Lastly, it was important to confirm that the grafted neurons actually behaved like natural dopaminergic neurons to prove that the cognitive increase of treated monkeys was due to an increase in dopaminergic activity. Through [F]-DOPA-Pet, researchers showed that transplanted monkeys did have higher rates of [F]-DOPA intake then non treated animals. From these studies, researchers are confident that grafting might be a viable option in the near future to treat, and even cure, PD.
Being Female is No Longer a Default Sex, But an Active Embryonic Decision
Every embryo contains both male and female reproductive ducts known as Wolffian ducts (male) and Mullerian ducts (female). Early literature suggested that sex determination occurred only though the development of male specific hormones. Without the presence of these hormones, the XX embryo would degrade the Wolffian duct and subsequently become female. If the embryo was XY, the male specific hormones would lead to the degeneration of the Mullerian duct and the embryo would develop as a male. This theory was well accepted in the field of developmental biology, and therefore has been the primary theory taught in developmental biology classes for decades. However, a group of researchers from the National Institute of Health Sciences in Research Triangle Park have recently revealed that this 70 year old principle is actually wrong. The research team began their investigation with the intention of better understanding the role of chicken ovalbumin upstream promoter transcription factor 2 (COUP-TFII) in communication between the outer layer and inner lining of the Wolffian duct. Using the Cre-Lox system, Coup-TFII was knocked out of the wolffian duct in male and female mouse embryos and the resulting embryos were analyzed for disruptions in reproductive duct communication. Interestingly, the analysis revealed that without expressible COUP-TFII, XX embryos maintained a Mullerian duct (as expected) as well as a Wolffian duct, despite not having any detectable levels of male hormone. To further investigate the role of COUP-TFII in duct formation, researchers analyzed COUP-TFII knockout XX animals for lifespan, ovary specific gene expression, male specific hormone production, and growth factor gene expression. The results of this analysis revealed that the effect of COUP-TFII was independent of male specific hormone and ovary specific gene expression. However, the data did reveal that inhibition of COUP-TFII expression was not only lethal, but also lead to the upregulation of Wollfian duct specific p-ERK, a member of the specific fibroblast growth factor (FGF) signaling pathway. From these results, researchers now believe that male and female reproductive ducts are actively degraded during development, as opposed to just the Wolffian duct as previously predicted.
Unraveling the Synthetic Process of the Psychedelic Compound Psilocybin
The psychostimulant psilocybin can be isolated from a wide range of “magic mushrooms” within the genus Psilocybe. This drug has been used recreationally for decades due to its potent psychotropic effects including visual hallucinations and sensory over-activation. Recently, clinical studies have shown that psilocybin is also able to reduce nicotine addiction and provide temporary relief from depression and anxiety in cancer patients. These beneficial effects lead researchers to become interested in identifying a way to synthetically produce psilocybin for large scale biotechnology production. However, up until recently it was relatively unknown how various strains of magic mushrooms synthesized psilocybin. Researchers from Freidrich Schiller University undertook this task by first sequencing two different strains of mushrooms within the genus Psilocybe, P. cubensis and P. cyanescens. The sequencing data revealed a grouping of 4 genes which corresponded to the four enzymes predicted to synthesize psilocybe; psiD (L-tryptophan decarboxylase), psiH (hydroxylase), psiM (SAM-dependent methyltransferae), and psiK (kinase). The sequences of these genes were then cloned to create expression plasmids prior to transformation into E.coli and subsequent purification via metal affinity chromatography. Each isolated enzyme was then exposed to various suspected precursors of psilocybin and used for LC-MS to identify the products of each individual reaction. After this experimental procedure was performed using all four enzymes, similar assays were conducted using varying combinations of enzymes and substrates. Cumulatively, these experiments were all performed in order to identify the specific sequence of enzymatic reactions, reactants, and products which lead to the synthesis of psilocybin. The findings of this study open the door to large scale industry production of psilocybin and its use in clinical trials to treat depression, anxiety, and a host of other psychological conditions.
Glucose Driven Nanoswimmers Engineered to Cross the Blood Brain Barrier
The blood brain barrier (BBB) is a dynamic protective membrane which guards the central nervous system from foreign invaders and disruptions in metabolic homeostasis. The BBB is able to accomplish this due to its minimal permeability and selectively placed carrier proteins. However, in order for the brain to function normally, the BBB has to allow for the constant passage of glucose, the brains sole source of energy. Knowing this key feature, researchers at the College of London were able to engineer polymersome nanocarriers to pass through the BBB in hopes of delivering chemotherapeutic cargo directly to brain tumors. Within the study, they engineered existing polymersomes, PMPC-PDPA, and POEGMA-PDPA, to self propel towards environments with higher concentrations of glucose. They accomplished this by encapsulating the enzymes glucose oxidase and glucose catalase within the polymersome, therefore inducing the conversion of endogenous glucose to D-glucono-δ-lactone and water. This reaction induces what is known as a a slip velocity on the surface of the nanocarrier, leading to an extremely sensitive propulsion toward areas with higher-concentrations of glucose, i.e, the brain. Once it reaches the BBB it is able to cross over into the brain parenchyma four times higher than similar, non chemotaxic polymersomes. The findings of this study make researchers hopeful that one day clinicians will not be worried if their drug of choice is passing through the BBB, but confident that through the use of this chemotaxic nanocarrier, they can reach any target with no issue.
A Cow's Immune System Can Produce Antibodies to Fight HIV in Humans
The HIV virus is designed to evade the human immune system. The virus's glycoprotein envelope contains a large amount of hidden antigenic regions, making it nearly impossible to be neutralized by human antibodies. This is because like most vertebrates, human CDR3 loops only contain 12-16 amino acids, rendering vertebrate antibodies to small to successfully recognize the concealed conserved epitopes on HIV's envelope. However, cow antibodies have much larger CDR3 regions, containing an average of 23 amino acids and a maximum of 70. To determine if cows could produce broad neutralizing antibodies against HIV, researchers immunized 4 cows with BG505 SOSIP, a soluble trimer which antigenetically mimics the human HIV viral envelope. After immunization, these cows had their blood drawn and subsequently utilized for longitudinal serum analysis and virus indicator panels. The results indicated that cows immunized with BG505 SOSIP were able to produce anti-HIV broadly neutralizing antibodies with high levels of breadth and potency. This immune response also occurred much faster than predicted, beginning as early as 42 days post-immunization. These astonishing results led the research team to try to identify what specifically could be causing the cows immune system to respond so positively to the HIV infection. As predicted, the isolated broad neutralizing antibodies contained very long CDR3 loops, and were eventually proven to be responsible for the strong immune response. This discovery opens the door to using cow's to produce antibodies for other difficult antigens, possibly helping researchers find a cure for HIV and other lethal infections.
The Genetic Cause of Dog's Hyper-Sociability
It is somewhat common knowledge that domesticated dogs are direct descendants of wolves. However, what remains unknown, is what evolutionary event led to this divergence. Researchers at Princeton University believe they have found specific genetic mutations which helped wolves evolve into mans best friend through a mechanism which they call "survival of the friendliest". The 2 genes, GTF2I and GTF2IRD1, were mutated in domesticated dogs which when faced with challenging tasks, looked directly for their human counterparts for help. Wolves, on the other hand, did not have any variation in these 2 genes and seemed to rely on their own instincts to figure out difficult tasks. Interestingly, researchers also noted that these genes are also similarly mutated in people which suffer from Willams-Beuren syndrome, a disorder which has been shown to cause hyper-sociability. Because of this connection, the identification of these 2 mutations could very well be a significant step in defining the genetics of behavior, possibly tackling the ever on-going debate of "nature vs nurture" and defining the evolutionary leap between wolves and man's best friend.
Novel Phagocytic Immune Cells Discovered Through Single Cell Transcriptomics
The identity of key immune cells has been known for decades, however, new sub-types of these immune cells are harder to discern. In order to identify specific cell surface markers which can distinguish between immune sub-types, researchers at MIT and Harvard analyzed 2400 HLA-DR+ cells from healthy human blood samples using single cell RNA sequencing, or transcriptomics. Through the use of this unique strategy, unbiased genomic classification, and characterization, these researchers were able to successfully discover 10 new phagocytic immune cell types; 6 dendritic cell subtypes and 4 monocyte subtypes. Prior to these experiments, one of these newly discovered dendritic cells was mistakenly classified as a plasmacytoid dendritic cell (PDC). This identification was made from a functional assay which showed that the newly identified cell was able to activate T-cells, an ability uncharacteristic of PDC's. This study was the first of its kind to use single cell transcriptomics to identify novel immune cell subtypes, and the authors are confident that it won't be the last.
Novel Antibody Vaccine Prevents Cytomegalovirus Transmission
Cytomegalovirus (CMV) can be transmitted to children and adults alike, however, healthy adults are usually asymptomatic and therefore easily can infect others, including expecting mothers. If a pregnant woman has unknowingly contacted CMV she will inevitably pass the virus to her unborn child through a process called placental transmission. Fetus's which contract CMV will likely be stillborn or born with severe developmental impairments and mental retardation. However, researchers at Duke University School of Medicine and Tulane National Primate Research Center have recently discovered a novel antibody vaccine which inhibits viral transmission and disease development of CMV in the offspring of infected rhesus monkeys. Specifically, researchers injected pregnant CD4+ depleted rhesus monkeys with hyperimmune globulin (HIG) produced from RhCMV-seropositive monkeys one hour before exposure to a mixture of RhCMV strains. The injected Dams showed a strong adaptive immune response, and therefore were able to combat any forthcoming infection with RhCMV. Because of this, the virus was not able to be transmitted to any offspring and the Turlane National Primate Research Center was able to welcome a new litter of healthy CMV free Rhesus Monkey infants.
Chronic Sleep Deprivation Could be Costing You Precious Memories
A scientist's greatest asset is their mind, so why do they risk their cognitive ability for small experimental victories? The answer is simple, they most likely are unaware of the damage that chronic sleep deprivation can have on their brains. A recent publication in the Journal of Neuroscience has revealed that sleep deprivation can up-regulate astrocytic phagocytosis (AP); the process by which astrocytes remove neural debris accumulated throughout the day. Specifically, Bellesi and her team discovered that astrocytes "eat" large pre-synaptic elements within a few hours of sleep deprivation. This lead them to hypothesize that the process of AP is a means of maintaining well used and relatively old synapses during periods of extended wake. However, if this period of wake is continued into the chronic range (5 days), microglial phagocytosis (MP) will become activated. MP is the process by which microglial cells remove unusable cells from the brain, however, during chronic sleep deprivation this process becomes rampant and has the capability of destroying healthy connections. In turn, the authors believe that chronic sleep deprivation predisposes the brain to secondary forms of insult, including neurodegenerative diseases such as Alzheimer's.
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Food allergies are linked to childhood anxiety and depression
Childhood allergy is a significant problem facing children and parents across the country, with increasing cases in childhood food allergy: nearly six million (almost one of every 13 children). Researchers never stop looking for what is the mechanism of food allergy development. "Hygiene factors hypothesis" explains that risks of allergic disease can be lowered by early exposure of immune system to germs/allergens. A recent article published in The Journal of Pediatrics investigated the prevalence of food allergy in low socioeconomic and ethnic minority populations. The results indicated a connection to anxiety and depression. The researchers also point out a possible explanation for not finding a link between food allergy and depression in children.
Training the immune system to produce antibodies against heroin
Heroin is one of the longest known and commonly abused psychoactive drugs, where opioid abuse has reached epidemic levels in US alone. The treatment options are still limited for addicts. A recent article published in JACS, showcased a heroin lead vaccine that is effective in monkeys, generating significant and sustained antidrug IgG titers. The heroin vaccine was developed through comprehensive evaluation of carrier protein, hapten structure, as well as vaccine adjuvant and dosing. As shown in the preclinical data, the long-lasting effects of this vaccine is proved to be durable for over 8 months, shedding light on prevention and treatment of opioid use disorders.
Fluorescent dyes to identify Whiskey counterfeits
The simple analysis of complex products is of great importance to tell the authenticity and batch-to-batch variations. This is particularly true for quality control and assurance for food and pharmaceutical products. Due to the difficulty in constructing specific sensors or assays for those analytes powerful alternative methods are desired. In a recent article from Chem, the drink whiskey is used as an example. The identification of a given whiskey sample usually requires a master distiller with years of experience to tell the brand, origin, blending state, age, and taste. The authors developed "a different kind of tongue" consisting of charged fluorescent dyes can differentiate more than 30 whiskies according to their fluorescence intensity modulated by different factors. Furthermore, those fluorescent dyes can also be applied to ID counterfeits and impurities in foods, drinks, drugs and perfumes.
We are what we eat: Diet and decision making
To some extent, it is true that "we are what we eat". Beyond the physical benefits of adequate nutrition, different types of food in-take and the ratio of carbs and protein correlate with our "decision making". A low-carb diet might make you a "better man", a more tolerant person. According to a new publication in PNAS, people who had fewer carbs at breakfast would make more forgiving decisions in a money-sharing games played several hours later. The reduction in carbohydrates intake usually is supplemented by a higher protein. It is also revealed what affect a precursor to a crucial compound in our blood, which further impact behaviors such as forgiveness and tolerance.
Why a "broken-heart" cannot repair itself?
Heart disease is the leading cause of death, partially due to the fact that heart muscle is one of the least renewable tissues in the human body. In a recent publication from Nature, it studied the following: 1) Hippo pathway which relates to stop renewal of adult cardiomyocytes, and 2) the dystrophin glycoprotein complex (DGC) pathway which is important for maintaining normal functions of cardiomyocyte. Components of the DGC pathway interacts with the Hippo pathway, and the consequences were studied in animal models. For the first time, it has been shown that dystroglygan 1 from the DGC pathway directly binds to Yap of the Hippo pathway, which further inhibits cardiomyocyte proliferation.
Cross-Fit and type 2 diabetes: New benefits discovered
It has been shown that physical activities and fitness exercises that can elevate heart rate are beneficial for beta-cell function and insulin secretion. However, patients with type II diabetes may find it hard to follow a strict work-out routine. Short functional-movement and resistance training workouts (F-HIT), such as CrossFit, combine functional movements, weights, and cardio training which minimum amount of time commitment. A group of adults with type II diabetes were enrolled in an F-HIT program, and their beta-cell function was further studied. The results show that "short-term F-HIT training significantly increased beta-cell and liver function", which improves insulin sensitivity and blood glucose levels.
Design deployable devices: What we can learn from Ladybug wings
It is fascinating to see ladybugs that are able to maintain their wings as rigid and strong during flight, then transform to compact and foldable state for easy storage while wandering on the ground. Previous studies have indicated that up/down movements in the complex crease patterns and the up/down movement in the abdomen contribute to the functional "folding process". However, the detailed process is difficult to observe since the ladybugs close their elytra before wing-folding. In a recent PNAS paper, a group of Japanese scientists take advantage of artificial elytron to further examined the mechanism, with valuable lessons learned for deployable structures design, such as medical devices and ordinary subjects in daily life.
Antibody linked biosensor enables point-of-care drug monitoring
Monitoring drug concentration in the blood from patients is critical, and an antibody-linked biosensor shows the potential be incorporated to use in the field or by patients at home. The previously established biosensors set-up include three components: 1) A protein that binds to the drug being monitored; 2) a light producing enzyme called luciferase; and 3) "SNAP-tag", a tagging molecule carrying a fluorescent ligand that the protein recognize when no drug is bound. From an article in Angewandte Chemie International Edition, a recent innovation has been made by replacing the binding protein of the biosensor with part of an antibody against the drug-of-interest.
Typically, the concentration of the antibody drug can be a million times lower than the serum antibody concentration, which makes it difficult to detect or quantify antibody drugs. Given their unique ability to identify drug antibodies in biological fluid, anti-idiotype (anti-ID) antibodies are widely used in drug development studies. Rabbit monoclonal antibodies (MonoRab™) show superior advantages in terms of high affinity and better specificity, which makes the rabbit mAbs perfect for developing anti-ID antibodies, and the following PK and immunogenicity assays/kits.
New study reveals how trout navigate to find their way home
The Earth's magnetic field is generated by the flow of molten metal inside the core, which is more than 100 times weaker than a refrigerator magnet. Many animal species can detect and take advantage of this week magnetic field for their navigation. Examples include sea turtles, bees, pigeons and etc. Without the help of GPS or compass, rainbow trout navigate themselves traveling hundreds of miles, back to the rivers where they were born from the sea. The underlying cellular and molecular machinery are yet to be found out by researchers, as well as the genetic basis. In a recent article published in Biology Letters, a set of genes have been identified that enables trout to complete their epic journey: changes in the gene expression and the disruption of rainbow trout's magnetic sense are revealed.
How one single tea leaf is packed with antioxidants and caffeine, and so many different flavors?
Green tea, black tea, oolong tea, white tea, chai and many others all come from the leaves of Camellia sinensis, also as known as "the tea tree". There are many different kinds of teas which are enriched with cultural and economic significance. However, we know little about tea leaves from the evergreen trees. Previous studies showed that the flavonoid, a group of antioxidants, help tea trees survive in their environments and also play a role in the tea flavors. In a recent article in Molecular Plant, scientists found in the tea tree genomes that make tea leaves so special and the genetic basis of different tea flavors.
Why people see differently in "the dress challenge"?
There has been considerable interest in the dress (as a "stimulus") that yield strikingly divergent subjective color perceptions between "observers": white-gold or black-blue has been argued. This challenged our entire color vision. Two years later, we finally know why people saw "the dress" differently. In addition, people's perceived color is also informed by their perception of lighting. Interestingly, circadian control also plays a role. Whether the stimulus was illuminated by natural light, artificial light, or under a shadow strongly affects the observers subjective interpretation. Smaller influence was observed for demographic factors, such as gender or age. Interestingly, people who identify themselves as "night owls" or "morning larks" showed correlations of the colors they see.
Traffic-related air pollution and cardiovascular disease
What is the mechanism on the correlation between air pollution and development of cardiovascular disease is uncertain. The connection may be explained by a reduction in the number of small cholesterol-depleted high-density lipoprotein (HDL) particles, resulting in higher average amount of cholesterol in the HDL particles. Researchers recently found that exposure to black carbon from air pollution induced by traffic is associated with the "good cholesterol", further increase the risk of cardiovascular disease. It is suggested that the number and functionality of HDL particles matter more than their cholesterol content. The change may happen as quickly as a short exposure to the polluted air. Men and women show different responses: with a higher impact in women. This is the beginning of understanding the biology behind.
Traffic-related air pollution and cardiovascular disease
What is the mechanism on the correlation between air pollution and development of cardiovascular disease is uncertain. The connection may be explained by a reduction in the number of small cholesterol-depleted high-density lipoprotein (HDL) particles, resulting in higher average amount of cholesterol in the HDL particles. Researchers recently found that exposure to black carbon from air pollution induced by traffic is associated with the "good cholesterol", further increase the risk of cardiovascular disease. It is suggested that the number and functionality of HDL particles matter more than their cholesterol content. The change may happen as quickly as a short exposure to the polluted air. Men and women show different responses: with a higher impact in women. This is the beginning of understanding the biology behind.
Zika virus pathogenesis can be enhanced: New studies
Antibodies against related flaviviruses can cross-react with Zika virus, even increase disease severity. Zika virus is spreading into regions around the globe where other flavivirus are regularly found. It is revealed in a recent article in Science that antibodies against related viruses could enhance Zika infection, which highlights cautions for flavivirus vaccines design. Low titers of dengue and West Nile antibodies enhanced Zika virus viremia. However, high titers of antibodies remain protective. This antibody-dependence enhancement may also help explain the severe disease manifestations behind recent Zika virus outbreaks.
Is there any correlation between intelligence and life-span?
The first evidence of learning-associated cost is revealed.
Does it worth it to being smart? Apparently not for bumble bees. Researchers found that smart bumblebees die faster and don not collect as much food over their life-span, compared with less intelligent peers and co-workers, according to a new study published in Scientific Reports. It was suggested that the energy demands of "being smart" consume the limited resources, leaving the intelligent bees with less energy for foraging, compared with their peers who are slow-learners. This is the first evidence of a learning-associated cost in the wild, which may have implications for other species as well.
Lisa J. Evans, et al. Fast learning in free-foraging bumble bees is negatively correlated with lifetime resource collection. Scientific Reports, 2017
New studies on contagious itching
Feeling an itch sparkled when watching others scratching themselves? Previous studies suggest that this phenomenon is more prevalent among highly neurotic people. It is always associated with "empathy" and innate behavior such as instinct. Humans and monkeys are not the only species that find they can catch an itch. A recently Science article reported that mice also start scratching when they see someone else is scratching. The mechanism behind how it is programmed in the brain's neurocircuitry is further explored. The role of a neuropeptide denoted as gastrin-released peptide is also revealed.
Yao-Qing Yu, et al. Molecular and neural basis of contagious itch behavior in mice. Science 2017
Your blood type can be determined within seconds using this new paper tool
Knowing the blood type of patients is crucial before a transfusion. Current blood type testing requires substantial amount of time spent with special equipment to centrifuge and separate red blood cells from plasma. In addition, blood tests can only be done by professionals with proper training. A recent article published in Science Translational Medicine, reported a new paper tool to test blood type, fast and cheap. Only one drop of blood in the center of a paper based chip (holding antibodies recognizing different makers), the blood type can be determined accurately within 3o seconds. This process can also be modified for testing rare blood types. Quick blood test like this will be beneficial to deal with emergencies in places with limited resources.
Hong Zhang, et al. A dye-assisted paper-based point-of-care assay for fast and reliable blood grouping. Science Translational Medicine 2017
Uniform glycan engineering for therapeutic antibodies
The configuration of sugar groups in the Fc region of antibodies plays a significant role in determining an antibody's capability to activate the immune response. The specific sugar combinations and configurations can enhance or suppress the signal of an antibody send to the immune system to attack intruders. Antibodies with identical structures often show naturally occurring differences in terms of the attached sugar groups (different glycoforms). Existing methods aiming to sort out glycoforms and select the most effective ones are often expensive, time-consuming, and not always effective. A recent PNAS article reported one first major step towards developing a method to produce "homogeneous glycoforms" which allows one to look at individual sugar forms directly and test the specific effects of a particular glycoform on the immune response.
Tiezheng Li, et al. Modulating IgG effector function by Fc glycan engineering. PNAS, 2017
Fresher and healthier food with biodegradable packages
Food packaging designed to preserve food for longer time usually consist of various types of plastic films, which are not eco-friendly, non-renewable, or non-biodegradable. An ideal type of food packaging would be composed by materials that are able to be naturally degraded and turn into fertilizer. Cellulose composites are under investigation by researchers in Kaunas University of Technology (KTU) for this purpose. They also go one step further by enriching the packaging materials with active components, which help preserve food fresh and healthy for a longer time. Active components from clove ethereal oil have anti-oxidizing effects, but lacking antimicrobial properties. This is overcome by adding ionic silver particles into the packaging film, which inhibits the growth of microorganisms and is able to remain active for an extended period of time.
The role of tissue stiffness in cancer's spread
Metastatic cancer is one type of cancer that has spread from the primary site (the part of the body where it started) to other parts of the body. As one of the physical-feedback mechanism studies between cancer cells and their environment, researchers form University of Pennsylvania have identified that physical forces exerted between the extracellular matrix (ECM) and cancer cells are strong enough to drive a "change of shape" that is necessary to make metastasis possible. According to a recent publication in PNAS, the authors further explained that cancer cells respond to an "optimal stiffness" of the surrounding ECM: neither too soft nor too stiff. One could predict whether the tumor will spread by just looking at what is going on outside the tumor. This finding suggests that drugs designed to target the stiffness of the ECM could be potentially used to prevent metastasis.
Hossein Ahmadzadeh, et al. Modeling the two-way feedback between contractility and matrix realignment reveals a nonlinear mode of cancer cell invasion. PNAS, 2017
The long-lived plasma cells are supported by regulatory T cells in bone marrow
Plasma cells are B cells found in bone marrow with an extensive lifespan that produces antibodies against previously encountered pathogens or vaccines. Being an important part of the immune system, plasma cells also contribute to the development of autoimmune diseases and certain types of cancers. According to a recent study published in Cell Reports, an unexpected interaction between regulatory T cells and plasma cells in bone marrow was observed. The presence of plasma cells are supported by regulatory T cells. How to control and target the population of the long-lived plasma cells will shed light on enhancing the vaccine efficiency, as well limiting or preventing autoimmunity or cancer.
Arielle Glatman Zaretsky, et al. T Regulatory Cells Support Plasma Cell Populations in the Bone Marrow. Cell Reports, 2017
The time spends indoors links to cells in dysfunction in retina
"The eye needs to stop growing at precisely the right time during childhood". If the eye grows too long, it causes images cannot be focused where they should be on the retina. Thus, corrective glasses or contact lenses are required to deal with the nearsighted vision. Recently, scientists have discovered a type of cells in the retina that regulates the growth and development of the eye. When the cells are dysfunctional, it may cause myopia. In addition, there is a surprising link between the amount of time one spends indoors as a child and the occurrence of retina cell dysfunction. Away from the "natural light", cells in the eye could be over stimulated by indoor light spectrum. This discovery reveals new therapeutic targets to control myopia.
Adam Mani, Gregory W. Schwartz. Circuit Mechanisms of a Retinal Ganglion Cell with Stimulus-Dependent Response Latency and Activation Beyond Its Dendrites. Current Biology, 2017
What causes heart failure: New clues
Each year, about one quarter of the 700,000 Americans who suffer a heart attack continue to develop heart failure. A new study shed light on how one condition leads to another. The long-term immune response leads the heart muscle to transform into scar-like stiff tissues after heart attacks. A set of signaling proteins produced in a layer of heart muscle (epicardium) is suggested to play an important role in this damage-response process. This finding highlights the importance of the interaction between heart and immune system. "The immune system is regulating how we heal from injury in every way."The role of epicardial YAP and TAZ, two key components in the Hippo signaling pathway is also examined.
Vimal Ramjee, et al.Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction. Journal of Clinical Investigation, 2017
Why feeling sleepy when sick, and is it good for you?
As a behavior sequence after getting sick, humans and other animals alike often feel fatigue and sleepy. During acute infectious illness in mammals, electrophysiological correlates of sleep behavior are observed. A new study published in eLife explains the mechanism behind this. It is revealed that a single nerve cell (ALA) coordinates an organism-wide promotion of sleepiness in nervous system. This sleepiness is induced by the release of neuropeptides (such as FLP-13) from ALA. FLP-13 causes the drowsiness by turning down activity in the nerves system cells that keeping the organism awake. Nevertheless, moderate amount of sleep and rest is very important for mammals and human to recover during the sickness. This study shed light on critical findings toward developing therapeutics to treat human excessive fatigueless with sickness and other conditions.
Michael J Iannacone, et al.The RFamide receptor DMSR-1 regulates stress-induced sleep in C. elegans. eLife, 2017
How come birds are always ready for a marathon flight?
As human beings are constantly feeling miserable of making new-year's resolution to keep fit (and give up very often every year), or undergoing intensive training for marathon, you may be very envy the bar-headed goose. The birds have the strength and endurance to fly over 4,000 km without the need of any work-out prep beforehand, and better yet, they are always ready for the epic migration flight. According to a recent publication in Science, the goose is among many birds that don't require regular work out to stay fit. As a matter of fact, they might need to stay away from unnecessary work out "training" since it is harmful to them, as opposed to humans. The birds are so well adapted to the routine and their muscles get enough oxygen to flow through. Extra exercise is not required for certain species to stay in shape and more work needs to be done to determine whether other animals are more like us or the birds.
Pennisi, Elizabeth. Birds don't need exercise to stay fit for epic flights. Science, 2017
Manipulate wounds to heal as regenerated skin rather than scars
What makes scars different from normal skin is the loss of adipocytes (fat cells) and hair follicles. Myofibroblasts are the most commonly seen cells in wound healing process, leading to the formation of scar tissue. It is commonly believed that myofibroblasts are incapable of forming other type of cells to avoid developing scars. However, researchers have recently discovered a new method to manipulate wounds to heal as smooth regenerated skin, rather than scars. It is revealed that the loss adipocytes and hair follicles happen to develop "separately but not independently". Myoblasts are engineered to regenerate as fat cells instead of scar formation. New hairs also grow on those fat cells to make it indistinguishable from normal skin. As the first study of this kind observed in mammals, this revolutionary way of generating fat cells from myoblasts also have the potential for common complication of other conditions characterized with "fat-cell loss".
Maksim V. Plikus, et al. Regeneration of fat cells from myofibroblasts during wound healing. Science, 2017
Easy peasy anxiety relief: Checking mini-apps on your phones
More than 20% of Americans show significant symptoms of anxiety and depression, among which only 20% of them receive adequate treatment. There is a trend for developing digital tools to address mental health issues. Millions of people (who need help and support, but cannot make it to a therapist's office) can benefit from digital mental health tools. Just imagine that one can reduce anxiety and depression simply by checking apps installed on the smartphone, as easy as finding a French restaurant. A new study published in Journal of Medical Internet Research described a novel suite of 13 speedy, easy-to-navigate mini-apps called IntelliCare which offers exercises to reduce worrying and self-criticism, based on the results on 96 participants in this study. Those apps are designed to prioritize interactive skills training over education and are designed for frequent but short interactions. It also revealed a 50% decrease in the severity of depressive and anxiety symptoms after 8 weeks of using those apps.
David C Mohr, et. al. IntelliCare: An Eclectic, Skills-Based App Suite for the Treatment of Depression and Anxiety. Journal of Medical Internet Research, 2017.
How long it takes to recover from concussion: Ask the brain protein tau
Around 4 million sports-related brain injuries occur every year in United States alone. Doctors may describe those brain injuries or concussions as "mild" initially since they are usually not life-threatening. Nevertheless, the effects of concussions can be serious. If the patients resume to play before their brains are healed, the risks of long-term physical and cognitive conditions at a later time are significantly elevated. However, there is no reliable or objective tool to evaluate when the players are ready to back to join their teammates in the field. Doctors usually have to depend on the patient's self-reported symptoms to evaluate the recovery time. A recent article published in Neurology suggested that the level of brain protein tau is associated with the recovery time followed by concussions, with a potential to be used as a tool for physicians to determine when it is safe for players to "back into action".
Jessica Gill, et. al. Acute plasma tau relates to prolonged return to play after concussion. Neurology, 2017.
Complicated relationship between OTC medicines and cancer patients
It not unusual for cancer patients under treatment to take over-the-counter (OTC) medicines at the same time, sometimes on a long-term basis. For an example, over 20 percent cancer patients are taking proton pump inhibitors (PPIs). However, seemingly harmless easy-to-obtain OTC medicines have complicated impacts for certain cancer patients. A recent study in JAMA Oncology recommended that gastric cancer patients under chemotherapy should avoid taking PPIs, which could reduce the overall survival rate by more than 2 months. As for OTC non-steroidal inflammatory drugs (NSAIDs), increased risk of dying in patients diagnosed with Type 1 endometrial cancers is indicated by a recent article in Journal of the National Cancer Institute. This finding is surprising since it is against previous studies that suggest NSAIDs (such as aspirin and ibuprofen) can reduce the risk of developing certain types of cancers, and decrease cancer-related death as well. Nevertheless, more detailed, systematic review, and meta-analysis are desired to examine the controversy.
Michael P. Chu, et. al. Association of proton pump inhibitors and capecitabine efficacy in advanced gastroesophageal cancer.JAMA Oncology, 2016.
Theodore M. Brasky, et. al. Nonsteroidal Anti-inflammatory Drugs and Endometrial Carcinoma Mortality and Recurrence.Journal of the National Cancer Institute, 2016.
New mechanism of developing food allergy revealed
Childhood allergy is a significant problem facing children and parents across the country, with increasing cases in childhood food allergy: nearly six million (almost one of every 13 children). Researchers never stop looking for what is the mechanism of food allergy development. "Hygiene factors hypothesis" explains that risks of allergic disease can be lowered by early exposure of immune system to germs/allergens. A recent study in Allergy and Asthma Proceedings suggests that food allergy has less profound associations with hygiene factors than asthma. In addition to exposure to a food allergen, accumulating evidence supports an association between food allergens through broken skin with the development of food allergy.
Ruchi S. Gupta, et. al. Hygiene factors associated with childhood food allergy and asthma.
New study: Social status impacts how well the immune system works
Is there any interesting correlation between social status and health? Does low social status impair health conditions, and individuals with high social status tend to be healthier or with a more robust immune system? A recent study published in Science may provide some scientific support for anyone who desires to "climb the social ladder". Proinflammatory responses to social subordination affects stress and health. The researchers found that a proinflammatory response is promoted as a result of being subordinated in primate social status. Furthermore, the consequences of social status on the immune regulatory are also examined in this study. Subordination also triggers the elevated level of expression for genes that are relevant to immune responses, lymphocyte proliferation, and cytokine responsiveness.
Snyder-Mackler, Noah et. al. Social status alters immune regulation and response to infection in macaques
Great minds think alike as you do
Memories are being stored and recalled consistently, and a so-called "cognitive limbo" has been well-established by researchers studying memory. As the neurons in the brain continues to fire, the short-term memory (working memory) usually lasts for several seconds long. If this working memory is so important to you that it is going to be stored by permanently altered neuron connections, thus converted into the long-term memory. For the time in between, a memory catalog is built for us to choose at a later time, with some of them being lost in this "catalog and storage process". Everyone wishes to think the way like Sherlock Holmes, who can make all possible connections based on every single piece of memory stored in his knowledge base as a readily available collection. A recent study showed a fingerprint pattern for people to recall the same event, an inter-subject pattern correlation framework, and how their brains organize and store the memories in an extremely similar way, just like any other "great minds, including Sherlock Holmes.
Chen, Janice, et. al. Shared memories reveal shared structure in neural activity across individuals
How controlling Insulin affects Alzheimer's
Scientists have recognized a mechanism shared by the brain and pancreas that could be used for Alzheimer's therapy, Kir6.2 channel blockade. In the pancreas blocking these channels increases insulin signaling, subsequently decreasing blood sugar. In the brain,Kir6.2 channel blockade also affects insulin signaling, but by activating CaM II kinase. This kinase activation has shown to increases memory retention. Researchers at Tohuku University have shown that memantine, a common Alzheimer's drug which is thought to act through N-methyl-D-aspartate (NDMA) receptors, also affects the Kir6.2 channels. This reveals a new target, pathway, and mechanism that can be manipulated in patients. Recognizing insulin's involvement in modulating this potassium channel raises the question of what other diabetic therapies can be translated to Alzheimer's patients.
Moriguchi, et. al. Blockade of the KATP channel Kir6.2 by memantine represents a novel mechanism relevant to Alzheimer's disease therapy MOLECULAR PSYCHIATRY
Cooking temperatures affect how healthy your food is
Everyone knows that fried food isn't healthy, but could you say exactly why? The first suspect is the oil used, with trans-fat oil being the worst culprit. But new evidence reveals it's not just what you eat, but how you cook it. A multi-nation study examined various cooking techniques and found a strong correlation between heart disease the use of high temperatures to cook. Evidently, temperatures above 150 centigrade drive chemical changes in fats, especially trans-fats, that make them toxic. These "neo-formed contaminants" or NFCs and glycation end-products can occur even in roasting. The temperature makes the poison, and exacerbate the poison in the case of trans-fats. Worse still, reusing oil only served to the effects. Braising, steaming, and boiling, lower temperature cooking techniques, were correlated with lower rates of heart disease. Lowering the use of bad fats in cooking is one step, but lowering the temperature can also help stave off heart disease.
Starvation technique aids cancer therapy
Cancer therapies which require the transplantation of stem cells from healthy donor's bone marrow, first requires space or a niche to be opened so that the transplanted bone marrow cells may expand and survive without a host immune reaction. Currently this ablation is achieved through radiation or chemotherapeutic means, not just destroying the unhealthy cell populations in the process, but also damaging healthy tissue as well, in addition to it being a very painful process for the patient to experience. Scientists at the University of Tokyo have discovered a technique that avoids this non-specific approach and it hinges upon a single amino acid, valine. After searching through specific amino acid requirements for hematopoiesis, they found that stem cells required valine in order to create the required immune cells. Valine starvation therefore was tested in mice to a significant effect, creating the required niche for transplantation. However, slow reintroduction to the amino acid was required to prevent metabolic shock from rapid exposure to valine. With such a simple approach, they could enter clinical trials within years, potentially immediately improving the therapy and condition of patients with an elegant, nuanced approach.
Is pain communicable?
"The smell of fear." A common movie line of how to deal with predators or wild animals seemed like pseudoscience or fantasy until we came to understand more about pheromones. As it turns out, pain can be sensed by mice who are co-housed with mice feeling pain. Scientists from the Oregon Health and Science University have found that pain can be sensed by mere exposure to bedding of animal who was experiencing pain. These findings are not that surprising as they fall within our understanding of chemical communications. The most interesting finding from the study is that the mice sensing the pain of others themselves were sensitized to pain themselves. By activation of nociceptors, sensory nerve cells that innervate the central nervous system, these bystander mice experience hyperalgesia in both alcohol withdrawal and persistent inflammation models. This furthers our understanding of socially induced pain that reaches beyond empathy and into physical manifestations.
Smith, et. al. Social transfer of pain in mice SCIENCE ADVANCES
Without photosynthesis and cross-pollination, how does this plant survive?
If it doesn't photosynthesize, or flower is it even still a plant? Well, yes, but certainly not your run of the mill variety. The plant in question has been termed Gastrodia kuroshimensis. It was recently discovered in on the island of Kuroshima, Japan. Curiously, it derives its energy from fungi, avoiding the need of sunlight. What's more, this novel species creates buds, but does not flower. In doing so, it restricts its propagation to a cleistogamous strategy, budding but not flowering and self-pollinating. Typically plants with this feature also have a set of chasmogamous flowers, a way to both carry the advantages of each reproductive strategy. Cleistogamous plants conserve energy by not flowering, and are able to retain only helpful genes when variants arise. However, as opposed to the genetic variety afforded by cleistogamous plants, this new species may be more susceptible to climate changes as the variety required for fast adaptation is lacking. Both of these traits have been seen before, but the presence of both fungi dependence and self pollinating inside an un-bloomed bud offers the opportunity to study how and why such a plant evolved in the first place.
Suetsugu, et. al. Gastrodia kuroshimensis (Orchidaceae), a new mycoheterotrophic and complete cleistogamous plant from Japan PHOTOTAXA
Genes of the black widow spider borrowed by bacteriophage
In a complex layering of infections, the genes responsible for the toxin of a black widow spider have been found in a virus. This marks the first discovery of animal-like DNA incorporated into a virus. The virus, specifically the WO bacteriophage infects Wolbachia, a bacteria which in turn infects arthropods worldwide, including the black widow spider. This came as a complete surprise as researchers have thoroughly studied the virus over the past decade, only performing genome sequencing in the spirit of thoroughness. This discovery opens the question as to how and why this gene transfer occurred. The initial hypothesis put forth by researchers suggests the bacteriophage use the toxin to break through both the cell walls of the arthropod host as well as the Wolbachia to reach the site of replication. Beyond evolutionary intrigue, as Wolbachia infects arthropods worldwide, this may prove a useful tool in engineering the bacteria for treatments involving Zika and dengue by killing the vector mosquitos.
Bordenstein, et. al. Eukaryotic association module in phage WO genomes from Wolbachia NATURE COMMUNICATIONS
New finding shows alternative mechanism for statins
The established mechanism of action for statins involve inhibiting HMG-COA reductase, blocking the pathway for hepatic cholesterol synthesis, increasing LDL uptake from the circulation, and decreasing prenylation, the addition of hydrophobic molecules. Another feature of statins is the decrease in inflammation. Sometimes viewed as a side-effect of the major mechanisms of actions, new research reveals it may play a larger part in major mechanism. In brief, Oxidized Low-Density Lipoprotein (OxLDL) induce DC maturation. Statins, modulated by microRNA, repress dendritic cells (DC), blocking their maturation. T-regulatory cells subsequently induced by IL-10, result in decreased inflammation. These studies are though to extend into other cardiovascular diseases beyond coronary artery disease and into stroke. Clearly, the exact mechanisms of statins are hidden within a complex milieu, but revealing a component of immunological manipulation offers yet another addressable target as we refine cardiovascular interventions.
Frostegård, et. al. Oxidized Low‐Density Lipoprotein (OxLDL)–Treated Dendritic Cells Promote Activation of T Cells in Human Atherosclerotic Plaque and Blood, Which Is Repressed by Statins: microRNA let‐7c Is Integral to the Effect JOURNAL OF THE AMERICAN HEART ASSOCIATION
Insight into how we sense our bodies in space
When thinking of our senses we quickly list sight, touch, taste, and hearing. These cover the external stimuli we my encounter in any given environment. However, proprioception, the ability to sense and control our own body position, is often overlooked and taken for granted. A study of 2 subjects with extremely rare stretch-gated PIEZO2 ion channel variants reveal how much this matters. While the subjects were able to perform normal tasks including walking and writing, aberrant touch detection and ataxia resulted when visual cues were removed. Without compensatory visual input, dramatic exacerbation of ataxia and sense of vibrations. These subjects reveal the rare insight into such a little thought of, yet critical sense. Although these patients present with such a phenotype due to single gene variants, it important to consider the other possible pathways which constantly integrate to allow us to position our limbs and body in space.
Chesler, et. al. The Role of PIEZO2 in Human Mechanosensation THE NEW ENGLAND JOURNAL OF MEDICINE
Implantable scaffold uses immune cells to snare cancer
Catching cancer early is critical to patient survival. Late stage disease progression at the time of diagnosis significantly decreases 5-year survival rates as compared to early stage disease diagnosis. Metastatic seeding is therefore something both heavily researched in regards to early diagnosis, in addition to therapy prior to wide dissemination of tumor seeds. A recent Cancer Research article introduces an implantable scaffold which simultaneously addresses both of these issues. By implanting microporous poly(ε-caprolactone) (PCL) scaffolds, researchers were able to both detect cancer earlier, as well as modify distant metastatic seeding. Upon sub-cutaneous implantation, these scaffolds activate the dynamic immune response. Recruited immune cells localized to the scaffold then capture metastatic cells. Probing this scaffold allows for earlier disease detection as compared to interrogation of common metastatic sites such as the lung, liver, and brain. As such, this micropourous PCL can serve as a "canary in the coal mine", detecting what would otherwise still qualify as occult disease. Furthermore, the ability of this scaffold to capture circulating cancer cells offers a protective effect. Acting as a sink, tumor cells preferentially seeded within this scaffold, reducing tumor burden elsewhere, and consequently improving survival rates. This study only investigated two types of scaffold materials in the context of breast cancer, but as this approach is tested and refined in other cancer models it should provide both earlier diagnostic capabilities as well as prophylactic therapy across the disease space.
Rao, et. al. Enhanced Survival with Implantable Scaffolds That Capture Metastatic Breast Cancer Cells In Vivo CANCER RESEARCH
How "water bears" survive extreme drought and radiation
Micro-sized aquatic animals known as tardigrades, more commonly known as "water bears", have been observed to survive in unimaginable conditions. After experiencing severe drought, just add water and they revive. Expose them to extreme temperatures or even X-rays, conditions that normally denature proteins and DNA, and they just shrug it off. This durability extends to hypoxia, genotoxic stress, and even oxidative stress. Until a recent Nature communication article, scientists haven't been able to fully explain how accomplish they this. After addressing a previously proposed theory of horizontal gene transfer, which they rule out in their investigation, they look towards the stability of the genome. What they found was a selective loss of stress response pathways and constitutive expression of genes found only in the tardigrade. Following this line of research further, they were able to find a unique protein they termed Damage suppressor (Dsup) which strongly colocalized with the nucleus. Recombinant expression of the protein in human HEK293 cells, and subsequent exposure to radiation, recapitulated the protective effects seen in tardigrades by reducing DNA damage by 40% vs non-transfected controls. While the present theory proposes these effects are due to physical shielding of the DNA by the Dsup protein, there are already implications for how it may be used in humans. The protective effects of Dsup could be leveraged during cancer treatment to protect normal adjacent tissue during radiation therapy or whole body protection for astronauts constantly bombarded with radiation while outside the protection of our atmosphere.
Hashimoto, et. al. Extremotolerant tardigrade genome and improved radiotolerance of human cultured cells by tardigrade-unique protein NATURE COMMUNICATIONS
A means of maintaining beige fat
Brown adipose tissue, responsible for non-shivering thermogenesis in infants, was once thought to be lost with age as mitochondrial density wanes, relegating the tissue to a phenotype of white fat. The discovery that, in fact, a similar type of energy hungry beige fat is not only present, but whose conversion is inducible in adults, has reinvigorated the field of research. A Cell Metabolism article continues this trend, outlining a mechanism which may be used to counter the obesity epidemic and it's myriad comorbidities. Beige fat can be acquired through environmental or pharmacological means. Exposure to cold or dosing with β3-AR induces conversion to phenotypically beige fat deposits, but once continued stimuli is removed, conversion to white adipocytes commences. Previous studies have investigated this phenomena, but none have demonstrated that the adipocytes convert directly from beige to white, rather than through a common, intermediate, precursor stage. Through GFP reporter mice, researchers were able to track this type of direct conversion of beige to white-like adipocytes. Furthermore gene profiling and Fuzzy C-Means (FCM) sequence analysis revealed decline in mitochondria biogenesis in step with white adipose tissue conversion. Autophagy degradation of the mitochondria, or mitophagy, was found to be required for this transition, with lower levels in beige fat deposits. As expected, genetic and pharmacological inhibition of the mitophagy pathways retained the beige fat phenotype and it's benefits such as a decrease in overall body fat and glucose tolerance maintenance. Understanding this mechanism may also inform studies of how induction of beige fat may be accomplished.
Altshuler-Keylin, et. al. Beige Adipocyte Maintenance Is Regulated by Autophagy-Induced Mitochondrial Clearance CELL METABOLISM
Multicomponent virus found in animals
To say viruses are diverse would be an understatement. RNA virus genome structure variety outnumbers that of any other type of creature on the planet. Perhaps this should come as no surprise as viral replication is dependent upon those less varied organisms, driving viral evolution to find many ways to infect a limited assortment of hosts. What is surprising is the seeming restriction of a virus type to plants and fungus. Multi-component viruses are identified by the packaging of their genome into distinct, segmented regions, and until recently were only discovered in plants and fungi. Evidence for this discovery in animals was made in a recent Cell article, noting the discovery of a 5-segment virus found in mosquitos, Guaico Culex virus (GCXV). Expanding the search further, researchers discovered a related virus in a red colobus monkey in Uganda, the Jigmen tick virus (JMTV). These viruses share properties with the larger flavirus genus which includes Zika, yellow fever, West Nile, and dengue to name a few. What is interesting from this study, beyond the presence of a multi-component virus in animals, is the new feature it carries with it, enveloped particles. Plant and fungal multi-component virus particles do not have such enveloped particles yet this feature is a common trait within the flaviviral genus. Furthermore, only 4 of the 5 segments of GCXV were found to be required for replication, with the one optional segment believed to play a role in pathogenesis. As the study of multi-component viruses in animals is still a relatively young field, more research is required to understand their evolutionary drive towards such a counter-intuitive means of genome structuring and delivery. Beyond how the virus came to be found in primates, its presence in primates also has implications for it's potential jump and threat to human health.
Ladner, et. al. A Multicomponent Animal Virus Isolated from Mosquitoes CELL HOST & MICROBE
New Mechanism: post-infarct angiogenic renovation requires demolition
As cancer researchers seek to turn off the formation of new vasculature in developing tumors, cardiovascular research seeks to do the opposite. By harnessing the body's ability to generate new blood vessels, known as angiogenesis, researchers hope to eventually treat even severe cardiovascular events with pharmacological solutions. One such therapy utilizes angiogenic growth factor with G patch and FHA domains 1 (AGGF-1) with success in recovering from myocardial infarct or coronary artery disease. However, the field still lacks clear understanding of the underlying processes. In a multi-national collaboration, scientists have revealed the key mechanism upon which the AGGF-1 angiogenic response works. Surprisingly, the critical mechanism of AGGF-1 protein therapy is autophagy. Markers for autophagy increased with AGGF-1 therapy and decreased with an Aggf1+/- KO mice, and while striking levels of autophagy were observed in recombinant AGGF-1 cells in vitro. Specifically, JNK activation was found to connect AGGF-1 activity and autophagy. This is a revelation in the field as researchers have questioned the causal relation between ischemia and increased levels of autophagy markers for years. Revealing this mechanism of action is invaluable in moving this research forward as the current window of therapeutic efficacy is very narrow. Angiogenic therapies at higher doses create unwanted vessel formation and increased permeability, while lower dosing lacking side-effects also proves ineffective.
Magnetically controlled nanobots seek and destroy cancer
Targeted drug delivery has struggled to live up to its name, due in part to specificity and efficacy. In the context of solid cancers, both issues result in disease progression permitted by limiting dose escalation due to off target effects, and simultaneous lack of response to therapy related to lack of tumor penetration. A new study published in Nature Nanotechnology has demonstrated an approach that speaks to both of these issues. Using MC-1 cells, a sub-2um bacterium which possesses both magnetic as well as aerotactic characteristics, researchers were able to deliver liposome encapsulated therapeutic drug payloads to the tumor. Through the application of a magnetic field, the bacteria were coarsely guided to the site of the tumor. Interestingly, this overcomes the major hurdle of off target effects as the bacteria take a more direct route to the tumor, rather than traveling through the circulation first. Upon reaching the lesion, aerotactic control allowed for autonomous progression of the bacteria deep into the hypoxic regions. In fact, this second phase of navigation lead to a striking 50% tumor targeting ratio. Further still, the MC-1 cells were able to access the deep hypoxic and necrotic regions of tumor, a significant challenge for many current therapies. While further refinements of nanocarriers such as MC-1 cells are required, innovations such as these may serve to drive breakthroughs where traditional therapies stall.
Felfoul, et. al. Magneto-aerotactic bacteria deliver drug-containing nanoliposomes to tumour hypoxic regions NATURE NANOTECHNOLOGY
Reactive oxygen species tip the scales in cancer
As with most biomolecular mechanisms, more evidence is mounting that oxidation may be a double edged sword. No longer do anti-oxidants enjoy a "more is better" status as new research brings to light the potential benefit of allowing oxidation. One such study from the Cold Spring Harbor Laboratory has demonstrated the critical role oxidation plays in tipping the balance of tumor maintenance towards apoptosis. Specifically, in regards to pancreatic cancer, the master regulator protein, NRF2, acts to control oxidative damage to cancer cells through EGFR and AKT, keeping them viable. When NRF2 is knocked out mRNA translation is impaired, leading to apoptosis. Furthermore, as opposed to studies which have seen growth in tumors with NRF2 activators, combination therapy mimicking the results of a NFR2 knockout revealed a potential means of therapy in vivo. This is not to discount the potential benefits of anti-oxidants in the context of a healthy subject, but merely notes how disrupting this endogenous anti-oxidant pathway allows for pushing cancer cells past the point of no return as a means of therapy.
The how and WHY of sunflower circadian rhythm
Time-lapse photography has revealed how sunflowers track the sun from east to west, returning eastward overnight in preparation for the next day. However, as sunflowers age, this heliotropism becomes less pronounced with mature flowers maintaining an eastward direction. A new study from the University of California has revealed that the genes responsible for this phenomena are differentially expressed on opposite sides of the plant. Thus, light signaling pathways balance and tune circadian oscillators, yielding larger biomass due to optimized energy acquisition. But why? The paper suggests that this phenomena ceases in mature plants in order to orient them east for reproductive purposes. Mature eastward flowers were found to attract five times more pollinators then westward facing controls due to their warmer, brighter blooms. When appropriate controls of heated westward facing flowers were measured, they too attracted more pollinators.
Atamian, et. al. Circadian regulation of sunflower heliotropism, floral orientation, and pollinator visits SCIENCE
Mood hormone improves calcium profile in dairy cows
The health of mammalian mothers and their offspring are deeply interconnected through gestation and into the nursing period. The critical connection between mother and young is highly dependent on the nutrition imparted through mother's milk. Human use of this resourse goes further still by consuming dairy cow milk throughout adulthood, citing high levels of calcium as a supporter of bone health. It should come as no surprise that this $200 billion industry is actively researching ways to optimizes the product. To that end, an interesting investigation from the University of Wisconsin-Madison shows how hormones typically involved in the mechanisms of mood alter the composition of milk from peripartum dairy cows. Specifically, the supplementation of cows with 5 hydroxl-L-tryptophan (5-HTP), the precursor to serotonin, altered calcium levels both in the circulation as well as their milk. However, scientists note that the increase in calcium was only observed in Jersey cows, yet absent in Holstein cows. While feed intake and milk volumes remained constant, much hypocalcemia variation was seen peripartum. While further studies are required to validate and clarify the findings, the current study's use of 5-HTP infusions has significant implications for overall mood and well-being of mothers in regards to the nutrition they provide their offspring.
Weaver, et. al. Elevation of circulating serotonin improves calcium dynamics in the peripartum dairy cow JOURNAL OF ENDOCRINOLOGY
Nose microbiota harbors new class of antibiotics
Scientists are coming to a consensus: it is only a matter of time before an antibiotic-resistant super-bug rises to epidemic, if not pandemic levels. The misuse of current antibiotics by patients and inappropriate prescription by doctors has driven the evolution of infectious diseases towards antibiotic resistance. Beyond appropriate use and application of current antibiotics, new drugs will be required to meet this need. Few new antibiotics are in development, and those that do prove useful are often simply variants within existing classes of antibiotics. Unfortunately, this approach merely delays the inevitable as developing resistance within a class of antibiotics is a trivial evolutionary step. Researchers from the University of Tϋbingen however have taken a novel approach to antibiotic discovery, investigating the existing human microbiota. This approach has revealed a class of antibiotics found in the nasal passages of humans, non-ribosomally synthesized by Staphylococcus lugdunensis. The new antibiotic, a cyclic peptide which includes thiazolidine, has been coined "lugdunin". Much excitement surrounds this new discovery as the commensal bacteria from which it comes is in constant competition with a common foe, S. aureus. Beyond the apparent broad bactericidal capacity against major pathogens, its ability to significantly decrease S. aureus colonization despite constant exposure suggests that evolutionary escape towards resistance is somehow avoided. Therefore, adding lugdunin to our antibiotic arsenal may push back the seemingly inevitable emergence of a superbug, as well as demonstrate the value in the practice of mining our microbiome for novel antibiotics.
Zipperer, et. al. Human commensals producing a novel antibiotic impair pathogen colonization NATURE
Pomegranate metabolites lead to longer lives with increased fitness
Dating as far back as 3300 BC, the pomegranate fruit has been touted as a superfood with myriad health benefits. Evidence for these assertions has been severely lacking, demonstrated by a cautionary letter from the FDA to POM Wonderful in 2010 for making such unsubstantiated claims. Believers in the wonders of the fruit now have some evidence to support their assertions as published in Nature Medicine in June 2016. Researchers from Switzerland have investigated a set of metabolites from the fruit in search of the mechanism of purported health benefits. The metabolites urolithin A through D, derived from ellagitannins, are the suspected mediators of the improved health. In fact, this study reveals that urolithin A (UA) in particular was able to significantly extend lifespan in c. elegans. The data shows the response to be related to their ability to clear defects through mitophagy, the selective degradation of mitochondria. Beyond extending lifespan in worms, the research also demonstrated that UA induced mitophagy in muscle cells of mice, resulting in increased exercise capacity. Mitophagy drives muscle cell quality over muscle cell quantity, as opposed to some exercise based responses. Ultimately, the clearance of damaged mitochondria allows for improvement or maintenance of aerobic function in cells, worms, and mice treated with UA. So long as the organism is able to generate healthy mitochondria following damaged mitochondria clearance, this seems to be a viable treatment for age related mitochondrial dependent diseases.
Ryu, et. al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents NATURE MEDICINE
Advancing immunotherapies shortcomings with advanced adjuvants
Despite advances in cancer immunotherapy in the recent years, mere access to the tumor microenvironment has proved limiting. Specifically, chimeric antigen receptor (CAR) T cells, checkpoint inhibitors, and cancer vaccines act to direct the immune response but lack durable surveillance and complete penetration into the tumor. Utilizing vaccinations as the proof of concept, researchers from the RIKEN center in Japan have explored activating dendritic cells (DC) to overcome this hurdle. DCs act to activate the adaptive immune response only after induction by natural killer T cells (NKT) and simultaneous cytokine stimulation. To recapitulate this response in the context of a cancer target, adjuvant vector cells (aAVC) were designed to carry tumor antigen mRNA while decorated with NKT ligand. The systemic activation of DCs was found to alter what researchers call tertiary lymphoid structures (TLS) comprised of antigen specific CD8+ T-cell clones, mobilized DCs, and tumor vasculature. These alterations allow for increased tumor access and infiltration by CD8+ T cells. Furthermore, an impressive memory response was achieved, demonstrated by re-challenging mice with tumor cells. Authors go on to note that this phenomena not only lends itself to cancer vaccines, but should also be investigated as one part of a multi-pronged approach to therapy, including checkpoint inhibitors.
Shimizu, et. al. DC Activation Modulates the Tumor Microenvironment and Shapes the Long-Lived Tumor-Specific Memory Mediated by CD8+ T Cells CANCER RESEARCH
Post-exercise cognition improvement linked to specific myokine
Anecdotal evidence has suggested a connection between exercise and improved cognition, but until now little evidence has been offered to firmly connect the two. Researchers at the Center for Neurodegenerative Diseases, Germany have implicated a contentious molecule released from muscles during exercise. The myokine cathepsin B (CTSB) has been shown to mediate neuronal cell death and Alzheimer's onset, yet also has evidence of involvement in protection and plasticity functions. This blood brain barrier permeable molecule, found elevated in mice, monkeys, and humans post-exercise, is now suggested to mediate memory functions. Comparison of wild-type and knock-out (KO) CTSB models show a clear differential between the two in spatial memory tests with wild-type controls out performing KOs. Confirming this result, sedentary mice vs. KO-active mice showed no differential. Furthermore, dentate gyrus neurogenesis was found to be decreased in the KO cohort. Finally, exercise induced elevation of CTSB was found to increase neurotrophin levels in progenitor cells of the hippocampus. Importantly for translational use, this is not an acute response as correlation to human performance has been reported over a course of weeks to months. Therefore, lifestyle may have more influence on memory and cognition rather than pointed exercise events matched with cognitive challenges.
Moon, et. al. Running-Induced Systemic Cathepsin B Secretion Is Associated with Memory Function CELL METABOLISM
Harmful bacterial profiles associated with breast cancer
Following research that revealed breast tissue contains bacterial populations, researchers have extended their studies to understand how this might effect the development of breast cancer. By sequencing bacterial profiles from women with breast cancer or a healthy matched cohort, they gained a glimpse into how the microbiome may contribute to the disease. Breast cancer patients harbor a higher amount of bacillus, enterobacteriaceae and staphylococcus. Furthermore, these bacteria harvested from patient tissues were able to induce DNA double strand breaks in vitro. Citing similar levels of these harmful strains in normal adjacent tissue as well, researchers suggest that the once thought sterile microenvironment of breast tissue can lay the groundwork for cancers to emerge, if not drive the phenomenon. While results are preliminary and require deeper investigation, it is interesting to note the simultaneous decrease in "good" populations including lactic acid bacteria. Ultimately, a balance between beneficial and deleterious bacteria may need to be struck in order to maintain optimal breast tissue health.
Urbaniak, et. al. The microbiota of breast tissue and its association with tumours APPLIED AND EVIRONMENTAL MICROBIOLOGY
Disrupting anti-angiogenic resistance through metabolic manipulation
As tumors develop they remodel their environment, recruiting new blood supply to support their growth through a process known as angiogenesis. Theoretically, inhibiting blood vessel formation through vascular endothelial growth factor (VEGF) inhibition should starve tumors of their nutrients and blunt growth. However, some tumors escape this anti-angiogenic treatment through recruitment of alternative pro-angiogenic pathways. To counter this resistance, multi-kinase inhibitors against these VEGF alternatives have been employed with some clinical success. Still, tumors escape therapy, but not through another anti-angiogenic workaround. Researchers from the University of Basel, Switzerland have revealed both a mechanism by which these tumors escape, and a means of disrupting it. Recognizing that multi-kinase inhibitor resistant tumors fail to recover blood vessels, they sought out other mechanisms offering survival. Evidence indicates that upon treatment with the small molecule anti-angiogenic nintedanib, tumor regions which lose vascularity become hypoxic and shift towards a hyperglycolytic state, producing lactate. The tumor region still close to blood vessels remain normoxic, symbiotically using the lactate product of hypoxic neighbors for oxidative phosphorylation afforded by retained proximity to blood vessels. This metabolic symbiosis clears lactate, produced through hypoxic glycolysis, allowing for multi-kinase anti-angiogenic inhibitor escape. Researchers went on to demonstrate that inhibition of either glycolysis or exportation of lactate are each sufficient to disrupt this metabolic symbiotic shift, recovering efficacy of anti-angiogenic therapies. The authors temper expectations however, citing other recent publications evidence of yet more escape mechanisms such as metabolic shift to lipid synthesis.
Pisarsky, et. al. Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy CELL REPORTS
Abnormal sensory input may be cause, not result of autistic behavior
Impaired or aberrant sense of touch, sight, sound, smell, and even taste are inherent in autism spectrum disorders (ASDs). While much research has been generated in regards to the role the brain plays in how ASD behaviors emerge, little is known or attributed to peripheral nervous system function. In a recent Cell article, Harvard School of Medicine researchers have published on the role of two genes involved in both tactile sensation and their role in development of ASD symptoms. X-linked methyl-CpG-binding protein 2 (Mecp2) and GABAA receptor subunit β3 (Gabrb3) are associated with human ASDs, and when mutated in mice recapitulate anxious behaviors. Looking specifically at the function of these genes in low-threshold mechanosensory neurons (LTMRs) in the dorsal horn, the region of the spinal cord responsible for sensory integration, they found that deletion leads to development of ASD behaviors. Evidence indicates that Mecp2 mutations involve lower expression of GABAA receptors, lowering presynaptic inhibition. This ultimately culminates with an inappropriate interpretation of tactile sensory input of the environment. Interestingly, while the lack of LTMR input to the dorsal horn during early development yielded typical anxious behaviors, deletion of the genes in adult mice led to diametrically opposite behavior, increasing aggression in dominance tests. This study underscores the observations that lower cognitive and social function are more prevalent in children lacking appropriate sensory input during development provided by physical attention from caregivers. Yet significant study of how and why these genes become mutated is required to fully understand ASD.
Paper: Orefice, et. al. Peripheral Mechanosensory Neuron Dysfunction Underlies Tactile and Behavioral Deficits in Mouse Models of ASDs CELL
Recovery from antibiotic destruction of microbiota reveals immune cell mediator of neurogenesis
Lack of antibiotic management and overuse has generated far reaching effects just in the context of antibiotic resistance. Beyond the threat of generating a superbug, emerging evidence now suggests that we weigh the threat of antibiotics themselves. Researchers from the University of Magdeburg, Germany have pointed to a delicate balance between immune cells, gut microbiota, and neurogenesis, disrupted by antibiotic administration. Upon noting a decrease in hippocampal neurogenesis in adult mice post-antibiotic treatment, researchers sought to reconstitute plasticity. Fecal transplant replacement of gut flora failed to restore function without inclusion of probiotics or exercise. Adding further complexity, the response is connected to innate immune cells, as the Ly6Chi monocyte population was found to be dramatically decreased after antibiotic treatment. Accordingly, gut flora reconstitution accompanied with probiotics or exercise increased the same pool of cells. Furthermore, adoptive Ly6Chi monocyte transfer to knockout or antibody treated mice rescued neurogenesis in vivo. Cell transfer also promoted sphere formation by neural progenitor cells in vitro, further demonstrating the integral role of these innate immune cells in regards to the mechanism of communication along this gut-brain axis.
Paper: Möhle, et. al. Ly6Chi Monocytes Provide a Link between Antibiotic-Induced Changes in Gut Microbiota and Adult Hippocampal Neurogenesis CELL REPORTS
Brain targeted therapy reveals new way to treat type-2 diabetes
Current anti-type-2 diabetes regimens include metformin to inhibit gluconeogenesis and/or insulin to improve glucose clearance from the circulation. These therapies necessitate daily dosing in order to maintain appropriate blood sugar levels. Simply put, the mechanisms of action of these drugs are too fleeting, with medications as supplements rather than steps towards remission. A recent publication in Nature Medicine examines a more durable alternative, intracerebroventricular injection of fibroblast growth factor (FGF). Previous studies have shown an antidiabetic response from peripheral administration of FGF1, or central administration of FGF peptides, FGF9 and FGF21with transient responses. FGF1 however activates all receptors, and within 7 days of central administration normalized glucose levels for the duration of the study, 17 weeks. No weight loss preceded the diabetic remission nor was food intake effected. Interestingly, these results appear to be mediated by increased glucose uptake by both the liver and skeletal muscle. While the outcome is promising, central administration is likely not the final route of therapy. However, this study has revealed a mechanism by which a long-lasting response may be achieved in otherwise drug-dependent type-2 diabetes patients.
Paper: Scarlett, et. al. Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents NATURE MEDICINE
Antidepressant effect of ketamine untied from psychoactive effects
Ketamine, an anesthetic often abused recreationally for it's hallucinogenic effects, has also been connected with relief of anxiety and depression effecting change within days rather than weeks as is the case with conventional therapies. While somewhat successful, until recently the mechanism of action has been theorized as wholly dependent upon N-methyl-D-aspartate receptor (NMDA) receptors, and intimately connected to the psychoactive and anesthetic effects. Researchers at the University of Maryland School of Medicine have outlined a pathway independent of the NMDA receptor activated by an enantiomer metabolite of ketamine, (2S, 6S; 2R,6R)-hydroxynorketamine (HNK). Metabolism from (R, S)-ketamine was shown to be required in order to elicit the antidepressant effects. Furthermore, (2R, 6R)-HNK is able to ameliorate depressive behavior despite lack of functional inhibition of NMDARs. The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) was found to mediate an increase in postsynaptic currents. AMPARs therefore, rather than NMDARs, act as the means of increasing frequency and amplitude of currents involved in glutamatergic inputs. With no evidence of inducing addictive behavior, or other deleterious side-effects, (2R, 6R)-HNK may be a potent, fast acting alternative to both (R, S)-ketamine as well as current anti-depressants.
Paper: Zanos, et. al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites NATURE
New means of melanin biosynthesis found in fungus
Melanin serves to protect against UV light, ionizing radiation, and oxidative stress in creatures across all kingdoms. Fungus also leverages melanin's protective functions to confer survival to their conidia, or spores, by neutralizing the pH in acidic environments such as that of phagolysosomes. A curiosity among fungus, Aspergillus terreus lacks the gene to make the dihydroxynapthalene-(DHN) melanin found in other species, yet by appearance seems to make melanin. Research conducted at the Hans Knoell Institute has identified the genes responsible for a new related pigment, Asp-melanin. Interestingly, these genes code for a non-ribosomal peptide synthetase (NRPS)-like enzyme leading to tryosinase-mediated spontaneous formation of the pigment. Furthermore, while this Asp-melanin does in fact protect against UV insult or predation by soil amoeba, it does not prevent phagolysosome acidification. This may be the most interesting revelation of the study as it offers a means of increased virulence to Aspergillus terreus. By not inhibiting phagolysosome acidification, the conidia are able to persist inside a would be predator without effect, laying dormant for future growth. Evolutionarily, this characteristic could be an adaptive means of spreading, be it in soil amoeba, or into systemic circulation from a primary lung infection by hiding inside macrophages of a human host.
Paper: Geib, et. al. A Non-canonical Melanin Biosynthesis Pathway Protects Aspergillus terreus Conidia from Environmental Stress CELL CHEMICAL BIOLOGY
Coenzyme balance found to extend life through recovering stem cell function
Mitochondrial dysfunction is commonly observed in response to a high calorie diet and age. Mechanistically, glycolytic metabolic depletion of the niacin (vitamin B3) derived nicotinamide adenine dinucleotide (NAD+) is thought to be responsible, as repletion rescues mitochondrial function. Until now, this concept has yet to be investigated in the context of senescent stem cells. Researchers at École Polytechnique Fédérale de Lausanne first looked at muscle stem cells (MuSCs) gene profile between mice 3 and 24 months in age. They found downregulation of mitochondrial respiratory genes OXPHOS and TCA, as well as those of the stress response pathway for unfolded protein response (UPR), confirming mitochondrial dysfunction with age. Supplementation with the NAD+ precursor nicotinamide riboside (NR) rescued this mitochondrial down regulation and markedly improved muscle function in aged mice, increasing running duration and distance by nearly 30% and grip strength by approximately 15%. Both oxidative respiration and UPR pathways improved with NR administration. Even more surprising is the finding that NAD+ supplementation is generalizable, benefiting both neural and melanocyte stem cells, recovering hair stem cell numbers and increasing lifespan. As all treatments were achieved through dietary supplementation, this approach may be easily implemented in humans, should the findings translate.
Paper: Zhang, et. al. NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. SCIENCE
Gill arch appendages and limb symmetry driven by single gene
Evolutionary biologists at the University of Cambridge have revealed a surprising connection between gills in a member of the same class as sharks, chondrichthyes, and the superclass to which humans belong, tetrapods. The commonality, sonic hedge hog (Shh), is a gene previously known to be responsible for tetrapod axial patterning of limbs, but has now been shown to be a driving force behind paired fins found in sharks, skates, and rays. Utilizing gene expression profiling, fate mapping, and loss-of-function experiments, researchers demonstrated gill arch, or branchial ray, development through axial patterning of gills. This contradicts previously held theories suggesting paired fins derived from a central fin which folded laterally to form bi-lateral structures. This serial homology, the repetitive segments such as gills and limbs, could lay evidence for a theory of conserved evolution, tying tetrapods to chondrichthyes at a possible common point of evolution. However, this could also merely be evidence of parallel or convergent evolution. Study of additional axial patterning in other "nested" body plans is required.
Paper: Gillis, et. al. A shared role for sonic hedgehog signalling in patterning chondrichthyan gill arch appendages and tetrapod limbs. DEVELOPMENT
Salamander approach to regeneration avoids pluripotency issues
Presently, most approaches in regenerative medicine seek to reconstitute damaged or old tissue through directing pluripotent stem cells towards tissue specific lineages. These vector based technologies have found limited success outside of bone marrow and fat derived grafting. Additionally, pluripotent stem cell origins risk malignant transformation, or teratomas, tumors which contain multiple tissue types. Rather than narrow cells from a state of induced pluripotency, researchers from the University of New South Wales, Australia, have taken to regeneration similar to that of salamanders, multipotency. Mature fat and bone cells treated with platelet-derived growth factor-AB (PDGF-AB) and 5-Azacytidine (AZA), were converted to renewable multipotent cells and differentiated into a myriad of tissues including bone, cartilage, fat, muscle, cardiomyocyte, neuroectodermal, and endodermal lineages. Osteocyte derived cardiomyocytes even displayed spontaneous rhythmic contractions, something bone marrow derived mesenchymal stem cells could not. While much additional research is required to fully understand the mechanism, PDGF-AB/AZA have revealed a sufficient combination of cytokine stimulation and gene demethylation to induce regenerative plasticity as yet unrealized by humans.
Paper: Chandrakanthan, et. al. PDGF-AB and 5-Azacytidine induce conversion of somatic cells into tissue-regenerative multipotent stem cells. PNAS
Aspirin disrupts cancer stem cell generation
Cancer relapse commonly occurs after initial response to chemotherapy. Cancer stem cells (CSCs) have been implicated in this phenomena, but little has been known about the driving mechanism let alone a means of disrupting it. Upon review of epidemiologic evidence of favorable prognosis in breast cancer patients who medicated with aspirin post-diagnosis, researchers at the Bose Institute, India interrogated this connection. They hypothesized that the anti-inflammatory affect of aspirin somehow diminished the ability of CSCs to acquire chemoresistance. Without anti-inflammatory treatment, chemotherapy results in the transformation of non-stem cancer cell (NSCC) to a CSC phenotype when in co-culture with CSC, evidenced by markers OC-4 and Aldh1 in the NSCC pool. Chemotherapy also creates a CSC pool with increased chemoresistance and migration potential. Both results were shown to be influenced by an NFκB-IL6 feedback loop created by preexisting CSCs. Utilizing a physiological relevant dose of aspirin, treatment of CSCs resulted in downregulation of NFκB, Bcl-2 and Cox2 through IL-6 signaling disruption. This therapy prevented both NSCC to CSC conversion in addition to the increased resistance and migration in preexisting CSCs. In fact, aspirin pretreatment sensitizes CSC cells to chemotherapy compared to controls, shown by increased apoptotic marker annexin V. While further in vivo investigation is required, the disruption of the common inflammatory NFκB-IL6 pathway with aspirin shows promise as a co-therapy for patients undergoing chemotherapy.
Paper: Saha, et. al. Aspirin Suppresses the Acquisition of Chemoresistance in Breast Cancer by Disrupting an NFκB-IL6 Signaling Axis Responsible for the Generation of Cancer Stem Cells. Cancer Research
T cell function enhanced with atherosclerosis drug
Recruitment and redirection of the immune system to target cancer cells has shown great promise in recent years. However, as the immune response is complex, there are still many opportunities to optimize therapeutic response. Researchers from the Chinese Academy of Sciences, Shanghai have revealed one such opportunity to potentiate CD8+ T cells through metabolic manipulation. T cell signaling and function is highly dependent upon clustering and the formation of immunological synapses. Such clustering and synapse formation is in part regulated by membrane lipid composition. Therefore, researchers hypothesized that manipulating cholesterol metabolism, a critical player in controlling membrane lipid composition, could increase CD8+ T cell response. Noting elevated cholesterol levels upon activation of CD8+ T cells, despite simultaneous increases in mRNA for cholesterol storage genes ACAT1 and Acat2, researchers investigated manipulation of this pathway. Removing cholesterol storage mechanisms through inhibition of ACAT1/ACAT2 increased cytolytic granules, cytokine release, and cytotoxicity. ACAT1 KO mice revealed a systemic decrease in cholesterol esterification and T cell potentiation resulting in reduced melanoma tumor burden and prolonged survival. This effect was confirmed to be T cell dependent as adoptive ACAT1 KO T cell transfer to wild type mice had similar results. Finally, pharmacological targeting of ACAT1 with the inhibitor avasimibe, a clinical trial candidate for atherosclerosis, demonstrated proof of targetability. Just as in the ACAT1 KO mice, avasimibe administration resulted in reduction in tumor growth and increased survival. Furthermore ACAT1 inhibition increased the effect of PD-1 checkpoint blockade.
Paper: Yang, et. al. Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism. Nature
Neuroplasticity mediated by astrocytes in response to direct current stimulation
Transcranial direct current stimulation (tDCS) is the administration of weak, 1 mA current applied to the scalp. While originally developed to treat brain injuries, some success in treating depression has also been reported. As this is a nascent field, little understanding of the cells and pathways mediating these results is known. Researchers from the RIKEN Brain Institute have recently revealed both cells and receptors involved. Using a new G7NG817 mouse model which expresses G-CaMP7, a GFP Ca2+ reporter in astrocytes and cortical neurons, they were able to image transcranial responses post-tDCS. Importantly, the conditions were sufficient to alleviate chronic-stress induced depression in an otherwise standard mouse model. As the supplemental videos vividly demonstrate, tDCS-induced Ca2+ surges, as compared to spontaneous surges, are much larger in amplitude. Critically, this phenomena of both Ca2+ surges and alleviation of depression was found to be lacking in inositol triphosphate receptor type 2 (IP3 R2) KO mice. Furthermore, tDCS induced plasticity in neurons was inhibited with prazosin administration, an alpha-1 receptor blocker. This further implicates the role of Ca2+ elevation in astrocyte mediated neuronal plasticity changes through tDCS and CA2+/IP3 signaling.
Monai, et. al. Calcium imaging reveals glial involvement in transcranial direct current stimulation-induced plasticity in mouse brain. Nature Communications
Fatty acid oxidation disruption: a therapeutic alternative for triple negative breast cancer
Hormone therapy is ineffective against triple negative breast cancers (TNBC) as they lack HER2, Estrogen, and Progesterone receptors. Therefore new targetable pathways are needed to halt the cancer's progression. Researchers at UCSF have outlined a means of treating TNBC through disruption of fatty acid oxidation (FAO). The pathway was first revealed as a potential target through metabolomics and gene signatures, identifying upregulated FAO intermediates in MYC-overexpressing TNBC samples. Considering the location, in the proximity of adipose-rich mammary glands, breast cancer FAO dependence pathway seemed to be a logical pathway. Subsequent inhibition of FAO with etomixir , an inhibitor of a major enzyme carnitine palmitoyltransferase 1 (CPT1) in the FAO pathway, lead to dramatic decreases in ATP production in MYC-overexpressing cell lines. Although a decrease in proliferation of cells in culture was observed viability remained unchanged. However, further testing of etomixir in vivo within patient derived xenograft models increased success of FAO disruption with a 4 to 6-fold decrease in relative tumor volume. The differential performance between in vitro and in vivo treatments indicates a need to recapitulate the actual tumor environment when studying metabolic manipulation regimens.
Paper: Camarda, et. al. Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. Nature Medicine
Running suppresses tumor growth through immune regulation
A strong correlation between exercise and cancer suppression or reduction in recurrence has been observed for some time. The mechanisms driving this observation have remained unclear. A recent study by researchers at the University of Copenhagen, Denmark has shed light on one mechanism of tumor reduction driven by running. Mice given access to running wheels averaged 4.1 km/mouse/day and demonstrated a 60% reduction in tumor incidence and growth. These results spanned five different tumor models including B16 melanoma and Lewis Lung cells. Analysis of equivalent tumors from running mice, compared to controls, revealed an increase in immune and inflammatory genes . Further confirmation via FACS and immunohistochemistry revealed not only an increase in NK cells at the tumor site but also an increase in activating ligands and cytokines for receptors NKG2D, MULT1 and H60a. Most notably, effective tumor reduction required both NK cell mobilization, dependent upon exercise induced epinephrine release, and simultaneous IL-6 release from muscles. While blocking IL-6 during exercise reduced the tumor suppression effect, IL-6 supplementation alone could not recreate the effect. Although elevated systemic IL-6 concentrations are associated with poor prognosis, increased intratumoral IL-6 levels are associated with positive prognosis. The key to tumor suppression through NK cells seems to depend upon the pulsatile combination of IL-6 and epinephrine.
Pedersen, et. al. Voluntary Running Suppresses Tumor Growth through Epinephrine- and IL-6-Dependent NK Cell Mobilization and Redistribution. Cell Metabolism
Staphylococcus aureus infection helps co-infecting bacteria via immune manipulation
The widespread use of broad-spectrum antibiotics has resulted in increased cases of multi-drug resistance. To combat this trend, new therapeutic approaches to infectious diseases are required. One such alternative which has yet to be embraced is a pathogen-specific approach. Hesitation stems from fear of pathogen-specific treatments merely opening a niche into which co-infecting bacteria will expand. However, a recent study from MedImmune has demonstrated that a narrowly targeted approach actually serves to decrease more than one bacterial population. By targeting the virulence factor of S. aureus, α toxin, rather than the bacteria itself, they were able to not only significantly reduce the S. aureus infection but also reduce bacterial lung burden of co-infecting P. aeruginosa as well by an order of magnitude. The greater insight comes from revealing that this effect was mediated by neutralizing α toxin's effect, the prevention of macrophage phagosome acidification. Neutralizing virulence factor α Toxin removed the immune manipulation enjoyed by other gram-negative bacteria, and allowed for traditional immune cell clearance. This monoclonal antibody therapy may therefore prove useful in broad-spectrum resistant infections.
Cohen, et al. Staphylococcus aureus α toxin potentiates opportunistic bacterial lung infections. Science Translational Medicine
Muscle mass and strength increase with therapeutic antibody drug
Loss of muscle strength, sarcopenia, is an accepted outcome of the normal aging process. Currently, there is no accepted therapy outside of poorly adhered to exercise and lifestyle changes to combat muscle weakening. Researchers at the Yale School of Medicine have revealed a therapeutic strategy with the promise of reversing aging-associated sarcopenia. By targeting myostatin, a member of the TGF-β superfamily and master regulator of skeletal muscle growth, they were able to significantly increase muscle strength in 22 month old mice. Inhibition of myostatin activity via anti-myostatin antibody therapy resulted in a dramatic 20% increase in grip strength. While the younger 10 week old cohort exhibited a significant alteration in body composition, a 7% increase in lean muscle and 35% decrease in adiposity, older mice merely experienced an increase in lean muscle by 7% without adiposity changes. While mice did not demonstrate any anaerobic glycolysis and lactic acidemia, a potential result of muscle hypertrophy, they did see other metabolic changes. One such change was an increase in whole-body insulin sensitivity attributed to insulin-stimulated skeletal muscle glucose uptake. These results suggest extension of such a therapeutic antibody drug beyond age-associated sarcopenia treatment and into the realm of metabolic disease therapy.
Change in seasons tied to cognitive performance
Seasonal affective disorder (SAD) and its associated symptoms of depression during winter months dominates discussions of human response to seasonal changes. However, new evidence published in PNAS connects seasonality to more than just emotional changes. Researchers investigated cognitive changes in 28 subjects across all seasons using fMRI and cognition dependent tasks. Following a two-day period of acclimation in a laboratory controlled environment devoid of seasonal cues, subjects were sleep deprived for a total wake time of 40 hours, and subsequently allowed 12 hours of recovery sleep. During the extended wake and post recovery sleep phase, 13 sustained attention and working memory tasks paired with fMRI sessions were performed. Maximum sustained attention was found to align with summer while minimal attention task performance occurred in the winter. Interestingly, the working memory performance peak occurred proximal to the autumnal equinox and while its nadir was found around the spring equinox. While more investigation is required to observe seasonality effects in other executive brain functions, such as task learning, this study revealed individual's cognitive performance does in fact change throughout the year, and with a rhythmic predictability.
Meyer, et al. Seasonality in human cognitive brain responses. PNAS
Germline point mutations create "selfish-selection" similar to cancer.
Many diseases, including autism and schizophrenia, are attributable to spontaneous germline mutations. While both parents have the potential for germline mutations, the majority of congenital diseases trace back to point mutations in the paternal germline. These mutations increase in frequency with age and are termed the paternal age effect (PAE). However, these mutations have yet to be traced back to their exact origin within the testes, informing the mechanism of age-related mutation increase. For the first time, researchers at the University of Oxford were able to visualize these de novo point mutations within the seminiferous tubules by studying testes of men ages 39-87 who had testicles removed for coincidental pathologies, but were otherwise healthy. Histology allowed for visualization of immuno-positive tubules, staining for melanoma antigen A4 (MAGEA4), PAE protein FGFR3, and phospho-v-akt (pAKT), all markers correlated with clonal mutations. Through extraction of DNA and whole genome amplification of adjacent, serial sections of these immuno-positive tubules, a set of mutations was discovered which although initially rare, conferred gain of function to spermatogonia. In fact, while these mutations confirmed gain of function in mutated FGFR, a driver of congenital and lethal perinatal disorders, they also revealed additional PAE mutations in HRAS and PTPN11 genes. Simultaneous visualization and sequencing revealed a "selfish" selection phenomena and clonal growth of mutated spermatogonia. This observed "selfish" selection, reminiscent of cancer progression, lays out a mechanism by which mutations increase with age in the male germline.
Attraction to leopard urine bolsters parasite manipulation hypothesis
The household protozoan Toxoplasma gondii is commonly found in domestic cat urine. Infection of rodents induces a switch in olfactory preferences from innate feline odor avoidance to attraction. This behavior modification highlights the "parasite manipulation hypothesis" which prompts mice to act in ways that increase feline predation, and thereby increase T. gondii transmission. T. gondii infection in humans is predominantly discussed in the context of pregnancy as transmission to the fetus can result in stillbirth or neurological damage. Outside of pregnancy, infection in humans has been viewed as merely inappropriate host selection; humans possess a conducive growth environment, but do not allow for transmission as they are not preyed upon by felines. Adult infection produces mild effects such as personality changes, prolonged reaction times, and decreased long-term concentration. Researchers are challenging this inappropriate host theory with evidence that T. gondii evolved with human ancestors. By examining the relative interest in human, leopard, or tiger urine between infected and non-infected chimpanzees, they were able to demonstrate that the preferences induced by T. gondii are tied to their appropriate predator. Uninfected chimpanzees rightly avoid leopard urine, while infected chimps approach and investigate urine from leopards more frequently than urine from humans or lions. Furthermore, this concept of coevolution and increased transmission fitness is supported by the 30% leopard predation risk in some chimpanzee populations. This study supports the evolutionary rationale for human parasite manipulation as our ancestors once were appropriate hosts, preyed upon by large cats.
Poirotte, et. al. Morbid attraction to leopard urine in Toxoplasma-infected chimpanzees. CURRENT BIOLOGY
Self-renewal genes activated by lineage-specific enhancers
Self-renewal and response to damage is typically driven through tissue-specific stem cells, as mature cells usually lack this capacity. An exception to this rule are tissue macrophages which do have the ability to self-renew despite their fully mature and differentiated state. Researchers at Centre d'Immunologie de Marseille-Luminy (CIML) France have revealed the means of achieving this otherwise stem-cell specific function. To investigate, they began with surveying genome-wide histone modifications, enhancer repertoires, and activation of state-dependent mechanisms to establish a signature of identity for macrophages. In mice, this revealed a subset of lineage-specific enhancers, H3K27ac/p300, usually repressed by transcription factors MafB and c-Maf, which access a self-renewal gene network. In vitro analysis further demonstrated the ability of resident macrophages to access this gene network is dependent upon transient down-regulation of such Maf transcription factors. Surprisingly, this self-renewal gene network is the same as in embryonic stem-cells, yet not adult stem-cells. Furthermore, self-renewal gene activation was found to be controlled via distinctly different enhancers between macrophages and embryonic stem cells, showing lineage-specific enhancers manipulate a common gene network in both mature and stem-cell populations.
Soucie, et. al. Lineage-specific enhancers activate self-renewal genes in macrophages and embryonic stem cells. SCIENCE
Blocking PD-1 Immune Checkpoint Clears Aβ-Plaques
Removing the brakes from immune system checkpoints via inhibition of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death-ligand 1 (PD-L1), and its receptor, programmed cell death 1(PD-1), has emerged as a promising approach for cancer therapies in recent years. Researchers from Weizmann Institute in Israel have discovered benefits conferred to Alzheimer's disease models from similar immuno-regulatory techniques. The central nervous system is considered an immune privileged site with tight restriction of leukocyte traffic through the choroid plexus, a gateway into the brain. Previous research revealed the permission of monocyte-derived macrophages and regulatory T-cells into the brain achieved through depletion of forkhead box P3 (FOXP3) regulatory T-cells. Subsequent activation of the immune system by cytokine interferon-γ (INF-γ ) resulted in Aβ-plaque clearance in mouse models. As the immune response in PD-1 blockade cancer therapy has also been shown to be INF-γ-activation dependent, they postulated that the same may hold true for Alzheimer's therapy. Two models of Alzheimer's disease, 5XFAD and APP/PS1 mice, showed significant behavioral improvements and reduction of plaque load in response to anti-PD-1 antibody therapy. This research contradicts previous notions that Alzheimer's disease may be treated through immune suppression as a means of controlling inflammation, the most common pathology of neurodegenerative diseases.
Baruch, et. al. (February 2016), PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease. Nature Medicine
Stress and Fat Metabolism Linked
Stress and fat retention has been inexorably linked for quite some time. More specifically, Angiopoietin-like 8 (ANGPTL8), otherwise known as the protein betatrophin has been implicated in various metabolic mechanisms including triglyceride and glucose metabolism. Betatrophin also gained notoriety as potential therapeutic for diabetes, with notions that it promotes β-cell proliferation in the pancreas. Despite intense research, the mechanism of action connecting betatrophin to lipid metabolism has remained unclear. Researchers at the University of Florida College of Medicine have finally established a betatrophin lipid regulation mechanism of action. The findings demonstrate that stressing cells via histidine deprivation results in RAS/c-Raf/MAPK pathway inhibition of lipid metabolism. This is in contrast to previous studies of amino acid starvation induced stress which showed general control non-depressible 2/activation transcription factor 4 (GCN2/ATF4) pathway involvement. Succinctly put, induction of stress through histidine starvation upregulates betatrophin which in turn decreases lipid metabolism via downregulation of adipose triglyceride lipase (ATGL). While the study does not eliminate the possibility of other players involved in the metabolic response to stress, it has finally revealed the involvement of betatrophin by defining this mechanism of action.
Zhang, et. al. (February 2016), Angiopoietin-like protein 8 (betatrophin) is a stress-response protein that down-regulates expression of adipocyte triglyceride lipase BBA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
Epithelial Derived Stem Cell Therapy for Cardiac Infarction
Persistent shortages of donor organs are driving researchers to find alternate means of treatment for patients with severely damaged hearts. Investigators at Kyoto University have moved one step closer to providing a feasible alternative to traditional heart transplant surgery. Their Nature Scientific Report outlines the use of epithelial derived induced pluripotent stem cells (iPSCs) for cardiac therapy. As previously shown, with appropriate media supplementation, stem cells can be converted to a cardiomyocyte lineage in culture. However, injection of in vitro iPSC-derived cardiomyocytes have yet to achieve significant engraftment and therapeutic success in vivo. The elementary key to improving this potential therapy was optimizing in vitro time of differentiation prior to injection. Peak in vivo expansion and persistence was found with iPSCs cultured for 20 days. Utilizing bioluminescent iPSC-derived cardiomyocytes, the group was able to visually observe successfully engraftment, expansion, and maturation up to 6 months after injection within the optimized cohort. Most notably, this improved stem cell therapy strategy translated to continued therapeutic benefit in a mouse infarction model up to 12 weeks. While further study is required to establish safety, this approach suggests that success with stem cell therapies may come down to a matter of timing.
Funakoshi, et al. Enhanced engraftment, proliferation, and therapeutic potential in heart using optimized human iPSC-derived cardiomyocyte NATURE SCIENTIFIC REPORTS
3 Dimensional Ex-Vivo for In-situ Tumor Growth
Brain tumors are both difficult to treat and hard to study because of the organ they affect. The structure of the brain is extremely sensitive to alterations. Until recently the study of architectural alterations and their effects was mostly restricted to in vivo experiments. Typical culturing of brain tissue requires disaggregation and manipulation into a 2-dimensional format, losing any anatomically relevant structure. To study the in situ brain structure, a new technique has been described by researchers from the University of Erlangen-Nürnberg. By carefully sectioning the brains of 4 day-old mice and placing them on a 0.4 uM pore-size transwell membrane 6 well plate insert within required culture medium, they were able to study the endogenous structure under varying conditions. They injected astrocytes or glioma cells with a micropipette into the slices, and investigated the structural changes brain tumors effect in their environment. Termed the Vascular Organotypic Glioma Impact Model (VOGIM), it revealed all the characteristic pathological alterations normally associated with the disease in vivo such as tumor size and borders, vessel length, vessel junctions, and vessel branches, microglia, cell survival, and neuronal modifications. As this method allows for live cell fluorescent observation, they employed the technique to observe cultures treated with the chemotherapeutic Temozolamide (TMZ, Temodal/Temcad®). Indeed they found reduced tumor growth in treatment groups vs controls, but also revealed surprising reduction in microglial cells in the peritumoral region. Additionally, they were able to observe the lack of response TMZ elicited from microglial in healthy regions of the tissue, despite its overall reduction in vascularization towards normal levels. The VOGIM technique allows for ex vivo study of brain tissue requiring three dimensional measurements, but may also be extended to other tissues with unique morphology such as kidney, liver, and intestine.
Ghoochani, et al. (December, 2015) A versatile ex vivo technique for assaying tumor angiogenesis and microglia in the brain ONCOTARGET
Small Molecule EPPS Breaks Up Amyloid Plaques
One of the hallmarks of Alzheimer's disease has been the generation of Amyloid-β (Aβ) oligomers, fibrils, and ultimately plaques. It is currently contended whether these plaques are a cause of Alzheimer's disease and related mental deficits, or merely an effect. Researchers at the Korea Institute of Science and Technology have demonstrated in vivo formation and disaggregation of Aβ plaques. They previously reported small ionic molecules which could accelerate the formation of Aβ plaques. Six small molecules which inhibited aggregate formation were discovered at the same time. One of these molecules, 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS), works as a therapeutic in a Alzheimer's mouse model. EPPS was found to be both orally available and cross the blood brain barrier where it directly binds to Aβ plaques. Double transgenic mice , APPswe/PS1-dE9 (amyloid precursor protein/presenilin protein 1) mice were administered EPPS in their drinking water for 3.5 months and compared to non-treated transgenic controls. EPPS treated mice both improved from their baseline and out-performed transgenic controls in both the Morris water maze and contextual fear response tests. Immunofluorescent staining of matched brain regions demonstrated elimination of Aβ plaques in the hippocampus of EPPS treated mice. Further study is required to completely understand the mechanism by which EPPS disaggregates the Aβ plaques. This study demonstrates the cause and effects Aβ plaque generation, and subsequent removal, has on Alzheimer's disease related cognitive function. Should the effect transfer to humans, this could prove a significant discovery for the treatment of Alzheimer's disease.
Kim, et al. (October, 2015) EPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 ice by disaggregation of amyloid-b oligomers and plaques Nature Communications
A new weapon for infants in the war against whooping cough
Pertussis Toxin (PTx) is an AB5-type exotoxin which binds via its five binding subunits and confers toxicity via the single enzymatic A subunit. Produced by Bordetella pertussis in the lungs of infected patients, its cytotoxic activity produces the classical violent coughing symptoms associated with whooping cough. Widespread vaccination has done a good bit to quell the spread of the highly contagious disease, however infants which are unable to be immunized until two months of age are the most susceptible. Worldwide, the annual mortality rate from B. pertussis is 195,000, highlighting the need for intervention between maternal immunization techniques and completed newborn immunization. As B. pertussis infection is difficult to discriminate from other pulmonary diseases, diagnosis often is delayed until the bacteria is well established. Acute and effective treatment critical to infant survival currently depends on erythromycin, clarithromycin, and azithromycin. These antibiotics also carry their own risk when administered to infants younger than 1 month of age. To strengthen the arsenal against pertussis, researchers at the University of Texas at Austin have developed two humanized murine antibodies against the A subunit of pertussis, hu1B7 and hu11E6. When administered concomitantly, these two antibodies were successful at prophylaxis in a mouse weanling model of whooping cough, outperforming the high-titer pertussis intravenous immunoglobulin (P-IVIG) . Better still, in the weanling baboon model the cocktail administration of hu1B7 and hu11E6 served to therapeutically protect against B. pertussis. They demonstrate that not only do both antibodies bind to PTx simultaneously, but the cocktail may have synergistic effects as seen by PTx neutralization in a morphology assay. It is therefore reasonable to assume they do not share an overlapping epitope and possibly act via complementary mechanisms. Supplementing current standard of care with these antibodies, thereby providing passive immunity to affected infants, may bolster the fight against Bordetella pertussis.
Nguyen, et al. (October, 2015) A cocktail of humanized anti–pertussis toxin antibodies SCIENCE TRANSLATIONAL MEDICINE
E. coli protects against intestinal insult and infection
Cachexia is the wasting of muscle and fat during bouts of illness or infection. Although little is understood about the mechanisms which drive this disease-wasting connection, a novel observation made by researchers at the Salk Institute demonstrates microbiome influence. Oral administration of dextran sulfate sodium (DSS), used to model colitis, causes inflammation and barrier disruption. DSS-colitis induced weight loss was observed to be strikingly different between two separately housed C5Bl/6 mice colonies. Protection was transferrable between mice simply through cohousing, which lead them to investigate the intestinal colonization of the protected mice. Cultures from the ceca of non-wasting vs. wasting-susceptible mice revealed a distinct strain of antibiotic resistant bacteria, E.coli O21:H+. This strain had no effect on weight, body composition, or food consumption under normal homeostatic conditions, but provided the host protection during DSS induced gut trauma. Additionally, the researchers went on to demonstrate the protective effect extended to both Salmonella Typhimurium and a pneumonic infection of Burkholderia thailandensis. E. coli O21:H+ was found to protect through the insulin-like growth factor 1/phosphatidylinositol 3-kinase/AKT pathway in skeletal muscle. This mechanism of action was found to be dependent upon the nucleotide-binding oligomerization domain receptor caspase activation and recruitment domain 4 (NLRC4) inflammasome. Beyond revealing a potentially targetable pathway for wasting diseases, this study suggests our relationship with E.coli bacteria may be more than just commensal.
Schieber, et al. (October, 2015) Disease tolerance mediated by microbiome E. coli involves inflammasome and IGF-1 signaling Science
Carcinoma cells use healthy tissue to alter the microenvironment
As cancer progresses, malignant cells invade healthy tissue, renovating the tumor microenvironment (TME) as they go. University of Delaware researches have uncovered one possible mechanism in which carcinoma cells are able to directly utilize their neighbors as accomplices in their plot to overtake healthy tissue. A three-dimensional co-culture of non transformed Madin-Darby Canine Kidney (MDCK) epithelial cells and murine sarcoma virus transformed carcinoma cells (MSV-MDCK) induced lumen filling and epithelial-mesenchymal transition (EMT) in the MDCK population, two early hallmarks of transdifferentiation. Matrix metallopeptidase 9 (MMP-9) released by the MSV-MDCK cells cleaves E-cadherin from the surface of normal MDCK cells. This generation of soluble E-cadherin (sE-cad) not only disrupts the adhesion signaling between cells, but the resulting sE-cad is itself pro-oncogenic, activating the epidermal growth factor receptor (EGFR) pathway in normal epithelial cells.
Patil, et al. (October 2015) Carcinoma cells induce lumen filling and EMT in epithelial cells through soluble E-cadherin-mediated activation of EGFR. Journal of Cell Science
Losing less than 1 gram of pancreatic fat alleviates Type 2 diabetes
Type 2 diabetes mellitus (T2DM) is not only characterized by loss of whole-body insulin sensitivity, but also lack of insulin secretion from pancreatic β-cells despite glucose stimulation. Researchers from Newcastle University, U.K. measured the amount of triacylglycerol lost from the pancreas in patients who entered diabetic remission following gastric bypass surgery with novel MRI technology. Between matched groups presenting T2DM or normal glucose tolerance (NGT) they found a mere 1.2% decrease in triacylglycerol deposition in the T2DM coincided with return of insulin secretory function, corroborating functional restoration of insulin secretion in fatty acid receptor knock-out studies. This is despite no change in peripheral tissue insulin-stimulated glucose clearance, offering a degree of pathological delineation of each arm of this disease, but requiring further study. Clarification could be had from specifically targeted triacylglycerol removal from the pancreas as present study results were attributed to surgical calorie restriction.
Steven, et al. (December 2015) Weight Loss Decreases Excess Pancreatic Triacylglycerol Specifically in Type 2 Diabetes. Diabetes Care
Fetal cells – foes or friends to maternal health?
Fetal cells have been associated with both positive and negative effects on maternal health. Are fetal cells friends or foes to the mother? A recent review article provides an evolutionary perspective on the role of fetal cells in maternal health and disease using cooperation and conflict theory. During pregnancy, microchimerism, the bidirectional exchange of fetal and maternal cells, causes the integration of fetal cells in the mother's tissues which persist for decades after parturition. In these tissues, the outcomes of the maternal-fetal give and take are important in maternal health. From an evolutionary perspective, the authors made testable predictions about the role of fetal cells in several conditions, including lactation, autoimmune disease, and cancer. With regards to cooperation, the authors predict that fetal cells in the breast increase maternal milk production and quality, as it's in the best interest of the offspring's fitness. On the contrary, fetal cells may contribute to the development and/or progression of cancer as these fetal cells have cancer-like properties. Similarly, fetal cells may increase the mother's susceptibility to autoimmune disease.
Amy M. Boddy, etc. (October 2015) Fetal microchimerism and maternal health: A review and evolutionary analysis of cooperation and conflict beyond the womb BioEssays
Blocking enzymes in hair follicles promotes hair growth
One of the major causes for hair loss is that the hair follicles (HF) failed to switch from resting phase (telogen) to the growth phase (anagen). A group of researchers from Columbia University found that when directly applied to mouse skin, small molecule inhibitors of Janus kinase (JAK) family of enzymes promote rapid and robust hair growth through activation of HF progenitor cells and restarting the anagen in wild type mice. Two of the FDA approved drugs, tofacitinib and ruxolitinib were tested in the experiments. Both lead to rapid hair growth in mice after only 4 days treatment. More promisingly, those two drugs showed hair-inducing activities in the human scalp skin grafted onto SCID mice with 4 weeks treatment. These findings opened a new venue for developing new treatments for human hair loss/baldness. However, whether those two drugs are effective to male pattern baldness is still under investigation. More research needs to be done before a conclusive answer can be reached.
Sivan Harel, etc. (October 2015) Pharmacologic inhibition of JAK-STAT signaling promotes hair growth. Science Advances
Surprising findings - Bacteria communicate like human neurons
Bacteria often viewed as simple organism, are in fact sophisticated in their social interactions and communications with each other as reported in a recent Nature publication. This group of researchers examined the long-range communications within biofilm and discovered that just like neurons in human brain, bacteria use ion channels to communicate and resolve metabolic stress. They showed that ion channels conduct long-range electrical signals within bacterial biofilm through spatially propagating waves of potassium. A metabolic stress triggered the release of intracellular potassium, which in turn depolarize neighboring cells, forming a positive feedback loop. By propagating this wave of potassium, bacterial cells coordinate the accessibility of nutrients between inner and outer layers of the biofilm, which allows the bacterial cells in the colony center keep alive and can survive attacks by chemicals and anti-biotics. Once the potassium channel is deleted from bacteria, such long-range communications no longer exist. These findings not only opened a new venue for treating biofilm, but also furthered our understanding of migraines and seizures, as they share the same mechanism in the signal conduction.
Arthur Prindle, etc. (October 2015) Ion channels enable electrical communication in bacterial communities. Nature
New discovery - Remote control of CAR-T cells
CAR-T cells have been emerging as an effective approach to treat cancer and autoimmune diseases. A problem with CAR-T cells is that once they are infused, they are on their own exerting autonomous activities, which can lead to severe side effects due to the extensive lysis of tumor cells. Researchers have been seeking ways to control CAR-T cells after they are infused to balance the desired therapeutic effect and the side effect. Recently, a group of researchers at UCSF found a way to control CAR-T cells after they are put into patients, through a rapamycine analogue gated chimeric receptor.
CAR-T cell system has two components: one is the recognition domain that binds to CD19 to target B cells; the other is the functional domain to activate cellular pathways to killing the targeted cells. Those two domains are typically preassembled. What this group of researchers did is to separate those two domains and make them come together only in the presence of the activating molecule, a rapamycine analogue. They showed that in the absence of the activating molecule, CAR-T cells still bound to CD19. But, they didn't kill the targeted cells unless the activating molecule was present. In addition, by adjusting the dose of the activating molecule, the strength of CAR-T cells activities can be titrated as well.
Chia-Yung Wu, etc. (October 2015) Remote control of therapeutic T cells through a small molecule–gated chimeric receptor. Science
New technology uncovered the stem cell niche in the bone marrow
Hematopoietic stem cells (HSCs) are so rare that it's difficult to comprehensively localize dividing and non-dividing HSCs. Thus, there has controversy about their specific location in the bone marrow. A recent Nature publication reported that the HSCs resides mainly in perisinusoidal niches through out the bone marrow and there are no spatially distinct niches for dividing and non-dividing blood-forming stem cells. This group of researchers at UT Southwestern Medical Center started the generation of a GFP knock-in for the gene Ctnnal1, a generic marker for HSCs in mice (α-catulinGFP mice) and confirmed that α-catulin-GFP+c-kit+ cells represent blood-forming HSCs by showing that α-catulin-GFP+c-kit+ cells gave long term multi-lineage reconstitution of irradiated mice. Using a tissue-clearing technique and deep confocal imaging, they were able to image thousands of α-catulin-GFP+c-kit+ cells and see their relation to other cells. This publication improved the understanding of the microenvironment of HSCs in the bone marrow, which would significantly improve the safety and effectiveness of bone marrow transplantation.
Melih Acar, etc. (October 2015) Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal. Nature
Targeting cell cycle protein for better sleep?
Sleep maintenance insomnia is a common problem affecting millions of people, especially for aging population: people wake up in the middle of the night and can't get back to sleep. Most sleeping pills work best for people having trouble to fall into sleep, but are not effective with people suffering sleep maintenance insomnia. A better solution is to specifically target the brain pathways that maintain sleep. A recent publication on Drosophila studies suggest that a drug targeting such a pathway is within reach. The authors reported that TARANIS (TARA), a conserved cell cycle protein is required for normal sleep pattern. TARA physically and genetically interact with Cyclin A to promote sleep while both are regulated by Cyclin-dependent kinase 1 (Cdk1) in the sleep regulation. Decreased level of Cdk1 rescued the short-sleeping phenotype in experimental fruit flies, while increased level of Cdk1 mimics the phenotype. In addition, the authors also reported the identification of a cluster of ~14 Cyclin A expressing neurons in the pars lateralis that function in wake-promoting.
Dinis J.S. Afonso, etc. (June 2015) TARANIS functions with cyclin A and Cdk1 in a novel arousal center to control sleep in Drosophila. Current Biology
New breakthrough! - A better alternative CRISPR system just identified
CRISPR-Cas9 system has revolutionized the field of genome editing since its first application in human cells was reported in 2012. A recent publication in Cell reported the identification of a different CRISPR system with the potential for even simpler and more precise genome editing. The newly identified CRISPR-Cpf1 system mediates robust DNA interference with features different from Cas9. Cpf1 possesses several advantages over the currently used Cas9 system.
- The Cpf1 system is simpler than Cas9 system as it requires only a single RNA for its DNA-cutting enzymatic activity.
- Cpf1 cut has shot overhangs on the exposed ends, allowing more efficient and precise genome engineering; while Cas9 cut produces blunt ends that often undergo mutations when rejoined.
- Cpf1 is smaller than Cas9, thus easier to deliver into the cells or tissues.
- Cpf1 cut is far away from the recognition site, leaving space for further editing if mutation occurred at the cutting site.
- The Cpf1 complex recognize very different PAM sequences than those of Cas9, adding more flexibility in choosing target sites.
These properties of Cpf1 and its potential with more precise gene editing expanded the application scope of CRISPR, from gene knock-out and knock-ins, genomic deletions, to even gene therapy.
Bernd Zetsche, etc. (September 2015) Cpf1 is a single RNA-guided endonuclease of a class 2 CRISPR-Case system. Cell
Sensory neuron detecting Earth's magnetic field just identified in C. elegans
Many organisms from bacteria, birds to human orient to the earth's magnetic field. However, the magnetosensory neurons responsive to earth's magnetic field have yet to be identified in any animal. A recent publication reported the identification of magnetosensory neurons in C. elegans the first time. The authors observed that worms move towards different directions during vertical burrowing migrations according to their fed-status and their origins. Well-fed worms migrated up, while starved worms migrated down. Worms isolated from northern vs. southern-hemisphere showed opposite migration preferences. To investigate the molecular mechanism for magnetosensation, the authors screened a serial of gene-mutated worms and found AFD sensory neurons are required for magnetotaxis. Furthermore, the authors elicited the sensory transduction pathway that mediated magnetic orientation in the AFD neurons, in which cGMP-gated ion channel TAX-4 is required to activate AFD neurons to respond to magnetic fields. Calcium imaging showed that this type of response happened even without synaptic input.
Andres Vidal-Gadea, etc. (June 2015) Magnetosensitive neurons mediate geomagnetic orientation in Caenorhabditis elegans. eLife
New findings from fruit flies: a novel way that parents influence the potential fitness of their offspring
By Red Queen dynamics theory, when facing new threats like bacteria or parasite infection, organisms must continually evolve to maintain the fitness of the species. A new publication in Science reported that Drosophila melanogaster produced a much greater proportion of recombinant offspring after either bacteria infection or predation by a parasite wasp. And this response is consistent across genetic backgrounds, developmental stages and parasite types. Surprisingly, this genetic diversity was not due to increased recombination rates, but rather an unequal allocation of gametes that have undergone recombination, a phenomena called transmission distortion. The result is that the offspring as a whole would have better chance to survive future threats from the same bacteria or parasite infection due to their genetic diversity. More interestingly, this reproductive response to infections was initiated early in the development - the lava stage, which is much before the beginning of egg production. The authors believe that such reproduction evolution is unlikely unique to fruit flies, as it represents a novel way that parents can influence the potential fitness of their offspring. However, whether other species can adapt the same reproductive response upon infections needs to be determined experimentally.
Nadia D. Singh, etc. (August 2015) Fruit flies diversify their offspring in response to parasite infection. Science
A consortium of 5 soil bacteria rescued plant from root rot
Root bacteria are known in improving plant's supply of nutrients. A recent publication revealed a more profound role of soil bacteria playing in plant health. A group of researchers inadvertently recapitulated a common agricultural dilemma in an experimental field: the accumulation of phytopathogens by planting a species of wild tobacco in the same field for 15 years. The authors noticed an increasing number of tobacco plants died from wilt diseases in recent years while the native plants in the same field showed no symptoms. Then, they tried multiple approaches in the field to solve the problem, including addition of known beneficial bacteria, applying conventional chemical fungicides, adding charcoal, etc. Only adding a mixture of beneficial soil bacteria reduced the mortality of the infected plants without slowing plant growth. Furthermore, the authors scrutinized the effect of the bacteria community and found that a consortium of 5 soil bacteria (K1, E46, A176, B55 and A70) are essential for the protective effect, suggesting that individual bacterial strain needs to cooperate with other bacterial strains to exert synergistic protective effect that contributed to the reduced mortality. This finding has significant implications on the sustainable agriculture as currently only individual bacterial strains had been applied in agriculture. This finding also revealed the complex ecology of plants and emphasized the importance of crop rotation to prevent the soil pathogen buildup.
Rakesh Santhanam, etc. (September 2015) Native root-associated bacteria rescue a plant from a sudden-wilt disease that emerged during continuous cropping. PNAS
New discovery: An enzyme shut off biofilm formation completely
Biofilms are responsible for the transmission and persistence of human diseases associated with inert surfaces, including medical devices for internal or external use. Biofilm infections are difficult to eradicate, leading to severe clinical complications. A recent publication made a breakthrough finding that an enzyme called oligoribonuclease (Orn) can completely shut off the signaling pathway of biofilm growth. It's well known that cyclic-di-GMP (c-di-GMP) is the signaling molecule that activates the biofilm formation. The degradation of c-di-GMP involves two steps. The first step is to linearize c-di-GMP to pGpG by PDE-As and the second step is to hydrolyze pGpG into two GMPs by PDE-Bs. The publication reported that Orn is the primary enzyme of PDE-Bs turning pGpG into GMP in the cell, thus completely switch off the biofilm formation. This study is done in Pseudomonas aeruginosa, but may apply to many other bacterial strains that have genetic and physiological similarities with P. aeruginosa. This finding could facilitate the development of new treatment for biofilms and make biofilm-related complications a distant memory.
Mona W. Orr, etc. (September 2015) Oligoribonuclease is the primary degradative enzyme for pGpG in Pseudomonas aeruginosa that is required for cyclic-di-GMP turnover PNAS
New findings: Low-carb is not necessary to lose body fat
Dietary carbohydrate restriction vs. dietary fat restriction, which is more efficient in reducing body fat in people with obesity? A recent publication provided the answer through a well controlled human study. 19 adults with obesity were admitted to the metabolic ward of the NIH Clinical Center and stay there for two weeks per study section. For the first 5 days, everyone was fed a eucaloric baseline diet that gave them the exact number of calories they needed to maintain their body weight. For the next 6 days, the participants were randomly assigned to two groups with either reduced-carbohydrate diet or reduced-fat diet. By measuring the amount of fat eaten and the amount of fat burned, the researchers found that the reduced-fat diet led to ~67% greater body fat loss compared to the reduced-carbohydrates diet, even though the reduced-carbohydrates diet reduced insulin and increased fat burning.
Kevin D. Hall, etc. (August 2015) Calorie for Calorie, Dietary Fat Restriction Results in More Body Fat Loss than Carbohydrate Restriction in People with Obesity Cell Metabolism
A universal flu vaccine? – Two new publications provided the proofs of concept
Are you thinking of getting your yearly flu shot as we are approaching the flu season of the year? Current flu vaccines provided some level of protection again seasonal flu, but didn't cover all subtypes of influenza virus. The subtypes of influenza didn't covered by the flu vaccine can spread quickly causing influenza pandemic, such as H1N1 swine flu pandemic in 2009. A universal flu vaccine targeting all subtypes of influenza virus would be ideal. Can this be possibly done? Two recently publications (one on Nature and the other on Science) provided the proofs of concept on developing a universal flu vaccine targeting the hemagglutinin (HA)-stem region that is highly conserved and recognized by antibodies capable of binding multiple HA subtypes. The Nature article reported a structure based-approach using HA stabilized stem on ferritin nanoparticles, which elicited immune protection in mice and ferrets against lethal heterotypic H5N1 influenza virus exposure. Side by side, the Science article used a rational design and library screening approach and identified a stable HA-stem antigen, called mini-HAs, which exerted full protection in mice and monkeys in lethal heterologous and heterosubtypic challenge models.
Antonietta Impagliazzo, etc. (August 2015) A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen. Science
Hardi M Yassine, etc. (August 2015) Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection. Nature
Is radiotherapy necessary to treat early breast cancer?
Ductal carcinoma in situ (DCIS) is also referred as stage 0 breast cancer and accounts for ~20% of the breast cancer detected by mammography. Women diagnosed with DCIS often experience a 2nd DCIS or invasive breast cancer. Thus, aggressive treatment, such as radiotherapy or even mastectomy was often chosen. However, a recent publication suggested that it might not be necessary. The authors abstracted data from 108,196 women diagnosed with DCIS and found that patients who received lumpectomy, radiotherapy reduced the risk of ipsilateral invasive recurrence at 10 years (2.5% vs. 4.9%), but has no significant impact on breast cancer specific mortality at 10 years (0.8% vs. 0.9%). This study also revealed high risk factors for death from breast cancer, including age at diagnosis and ethnicity. Women who diagnosed before age 35 and blacks are at high risk of breast-cancer specific mortality.
Steven A. Narod, etc. (August 2015) Breast Cancer Mortality After a Diagnosis of Ductal Carcinoma In Situ JAMA Oncol.
A subset of cells responsible for liver cell renewal identified
Liver regenerative therapy has been a promising approach to treat some liver diseases, such as liver fibrosis. However, how new hepatocytes are produced and regulated in the adult liver is an open question. A recent publication revealed a subset of hepatocytes adjacent to the central vein in the liver lobule being responsible for maintaining liver mass. This subset of liver cells express the early liver progenitor marker Tbx3 and can replace all hepatocytes during liver homeostasis in mice. In addition, this subset of liver cells are regulated by Wnt signals provided by the adjacent central vein endothelial cells. These findings significantly advanced our understanding of liver homeostasis and shed light on developing new therapeutic approaches to treat liver diseases.
Bruce Wang, etc. (August 2015) Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver Nature
New interactive online database help to choose the right Ab for your application
It has been a challenge for researchers to find reliable antibodies for their specific applications. Unreliable antibodies have led to numerous false findings, failed experiments, wasting money and resources. A recent publication reported the creation of an interactive online database for Histone antibodies, a subset of antibodies used often in epigenetics studies. Instead of relying on the manufacturers' claims, the histone antibody database contained experimentally validated test results for over 100 commercially available histone antibodies, allowing researchers to compare the real data and choose the right antibody for their own applications. In addition, this interactive database allows researchers to upload their own test result, which allows the database to continue to grow. Check out http://www.histoneantibodies.com for more features.
Scott B. Rothbart, etc. (August 2015) An Interactive Database for the Assessment of Histone Antibody Specificity Molecular Cell
Why can't you ignore a screaming baby? –underlying neuropsychological mechanism revealed
Why can't you ignore a screaming baby or alarm sound? A recently publication provided an explanation. Scream and alarm sound both possessed a unique feature – the roughness, which refers to how fast a sound changes in loudness. Using the modulation power spectrum analysis, the authors showed that human screams cluster between 30 and 150 Hz modulation rates. Using fMRI, the authors showed that the roughness of the sound selectively activated amygdala, which is involved in danger processing, triggering fear circuits in the brain. And the increases in roughness correspond to more activation of the fear response. These findings provided some interesting insight on how brain responds to vocalization.
Luc H. Arnal, etc. (July 2015) Human Screams Occupy a Privileged Niche in the Communication Soundscape. Current Biology
Special mushroom fight obesity via altering gut microbiome
The prevalence of obesity represents a major threat to public health as it often accompanied with a panel of diseases due to low grade chronic inflammation, including type 2 diabetes, high blood pressure, cardiovascular diseases, stroke, etc. There is a great need for safe and effective anti-obesity treatments. In a recent publication, researchers showed that the water extract of a special mushroom G. ludidum (WEGL) reduced obesity in high fat diet fed (HFD) mice by altering gut microbiome. And this anti-obesity effect is transmissible, demonstrated by faeces transplantation from WEGL treated mice to HFD mice. This group of researchers were also able to pinpoint the active ingredient in WEGL, the high molecular weight polysaccharides (>300kDa), which exert the microbiota-modulating and anti-obesity effects.
Chih-Jung Chang, etc. (July 2015) Ganoderma lucidum reduces obesity in mice by modulating the composition of the gut microbiota. Nature Communications
What drives the diversification of life on earth? – Genetic basis revealed
Coevolutionary interactions are considered as the driver of the diversification of life on earth. However, its genetic and evolutionary basis were yet to be elucidated. A recently PNAS paper provided an answer to it. By studying the coevolutionary interactions between the ancestors of mustards and butterflies, this group of researchers from University of Missouri discovered an escalating evolutionary chemical arms race that is backed up by the gene and genome duplications, but not allelic turnovers. In this processes, the ancestors of mustards evolved defenses to avoid being eaten by insect by producing and intensifying a chemical called glucosinolates, which is responsible for the sharp taste of mustard, horseradish and wasabi etc. Most insects don't like it, but interestingly, we human found it to be favorable.
Patrick P. Edger, et al. (July 2015) The butterfly plant arms-race escalated by gene and genome duplications Proc. Natl. Acad. Sci. USA
How fructose leads to heart failure? – Underlying molecular mechanism revealed
Fructose has been used as an alternative for glucose in the food industry as it was supposedly safer than glucose for not causing significant increased on blood sugar and insulin activity. Is fructose truly less harmful than glucose? A recently publication revealed the molecular mechanism of high fructose leading to uncontrolled cardiomyocytes growth and eventually heart failure. Under hypoxia condition, cardiomyocytes produced HIF1alpha, which drove SF3B1 for the production of KHK-C, a key enzyme for fructose metabolism. This forms a positive feedback loop among HIF1alpha/SF3B1/KHK-C without an internal shut-off control, resulting in abnormal heart muscle growth. The same pathway can be activated in cancer cells as well.
Peter Mirtschink, etc. (July 2015) HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease. Nature
New technique enables early cancer detection by tracking cell signaling in situ at single cell level
A recent paper reported a new technique called Digital Microfluidic Immunocytochemistry in Single Cells (DISC). DISC can track signaling kinetics at single cell level in the order of seconds, which allows the cell signaling cascade being recorded in real time. Flow cytometry and Mass Spec. have been used to track cell signaling in single cells, however, none of them has such high temporal resolution. DISC can have broad applications, especially in early cancer detection. When it's tested in breast cancer cells, it enabled the identification of "rapid responders", a small group of cells that responded much quickly and strongly than the rest of the population, indicating an early stage of malignancy.
Alphonsus H.C. Ng, et al. (June 2015) Digital microfluidic immunocytochemistry in single cells Nature Communications.
A genetic link between creativity and psychiatric illnesses
The idea of a link between "madness" and "genius", no doubt brings to mind a few notable examples: Vincent Van Gogh, the recently deceased John Nash, Virgina Woolf, the list goes on. Added to this, previous studies have shown that psychiatric disorders tend to run in families where creative professions are prominent. Despite the seemingly obvious connection of psychiatric illness to creativity, scientists have not been able to pinpoint whether the association is due to common genes or simply shared environmental factors. That is, until a recent study published in Nature Neuroscience found a common genetic link between creativity and the development of schizophrenia and bipolar disorder, implying the underlying mental processes also partly overlap. The results were based on an analysis of genetic data from 86,292 people in Iceland; revealing genetic risk scores for both schizophrenia and bipolar disorder were significantly higher among those defined as 'creative'.
Would you be defined as 'creative'? Researchers define 'creativity' as someone who takes "novel approaches requiring cognitive processes that are different from prevailing modes of thought or expression." In the study by Power et al., creative individuals were defined as those belonging to the national artistic societies of actors, dancers, musicians, visual artists and writers.
Does this answer the age-old question of "nature vs. nurture" for certain psychiatric illnesses? The answer to this question may best be put into words by the author himself, Dr. Robert A. Power: "Our findings suggest that creative people may have a genetic predisposition toward thinking differently which, when combined with other harmful biological or environmental factors, could lead to mental illness."
Power et al. (June 2015). Polygenic risk scores for schizophrenia and bipolar disorder predict creativity. Nat Neurosci.
Sci-fi inspired medicine: syringe-injectable electronics with bio-monitoring potential
In a recent issue of Nature Neuroscience, scientists developed an electronic device so flexible it can be rolled up, drawn up into a small needle and injected into living tissue. The electronic mesh device significantly improves on existing implantable structures which are relatively crude in comparison to the way the brain is wired and require surgical implantation to reach precise areas of the body. In contrast, syringe-injectable electronics now make it possible to precisely control delivery to target tissues in a non-invasive fashion. In tests designed to assess the behavior of the electronic mesh device, the team used a glass needle to inject the device into mice in both the lateral ventricle and hippocampal regions of the brain. The experiment was conducted over a 5-week period in which the team was able to both monitor and stimulate individual neurons. Unlike previous techniques, mice showed no signs of an elevated immune response and the electronic structures even began to network with healthy neurons. Such flexible, implantable electronics possess broad potential for treating such conditions as Parkinson's and paralysis, checking electrophysiological signals related to epilepsy and arrhythmia, even for unraveling the inner workings of the brain in never-before-seen detail.
What are some unique applications of injectable mesh electronics? Despite the plethora of information obtained in recent years, neuroscientists still do not know how individual activities of cells actually translate to higher cognitive functions, such as working memory, mental imagery, perception and emotion. The main bottleneck for such studies has been a technology which allows scientists to study thousands, or even millions of neurons at once. The biological compatibility of syringe-injectable electronics presents a viable solution to this problem, potentially allowing the study of large numbers of neurons for long periods of time, with minimal damage to tissue. Many experts hope the new technology will help break through many of the experimental roadblocks associated with the study of the brain and potentially, unlock secrets to how the brain works.
Liu et al. (June 2015). Syringe-injectable electronics. Nat Nanotechnol.
Scientists discover epigenetic regulation controls aging in human cells
A new study published in Nature's Scientific Reports challenges the popular theory of mitochondrial aging with data revealing age-associated mitochondrial defects are controlled by epigenetic regulation, not by mutations within mtDNA. Researchers compared mitochondrial function in human fibroblast cell lines from two different age groups: young people (aged 0-12 years) and elderly individuals (aged 80-97 years). The team expected the reduction in mitochondrial respiration in the elderly group, but they did not expect the amount of DNA damage between the two groups to go unchanged. This led scientists to entertain a new hypothesis - that epigenetic regulation may be the causal agent for the age-associated effects seen in mitochondria. To test this theory, the human fibroblasts were reprogrammed to an embryonic stem cell-like state and then back into fibroblasts. Theoretically, any epigenetic changes associated with the mitochondrial DNA would be removed as a result of this process. Remarkably, the age-associated defects in mitochondrial respiration rates were reversed, indicating the aging process in the mitochondrion is controlled by epigenetic regulation.
What epigenetically-controlled genes were implicated in age-associated mitochondrial defects? Researchers showed that by changing the regulation of two genes involved in the production of glycine, CGAT and SHMT2, they could induce defects or restore mitochondrial function in the fibroblast cell lines. What's more, adding glycine to the culture media of the elderly fibroblast cell line for 10 days, also restored respiratory function. Now one lingering question remains: Can epigenetic regulation also control aging in humans?
Hashizume et al. (May 2015). Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects. Sci Rep.
Humanized yeast may be better model for genetic diseases than previously thought
We may have had a billion years to evolve, yet hundreds of genes shared between humans and yeast persist nearly unchanged in both species, according to a recent study published in Science. This shocking evolutionary stability was observed in certain groups of genes by taking human DNA and replacing the matching DNA in a yeast cell. Out of 414 human-to-yeast gene replacements, 43% were able to support the life of the yeast cell. Moreover, scientists speculate there could be upwards of 1,000 more pairs of swappable genes between humans and yeast. While similar studies have been done in the past for single genes, this study marks the first large-scale study to swap hundreds of gene pairs and now provides information for researchers to begin replacing entire systems involving dozens of genes at a time. The possibility of such experiments has significant implications for human health given some genetic diseases could be studied in entirely new ways.
What makes a gene swappable? Surprisingly, the most predictive factor for a gene pair's ability to be swapped was whether other genes within the same given pathway could also be swapped. For highly similar protein pairs, which shared >50% of their amino acid sequences, the likelihood of successful swapping increased. However, for pairs in the middle range, 20-50% shared amino acid sequences, the degree of similarity was not a contributing factor. These observations led scientists to conclude that if a process as a whole has changed between yeast and humans, then most likely its protein have all changed concurrently.
Kachroo et al. (May 2015). Systematic humanization of yeast genes reveals conserved functions and genetic modularity. Science.
Smartphone video microscope may help eradicate parasitic worm diseases
It is estimated that river blindness, caused by infection from the parasitic worm Onchocerca volvulus, affects nearly 25 million people, making it the second-leading cause of infectious blindness worldwide. Lymphatic filariasis, transmitted by mosquitos, leads to elephantiasis, a condition characterized by painful swelling and disfigurement. It is the second-leading cause of disability, affecting more than 120 million individuals in 73 countries. Both parasitic diseases are highly endemic in certain regions of Africa and while the antiparasitic drug ivermectin (IVM) can be used to treat these diseases, mass drug administration (MDA) efforts have largely been halted due to the potentially fatal side effects of IVM in individuals co-infected with Loa loa, or African eye worm. The standard method of screening for Loa loa is impractical for field settings which would be necessary during mass campaigns to administer IVM, creating a significant roadblock in efforts to eradicate river blindness and lymphatic filariasis. Recently, however, a team of scientists tackled the need for a rapid field test with the design of an automated smartphone video microscope that analyzes the "wriggling" motion of the worms, offering a quick, 2-minute diagnostic solution.
How does the smartphone video microscope work? In short, the researchers coupled a smartphone with a 3D-printed base where blood collected from a finger prick can be loaded and subsequently analyzed. Control of the device is negotiated through a specially-designed app. Thus, at the single touch of the smartphone screen, gears move the sample in front of the camera and an algorithm automatically analyzes the motion of the worms, capturing their movement through the phone-mounted video microscope. The short, 2 minute processing time allows healthcare workers to quickly and accurately determine in the field whether or not an individual can safely receive IVM treatment. Based on the nearly 100% accuracy rate of the smartphone diagnostic device, the team estimates only 1 in 10 million individuals at high risk for serious side effects would mistakenly receive IVM treatment in future MDA campaigns.
D'Ambrosio et al. (May 2015). Point-of-care quantification of blood-borne filarial parasites with a mobile phone microscope.
Genes have seasonal cycles – How is this affecting your health?
Certain chronic diseases are notoriously seasonal: Type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and even cardiovascular disease. In fact, in the UK, deaths from heart disease go up by 20 percent in the winter months. Why? This decades-long question may be nearing an answer - In a recent issue of Nature Communications, researchers revealed the activity of almost a quarter of our genes (5,136 out of 22,822 tested) vary according to the season. Even the composition of our blood and adipose tissue changes depending on the time of year. The most striking pattern was the discovery of seasonal variation in 147 genes involved in the immune system.
Could this effect how we treat certain autoimmune diseases that strike during the winter months? While the mechanism that governs seasonal gene fluctuations remains unknown, scientists do expect that one possible outcome is that treatment for certain chronic diseases could be more effective depending on the season in which they are administered. The work also reveals an unexpected biological mechanism that leaves the body seasonally vulnerable to such autoimmune attack as that seen in Type 1 diabetes.
What seasonal gene garnered the most attention? One gene which captured the eyes of scientists the most was ARNTL. It is a gene that in mice has been found to suppress inflammation. Interestingly, ARNTL was found to be more active in the summer and less active in the winter months. As inflammation is a risk factor for a number of diseases, scientists postulate that drugs targeting mechanisms underlying inflammation may more effectively treat such conditions during the winter.
While considerable work remains to untangle the complexities of genetic and environmental factors behind a diagnosis, this new evidence suggests we should perhaps watch our health more closely in the winter
Dopico et al. (May 2015). Widespread seasonal gene expression reveals annual differences in human immunity and physiology. Nat Commun.
Breakthrough mitochondrial editing technique prevents genetic diseases in mice
Approximately 1 in 5,000 people worldwide has a disorder caused by mitochondrial defects. Known collectively as ‘mitochondrial diseases’, each disease can present very differently among individuals, exhibiting symptoms such as poor muscle development and weakness, hearing, vision and neurological deficits, learning disabilities, and heart, liver, GI and respiratory diseases. In a recent issue of Cell, scientists gave hope to thousands of women around the world that carry defective mitochondrial DNA by demonstrating the ability to prevent mitochondrial disease by successfully eliminating mutated mtDNA using the TAL effector nuclease technique.1 To do this, researchers injected heteroplasmic mouse embryos with TAL effector nucleases engineered to specifically target mutated mtDNA. The result – nearly 60% of mutated mtDNA was destroyed, and the embryos developed into normal, healthy mice.
Was the technique able to prevent the inheritance of human disease? To determine the applicability to human disease, researchers created hybrid cells by fusing mouse eggs with mitochondria from people with mitochondrial disease. In fact, the team was able to successfully reduce human mutated mtDNA levels responsible for Leber's hereditary optic neuropathy (LHOND), as well as neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) using the mitochondria-targeted TAL effector nucleases.
TAL effector nuclease technique vs. the CRISPR/Cas9 system – How do current gene editing studies compare? The mitochondria-targeted TAL effector nuclease technique discussed here was published in the wake of a highly controversial paper which aimed to genetically modify human embryos using the CRISPR method.2 Of the 71 embryos that survived injection of the CRISPR/Cas9 system, only 28 were successfully spliced, and at that, only a fraction actually contained the replacement genetic material. Complicating matters further, researchers found a shocking number of off-target mutations, presumably due to the CRISPR/Cas9 complex targeting other portions of the genome. While it appears the TAL effector nucleases seemed to target only the mitochondria1, experts are quick to point out the technique could prove harmful if even a very low amount of the TAL effector nucleases' genetic instructions escaped into the nuclear genome. Clearly many ethical and technical questions remain for both gene editing systems and while the results in mice are promising, we have a long way to go before any such technology can be used to help humans.
1 Reddy et al. (April 2015). Selective elimination of mitochondrial mutations in the germline by genome editing. Cell.
2 Liang et al. (April 2015). CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein & Cell.
Hot off the press: 3D printed organs may soon be coming to a body near you
You name it, food, apparel, firearms, even automobile and aircraft parts have been made by 3D printers. The fascinating world of 3D printing technology appears limitless, using materials ranging from liquids and powder to plastic, sand, metal and now, printing with live cells. While 3D-printed polymer bones, prosthetics and primitive organs have recently been reported, scientists are now working to print tissues using live cells as 'ink' and assembling them layer-by-layer into tissues. The long-term goal, scientists suggest, is to use this emerging technology to fabricate hearts, kidneys, and other vital human organs. Not only does 3D-printing help scale up the current processes used to engineer organs in the lab; the ability to use a patient's own cells to create such organs could eliminate problems associated with tissue rejection.
What is 'fugitive' ink? Creating vasculature to carry blood and nutrients to 3D-printed organs is perhaps one of the biggest challenges for 3D printing technology. Scientists at Harvard University, however, recently found a solution with the design of a 'fugitive ink' that melts upon cooling. Once printed, 'fugitive ink' can be suctioned off creating hollow channels that can function as blood vessels.
How exactly do scientists use live cells as 'ink'? The process begins by taking a biopsy of the organ that is to be replaced. Cells with regenerative potential are then isolated, multiplied, and mixed with a liquid material that can provide oxygen and nutrients throughout the printing process. This cell mixture can then placed in one printer cartridge while a biomaterial is loaded into a second cartridge for the printing of an organ-shaped structure. Once the "print" button is pushed, the printer can build the structure layer-by-layer, embedding the cells into each layer of biomaterial.
Ledford et al. (April 2015). Printed body parts come alive. Nature.
A painful cure for baldness? It's all in how many hairs you pluck
Frustrated by hair loss? In a recent issue of the journal Cell, scientists reveal that patterned hair plucking triggers the release of immune signals capable of promoting widespread hair regeneration. Just what exactly is 'patterned hair plucking'? Scientists found that the optimum regrowth response was achieved when they plucked 200 hairs in a circle 5 millimeters in diameter. As a result, nearly 1300 nearby hairs transitioned into the growing phase.
How does the immune response coordinate this process of tissue regeneration? Through molecular and genetic analyses, scientists outlined a two-step mechanism in which plucked follicles release CCL2 that leads to recruitment of TNF-α-secreting macrophages to the plucked region. The macrophages, in turn, activate regeneration of all hair follicles in the region, regardless of whether they were plucked or not. Researchers hope such a quorum-sensing mechanism, once fully understood, could be manipulated in the future to increase regenerative capacity beyond just hair follicles.
Chen et al. (April 2015). Organ-level quorum sensing directs regeneration in hair stem cell populations. Cell.
Contagious cancer – a rare phenomenon or growing concern?
For the last 40 years, outbreaks of a leukemia-like disease have been ravaging populations of soft-shell marine bivalves, Mya arenaria, along the East Coast of the United States. Perplexed by its cause, scientists first pointed to environmental factors and had only recently come to suspect the disease was transmitted by a virus. Upon sequencing the genes of the clams, however, researchers made a startling discovery: A fatal cancer, known as haemic neoplasia, was traced back to a single case of cancer in one clam. To date, only two other known cases of contagious cancers have occurred in mammals; the Tasmanian devil facial tumor disease (DFTD) and the canine transmissible venereal tumor (CTVT). Given the similarity of haemic neoplasia to other diseases found in cockles, mussels, and oysters, scientists suggest contagious cancers may, in fact, be more common in nature than we think.
Are humans at risk by eating clams with transmissible leukemia? The authors of this study clearly point out the only thing humans may get from encountering clams with haemic neoplasia is perhaps insight into the complex mechanisms of cancer metastasis. After all, cancers are adapted to individual species and the human immune system is adept at blocking any such foreign tissue.
Metzger et al. (April 2015). Horizontal transmission of clonal cancer cells causes leukemia in soft-shell clams. Cell.
Novel HIV reservoirs found using a new live imaging technique
In a recent issue of Nature Methods, scientists borrowed a rather common live imaging technique used with cancer patients to reveal unexpected hideouts of the simian AIDS virus, or SIV. The innovative method, referred to as 'immunoPET', utilizes a radiolabeled antibody that targets a surface protein of SIV. Once administered in monkeys, a PET scan detects the antibodies, generating a striking real-time map of SIV replicating in the entire body of the animal. The technique allowed detection of SIV reservoirs, despite the lack of detectable virus in blood samples of monkeys given antiretroviral (ARV) therapy.
What locations of SIV startled scientists the most? The investigators found surprisingly high levels of the SIV antibody in the nasal cavity and genital tract of males, a particularly unusual finding given that sexual transmission of the AIDS virus does not occur that readily. In addition, the virus was also prevalent in the lung, a region not typically of interest to HIV researchers.
How does this impact HIV research and treatment in humans? Scientists hope the tool may be used to determine what happens in humans during the first weeks following infection with the AIDS virus. For instance, information on where the virus goes, how it travels, and why certain regions of the body provide benefits to the virus could help guide drug, vaccine and cure research in humans. In addition, the immunoPET technique may offer a non-invasive means to identify which tissues harbor HIV reservoirs in fully-suppressed individuals and to evaluate the efficacy of new methods to deliver ARV drugs to these hard-to-reach regions.
Santangelo et al. (May 2015). Wholebody immunoPET reveals active SIV dynamics in viremic and antiretroviral therapytreated macaques. Nat Methods.
Will the FDA approve release of mutant mosquitoes to fight dengue virus?
Mosquito-borne diseases pose a tremendous threat to human health in virtually every country in the world. It is estimated that approximately 50 to 100 million people contract dengue each year, with more than 20,000 succumbing to the disease. Aedes aegypti mosquitos, known to transmit dengue and chikungunya viruses, present a year-round public health problem for residents of the U.S. Florida Keys and with insecticides proving useless, the FDA is currently considering approval of a plan to release bioengineered mosquitos (GM mosquitoes) which carry a genetic “kill switch”. In 2009, a privately funded research company released male GM Aedes aegypti mosquitos into the wild on an island near Grand Cayman, the result of which was an 80% reduction in the local Aedes aegypti population. Also, in 2012, a similar experiment was conducted in Juazeiro, Brazil. Both trials were met with mixed opinions by local residents. As the proposed field trial in the Florida Keys undergoes consideration by the FDA, many communities have taken a strong stance, raising concerns regarding public health and environmental risks, as well as religious and philosophical objections to the release of GM mosquitoes. The ethics of such a trial take center stage, as many people in the community will be affected despite whether or not they consent to their release. The question remains: Should the trial be conducted at all?
How does the GM mosquito work? The Aedes aegypti mosquitoes are given two genes: a color marker, in the form of a fluorescent protein, and the 'self-limiting' pest control gene. Male GM mosquitoes are released into the environment to mate with wild females resulting in the passage of both genes, and 96% of offspring die before reaching maturity. The color marker allows scientists to monitor mating success and adjust the number of GM mosquitoes to optimize control of the Aedes aegypti population.
Resnik et al. (April 2014). Ethical issues in field trials of genetically-modified disease-resistant mosquitos. Dev World Bioeth.
Treating Alzheimer's disease with sound?
For years, ultrasound has served as an invaluable tool for imaging babies to fragmenting kidney stones. Now, scientists have developed a method to unleash the technology on brain diseases. In a recent issue of Science Translational Medicine, scientists safely used scanning ultrasound treatments (SUS) to energize microscopic bubbles and permeate the blood-brain barrier (BBB) in a mouse model of Alzheimer's disease (AD). The non-invasive, drug-free approach cleared amyloid-β plaques in 75% of mouse brains subjected to SUS, and restored lost memory and cognitive function.
The strategy uses ultrasound to energize microscopic blood-borne bubbles, which briefly open the BBB as they expand and contract. Researchers involved in the study suggest the technique may not only prove important for allowing drugs into the brain, but as their results demonstrate, it is equally capable of stimulating microglia to remove harmful amyloid-β plaques.
Can we expect the same results from SUS therapy in humans? The successful application of this technique in humans hinges on the ability to gently permeate the BBB without damaging brain tissue, potentially triggering a devastating immune reaction or hemorrhage. Early studies of SUS in rabbits and monkeys, however, have produced no negative side effects, ushering in clinical trials to determine if SUS can increase chemotherapy delivery to human brain cancer patients.
Leinenga et al. (March 2015). Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer's disease mouse model. Sci Trans Med.
Will new finding of 'beige' fat in humans make us thinner and less prone to diabetes?
The promising concept of brown fat recruitment to fight obesity and its metabolic complications has captivated scientists for years. However, until recently, it had not been demonstrated that a recruitable form of human brown adipose tissue (BAT) actually exists in humans. A recent issue of Nature Medicine finally advances the concept of brown fat recruitment as scientists isolate and characterize 'beige' fat-burning cells from adult humans. In a population of uncoupling protein 1 (UCP1)-positive clonally derived adipocytes, researchers identified molecular markers which include: potassium channel K3 (KCNK3) and mitochondrial tumor suppressor 1 (MTUS1), both of which were necessary for 'beige' adipocyte differentiation and thermogenic function.
What makes "brown fat" brown? The distinctive color of brown fat is due to the presence of dense regions of mitochondria, organelles responsible for producing the energy currency of the cell, ATP.
Shinoda et al. (March 2015). Genetic and functional characterization of clonally derived adult human brown adipocytes.
New CAR T-cell therapy tackles deadly form of brain cancer
Glioblastoma (GBM) is the most dangerous and aggressive form of brain cancer with treatment almost never producing a cure. While CAR T-cell therapy has shown promising results against hard-to-treat blood cancers, its application in treating solid tumors has been wrought with challenges. In a recent groundbreaking study, scientists advance the field of cancer immunotherapy with the successful application of engineered T-cell technology to solid tumors. CAR T-cells were designed to target a mutation in EGFRvIII, a tumor-specific protein found in nearly 30% of all human GBM cases. To do this, the team developed and tested multiple single chain variable fragments (scFv) to obtain an scFv with specificity toward mutated EGFRvIII and which did not bind normal EGFR proteins expressed in healthy tissue. They next generated a panel of humanized scFvs and tested their functionality in CAR-modified T-cells, ultimately selecting the optimal lead candidate to test for anti-cancer efficacy. Their studies revealed the novel "hunter" T-cells effectively controlled tumor growth in several mouse models of GBM, ushering in clinical trials of EGFRvIII-directed CAR T-cell therapy in humans.
Harnessing the power of a patients immune system has already demonstrated unprecedented potential for the treatment of aggressive cancers. While current T-cell engineering strategies have been limited to small clinical trials, the outcomes from such studies have been anything but ordinary. In a recent trial of CAR T-cells in adults and children with leukemia and lymphoma, all signs of cancer disappeared in 27 of the 30 patients treated, and 19 of the 27 remained in remission at follow-up (Maude et al.). In addition, similar findings have been found for patients with ALL and advanced diffuse large B-cell lymphoma. Experts are optimistic that CAR T-cell therapy will eventually become a standard treatment option for some B-cell malignancies and even currently untreatable cancers.
Maus et al. (March 2015). Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma. Sci Trans Med.
Maude et al. (October 2014). Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med.
Novel technique may enhance DNA immunization efficiency by boosting recombinant protein production
Effective methods to safely and efficiently deliver DNA are critical to the development of successful DNA vaccines and gene therapies. In a recent issue of PNAS, researchers made a startling discovery – cotransfection of retroviral sequences resulted in ~5- to 10-fold increases in recombinant protein expression.
How did retroviral DNA increase novel protein production in cells? The retroviral DNA was found to increase translation of co-transfected genes in trans by an mTOR complex 1-independent signaling mechanism. By increasing the production of specific proteins within cells, scientist believe this new method may help elicit a stronger immune response to DNA vaccines and make smaller vaccine doses possible to reduce the risk of immunotoxicity.
Gou et al. (March 2015). Retroviral vectors elevate coexpressed protein levels in trans through cap-dependent translation. PNAS.
New finding - Processed foods wreak havoc on gut microbiota and promote obesity
Glance at the label of many of your favorite foods; ice cream, salad dressing, breads, cookies, pasta sauce, and you will likely see a number of food additives known as emulsifiers. A new study published in Nature reports two common dietary emulsifiers, carboxymethylcellulose (CMC) and polysorbate-80 (P80), alter the gut microbiota and induce obesity/metabolic syndrome in mice. Interestingly, microbiota transplants from emulsifier-treated mice to germ-free mice were sufficient to transfer some parameters of low-grade inflammation and metabolic syndrome, establishing a dominant role of microbiota in mediating the detrimental effects of emulsifiers.
Are altered microbiota to blame for excess eating? While the research team does not dispute the widely held assumption that excess caloric consumption is the dominant factor contributing to the rising incidence of obesity/metabolic syndrome, their findings do support the concept that low-grade inflammation resulting from alterations in gut bacteria can be an underlying cause of over-eating.
Chassaing et al. (February 2015). Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature.
Powerful new antibody fights influenza and pneumonia
In a recent breakthrough study, scientists revealed a new antibody targeting host protein angiopoietin-like 4 (ANGPTL4) reduced lung damage and accelerated recovery in a mouse model of influenza pneumonia. The findings that influenza infection directly stimulates ANGPTL4 and levels of the protein correlate with degree of lung inflammation, have led researchers to take the next step and begin developing a diagnostic kit. Packaging the new antibody in a convenient kit will allow doctors to accurately diagnose the severity of pneumonia, as well as track the efficacy of prescribed treatments in an attempt to boost survival chances in patients suffering from this condition.
Li et al. (February 2015). Angiopoietin-like 4 increases pulmonary tissue leakiness and damage during influenza pneumonia. Cell Reports.
Electrifying new technique propels anti-cancer drugs into solid tumors.
Nearly three quarters of patients who develop pancreatic cancer die within the first year following diagnosis. A major contributing factor to this poor prognosis is the limited therapeutic potential of IV chemotherapy due to systemic toxicity and poor tumor perfusion. Recently, scientists at the University of North Carolina and Duke University developed a novel iontophoretic device designed to improve the efficacy of cytotoxic agents via site-specific delivery directly into solid tumors. The team revealed that device delivery of gemcitabine resulted in a 7-fold increase in local drug concentrations and 25-fold lower systemic drug levels compared to IV chemotherapy treatment. When combined with IV chemotherapy, researchers observed significant reductions in tumor growth and increased survival time in murine models of human breast and pancreatic cancers. Researchers hope the potential clinical applications of such a device will help an important segment of the cancer patient population for which traditional chemotherapy treatment has proved ineffective.
Byrne et al. (February 2015). Local iontophoretic administration of cytotoxic therapies to solid tumors. Sci Transl Med.
Adipocytes fight infection?
A new paper published in Science may change the way you think of those stubborn last few winter pounds. Researchers at the University of California, San Diego School of Medicine recently reported dermal adipocytes participate directly in the protection of skin against S. aureus infection. In studies performed in a murine model of MRSA infection, scientists detected a marked increase in dermal adipose tissue, a response accompanied by release of the antimicrobial peptide, cathelicidin. Identifying this new role of adipocytes in the body's defense against infection certainly makes sense from an evolutionary perspective, but then why is obesity associated with an increased risk of skin and soft tissue infection in humans? Researchers suggest one explanation could be due to insulin resistance and other characteristics of metabolic syndrome which disturb the adipogenesis-cathelicidin pathway. Such mechanisms could include: altered adipokine signaling leading to impaired expression of cathelicidin or defective posttranslational cleavage of the antimicrobial peptide due to obesity and metabolic syndrome.
Zhang et al. (January 2015). Dermal adipocytes protect against invasive Staphylococcus aureus skin infection. Science.
Novel approach boosts anti-HIV-1 antibody efficacy through intra-spike crosslinking
Most viruses are covered by hundreds of virion spikes, the natural targets for neutralizing antibodies. Conversely, the surface of HIV is dotted with comparably fewer with estimates ranging from only 10-20 spikes per virus particle. This characteristic inspired scientists at the California Institute of Technology to question whether the low spike density and spike structure of HIV prevent bivalent antibody binding through inter-spike and intra-spike crosslinking, respectively. Utilizing engineered antibody-based molecules, the team employed DNA as a "molecular ruler" to effectively measure intra-epitope distances. Once determined, the DNA was replaced with a protein linker of similar length, resulting in molecules capable of intra-spike crosslinking. These unique bivalent reagents demonstrated a stunning 100-fold increase in HIV-1 neutralization potency. Furthermore, intra-spike crosslinking was found to lower the concentration of antibodies needed to evoke neutralization, thus paving the way for more effective therapeutics to prevent or treat HIV-1 infection.
Galimidi et al. (January 2015). Intra-Spike Crosslinking Overcomes Antibody Evasion by HIV-1. Cell.
Unexpected role of EGFR in cancer drug resistance
The mechanism behind EGFR inhibition for cancer treatment has been clearly established, but the failure of EGFR TKIs to halt cancer growth in patients with WT EGFR has left scientists and physicians bewildered. That is, until a new study published in the journal Cell cracked the case: EGFR TKIs activate a role for inactive EGFR in autophagy which confers a survival advantage in WT EGFR-expressing cancers. The team found that in metabolically stressed conditions LAPTM4B helps transport inactive EGFR to endosomes, where it then recruits the Sec5 exocyst subcomplex. This complex then binds the autophagy inhibitor Rubicon, resulting in the liberation of Beclin 1 and hence, the initiation of autophagy. This new finding suggests co-targeting EGFR and autophagy could deliver a one-two punch to stop the growth of tumors lacking EGFR mutations.
Tan et al. (January 2015). A kinase-independent role for EGF receptor in autophagy initiation. Cell.
Transgenerational effects of HDAC inhibitor on Huntington's disease
Is it possible therapies that change gene expression in parents could also help their children? In a recent issue of the journal PNAS, scientists at The Scripps Research Institute suggest yes, reporting treatment of Huntington's disease (HD) transgenic mice with an HDAC inhibitor (HDACi 4b) induced epigenetic changes and remarkable symptom improvement in both parents and their offspring. The genes most significantly altered in expression were those encoding enzymes related to the control of DNA methylation: Dnmt1, Dnm3a, Gadd45b, Parp1, and RING finger protein 4 (Rnf4). Moreover, the offspring of HDACi 4b-treated male HD transgenic mice also exhibited delayed onset and reduced symptoms of Huntington's disease including both improvements in memory and motor skills. What's next? Scientists hope to unravel more details as to the extent of penetration among subsequent generations, as well as whether or not HDAC inhibitors approved to treat certain cancers and bipolar disorders also promote beneficial transgenerational effects.
Jia, et al. (November 2014). HDAC inhibition imparts beneficial transgenerational effects in Huntington's disease mice via altered DNA and histone methylation. PNAS.
New neutralizing Abs target all 4 serotypes of mosquito-borne DENV
Designing effective vaccines against DENV poses significant challenges due to the unstable structure of the virus and appreciable differences among the four serotypes. Furthermore, a phenomenon called antibody-dependent enhancement, in which individuals exposed to one DENV serotype suffer more serious symptoms upon subsequent infection with a second serotype, necessitates development of a vaccine with the ability to protect against all four DENV strains. In a recent article published in Nature Immunology, a brilliant team of scientists characterized 145 human monoclonal antibodies against DENV. The effort culminated in the discovery of a new class of antibodies to a unique envelope dimer epitope (EDE) that effectively neutralized all four serotypes of the virus. These broadly reactive antibodies demonstrated 50% neutralization activity in the low picomolar range and were effective against viruses produced in either insect or mammalian cells. In addition, they had the unique ability to bind only to the higher level structure of an intact virion. What makes the EDE truly remarkable? It is present in all four serotypes of DENV; a quality scientists hope will pave the way for a future universal DENV vaccine.
Dejnirattisai et al. (December 2014). A new class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected with dengue virus. Nature Immunology.
New subset of T cells discovered: Implications for MS treatment
It is estimated nearly 2.5 million individuals suffer from multiple sclerosis (MS), an inflammatory disease in which an abnormal response of the body's immune system attacks myelin. The resultant distortion and interruption of nerve impulses produce the wide range of symptoms characteristic of this disease. Since first described in 1868, the causes of MS have remained unclear and medications have proven to be only modestly effective. Recently, however, a team of scientists made a breakthrough discovery: IL-7, signaling through STAT5, induced a distinct subset of TH cells which predominantly expressed GM-CSF. This new type of TH cell, named TH-GM, was found to be critical for autoimmune neuroinflammation, thus uncovering a mechanistic link between IL-7/STAT5 signaling and TH cell-mediated pathogenicity. The findings suggest future efforts to block IL-7 or STAT5 could provide a significant therapeutic benefit for MS patients. Going forward, the research team plans to define the physiological function of TH-GM in an effort to impact future therapeutic intervention for a number of human autoimmune diseases.
Sheng et al. (November 2014). STAT5 programs a distinct subset of GM-CSF-producing T helper cells that is essential for autoimmune neuroinflammation. Cell Research.
New method to produce fully humanized antibodies in large quantities
Hantaviruses are known to cause a potentially fatal condition known as Hantavirus Pulmonary Syndrome (HPS). Despite a 35-40% fatality rate, there are currently no licensed vaccines or antiviral therapeutics available to treat or prevent this disease. While modest success has been achieved using immune plasma from HPS survivors, short supply and the need to match each patient's blood type have limited the scalability of this approach.
A groundbreaking study recently published in Sci. Transl. Med. unveiled an efficient method to produce large quantities of fully human pAbs in transchromosomal bovines (TcBs) using two hantavirus DNA vaccines. The purified human antibodies exhibited potent antiviral neutralizing activity against both the Andes and Sin Nombre viruses, as well as offered protection in a hamster model of HPS. Unlike other animal-derived pAb approaches, "despeciation" was not required. Authors speculate this may allow the human antibodies to mediate a more natural immune response to effectively neutralize and clear the virus. In addition, the development time from the first vaccination to high titer, fully human antibody was just a few months with each TcB able to produce several hundred to 1,000 human doses of antibody per month. Researchers hope this method may eventually be used to produce human Abs against a broad range of pathogens to facilitate rapid responses to life-threatening diseases.
Hooper, et al. (November 2014). DNA vaccine-derived human IgG produced in transchromosomal bovines protect lethal models of hantavirus pulmonary syndrome. Sci Transl Med.
Will checkpoint blockade soon become first-line therapy for cancer?
A five paper series recently published in Nature revealed checkpoint blockade with a monoclonal antibody against PD-L1 (MPDL3280A) produced robust anticancer responses in patients harboring a variety of cancer types, broadly extending the scope and impact of treatment for this class of therapeutics. Accompanying this data, scientists also published advancements in predicting what type of patient can benefit from cancer immunotherapy. Their analysis revealed that tumors in which the invading immune cells produced significant amounts of PD-L1 exhibited a more robust response to antibody therapy. For melanoma in particular, the best response to treatment was in tumors that possessed a large amount of cytotoxic T cells at the tumor margin. These data suggest that tumors which have already been recognized by the immune system are particularly susceptible to immune-checkpoint blockade.
When do scientists think will be the best time to apply this approach to reach maximal effect?
It has been suggested that cancer immunotherapy may be most beneficial in cases where there are fewer tumor cells to destroy, such as in an adjuvant setting, after surgical excision of a localized tumor. It is here scientists believe immune checkpoint inhibitors may reduce the risk of cancer recurrence and make the possibility of a cure within reach.
Reprogram fibroblasts directly into functional pain-sensing neurons with 5 transcription factors
After numerous setbacks over the past six years, scientists at the Harvard Stem Cell Institute finally achieved success converting mouse and human skin cells into pain-sensing neurons capable of responding to a variety of stimuli that cause acute and inflammatory pain. To do this, researchers studied mature pain neurons from mice and identified three novel transcription factors, which when combined with two previously described factors were able to reprogram mouse and human fibroblasts directly into noxious stimulus-detecting (nociceptor) neurons. The combination of 5 transcription factors needed for nociceptor production included: Ascl1, Myt1l, Ngn1, Isl2, and Klf7. Derived nociceptor neurons exhibited TrpV1 sensitization to PGE2 and oxaliplatin, thus providing an elegant model of inflammatory pain hypersensitivity and chemotherapy-induced neuropathy. Scientists hope this method of enforced expression of lineage-determining transcription factors will streamline production of such nociceptors for use in future studies to pave the way for new pain medications and a greater understanding of a variety of human pain and neurodegenerative conditions.
Wainger, et al. (November 2014). Modeling pain in vitro using nociceptor neurons reprogrammed from fibroblasts. Nat Neurosci.
A friendly virus? – New study reports enteric virus may help maintain a healthy gut
The intestinal microbiota and commensal bacteria are often used interchangeably. Not surprising given studies on the microbiome and human health have primarily focused on the bacterial component, revealing microbial communities play a significant role in the proper functioning of the digestive tract, immune system, skin and other bodily systems. Recent deep sequencing efforts, however, have revealed the existence of an enteric virome whose members include: noroviruses, Anelloviridae and Circoviridae, as well as uncharacterized viruses which display minimal homology with their known counterparts. Scientists at New York University's Langone Medical Center sought to determine whether these eukaryotic enteric viruses could interact with their host in a symbiotic manner, comparable to commensal bacteria. Their startling findings in MNV-infected germ-free or antibiotic-treated mice are summarized below:
- MNV restored intestinal morphology and lymphocyte function without causing inflammation or disease.
- MNV facilitated recovery of murine intestines following antibiotic insult.
- MNV offered protection against infectious and non-infectious secondary challenges to the G.I. tract in mice treated with antibiotics.
- MNV stimulated an immune response involving type I interferon (IFN) signaling.
- The IFN-α receptor was necessary for MNV to compensate for the lack of commensal bacteria.
Further defining how MNV protects its host may prove to be the biggest hurdle yet for scientists. Why? Technical difficulties surround analyzing the virome given that viruses are not detected by normal sequencing approaches. In addition, there are huge variations between different viruses which complicate the determination of whether or not particular sequences actually come from viruses. Despite these obstacles, scientists hope to move forward and delineate functions of the virome which could lead to diagnostic and therapeutic targets for diseases such as, IBD and obesity.
Kernbauer et al. (December 2014). An enteric virus can replace the beneficial function of commensal bacteria. Nature.
Treating Alzheimer's Disease via transferrin pathway – new finding in Monkeys
Twenty years ago scientists identified a potential route to transport antibodies across the formidable blood-brain barrier (BBB); the transferrin receptor-mediated transcytosis pathway. This novel approach began to materialize in 2011 when a team of scientists led by Dr. Ryan Watts at Genentech first reported on the design of an antibody targeting two proteins: the transferrin receptor (TfR), to improve brain exposure, and β-secretase (BACE1 - β-amyloid cleaving enzyme-1), to reduce brain amyloid-β(Aβ) levels for the treatment of Alzheimer's disease. The success of this bispecific antibody, however, was met with challenges surrounding its dissociation from the BBB and devastating effects on red blood cell levels in mice. Over the next three years, Watts and his team would bring forth a newly designed low-affinity anti-TfR bispecific antibody, poised to enter a proof-of-concept study to hopefully pave the way for human trials. Using a non-human primate model, Watts and colleagues demonstrated a humanized anti-TfR/BACE1 bispecific antibody not only effectively traversed the BBB and reduced Aβ levels in CSF and brain tissue, the red blood cell damage previously observed in mice did not occur in monkeys. These data lend support to this, as well as similar approaches utilizing TfR to cross the BBB for the treatment of Alzheimer's and other neurodegenerative diseases.
Yu et al. (November 2014). Therapeutic bispecific antibodies cross blood-brain barrier in nonhuman primates. Sci Transl Med.
Top 10 ideas that could speed up drug development for Rare Diseases research
On April 30, 2014, members of the U.S. House Energy and Commerce Committee said enough is enough with their announcement of the launch of 21st Century Cures1, an initiative expected to culminate in major legislation to change the way the NIH, FDA, and private stakeholders identify and develop new therapies, in particular, those for Rare Diseases. The ultimate goal? Accelerate the pace of cures and medical breakthroughs. Since the first roundtable convened on May 6th, 21st Century Cures has sought input from interested parties. Their recommendations are summarized below.
Top 10 ideas to speed up drug development for Rare Disease research:
- Update FDA regulations to allow new predictable scientific criteria for biomarker endpoints.1.2
- FDA to accommodate more flexible application of safety data.2
- Make patients true partners in advancing medical research.2,3,4
- Ensure stable, predictable funding for both the FDA and NIH.2,3
- Improve the specialization of the FDA drug review divisions and commission a “National Plan for Rare Diseases”.3
- Enhance the focus on clinical trial design and analysis paradigms for Rare Disease clinical studies. Encourage the FDA to allow alternative clinical study designs and analysis.2.3
- Protect current and seek additional incentives for industry to ensure lifesaving medicines for Rare Diseases are economically viable to develop.2
- Incentivize cross-sector collaboration (academia, government, industry, investors, and nonprofits) throughout the R&D process.4
- Improve the risk-return ratio for early stage research.4
- Invest in basic and translational research infrastructure by: strengthening publicly-funded academic research, as guided by the NIH and NSF; advancing systems improvement in the translational phase, and investing in the next generation of scientists.4
Is cancer contagious? – The role of exosomes
A new study in the journal Cancer Cell reported cancer exosomes don't just house microRNAs; they actually bioengineer specific microRNAs with the help of Dicer and the multi-protein complex known as RISC. Together, this Dicer-exosome interplay creates an "oncogenic field effect" by allowing cancer cells to reprogram the transcriptome of surrounding cells and thus, provoke tumor growth and metastasis. Interestingly, inhibiting the action of Dicer significantly impaired tumor growth, lending support to the team's hypothesis that miRNA's in exosomes contribute to the spread of cancer. What's next? The researchers suggest Dicer could be used as a biomarker for the clinical detection of cancer.
Melo et al. (November 2014). Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell.
Could stem cell therapy without cell transplantation be possible?
Extracellular vesicles have increasingly been studied for their potential as indicators of disease, as well as for prospective new treatments. In a recent article published in Molecular Cell, researchers expand on the role of these tiny membranous structures, shedding light on the mechanisms of intercellular information exchange mediated by extracellular vesicles (EVs) from neural stem cells (NSCs). Using a model of inflammation, scientists found that NSCs are able to detect the inflammatory cytokine IFN-ϒ and launch a receptor-specific response. This response entails packaging of EVs with very specific messenger RNA cargo, which scientists observed, mimics the response of the parental cell to its environment. Subsequent delivery of EV-associated IFN-ϒ triggered Stat1 activation in target cells, illustrating how EVs mediate NSC communication with the host immune system. This research represents a remarkable finding with potential to be translated into a stem cell-free approach to treat conditions such as stroke, spinal cord injury, and multiple sclerosis.
Cossetti et al. (October 2014). Extracellular vesicles from neural stem cells transfer IFN-ϒ via lfngr1 to activate Stat1 signaling in target cells. Mol Cell.
New finding – How cancer cells become resistant to chemotherapy?
Charles Darwin could have never anticipated his theories on biological diversity and natural selection would some day be used to illustrate cancer cell diversity and drug resistance. Just as species develop new traits better suited to their changing environment, so too do cancer cells in response to drug treatment. The article by Lee et al. points out that cancer cells treated with chemotherapy achieve functional diversity and survive drug insult through subtle changes in their RNA, a process which occurs more rapidly than previously thought. One of the surprising observations was the extent of diversification among cells. Specific transcriptional programs drove heterogeneity between single cells, within and between treatment groups. Unlike Darwin's theory, however, drug-tolerant cells regained normal gene expression patterns, as well as drug sensitivity after a few population doublings.
Also intriguing was the finding that precancerous cells evolved significantly faster and became even more drug resistant following chemotherapy then either normal or cancerous cells. These data, while highly intriguing and useful, may just be the tip of the iceberg in the quest to find a diversification “switch” to turn off drug resistance.
Lee et al. (September 2014). Single-cell analyses of transcriptional heterogeneity during drug tolerance transition in cancer cells by RNA sequencing. PNAS.
New target to prevent severe asthma attacks brought on by the common cold
For most individuals, the common cold is nothing more than a bi-yearly nuisance kept under control by OTC remedies and rest. Viruses that infect the airways, however, can bring on life-threatening symptoms in individuals with asthma. Until recently, the mechanism underlying this response remained elusive. Scientists at Imperial College London and King's College London solved a major piece of this puzzle with their finding that rhinovirus infection induced IL-25 in individuals with asthma. Furthermore, Increased levels of IL-25 led to production of type 2 cytokines that ultimately provoked the type 2 immune response. What does this mean for people with asthma? Promising data from antibody-mediated blocking of IL-25 suggests IL-25 could be a new target for treatments to prevent asthma attacks brought on by the common cold.
Antibody therapy against IL-25 vs. antibodies that block type 2 cytokines. When comparing therapeutic strategies for asthma, it is important to consider the heterogeneous aspect of this disorder. A variety of cytokines released by T cells, innate and structural cells contribute to the symptoms of asthma. Thus, specific anti-cytokine therapies may only be effective in certain subsets of the condition. Recent trial reports of anti-type 2 cytokine therapies reveal only modest therapeutic effects, leading many in the asthma research community to believe it may be necessary to block the expression of more than one cytokine to reap significant therapeutic benefits. The hope of Beale and colleagues, presented in the October issue of Sci. Transl. Med., is that blocking IL-25 may potentially stop the cytokine cascade upstream, thereby eliciting a much greater therapeutic effect for the treatment of asthma.
Beale et al. (October 2014). Rhinovirus-induced IL-25 in asthma exacerbation drives type 2 immunity and allergic pulmonary inflammation. Sci Transl Med.
Stem cell booster: Small molecule allows multiplication of stem cells in cord blood
While HSC transplant offers the only cure for a number of hematologic malignancies, current data estimates 30-40% of patients will not have a suitable donor. The alternative, cord blood transplant, offers a number of advantages including: reduced need for human leukocyte antigen (HLA) matching and decreased risk of chronic graft-versus-host disease. Unfortunately, only 5% of cord blood samples contain enough stem cells to treat an adult. Scientists at the Institute for Research in Immunology and Cancer (IRIC) at the University of Montreal are paving the way to change this statistic with the discovery of a synthetic molecule termed UM171. Their data suggest UM171 acts to boost human long-term-repopulating HSC self-renewal mechanisms independently of AhR suppression. The result? UM171 has the potential to increase the number of cord blood units available for transplant in adults 10-fold, thus reducing the complications associated with stem cell transplantation.
For their studies, the scientists at IRIC developed a new type of bioreactor for stem cell culture. The automated system allows for fine tuning of stimulatory and inhibitory factors by utilizing a controlled fed-batch media dilution approach. Though requiring only a small culture volume, scientists were able to rapidly expand HSCs, as much as 11-fold, in as little as 12 days.
Fares et al. (September 2014). Pyrimidoindole derivatives are agonists of human hematopoeitic stem cell self renewal. Science.
The bitter truth about artificial sweeteners
An article recently published in the journal Nature suggests no-calorie artificial sweeteners (NAS) may contribute to the very health issues consumers are trying to avoid, namely metabolic disease. Saccharin, in particular, was found to alter blood glucose levels to the greatest extent and nurtured a distinct gut bacterial population that researchers suggest was the driving force behind the development of glucose intolerance. While questions remain surrounding the observed bacterial community shift, the data support a direct link between NAS-induced dysbiosis and glucose intolerance.
Is this true in humans? Suez et al. conducted a preliminary study which found four out of seven human volunteers, given a high dose of saccharin over a period of six days, developed signs of glucose intolerance. This finding, however, has set in motion more questions than answers.
What is the current scientific data on NAS effects in humans?
- A study composed of 2,680 men aged 40-75 followed over 20 years found sugar-sweetened beverage consumption was associated with a significantly increased risk for diabetes. The association between NAS-beverages and type 2 diabetes was largely explained by health status, weight change, dieting and BMI.
- The Multi-Ethnic Study of Atherosclerosis (MESA) found associations between diet soda consumption and risk of metabolic syndrome and type 2 diabetes.
- The Nurses' Health Study composed of 116,671 female US nurses aged 24-44 found diet soft drink consumption was associated with a slight, non-significant increase in diabetes risk after adjusting for baseline BMI.
- As part of the InterAct project, a study composed of 340,234 individuals from eight countries; researchers found a connection between sugar-sweetened beverages and diabetes, but did not find an association between NAS-beverages and diabetes.
J. Suez et al. (September 2014). Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature.
Molecular mechanism of splicing dysregulation in cancer just unveiled
Cancer-related splicing dysregulation is a well-known phenomenon; yet targeting the proteins involved is anything but an ordinary approach to fighting cancer. Scientists at the University of North Carolina Health Care recently discovered splicing factor RBM4 plays an integral role in gene splicing within cancer cells, expression of which was found to be drastically reduced in lung and breast cancer patients. The repercussions related to low levels of RBM4 involve dysregulation of Bcl-x, a bcl-2 gene family member, as well as splicing regulator, SRSF1. When present at sufficient levels, RBM4 normally functions to inhibit alternative splicing, thereby producing the short form of Bcl-x known to induce apoptosis. In cases where RBM4 is low, however, the long form is produced, thus promoting cancer growth and metastasis. In addition, low levels of RBM4 allow the oncogenic splicing factor SRSF1 to go unchecked, resulting in mTOR activation and cancer cell proliferation. The study determined that RBM4 activation could actually reverse cancer progression in mice, establishing it as a new tumor suppressor with prognostic and therapeutic potential.
Wang et al. (September 2014). The splicing factor RBM4 controls apoptosis, proliferation, and migration to suppress tumor progression. Cancer Cell.
Tissue-specific activation of AMPK acts as a 'remote control' to delay aging
Studies in recent years have brought to light that a number of evolutionarily conserved anti-aging mechanisms converge downstream via induction of autophagy; a cellular process involving the degradation and removal of old, damaged cellular material. Still, questions have remained as to the interplay between cellular energy homeostasis, tissue-specific autophagy induction, and lifespan determination.
It is presumed that delaying aging would require protecting multiple organ systems, a feat which could prove technically difficult, particularly in the context of the brain. Scientists at UCLA may have found a method to circumvent this problem with their discovery that AMPK activation in the intestine or nervous system induced autophagy, slowing the process of aging beyond the organ system in which it was initially activated. Identification of a ‘remote control’ such as this could prove useful for interventions based on autophagy induction or AMPK activation in difficult to reach areas of the body. In theory, researchers suggest this could change the approach to studying diseases related to aging such as, Alzheimer’s disease, cancer, and Parkinson’s, from targeting the disease itself, to intervening in the aging process to delay or prevent its onset.
Ulgherait et al. (September 2014). AMPK Modulates Tissue and Organismal Aging in a Non-Cell-Autonomous Manner. Cell.
Clostridia-containing microbiota protect against food allergies through IL-22
Between 1997 and 2011, food allergy rates among children rose by approximately 50%. This staggering increase is in part due to environmental factors, in particular, antibiotic use during infancy. Until recently, however, the underlying mechanism by which intestinal microbiota control food allergy sensitization remained largely unknown. Scientists at the University of Chicago shed light on this question with the discovery that Clostridia-containing microbiota conferred protection against sensitization to food allergens. What was the mechanism controlling uptake of food allergens? Researchers determined Clostridia colonization induced IL-22 production by innate lymphoid cells, as well as T cells in the intestinal lamina propria. Furthermore, this cytokine was found to reinforce the intestinal epithelial barrier, thus reducing intestinal permeability to food allergens.
Intestinal microbiota facts: Gut microbiota can weigh up to 2 kg and are composed of at least 1,000 different species of bacteria with over 3 million genes represented. While one third of these bacteria are common to most people, two thirds are unique, acting as an identity card of sorts. Commensal bacteria have a direct influence on our health; helping to digest food, produce vitamins, combat other microorganisms, and importantly, they play a key role in our immune system by serving as a protective barrier.
Stefka et al. (August 2014). Commensal bacteria protect against food allergen sensitization. PNAS.
Vectored immunoprophylaxis: A promising new approach for preventing infectious diseases
Why is an effective malaria vaccine so far out of reach? The answer is largely based on the fact that a single Plasmodium falciparum sporozoite can initiate infection. While it is known that mAbs directed against the circumsporozoite protein (CSP) of P. falciparum can be effective at neutralizing the infectious form of the parasite, current vaccines have failed to induce sustained high-titer antibodies necessary to prevent infection.
What is VIP? Vectored immunoprophylaxis (VIP), developed in the lab of Dr. David Baltimore at the California Institute of Technology, provides a way to “engineer immunity” using AAV8-mediated delivery of pre-formed mAb genes in vivo to facilitate long-lasting expression of protective mAbs. An article recently published in PNAS applied this Ab gene delivery technique in a rodent model with surprising results: mice receiving the VIP vector exhibited long-lasting mAb expression and were completely protected from mosquito bite challenge when mAb levels reached 1 mg/ml or greater. This study provides proof of principle that such a technology may be useful in the fight against the deadliest form of human malaria.
What should you know about malaria? Malaria ranks fourth as a cause of death among infectious diseases, taking the lives of between 500,000 to 800,000 people in Africa alone in 2012. Current approaches to treat malaria have fallen short in recent years due to growing drug resistance among parasites, insecticide resistance, and the plan to reduce funding for malaria prevention by the WHO. In order to effectively combat this lethal disease, new approaches must be added to the existing arsenal of tools.
Deal, et al (August 2014). Vectored antibody gene delivery protects against Plasmodium falciparum sporozoite challenge in mice. PNAS.
Whole-organ imaging made possible with new tissue-clearing technology
One can probably best compare a new tissue clearing technology to that of plastination, a technique on display at the world-renown exhibit Body Worlds. Viviana Gradinaru, the professor of biology at Caltech who led the project, admits the exhibit sparked her curiosity, which later manifested itself in the PARS technique. This method directly infuses tissue-clearing reagents through systemic circulation, rendering them almost transparent. Compared to other clearing methods, PARS preserves tissue architecture, as well as fluorescent and protein-based signals, allowing high-resolution imaging on a large scale in whole organs, all the way down to fine-scale analysis of subcellular interactions.
Yang, et al (August 2014). Single-cell phenotyping within transparent intact tissue through whole-body clearing. Cell.
Detour to functional dystrophin – take exon 5 to reach the IRES
In 2009 researchers made a striking observation that some patients, despite having a mutation in exon 1 of the gene encoding dystrophin, only exhibited mild symptoms of DMD. The explanation, recently published in Nature Medicine, involves the use of an IRES in DMD exon 5, which allows protein translation within exon 6, leading to functional dystrophin production. The scientists next sought to mimic IRES-activating mutations using an approach termed exon skipping. The study generated striking results: restored running ability in a mouse model of DMD. These data suggest such an approach could offer hope for patients harboring mutations within the first few exons of dystrophin.
Wein, et al (August 2014). Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice. Nature Medicine.
Protein painting: A new technology to advance discovery of protein interaction drug targets
Current methods to define the amino acid sequences within protein-protein interaction hot spots are not only time-consuming, but often require extensive modification to the native protein complex. Enter protein painting: a team of scientists recently created an innovative technology which coats the protein surface with molecular paints. These synthetic aryl hydrocarbon-containing dyes mask trypsin cleavage sites, leaving regions within the interaction interface vulnerable to proteolytic enzymes. Thus, following digestion, resultant peptides, exclusively from hot spot regions, are sequenced and identified by MS. Validating this technology, researchers characterized a unique contact region between members of the IL1β complex that when targeted with synthetic peptide mimetics or mAbs, disrupted IL1β signaling.
Luchini, et al (July 2014). Protein painting reveals solvent-excluded drug targets hidden within native protein-protein interfaces. Nature Communications.
Don't forget your sunscreen – BRAF (V600E) has a new accomplice in UVR-driven melanoma
The molecular mechanism underlying the link between UVR and melanoma risk has remained largely obscure until a recent study published in Nature shed light on the genetic mutations at play. Researchers found that mutations in TP53, previously not thought to play a major role in melanoma, were found to work in concert with BRAF (V600E), actually accelerating melanomagenesis. While sunscreen offered partial protection, 40% of mice carrying the BRAF (V600E) mutation were found to develop mutations in TP53 following UVR exposure. This study was the first to provide insight into how UVR contributes to acquired naevi and establishes TP53 as a UVR-target gene and accomplice of BRAF (V600E).
Viros, et al (July 2014) Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53. Nature.
Neurodegenerative diseases – unlocking the mechanism behind a common mutation
A study recently reports a compelling clue to the pathology of neurodegenerative diseases: missense mutations in TREM2 impair phagocytic activity, triggering inflammation and hastening neurodegeneration. These data come 30 years after Thomas Bird and colleagues first linked TREM2 to AD and nearly two years following data suggesting TREM2 raises the risk for AD to the same extent as that of the well-known risk factor, ApoE4. The study finds that mutations in TREM2 have an effect at the cellular level, reducing receptor maturation and shedding. These data translate to nearly absent levels of soluble TREM2 in the CSF of patients with FTD-like syndrome, and decreased levels in individuals with AD and FTD.
Kleinberger, et al (July 2014). TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med.
New Tuberculosis Treatment – Augment Innate Immune Response Based on IL-1/IFN Crosstalk
In studies performed in TB-infected mice and humans, researchers defined the counter-regulatory relationship between IL-1 and type I IFN during TB infection. Specifically, reduced levels of IL-1 and/or elevated levels of IFN resulted in disruption of the eicosanoid balance necessary to fight TB infection. IL-1 directly promoted synthesis of prostaglandin E2 (PGE2) in infected primary human macrophages and administration of clinically approved drugs to raise PGE2 levels prevented acute mortality in infected mice. These data shed light on the mechanism underlying IL-1-mediated host resistance and establish host-directed immunotherapy as a feasible alternative treatment for MDR-TB.
Mayer-Barber et al. (July 2014) Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk. Nature.
Inhibiting insulin degradation enzyme – is it effective in treating type-2 diabetes?
A recent paper identified a physiologically active insulin degradation enzyme (IDE) inhibitor from a DNA-templated macrocycle library, which allowed the researchers to investigate the relationship between IDE and glucose hemostasis in a more specific manor than IED knockout mouse model could. They found in mice that administrating this IDE inhibitor after oral glucose intake can greatly improve glucose tolerance through boosting both insulin and amylin levels, suggesting that modulating IDE activity can be a new therapeutic strategy to treat type-2 diabetes.
Maianti JP, et al (July 2014) Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones. Nature.
Enhance stem cell pluripotency – is CCL2 better than bFGF?
A recent publication showed that CCL2, a chemokine involved in the inflammatory immune response could be a better choice than the putative bFGF on enhancing stem cell pluripotency. Cells cultured with CCL2 demonstrated a higher tendency of colony attachment and greater efficiency of cellular differentiation than that with bFGF. In addition, using CCL2 and LIF coated cell culture dish, the human embryonic stem cells and hiPSCs can be cultured in a feeder-free condition to minimize the possible contamination from mouse fibroblast feeder cells. It could lead the development of more efficient clinically useful stem cells.
Hasegawa Y, et al (June 2014) CCL2 enhances pluripotency of human induced pluripotent stem cells by activating hypoxia related genes. Sci. Rep.
Mitochondrial dysfunction beyond Parkin/PINK identified in Parkinson's disease
Parkinson's disease is the second most common neurodegenerative disorder in US, which is presumably caused by mitochondrial dysfunction and in particular by inefficient removal of defective mitochondria. Parkin and PINK1 are two enzymes that ubiquitinate defective mitochondria for clearance via mitophagy. Mutations in parkin or PINK are often found in Parkinson's patients. A recent publication identified USP30, a deubiquitase counteract the effect of Parkin/PINK in a fly model, suggesting USP30 can be a druggable target for Parkinson's disease and even mitochondrial disorders in general.
Baris Bingol, et al (June 2014) The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature.
New proteomic map – Do we really know the rules of our genome?
It has been a long existing gap between transcriptome and proteome, due to the existence of post-transcriptional modifications, such as alternative splicing that can give rise to different proteins from the same DNA sequence. Two recent Nature publications drafted the human proteomic map, which bridged the gap and brought new insight on the relationship between genes and proteins. The newly constructed proteomic map can be accessed via http://www.humanproteomemap.org
Mathias Wilhelm, et al (May 2014) Mass-spectrometry-based draft of the human proteome. Nature.
Min-Sik Kim, et al (May 2014) A draft map of the human proteome. Nature.
Turn T cells into super effective cancer killers by mAb
Is it possible to treat all types of cancers with a single approach? A recent study showed that stimulating γδT cells with monoclonal anti-CD3 antibody turned these cells into super effective cancer killers. Once mAb bound to γδ receptor, it induced CD3 conformational change that promoted proximal signaling event in γδT cells, leading to the lysis of all cancer cells in culture. Currently, animal experiments and clinical collaborations have been planned. It would be very interesting to see whether such stimulated T cells can exert the same effect clinically as shown in petri dish.
Dopfer EP, et al (June 2014) The CD3 Conformational Change in the γδ T Cell Receptor Is Not Triggered by Antigens but Can Be Enforced to Enhance Tumor Killing. Cell Rep.
Increase life span without calorie restriction – just minimizing pain
TRPV1 known as a pain receptor is broadly expressed in the body, including both brain and pancreas. A recent publication showed that TRPV1 knockout mice lived longer than their wild type counterparts. Those mice also demonstrated much more robust ability of switching from glucose to fat metabolism late in life due to their diminished TRPV1/CGRP pathway signaling in pancreas, in which activation of TRPV1 leads to increased level of calcitonin gene-related peptide (CGRP), which in turn blocks insulin secretion. This finding not only identified an independent longevity mechanism other than the putative caloric restrictions that involved insulin-like growth factor-1 (IGF-1)/sirtuins signaling, but also raised the probability of pain killers in improving metabolic profile, thus expanding life span.
Molecular mechanisms of Viagra on treating female heart failure in a mouse model
A recent study showed that in a mouse model of heart failure, the heart protective effect of Viagra, a cGMP-specific phosphodiesterase 5 (PDE5) in female mice depend on the estrogen levels. Only female mice that have high estrogen level were benefited from Viagra treatment, but not mice that suffered ovary removal. However, estrogen replacement restored the beneficial effects of Viagra in those mice, indicating the PDE5 inhibitor efficacy is estrogen dependent in female mice with heart diseases. This study also explored the underlying mechanism, indicating the activation of PKG by Viagra required estrogen, which increased cardiomyocyte cGMP synthesis via an eNOS/soluble guanylate cyclase pathway. Of note, this study was using a mouse model of heart failure, which may be different from human.
In a broader sense, this study provided scientific proof that aligns well with NIH's new initiative to demand its grantees balance the sex of model systems from cell cultures up to clinical trials.
Sasaki H, et al (May 2014) PDE5 inhibitor efficacy is estrogen dependent in female heart disease. J Clin Invest
Blueprint of metabolic pathways & regulatory genes accessible via a newly constructed database
The most comprehensive genome-wide association study so far was reported recently. This study scanned close to 8,000 adults, almost 500 metabolites, and ~2.1 million SNPs, with over 100 new associations identified between common genetic variants and the levels of different metabolites in blood. Those novel loci will empower future drug development in several key areas, including metabolic diseases, brain disorders and more. More importantly, a part of the study is to develop an open-access database that allows both commercial and academia investigators to use for better understanding of the genetic influences on human blood metabolites.
Does calcium hypothesis explain synaptic loss in Alzheimer's disease?
Study ties Alzheimer's-associated synapse loss to perturbed calcium regulation in dendritic spines. The researchers found that both mice expressing an Alzheimer's disease (AD) gene and also human brains with sporadic AD displayed less calcium sensor STIM2 and that overexpressing STIM2 rescues spine deficiency. This observation has lead researchers to question whether this may be the common mechanism for memory loss-associated spine loss in both AD and aging.
New mouse model could have detected fatal hepatoxicity in humans
A recent study describes a mouse model with a humanized liver which can be used for detecting hepatic drug toxicity prior to human testing. If these TK-NOG mice were available to be used for preclinical testing in 1993, the tragedy of the FIAU trial could have been avoided in which 5 subjects died.
Transport of histones to DNA copying hubs is regulated by enzyme TLK1
Enzyme TLK1 has been demonstrated to control delivery of histones to sites of DNA replication in a precise, fast and timely manner, through phosphorylation of ASf1, a key histone H3-H4 chaperone.
Injecting stem cells directly into heart is effective in treating heart disease in humans
A new clinical trial demonstrates that injection of stem cells found in bone marrow directly into the heart muscle of patients with severe ischemic heart disease improves heart function. Ischemic heart disease is the #1 cause of death for both men and women in the US.
How are angiogenesis and osteogenesis coupled in bone?
A recent Nature publication identified a specific vessel subtype as the coupler of angiogenesis and osteogenesis in bone, which is significantly reduced in bones of aged animals. Another publication in the same issue of Nature further revealed Notch signaling as the underlying molecular mechanism that promote angiogenesis in bone, which is opposite to the well-known function of Notch in other organs. Manipulation of these pathways was sufficient to restore age-associated loss of bone mass.
Stem cells generated from stress alone? Misconduct found in two Nature papers
The stem-cell scientist responsible for two publications claiming the ability to generate stem cells from fully differentiated cells using only certain stresses, has been found guilty of scientific misconduct. Since publication, six data issues have been identified with these articles , including use of incorrect or misleading images and fraudulent labeling. While four of these problems have been dismissed as innocent error, two have been branded as scientific misconduct.
Original 2 papers
ApoE induction reduces metastatic tumor size by 80%
Recent work reveals that activation of tumoral and stromal apolipoprotein-E (ApoE) resulted in broad-spectrum therapeutic suppression of metastatic melanoma, decreasing tumor size by up to 80%. The oral administration of multiple agonists to liver-X-nuclear hormone receptor (LXR) caused transcriptional induction of ApoE and suppressed tumor growth and metastases across multiple melanoma lines.
New class of antibiotic effective against MRSA
A team of scientists have discovered a new class of antibiotics to fight drug-resistant bacteria including MRSA. This new class, called oxadiazoles, was discovered in silico and inhibits a penicillin-binding protein and other features which enable a bacteria to resist other drugs currently available. In the United States, 278,000 people are hospitalized each year due to MRSA infections and resistance to all 3 effective drugs already exists.
Antibody can predict Crohn's disease response to treatment by in vivo imaging
A recent publication in Nature Medicine describes how fluorescent imaging of antibodies against membrane-bound tumor necrosis factor (mTNF) can predict clinical response of Crohn's disease patients to treatment. Patients with higher initial levels of mTNF cells showed more robust short-term response to treatment with anti-TNF therapy compared with patients with initially lower mTNF levels.
3 Benefits of preventing thrombosis using monoclonal antibody
A recent publication in Science Translational Medicine describes the use of a humanized monoclonal antibody against activated FXIIa, identified using phage display, to prevent the formation of blood clots without increasing the risk of bleeding. Preventing thrombus formation while using a bypass system often leads to unwanted bleeding, sometimes in the brain, making this breakthrough treatment an attractive alternative to heparin.Top 3 Benefits of using an antibody to prevent thrombosis
- Antibody can provide instant anticoagulation
- Antibody can be produced in a controlled way with high purity
- Antibody does not need to be neutralized after use
Environmental stimuli sufficient to generate differentiated cells from pluripotent?
For the first time, researchers have generated pluripotent stem cells from fully differentiated cells only by transiently exposing cells to certain stresses (such as low pH). Using real-time imaging and gene rearrangement analysis, this group was able to identify committed somatic cells give rise to STAP (stimulus-triggered acquisition of pluripotency) cells. These findings suggest that environmental cues can be used to determine the fate of mammalian cells in the absence of gene manipulation.
Senescence in cancer cells induced by chiral selective interactions with telomere
Researchers have identified a compound with chiral selectivity in cancer cells. This compound, NiP (zinc-finger-like alpha helical chiral metallo-supramolecular complex, [Ni2L3]4+-Penantiomer) can selectively induce telomere uncapping and trigger DNA damage responses at telomeres, causing degradation of the telomeric G-overhangand delocalization of the sheltrin complex. Cellular apoptosis and senescence is induced in cancer, but not normal cells with NiP exposure. Interestingly, NiP's enantiomer has no such effects.
- These researchers used anti-?-H2AX produced by GenScript's Custom Monoclonal Antibody Services for this publication
Administration of a specific antibody fragment targeting soluble aggregates responsible for cell toxicity and death associated with Alzheimer's is effective at removing the Aß oligomers which cause the disease. Recently, researchers have determined that the cell death associated with Alzheimer's is not due to the presence of plaques in the brain as previously believed, but from the toxicity of soluble aggregates (oligomers) coming from them. The use of an antibody fragment to neutralize these aggregates is an improvement on previous strategies using full-length antibodies, which wereshown to induce an immune response during trials.
- These researchers used polyclonal antibodies produced by GenScript's Custom Polyclonal Antibody Services for this publication
Increase of C1q Protein in the CNS during Aging
A recent study indicates that a protein called C1q, a key initiator of immune response, is concentrated at the contact points connecting nerve cells in the brain, which potentially makes those nerve cells vulnerable to destruction by brain-dwelling immune cells trigged by brain injury or systemic infection. The researchers used hundreds of antibodies to identify the potential protein which raises its expression level as much as 300 fold in aging brains concentrating at synapses. These findings disclosed an innovative mechanism for the cause of neurodegenerative disorders.
- GenScript offers High-throughput Protein Variant Service which can produce up to 1,000 protein variants in 30 days.
New Therapeutic Intervention for Blindness
A breakthrough finding has identified a potential therapy for GPCR-related human blindness. This paper suggests that negative regulation of the novel protein norpAp24 suppressor, diehard4, is responsible for the inability of endo-lysosomal rhodopsin trafficking and retinal degeneration in Drosophila models of retinal dystrophies, a major cause of human blindness. The identification of additional components of molecular machinery,may shed light on possible therapies for retinal degeneration and GPCR-related human diseases.
- These researchers used polyclonal antibodies produced by GenScript's Custom Polyclonal Antibody Services for this publication
Single Antibody as Innovative Treatment for Incurable Blood Cancer
The researchers have foundthat an antibodyBI-505, had a powerful therapeutic effect on tumor cells in both cell and animal models, making it potentially an innovative treatment for multiple myeloma. An initial safety study of seriously ill patients has been completed and larger-scale studies onits efficacy will continue givenpromising results.
A Breakthrough Finding on Human Cytomegalovirus Prevention
This study reveals that a modified Ankara virus expressing the UL128C of rhesus cytomegalovirus (RhCMV) triggers the expression of neutralizing antibodies in vaccinated rhesus macaques. With more studies, an effective vaccine may be developed to eliminate the risk of congenital HCMV infection.