This page highlights the latest research on the design and application of Custom Synthetic Peptides in science, medicine, and technology. GenScript is proud to be part of the discovery research taking place all around the globe. To see how GenScript Peptide Services are making an impact, view our Peptide Publications webpage.

Treating Glioma Through Targeting Tumor Microenvironment

October 10

Brain Tumor High-grade gliomas are a diverse group of cancers of the brain and spinal cord that occur in both children and adults. Researchers have been trying to treat glioma by targeting cancer cells, however, these approaches only translated to limited success in clinical studies. A recently published study in Nature suggested an alternative approach to treating glioma through targeting the tumor microenvironment.

Venkatesh et al. studied the necessity of neuroligin-3 (NLGN3), a synaptic adhesion molecule involved in promoting cell proliferation through activating the PI3K-mTOR pathway, in glioma growth. The authors found that patient-derived orthotopic xenografts of both pediatric and adult glioma fail to grow in Nlgn3 deficient mice. Furthermore, by using a inhibitor to prevent the release of NLGN3, mice bearing glioma xenografts exhibited pronounced tumor reduction, suggesting that high-grade glioma growth is dependent on microenvironmental NLGN3. These novel findings offer a promising strategy for treating high-grade glioma via targeting surrounding microenvironment, such as NLGN3 secretion.

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Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma. Nature. (2017) September 20; doi:10.1038/nature24014.

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Researchers Suggested A Novel Approach to Stopping Binge Eating

September 28

binge eating Eating disorders, including restricted-eating and binge-eating, are a class of mental illnesses featured by uncontrollable emotions, attitudes, and behaviors toward body image, weight and meal patterns. Thus far, psychotherapies and antidepressants are commonly used in treating eating disorders. It is now agreed that both environmental stress and genetic variations contribute to the development of eating disorder. However, the importance of genetic variations in the pathogenesis of eating disorder has not been fully understood.

Lutter et al. aimed to study the genetic basis of eating disorders and find more specific therapeutic approaches. In this study, 93 unrelated individuals with eating disorders were analyzed by whole exome sequencing. Novel damaging variants were uncovered in 186 genes in the restricted-eating group and 245 genes in the binge-eating group. Importantly, these genes are extensively involved in neuropeptide pathways implicated in appetite regulation. By administrating an agonist for glucagon-like peptide 1 (an essential peptide hormone in appetite regulation) receptor, it significantly reduced food intake in “binge-eating” mouse model. These new findings implicated that glucagon-like peptide 1-receptor agonists may be used as a binge-eating treatment in human.

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Novel and ultra-rare damaging variants in neuropeptide signaling are associated with disordered eating behaviors. PLoS ONE, (2017) Aug 28; 12(8): e0181556.

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Understanding and Preventing Preeclampsia: Breakthrough Insights from A Mice Study

September 25

preeclampsia Complications during pregnancy pose great risks to both mothers and infants. Preeclampisa (PE) a rapidly aggressive complication characterized by the onset of hypertension and the presence of protein in the urine, occurs in up to 8% of all pregnancies and is the leading cause of fetal and maternal illness and death. Not until recently, a paper published in Science reported breakthrough insights into the mechanisms underlying PE development and the critical role of a circulating peptide during this progression.

Ho et al. reported that ELABELA(ELA), a circulating peptide ligand for the apelin receptor, is secreted by the placenta and essential in regulating placental angiogenesis in mice. In addition, Elabela knockout induced proteinuria and hypertension, symptoms of PE, in pregnant mice. Importantly, ELA infusion in Elabela knockout pregnant mice normalized proteinuria, hypertension, and the birth weight of offsprings. These findings suggested that ELA, abundant in human as well, is critical in regulating both fetal and maternal cardiovascular development during pregnancy and may provide a new paradigm for PE prevention in human.

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ELABELA deficiency promotes preeclampsia and cardiovascular malformations in mice. Science, (2017) Aug 18; 357(6352).

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Immunotherapy is safer in treating type 1 diabetes: a new clinical trial study

September 18

Type I diabetes Type 1 diabetes is a chronic condition characterized by the loss of pancreatic β cell mass and function, thus the inability to produce adequate insulin. Despite decades of research, the most accepted treatment method, insulin administration, still leads to unavoidable chronic hyperglycemia and other complications in most patients. As immunotherapy has demonstrated its efficacy in treating autoimmune diseases, the possibility of using peptide immunotherapy as a better tolerated treatment option for type 1 diabetes was explored.

Researchers found that injection of human proinsulin peptide every 2 or 4 weeks, when compared to placebo group (insulin administration), is better tolerated in new-onset type 1 diabetes patients. No acceleration in β cell damage was observed during proinsulin peptide immunotherapy treatment period, whereas the daily usage of insulin in placebo group increased by 50%. Other biomarkers representing β cell mass and function were also tested and support that proinsulin peptide immunotherapy is safer in treating new-onset type 1 diabetes without accelerating disease.

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Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes. (2017) Sci. Transl. Med. 9.

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A neuropeptide determines caste identity in ants

September 11

ants, queen Social insects are great models to study the role of gene regulation in behavior because the distinct castes within each insect colony are derived from the same genome. For example, the queens are solely responsible for reproducing ants, whereas the workers are always foraging. When the colony queen is no longer reproductively active, a ritualized "tournament" within the colony begins and a new queen is established. However, molecular and neural mechanisms that determine the competiveness of workers during this behavior transition is not yet fully understood.

Janko et al. employed Harpegnathos saltator ant as a social insect model and studied the molecular mechanisms that activate different social behavior in different castes. In this study, the authors analyzed brain transcriptomes during the behavior transition and identified a neuropeptide, corazonin, responsible for regulating caste identity and behavior in social insects. Their study demonstrated that, in transitioning ants, injecting corazonin induces worker-like hunting behaviors and inhibits reproductive behaviors.

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The Neuropeptide Corazonin Controls Social Behavior and Caste Identity in Ants. (2017) Cell 170, 748–759.

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Researchers found a better solution for dry eyes

September 4

dry eye Dry eye disease is an inflammatory disease that affects more than 20 million Americans. The most common treatment for dry eye disease is administering anti-inflammatory eye drops. Recently, researchers isolated a peptide from the extra-cellular matrix collagen and showed that it significantly recovered tear production in desiccation stress induced dry eye mouse model. Furthermore, this peptide, hydroxyproline-GQDGLAGPK, improved tear film stabilization, increased the number of goblet cells, and inhibited the expressions of lacrimal gland inflammation markers in mice with dry eye disease. When compared to three popular anti-inflammatory eye drops on the market for treating dry eye disease, the authors found that this peptide eye drop exhibited better anti-inflammation effects in relieving dry eye symptoms. Thus, this peptide eye drop has a great potential to be used in treating dry eye disease in human.

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Anti-inflammatory effect of hydroxyproline-GQDGLAGPK in desiccation stress-induced experimental dry eye mouse. Scientific Reports, (2017) August 07; 7.

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A Novel Ligand Helps Extend the Half-life of Therapeutic Peptide from Minutes to Days

August 29

heart injection drug Peptide drugs have many advantages in vivo when compared to conventional drugs, including their high selectivity, efficacy, and safety. However, the rapid clearance rate of peptides from circulation limits their application as disease therapeutics. To overcome this obstacle, Zorzi et al. developed a novel approach to extend peptide half-life. They constructed a ligand that can be easily conjugated with therapeutic peptide and exhibit high affinity for serum albumin. By conjugating this ligand to an antithrombotic peptide inhibitor, the half-life of peptide extended from 13 minutes to over 5 hours in rabbit. As the ligand has higher affinity for human albumin, it can potentially extend peptide half-life from minutes to days in human. Thus, this novel approach further strengthened the application of peptides as therapeutics.

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Acylated heptapeptide binds albumin with high affinity and application as tag furnishes long-acting peptides. Nature Communications, (2017) July 17; 8.

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Researchers Found a Novel Treatment for Zika Virus Infection Using A Synthetic Peptide

August 22

mosquito and pregnancy The devastating consequences of Zika virus infection in pregnant women have attracted growing attention towards developing vaccines and drugs. However, no specific therapeutics are currently available. Recently, however, scientists have developed a synthetic peptide that can specifically inhibit Zika virus infection.

Yu et al. synthesized a peptide (Z2) derived from the conserved stem region of the Zika virus envelop protein. In their study, Z2 exhibited potent inhibitory effect on Zika virus infection both in vivo and in vitro. Specifically, Z2 disrupted Zika virus membrane integrity and inactivated Zika virus virions at early viral replication stage. What is more exciting is that this synthetic peptide drug could penetrate the placental barrier and prevent Zika infection in the fetus. Thus, Z2 has the potential to be developed as a safe and low-cost therapeutic drug against Zika virus in high-risk populations, including pregnant women.

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A peptide-based viral inactivator inhibits Zika virus infection in pregnant mice and fetuses. Nature Communications, (2017) July 25; 8.

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Association of Poor Sleep with a Life-Changing Disease

August 15

sleepy Previous research had shown that poor sleep negatively affects the cardiovascular system by increasing the risk of high blood pressure and stroke. Now, a new study reveals an association between sleep deprivation and Alzheimer’s disease (AD) pathology in cognitively healthy adults. Subjects of this study were 101 cognitively normal adults who underwent sleep assessment and their cerebrospinal fluid (CSF) was collected. CSF was then assayed for biomarkers of amyloid metabolism and plaques, tau pathology, neuroinflammation/astroglial activation, neuronal/axonal degeneration, and synaptic dysfunction/degeneration. Using multiple regression and after controlling for age, sex, time between sleep and CSF measurements, and CSF assay batch, the relationship between sleep scores and CSF biomarkers of AD were assessed. Analysis of results showed that CSF of individuals with worse sleep quality, more sleep problems, and daytime somnolence was associated with greater AD pathology. Whereas future studies are warranted to elucidate whether poor sleep quality is indeed the culprit of AD pathology and not its consequence, this study serves as a good health reminder for restoring the quality of our sleep.

Poor sleep is associated with CSF biomarkers of amyloid pathology in cognitively normal adults. Neurology. 2017 Aug 1; 89(5).

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Successful Neoantigen Vaccination Heralds A New Era in Personalized Oncotherapy

August 8

immune cells Conventional forms of cancer therapy are known to be associated with toxicity and lack of selectivity. On the other hand, different forms of immunotherapy like PD-1 checkpoint blockers, can result in serious immunological side effects and lack tumor-cell specificity. To overcome these challenges, much attention has been given to the use of neoantigens for precision T-cell therapy for targeting tumors.

Neontigens are a class of HLA-bound peptides that arise from tumor-specific mutations. Since these antigens are not present in normal cells and bypass thymic tolerance, they are highly immunogenic and, therefore, potent in stimulating a strong immune response. Taking advantage of the unique features of neoantigens, researchers at Dana-Farber Cancer Institute, first conducted a whole-exome sequencing of matched tumor- and normal-cell DNA from patients with advanced melanoma to identify somatic mutations. These mutations were further validated using RNA-seq to predict the likelihood of their HLA-binding. Next, immunizing long peptides targeting up to 20 antigens per patient were synthesized and pooled into 4 groups. Finally, conducting the full series of five priming and two booster vaccinations in 6 patients, revealed the efficiency and safety of the personalized peptide vaccines. Results showed that besides general vaccine side effects such as flu-like symptoms or injection-side reactions, there was no sign of tumor recurrence in four patients after two years. The other two patients also experienced complete tumor regression following an anti-PD-1 therapy. The favorable outcome of this phase I clinical study, which addressed both tumor heterogeneity and the chance of antigen loss, has now set the stage for full protocol adoption in other types of cancer as well as protocol improvements for future trials.

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An immunogenic personal neoantigen vaccine for patients with melanoma. Nature. (2017) July 5; 547(7662).

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Phonological Knowledge Formed in the First Few Months of Life

August 1

infant language How early can we recognize familiar sounds around us? Is there a difference in such recognition between native or non-native languages? We tend to rely on our own experiences or anecdotal stories to make inferences rather than finding a solid evidence for answering these questions. Linguistics and neuroscientists, however, need to develop scientific methodologies to clearly unravel such mysteries. A simple yet appropriate methodology was recently used to demystify the age at which we form phonological knowledge.

In a research conducted in the Netherlands, a group of Dutch-speaking adults who were adopted from Korea at 3-5 months or after 17 months, were asked to participate in a short class on Korean consonants. Next, participants' performance in identifying the consonants with no equivalence in Dutch or English were tested. Interestingly, regardless of the age at adoption, adoptees were found to learn difficult and unfamiliar phonetic contrasts significantly faster than the control group. Moreover, researchers noticed that even a few months of exposure (i.e. less than 6-months), was enough to establish sound recognition even if the language was not used for decades. Now, with our competitive and know-it-all world environment, one has to see how our society uses this information for teaching infants a second (or third!) language.

Early phonology revealed by international adoptees' birth language retention. PNAS. (2017) July 11;114(28)

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Parkinson's-Derived Peptides Stimulate the Immune System

July 24

Parkinson's disease The association between Parkinson's disease and immune system was put forth by geneticists several years ago. Now, a new study on cohorts of healthy and diseased patients provides the first solid evidence in support of this link. After 14-days of stimulation with pools of α-synuclein peptides which were derived from Parkinson's aggregates and predicted to bind or stimulate common HLA class I & II types, interferon-γ and interleukin-5 levels were measured in blood samples of subjects. Results showed activation of helper and cytotoxic T cell by the antigenic epitopes of peptides in patients with Parkinson's disease, and not healthy subjects. While it remains to further elucidate whether this phenomenon is a culprit in Parkinson's pathogenesis or a result of it, this evidence provides a promising point of therapeutic intervention for the future.

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T cells from patients with Parkinson's disease recognize α-synuclein peptides. Nature. (2017) June 29; 546 (7660)

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The Scaffold Protein Vimentin Regulates Angiogenesis

July 16

blood vessel In recent years, the canonical role of scaffold proteins in mechanical functions are increasingly expanded to novel roles in metabolism, cell signaling and its regulation in a variety of cellular processes. Now, a well-known scaffold protein, Vimentin, is found to play a key and unrecognized role in angiogenesis through the Notch signaling pathway. Using chimeric ligands and mouse embryonic fibroblasts derived from WT and Vimentin knockout mice, Vimentin was found to affect the equilibrium between the inhibitory Dll4-Notch signaling and promoting Jagged-Notch signaling pathways. In vivo assessment of the underdeveloped vasculature in Vimentin knockout embryos and placental tissue which was rescued by reactivating Notch signaling provided further evidence on this novel role for vimentin. Given the importance of angiogenesis in embryonic and adult life as well as the co-expression of Vimentin and Notch signaling in other systems, this discovery has vast implications in therapeutic intervention of angiogenic disorders and cancer as well as research in stem cell differentiation.

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Selective regulation of Notch ligands during angiogenesis is mediated by vimentin. PNAS. (2017) May 22, 114 (23).

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Structural Biologists Reveal the Key to the Treatment of Diabetes and Obesity

July 10

obese diabetic person The worldwide concern about the rise of diabetes and obesity has called upon all scientists to develop novel strategies to curb or fight this epidemic. Now with the help of structural biologists the Achilles heels of its therapeutic intervention might have been identified. Scientists at Heptares Therapeutics focused on designing peptide analogues that could replace injectable, degradable and costly agonists of Glucagon-Like Peptide 1 (GLP-1), which is key in regulating glucose metabolism. First, they designed truncated peptides that could bind GLP-1 receptor and then resolved the crystal structure of the agonist bound to the receptor with the peptide candidate that could best recapitulate the affinity and potency of the full-length GLP-1. By further fine-tuning the peptide candidate, plasma stability and pharmacokinetic properties were next improved. Finally, in vivo testing of the peptide analogue in rats challenged with a glucose tolerance test proved the glucose-lowering effects of the peptide analogue. The successful design of this peptide therapeutic based on crystallographic data ends the difficult search for a small molecule mimic for glucose regulation.

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Crystal Structure of the GLP-1 Receptor Bound to a Peptide Agonist. Nature. (2017) June 8; 546 (7657).

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Spider-Inspired Solution for Biosynthesizing Peptide Therapeutics

July 1

building blocks Recombinant production of peptide-based therapeutics with hydrophobic or aggregation-prone regions has been challenging. In addition, performance of existing solutions such as incorporation of solubility tags can be poor and restrictive. To find an alternative solution, scientists studied the strategy used by spiders in producing Spidroins; aggregation-prone components of their webs. In this strategy, a conserved N-terminal hydrophilic domain forms the shell of a micelle to contain the aggregation-prone regions. By modifying this domain scientists first increased the useful pH range of the micelle-forming sequence to avoid its dimerization. Next, they tethered the modified domain to the mature lung surfactant protein C, which is the most hydrophobic peptide isolated from mammals. After recombinant expression and successful purification of the fusion protein without chromatography, the peptide lung surfactant was tested in premature newborn rabbits. Histological and functional lung analyses of animals treated with the new peptide surfactant vs existing ones purified from lungs of animals proved the efficiency of this novel adopted strategy. It is foreseen that the application of this low cost approach would help with the treatment of premature babies and adults with respiratory distress and Alzheimer's disease.

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Efficient Protein Production Inspired by How Spiders Make Silk. Nature Communication. (2017) May 23; 8.

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A Sophisticated Approach in Synthetic Biology Gives "Vision" to Bacteria.

July 26

building blocks As a young, but rapidly advancing field, synthetic biology aims at developing new functions through mimicking nature and converting cells into programmable units. A recent effort in this realm has led to the generation of bacteria with a visual capacity for detecting red, green and blue colors to make color photocopies of images they are exposed to. Successful execution of this sophisticated research endeavor was based on constructing a genetic program comprising 18 genes, 14 promoters, 18 terminators and 4 plasmids. These building blocks formed four functional units: sensory arrays received light signals, circuits processed incoming signals, a resource allocator linked circuit outputs to the final unit of actuators for complete execution of the signal in the form of a biological function. Next, colored images were projected onto plates and with the help of enzymes capable of generating color pigments, a color photocopy of the image was produced on plate in 8 hours. While we may never replace our photocopy machine with "vision-enabled" bacteria, the development of this optogenetic tool will be instrumental in using colored lights for patterning cells, building tissues, communicating with cells from a distance or between an electronic device and a cell. Similarly, insights from this genetic design will be useful in the application of peptides for building novel structural and functional components in synthetic biology.

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Engineering RGB color vision into Escherichia coli. Nat Chem Biol. (2017) May 22.

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A Genetic Program, not Lifestyle, Dictates Middle-Age Weight Gain.

July 20

weight gain AND middle age Poor lifestyle and laziness have for long been considered the root cause of middle-age weight gain. Yet, there are many people who gain weight as they age in spite of having a good diet and active lifestyle. Now, a recent study shows how a genetic program can cause a decline in our metabolism as we age.

Knowing that mitochondrial biogenesis and function decline in skeletal muscles over time, researchers examined molecular changes in young and old mice as well as rhesus macaque monkeys. Results of their work showed an association between DNA double-stranded breaks and activity of the enzyme, DNA-dependent protein kinase (DNA-PK): ageing increases DNA breaks and phosphorylation of DNA-PK which in turn decreases the chaperone activity of HSP90α and hence mitochondrial biogenesis through AMPK. Inhibition of DNA-PK in obese and middle-aged animals in turn was found to be protective against mitochondrial loss and diabetes, and led to improvements in fitness. Identifying this driver of mitochondrial metabolism not only shifts the blame for weight gain to a genetic program, but also provides a direction for future clinical interventions.

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DNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During Aging. Cell Metabolism, (2017) May; 25(5).

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Nature-Inspired Glue for Scarless Skin Regeneration

June 12

scar surgery From acne to surgery, dermal injuries leave us with undesired scars that are difficult or impossible to remove. Impaired scars are the result of disorganized assembly of collagen fibers with no similarity to the basket weave pattern of a fully-healed skin. Available treatments for scar removal are based on correcting this abnormal process after the scar is already formed. Now, with a focus on preventing the abnormal collagen assembly in the first place, scientists have come up with a promising solution.

The foundation of this approach is based on two earlier discoveries: (a) application of decorin involved in collagen assembly prevents scarring, but due to the difficulty in synthesizing decorin it cannot be clinically used; (b) mussel adhesive protein (MAP) secreted by marine mussel can bind collagen and be easily synthesized by bacteria. So by using MAPs containing different collagen-binding peptides derived from decorin, scientists created a glue that could successfully prevent scar formation in rat's skin. With blood vessels and sebaceous glands, the regenerated skin looked more like a fully-healed skin. In spite of the differences between the skin of rats and humans, this biomimetic engineering approach offers a promising solution for tissue regeneration and healthy skin healing.

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Natural healing-inspired collagen-targeting surgical protein glue for accelerated scarless skin regeneration. Biomaterials, (2017) July; 134.

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Peptide Conjugation of Morpholinos Leads to Systemic Exon Skipping in Muscular Dystrophy.

June 5, 2017

Peptide Conjugation of Morpholinos Leads to Systemic Exon Skipping in Muscular Dystrophy. Recent advancements in molecular biology have helped decades-long efforts in treating lethal, genetic diseases come to fruition. A prominent example is the current application of morpholino-mediated exon skipping for correcting dystrophin mutations in Duchenne Muscular Dystrophy (DMD). Existing drugs tested in clinical trials fail to restore dystrophin expression in cardiocytes and penetrate just as far as skeletal muscles. Given that cardiac myopathy is the leading cause of death in patients with DMD, the therapeutic potency of current treatments has to be improved for systemic effects. Towards that goal, a team of researchers in Canada conjugated a cell-penetrating peptide, containing arginine, 6-aminohexanoic acid, and/or β-alanine to phosphorodiamidate morpholino oligomers (PMOs) and tested its efficacy in a dog model of DMD. Two weeks after peptide-conjugated PMO injection, significant changes in cardiac morphology and function were noticed: expression of full-length dystrophin in myocardium was restored, vacuole degeneration in Purkinje fibers was decreased, and cardiac conduction abnormalities leading to arrhythmia were reduced. There is hope that data from this study can help improve existing PMO-based drugs for future human clinical trials. Yet, the first step in realizing that promise is to overcome current manufacturing limitations in order to have sufficient amounts of peptide-conjugated PMO for large animal model and human testing.

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Effects of systemic multiexon skipping with peptide-conjugated morpholinos in the heart of a dog model of Duchenne muscular dystrophy. PNAS, (2017) May 18; 114 (16).

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How Does Vitamin C Help With Pain Management

May 27, 2017

vitamin c pain Vitamin C therapy has long been known to be effective for the treatment of scurvy patients with severe vitamin C deficiency. In recent years, emerging clinical data have provided evidence on the benefits of vitamin C therapy for another group of patients: pain sufferers. Successful treatment of patients with high doses of vitamin C is indicative of analgesic properties of this vitamin for post-surgical, orthopedic and cancer-related pain management. Interestingly, epidemiological studies show an association between sub-optimal vitamin C levels and spinal pain. Inquiries into the underlying mechanisms behind this effect of vitamin C is mainly focused on the anti-oxidant and -inflammatory properties of this vitamin. Now, a novel mechanism proposed by Carr and McCall suggests that the analgesic effect of vitamin C is a result of its role in the biosynthesis of amidated opioid peptides. Amidation of peptide hormone precursors is required for their subsequent stability and biological activity. According to this proposed mechanism, vitamin C serves as a cofactor for the amidation process mediated by the enzyme peptidylglycine α-amidating monooxygenase, for which vitamin C is a cofactor. Given that many of the amidated neuropeptides such as endomorphines are abundantly distributed throughout the nervous system and display strong analgesic properties, one can understand why vitamin C therapy can help with pain management. Whichever mechanism vitamin C relies on to alleviate pain, this is good news for individuals suffering from pain whose cost of pain management is reported to be greater than the annual costs of heart disease, cancer and diabetes in the U.S. alone.

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The role of vitamin C in the treatment of pain: new insights. J. Translational Medicine, (2017) Apr 14;15(1).

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Evidence on a Carcinoma-Specific Peptide Making Chemotherapy More Effective

May 22, 2017

drug delivery cancer Early diagnosis and tumor specific treatment are key in increasing cancer survival rate. In oral squamous cell carcinoma (OSCC), however, lack of these two elements has led to a survival rate of 50% in patients. Mainstream chemotherapy in the form of treatment with the antibiotic doxorubicin does not reach the tumor effectively and is also associated with heart damage and other side effects. In order to provide patients with a more specific and less toxic therapy, a group of scientists improved the existing doxorubicin treatment with the aid of the latest discoveries and technologies.

In this novel approach, Wang et al. took advantage of the HN-1 peptide discovery, which was identified by a phage-displayed peptide library screening. Based on the fact that this peptide is capable of targeting and penetrating OSCC, scientists modified the surface of PEGylated doxorubicin with HN-1 and tested it in vitro and in vivo. Treatment of OSCCs with the modified nanoparticle in vitro showed less toxicity, higher cellular uptake and specificity over another cancer cell type. Similarly, treatment of nude mice bearing the OSCC tumor led to a significant decrease in tumor growth along with less side effects compared to the non-modified doxorubicin. This simple but effective delivery system built on the cell penetrating properties of a cancer-specific peptide can now be adopted for developing more efficacious chemotherapies for other types of tumors.

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PEGylated doxorubicin nanoparticles mediated by HN-1 peptide for targeted treatment of oral squamous cell carcinoma. Int J Pharm. 2017 Apr 12;525(1).

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Complete Tumor Remission Following a Single-Dose Peptide Vaccination

May 22, 2017

lung cancer vaccine Among the rapidly growing arsenal of anti-cancer preventive and therapeutic options, vaccination is the one showing great promise. With the successful application of the three FDA-approved vaccines for HPV, HBV and metastatic prostate cancer and ongoing clinical trials for others, the quest is now to understand whether and how vaccination can help late stage cancer patients. Results of a recent work carried out in Norway has managed to successfully shed light on both fronts.

In this study, the unique immune response of a stage IV lung cancer patient who had gone into complete remission after having received just one single injection of a peptide vaccine was analyzed. This vaccine (GV1001), which is a 16-mer peptide matching the cancer cell-specific hTERT telomerase, elicited a very broad immune response in T helper cells of the patient. An in-depth immunological analysis of patient's peripheral blood mononuclear cells showed extensive intramolecular epitope spreading in CD4+ T (helper) cells. In addition, CD8+ T (cytotoxic) cells were also found to have recognized novel epitopes embedded within GV1001. Using a library of overlapping hTERT peptides, this team of researchers could further identify unique, reactive epitopes other than the vaccination peptide. These findings not only offer hope to advanced cancer patients, but also can offer insights for the design of future vaccines where manipulation of more than one cell type and incorporation of multiple epitopes would elicit a more efficient response towards eradicating tumor cells.

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Widespread CD4+ T-cell reactivity to novel hTERT epitopes following vaccination of cancer patients with a single hTERT peptide GV1001. Oncoimmunology (2012) Aug 1;1(5).

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A New Endocrine Role for Bone: Appetite Suppression

May 8, 2017

heart disease Obesity and pathological weight loss are two extreme ends of dietary intake and energy expenditure. We know that a variety of peptide hormones such as ghrelin, leptin, and cholecystokinin that are secreted by well-known endocrine glands regulate hunger and satiety via the master regulator, hypothalamus. Now, a new study has added one more player to the list: a bone-derived peptide called lipocalin2 (LCN2)!

As an adipokine, LCN2 was previously known to be associated with obesity. However, research by Mosialou and colleagues showed that this peptide is enriched by 10-fold in osteoblasts. They then generated LCN2 knock-out mice and observed an increase in appetite, fat mass and body weight. Upon injection of LCN2 in these mice, LCN2 was found to pass the blood-brain barrier and stimulate hypothalamus through the appetite-regulating receptor, melanocortin 4 receptor (MC4R). Furthermore, LCN2 affected insulin secretion, increased insulin sensitivity and glucose tolerance. More significantly, these findings were found to have a biological relevance to humans where serum levels of LCN2 was discovered to be inversely correlated to body weight in patients with type 2 diabetes. While the translational arm of this research towards therapeutic intervention of weight disorders requires further work, it reminds us of the complex nature of energy metabolism in our body.

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MC4R-dependent suppression of appetite by bone-derived lipocalin. Nature, (2017) March 16; 543: 385-390.

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Will Peptide Therapy Increase our Lifespan

May 2, 2017

ageing AND clock The quest to conquer the process of aging has for long been at the forefront of biomedical research. With a focus on the removal of senescent cells, a multi-center research effort by several scientists recently demonstrated the successful application of peptide therapy in reversing signs of aging in mice. Senescent cells, which are withdrawn from cell cycle and induce a chronic state of pro-inflammation, were thought to be involved in aging. To investigate whether therapeutic targeting of these cells can overcome associated symptoms, Baar and colleagues aimed at identifying the Achilles' heel in the balance between senescence and apoptosis. They discovered that the interaction between two transcription factors, FOXO4 and p53, is key in modulating the fate of cells from senescence towards apoptosis. They, therefore, designed a cell-permeable peptide comprised of the domain in FOXO4 that interacts with p53 to structurally interfere with the function of FOXO4. Furthermore, to allow abundant and stable intracellular levels of the peptide over a long period, scientists paid specific attention to including a basic and hydrophilic sequence in the synthetic peptide. They next injected the peptide in three in vivo models of senescence (chemotoxicity, accelerated and natural aging) and assessed various markers of aging. Results showed a clear reversal of signs of aging, such as fur coat recovery, ability to run longer distances and improved kidney function. While this successful selective targeting of senescence through p53-mediated apoptosis, which spares healthy cells, awaits further testing in humans, it provides a clear example of peptide therapy for reversal of natural or accelerated aging as a result of chemotherapy treatments.

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Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell, (2017) Mar 23;169(1).

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Where Tumor-Targeting Peptides Meet Novel Oncogene Silencer

April 25, 2017

heart disease Contrary to our assumption, the growing knowledge of oncogenes doesn't directly translate into treatment options for patients. Identified genes need to be effectively targeted; otherwise, they are considered "undruggable". Overcoming this problem requires an in-depth understanding of both the context and accessibility of the tumor associated with that oncogene for developing therapeutics that ensure effective delivery and action. Using a novel approach, recently a group of researchers at Rutgers University set out to solve the same problem in targeting two undruggable oncogenes, KRAS and MYC, in pancreatic ductal adenocarcinoma (PDA). These two oncogenes are known to be highly associated with PDA tumorigenesis; however, they were deemed undruggable: (a) PDA has a dense fibrotic stroma which renders drug delivery difficult, and (b) existing drug delivery methods based on dendrimer nanocarriers show low solubility, high toxicity and large-scale production hindrance.

To overcome these barriers, researchers designed a dendrimer-free delivery system, which took advantage of tumor-targeting RGD peptides and an efficient gene silencing system called U1 Adaptor-created by the same group. By non-covalently linking the tumor-targeting peptide to U1 Adaptors, the poly-adenylation process of of premRNAs for both MYC and KRAS were selectively inhibited. As a result, RNAs of both oncogenes were degraded in the nucleus of tumor cells leading to modulation of downstream signaling pathways, inhibition of cell proliferation and induction of apoptosis. Furthermore, peptide-linked U1 Adaptor injection of mice xenografted with PDA tumors resulted in significant tumor regression. The successful application of RGD peptides for gene silencing in this study is another proof of designing new strategies based on creative combination of existing reagents and technologies.

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U1 Adaptors suppress the KRAS-MYC oncogenic axis in human pancreatic cancer xenografts.; Tsang et al., Molecular Cancer Therapeutics. (2017) April 4.

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Peptides to the Rescue: Reversing the Process of Fibrosis by Peptide Therapy

April 18, 2017

heart disease A variety of physiological or pathological stimulants can cause cardiac hypertrophy, which is associated with tissue fibrosis. In congestive heart failure, activation of myofibroblasts secreting excess amounts of extracellular matrix collagens along with migration of monocyte and their differentiation into myofibroblasts creates a never-ending cycle of tissue fibrosis and organ dysfunction. Interestingly, these cellular and molecular changes have been associated with lower levels of a protein called caveolin-1. This scaffolding protein is a key component of caveolae plasma membranes in the majority of cell types and links subunits of integrin to intracellular signaling pathways to promote cell cycle progression, signal transduction, and endocytosis. Based on these facts, Dr. Pleasant-Jenkins and colleagues at Gazes Cardiac Research Institute in South Carolina, developed a therapeutic strategy to suppress cardiac fibrosis.

In doing so, they took advantage of a key domain in the structure of caveolin-1, which is called Caveolin Scaffolding Domain (CSD). This domain is part of the oligomerization domain located at the N-terminal region of the protein and mediates interaction with a large number of signaling molecules. Using a cardiac hypertrophy mouse model, researchers injected mice with synthetic CSD peptide on a daily basis for 2, 4 and 6 weeks. After analyzing various endpoints such as echocardiography, abundance of fibrosis-related cell types and associated markers, researchers discovered that peptide therapy has been successful in reducing fibrosis and improving heart function. Findings of this study with a focus on surrogate peptide therapy in an in vivo cardiac model, holds promise for developing peptide-based therapies for not only patients suffering from various organ fibrosis, but also in reducing the process of ageing which is associated with fibrosis.

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Reversal of maladaptive fibrosis and compromised ventricular function in the pressure overloaded heart by a caveolin-1 surrogate peptide; J. of Laboratory Investigation (2017) 97, 370–382.

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Embryo created from embryonic stem cells for the first time

March 27, 2017

embryogenesis Embryonic stem cells (ESC), which are derived from embryonic pre-implantation epiblast cells, can differentiate into multiple tissue types in vitro as a result of their pluripotency. They have shown little ability, however, to regenerate into a functional embryo, and this has been suspected to be due to a lack of adequate external stimuli, either physical or biochemical. To better understand this, and in attempt to drive the formation of an embryo from stem cells, scientists have taken a deeper dive into understanding the steps involved in embryogenesis and then trying to recreate them in vitro.

In this recent study published in Science, the authors set up a 3D culture system composed on ECM in Matrigel with an ESC and extra-embryonic trophoblast stem cell (TSC) co-culture. This combination appeared to be a key in recreating the embryonic phenotype, in combination with Nodal and Wnt/BMP signaling. Together, the stu dy produces early evidence that artificial embryos derived from stem cells are not far off.

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Harrison et al. Assembly of embryonic and extra-embryonic stem cells to mimic embryogenesis in vitro. Science. 2017. DOI: 10.1126/science.aal1810.

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New microbiome-based lotion helps prevent bacterial infections

March 22, 2017

probiotic Microbial dysbiosis is at least in part to blame for bacterial infections that can cause diseases such as atopic dermatitis (AD). Patients with AD have a lower abundance of antimicrobial peptides (AMPs), which would normally curb the population of Staphylococcus aureus, which causes itchy and inflamed skin. Since the presence of good bacteria, like Staphylococcus epidermidis, can help curb the population of S. aureus, scientists hypothesized that topical application of this good bacteria could ease AD symptoms. After confirming which bacterial populations were missing in AD, the authors restored the missing bacterial populations and tested the impact on S.aureus. The result: the missing commensal bacteria successfully inhibited overgrowth of S.aureus. To test the clinical impact of this, they developed a lotion supplemented with the "good" bacterial populations to see if it could relieve AD symptoms. In fact, this lotion successfully inhibited inflammation, suggesting that personalized probiotic lotions could be a viable treatment option (albeit expensive) for topical bacterial infections.

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Nakatsuji et al. Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Science Translational Medicine.
2017. DOI: 10.1126/scitranslmed.aah4680

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Fetal sex affects mother's immune system differently

March 14, 2017

immunity Having the sense of whether or not you are pregnant with a boy or a girl may go beyond just maternal instinct – it turns out that the gender of the fetus can actually impact the mother on a physiological level. For many women, there were indications of increased illness when women were carrying female versus male fetuses, however why this was the case was never investigated. To address this, scientists analyzed the expression of different inflammatory cytokines in the serum of 82 women at different stages of pregnancy. What they found was that women pregnant with girls had higher serum levels of IL-6 and TNF-α. These differences in cytokine expression could explain why women tend to feel more sick when pregnant with girls; however, what exactly causes this difference in immune response is unclear.

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Mitchell et al. Fetal sex is associated with maternal stimulated cytokine production, but not serum cytokine levels, in human pregnancy. Brain, Behavior and Immunity. 2017. DOI: 10.1016/j.bbi.2016.06.015

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Synthetic bacteria reduce tumor volume in mice

March 6, 2017

viral communication Bacterial cancer therapy (BCT) is an immunotherapy strategy that uses attenuated bacterial strains to suppress tumor growth. While the strains are attenuated, there is still a safety risk associated with their use, and this has prompted investigation into alternative BCT methods. In a recent Science Translational Medicine publication, researchers have actually engineered a bacterium to fight tumors by overexpressing and unlikely protein. In this paper, flagellin protein (FlaB) was overexpressed in Salmonella typhimurium strains. The rationale behind this was that flagellin is known to activate immune responses via Toll-like receptors, specifically TLR5, which would make it a good cancer immunotherapy candidate. These modified bacteria were delivered into tumors in mice, and the impact on tumor volume and TLR signaling was analyzed. The authors discovered that following delivery of the engineered Salmonella, there was a localized increase in immune cells, such as monocytes and macrophages, as a result of TLR4 signaling. Subsequently, the increased immune response inhibited metastasis and tumor growth, further promoting recovery in mice without any deleterious effects from the microbes. Together, these results provide renewed support behind the use of modified bacteria for cancer therapy.

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Zheng et al. Two-step enhanced cancer immunotherapy with engineered Salmonella typhimurium secreting heterologous flagellin. Science Translational Medicine. 2017. DOI: 10.1126/scitranslmed.aak9537

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Viruses communicate with each other to decide infected cell's fate

February 27, 2017

virology How does a virus know when to kill or save an infected cell? The decision point for entering lysogenic or lytic phase has long been somewhat unclear; however scientists have recently reported in Nature a mechanism for how virus make this decision – and it actually has to do with some form of communication. Using Bacillus subtilis as a model, the authors investigated this phenomenon in more detail and identified a peptide that appeared to protect bacterial cells from lysis after infection by a bacteriophage. In fact, this peptide, which they coined Arbitrium, turned out to be released by phages after they entered lysogenic cycle, and instead of protecting bacteria per se, it told other phages to become lysogenic instead of lytic. Ultimately it is the first known communication mechanism between viruses, and may be a way for these viruses to continue infecting future generations of bacteria.

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Erez et al. Communication between viruses guides lysis–lysogeny decisions. Nature. 22017. DOI: 10.1038/nature21049

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New gene-blocking therapy prevents Tau protein accumulation in Alzheimer's models

February 20, 2017

Tau protein, Alzheimer's Reducing the cognitive decline of individuals suffering from Alzheimer's Disease is one of the main goals when designing new and improved treatment strategies. While therapeutics targeting beta amyloid are more prevalent, there is greater attention being turned to Tau protein, which is also known to have an important role in cognitive decline. A recent example of this has been published in Science Translational Medicine, in which the authors targeted expression of Tau from a translational level using antisense oligonucleotides (ASO). Using an Alzheimer's mouse model, the authors delivered the Tau ASOs at the base of the spine and examined the effects both on Tau levels in the brain and cognitive ability. In fact the treatment proved successful: not only was Tau expression significantly reduced, but treated mice lived longer and retained cognitive abilities. Together this paper demonstrates the potential ASOs can have in alleviating the symptoms of Alzheimer's.

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DeVos et al. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with taupathy. Science Translational Medicine. 2017. DOI: 10.1126/scitranslmed.aag0481.

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Variants that give tomatoes their flavor identified in genome-wide screen

February 15, 2017

genetically modified organism Generally, the goal of genetically modifying crops is to improve yield or size. However, an unfortunate side effect of modifying some of these fruits and vegetables is that we start to lose something else important – taste. Modifying crops to adjust what makes them flavorful has been a lot less obvious, especially since some attributes can be subjective. To tackle this particular problem, scientists underwent a comprehensive analysis of the chemicals and genes that impact tomato flavor. From this GWAS screen, the authors identified the loci that are associated with glucose and fructose content, along with other compounds and enzymes that contribute to fruit ripening. In addition, they also discovered a correlation between tomato size and alterations in expression of these genes, confirming that by engineering bigger tomatoes, we are sacrificing taste. Now that we have a better grasp on the genetics behind this fruit's flavor, we may now be able to improve size and yield without compromising taste.

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Tieman et al. A chemical genetic roadmap to improved tomato flavor.
Science 2017. DOI: 10.1126/science.aal1556

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Retroviruses are confirmed to be the oldest existing virus

February 6, 2017

retrovirus The evolutionary history of microbes, such as viruses, is particularly interesting because it has never been completely clear how far back they originate. Retroviruses have generally been considered as the oldest viruses; however, a recent study published in Nature Communications has finally uncovered exactly how old they are. To do this, the authors turned to a retrovirus with well understood evolutionary dynamics – the foamy virus. The foamy virus, which is a type of retrovirus, is known to infect many different types of species and can even leave viral genomic fossils in the host genome. In this paper, the authors developed a mathematical formula to calculate the evolutionary rate of the viral genes, and were able to deduce that retroviruses were much older than previously expected – their DNA could be traced to nearly half a billion years ago. Together, the authors present a unique evolutionary history for this medically important virus.

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Aiewsakun et al. Marine origin of retroviruses in the early Palaeozoic Era.
Nature Communications. 2017. DOI: 10.1038/ncomms13954

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New research suggests pathogens have evolved sex-specific virulence

January 30, 2016

inheritable disease It seems that sometimes, men seem to become more sick with viral infections than women. Is it really because of weaker immune systems? A study recently published in Nature Communications set out to determine if there could actually be a genetic explanation for these observations. In this report, the authors used a mathematical model to determine how different transmission routes (vertical or horizontal) may result in sex-specific differences in virulence. As a real world example, the authors modeled the transmission of human T-cell lymphotropic virus type 1 (HTLV-1), a virus that known to impact men 2-3.5 times more than women in Japan (where long-term breastfeeding happens to be common). Using their model, and this example, they could confirm that societies where breast feeding is common, pathogens will be transmitted both horizontally and vertically.

The question still remains – can viruses really tell when they infect men versus women? Hormones may have something to do with it, but more research will be required to really understand this mechanism.

Ubeda et al. The evolution of sec-specific virulence in infectious diseases.
Nature Communications. 2016. DOI: 10.1038/ncomms13849

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Older donors produce iPSCs with potentially detrimental mutations

January 23, 2016

inheritable disease Induced pluripotent stem cells (iPSCs) have great potential in regenerative medicine: they can be relatively easily derived from multiple differentiated cell sources, and their use circumvents any ethical concerns. Yet as they become more popular, there have not yet been any guidelines established for their use in disease modeling and other clinical studies - for instance, does it matter where your iPSCs come from? To address this, a recent Nature Biotechnology report profiled the fibroblast-derived iPSCs from donors between 21-100 years of age. The authors looked for any epigenetic aberrations in the iPSCs and noticed something striking: CpG methylation sites were higher in older donors compared to young donors. The significance of these findings is that some of these mutations could end up being deleterious – the cells could become tumorigenic or have some other dysfunction. Together the data presented that not all iPSCs were created equal, and donor source needs to be a consideration prior to their use in a clinical setting.

Lo Sardo et al. Influence of donor age on induced pluripotent stem cells. Nature Biotechnology.
2016. DOI: 10.1038/nbt.3749

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Whole genome sequencing uncovers novel variants for inheritable diseases

January 16, 2016

inheritable disease Proper diagnosis of diseases, like cancer or other inheritable conditions, first requires an accurate and distinguishable biological marker. Not only can this accelerate drug development to treat these individuals, but it can also help diagnose the diseases more quickly. In an effort to screen for some of the more rare genetic variants that may be responsible for some of these diseases, researchers at the Geisinger Health System and Regeneron Genetics Center used high throughput sequencing to screen the genomes of over 50,000 adults, who were part of a collaboration called DiscovEHR, an electronic health record. By sequencing the protein coding regions if over 18,000 genes, the group found novel variants linked to hereditary cancers, including familial hypercholesterolemia, a condition that results in high low-density lipoprotein (LDL) levels and increased cardiovascular disease risk. Through identification of these new variants, they were actually able to review the analysis with some of the adults screened, and could facilitate the diagnosis of some rare conditions that otherwise wouldn't have been discovered. Together these papers represent the potential such large sale screening studies can play in the development of new and improved therapeutics.

Dewey et al. Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study. Science. 2016.

Abul-Husn et al. Genetic identification of familial hypercholesterolemia whithin a single U.S. health care system. Science. 2016.

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Genes that give seahorses their unique physical traits identified

January 9, 2016

soil microbiome The seahorse, a unique sea-dwelling creature of the Syngnathidae family, is defined by its unusual physical characteristics, such as its horse-like tubular nose, its spiny body, and male brood pouch. These physical characteristics have made the seahorse particularly compelling; however, the genetic explanation behind these "weird" features has never been investigated. In a recent Nature publication, scientists have sequenced the genome of Hippocampus comes for the first time to better understand its features.

In this paper, comparative genomics was used to identify key genes expressed at higher levels compared to the better characterized zebrafish. The male brood pouch could be explained by upregulation of patristacin (pastn), a gene that might explain the ability of male seahorses to carry offspring. Another notable genetic discrepancy was the expression of tbx4, which in zebrafish is demonstrated to be associated with pelvic fin loss. Lack of tbx4 expression could explain why seahorses only have pectoral fins. Other notable gene losses included those for secretory calcium-binding phosphoproteins (SCPP), which typically regulate enamel formation. Ultimately, this study has now presented genetic support for how unique this creature really is.

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Lin et al. The seahorse genome and the evolution of its specialized morphology. Nature. 2016. DOI: 10.1038/nature20595

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City park microbes produce useful compounds for new and improved drugs

January 2, 2016

soil microbiome Microbes are the source of many different types of therapeutically relevant natural products (NPs). In turn, as the diversity of bacterial species increases, so potentially would the number of therapeutic NPs. In a recent PNAS publication, the authors hypothesized that diverse bacterial ecosystems, such as those found in cities, might be a source for new and improved anticancer and antimicrobial drugs. To assess the biosynthetic diversity of these microbes, the authors collected soil samples from parks located in New York City. Using genomic sequencing, they discovered a diverse microbial population rich in biosynthetic diversity, with the potential to produce a variety of small molecules such as nonribosomal peptides and polyketides. Both of these compounds have relevance in the development of anti-cancer therapeutics, such as Epothilone or Ixabepilone. Together the results of this study highlight the potential of turning to city microbes as a new source of important drugs.

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Charlop-Powers et al. Urban park soil microbiomes are a rich reservoir of natural product biosynthetic diversity. PNAS 2016. DOI: 10.1073/pnas.1615581113

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Common skin bacteria protect against harmful reactive oxygen species

December 12, 2016

skin microbiome The human microbiome is a topic of increasing interest, as many different bacterial species found throughout the body appear to play an important role in maintaining health. The skin microbiome has also been studied recently to better understand how bacteria on the skin prevent or promote specific diseases. In this study, the authors investigated a common skin bacterial population, Propionibacterium acnes, and how it contributes to human health. Recently, this bacterium was observed to produce a protein that appeared to be important for maintain bacterial survival. This protein turned out to be a previously unidentified antioxidant, coined as RoxP (radical oxygenase of Propionibacterium acnes), whose antioxidant properties protected molecules from oxidation. In fact, this antioxidant promoted a healthy host-microbe interaction, with protective effects against skin-related diseases.

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Allhorn et al. A novel enzyme with antioxidant capacity produced by the ubiquitous skin colonizer Propionibacterium acnes Scientific Reports. 2016. DOI: 10.1038/srep36412.

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Stripes on rodents' backs the result of an evolutionary genetic change

December 5, 2016

developmental biology In non-vertebrates, pigment changes and patterning originate from different types of pigment cells. Mammals, however, only have one type of pigment-producing cell, melanocytes. This has begged the question, how do mammals such as chipmunks develop the unique black and white patterning across their backs with only 1 type of pigment-producing cell? Scientists have recently tackled this question and reported their findings in Nature. Taking a molecular approach, the authors found that white and black fur coloring results not from a loss or overproduction of melanocytes in specific areas, but differential expression of the gene Alx3. This gene – which was not previously known to be involved in pigmentation – is expressed at higher levels in light or white stripes compared to darker stripes. When expression of Alx3 is increased, activity of a gene called Mitf, which regulates melanocyte maturation, is inhibited. This inhibition is what switches hair color in mice and chipmunks.

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Mallarino et al. Developmental mechanisms of strip patterns in rodents. Nature.
2016. DOI: 10.1038/nature20109

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New RNA evidence identifies the real "Patient Zero" of the AIDS epidemic

November 28, 2016

HIV At what point did HIV come to the United States? For years, Gaétan Dugas, a flight attendant from Canada, supposedly contracted HIV in Haiti or Africa and brought the virus to the US prior to his death in 1984. Considered Patient "O", or the only AIDS case "outside" of California, soon became known as Patient Zero. However, with the thousands of cases observed on both the East and West coast, scientists set out to determine to true origin of HIV by analyzing blood samples of individuals that passed away from HIV in the 1970s and 80s. To do this, scientists used a unique sequencing approach, coined "RNA jackhammering" to reconstruct the HIV-1 genome from blood samples. From these sequences, the authors found that HIV-1 infections in San Francisco occurred around 1978, and were linked to a transfection from NYC in 1976. After additional analysis of the HIV-1 genome in Patient 0, it appeared that this genome was typical of HIV strains in the US and not those from the Caribbean, where it was assumed Dugas contracted the virus. Consequently, Gaétan Dugas can no longer be blamed as the original source of HIV in the US.

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Worobey et al. 1970s and 'Patient 0' HIV-1 genomes illuminate early HIV/AIDS history in North America. Nature. 2016. DOI: 10.1038/nature19827

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Protein found in dolphins, Vanin-1, has protective, anti-oxidant properties

November 21, 2016

aging, anti-oxidant Are dolphin proteins the new fountain of youth? Marine mammals such as dolphins can survive prolonged periods in hypoxic environments, such as deep sea, without any significant damage to oxygen-sensitive tissues and organs. In a recent Scientific Reports manuscript, scientists set out to uncover how mammals such as dolphins have adapted to survive these otherwise prohibitive conditions. In this study, the authors comprehensively screened serum proteins in dolphins, and compared them with those in humans and pigs. From this screen, they identified 11 proteins uniquely upregulated in dolphins compared to either other species. From this proteomic study, they identified one protein in particular, Vanin-1, to be particularly abundant in dolphins. Vanin-1, which function as as an anti-oxidant, likely helps protect dolphins from metabolic syndromes. Together, these findings present a new potential therapeutic option for treatment or prevention of heart attacks or strokes in which free radicals damage organs.

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Solobesky et al. Proteomic analysis of non-depleted serum proteins from bottlenose dolphins uncovers a high Vanin-1 phenotype. Scientific Reports 2016. DOI: 10.1038/srep33879

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Fertile eggs have been successfully created from induced pluripotent stem cells

November 14, 2016

iPSC Induced pluripotent stem cells (iPSCs) have the potential to differentiate into any cell type, and the variety of functional cells these stem cells can become is steadily expanding. A recent report in Nature, however, describes a revolutionary application: restoration of fertility. Here, the authors have described a way to turn skin cell-derived iPSC into fertile, mature eggs.

To accomplish this, the authors reproduced the oogenesis process in vitro. During this 3-stage process, iPSCs were exposed to various culture components to guide differentiation. Once differentiated into immature egg cells, the authors co-cultured the cells with ovarian tissue to turn the cells into functional, mature eggs. To confirm that these eggs could actually produce babies, the eggs were fertilized and implanted into the uterus of mice. It worked – of the 1348 embryos made, 8 pups were born. While more work still needs to be done, these results demonstrate the potential of iPSCs to eradicate infertility.

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Hikabe et al. Reconstitution in vitro of the entire cycle of the mouse female germ line. Nature. 2016. DOI:10.1038/nature20104

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Childhood stress impacts telomere length during adulthood

November 7, 2016

aging, telomere What is the real impact of childhood stress? Researchers recently addressed this issue in a PNAS publication, and specifically investigated the impact of stress on cellular aging. In this report, scientists examined the relationship between childhood and adult adversity on telomere length – which has been well described to impact aging on a cellular level. The researchers examined over 4,500 men and women and had them describe traumatic or difficult experiences during their youth, such as financial difficulties, parental substance or physical abuse, and illness among others. In addition, saliva samples were also collected to extract DNA data pertinent to evaluation of telomere length. Together, the authors discovered that individuals with early childhood stress had a greater impact on telomere length compared to exposure to stress later in life, and may provide guidance for targeted interventions.

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Puterman et al. Lifespan adversity and later adulthood telomere length in the nationally representative US Health and Retirement Study. PNAS. 2016. DOI: 10.1073/pnas.1525602113

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Alzheimer's and other neurological diseases linked to bacteriophage infection

October 31, 2016

bacteriophage There is increasing evidence that the human gut microbiome can have a significant impact on multiple conditions and diseases, especially where there is dysbiosis. Like the gut microbe population, intestinal barrier dysfunction, or when the mucosal barrier becomes abnormally permeable, can also contribute to pathologies such as inflammatory bowel disease, neurodegenerative diseases and cardiovascular disorders. Yet while this association had been observed previously, the cause of this dysfunction has not been clear. To address this, a report recently published in Gut Pathogens presented a new, previously unknown player – bacteriophages. A cocktail of bacteriophages were distributed to mice, and the impact on mucosal permeability was examined. The authors found that bacteriophage challenge increased intestinal permeability, and in turn, exacerbated the phenotypes of neurological and other diseases.

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Tetz et al. Bacteriophage infections of microbiota can lead to leaky gut in an experimental rodent model. Gut Pathogens. 2016. DOI: 10.1186/s13099-016-0109-1

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New evidence debunks the mythical "Five Second Rule"

October 24, 2016

muscle mass The "Five Second Rule" – or the myth that it takes about 5 seconds for dropped food to become contaminated with microorganisms – has long been adopted by popular culture. Interestingly, though, this concept had never been tackled in peer-reviewed literature. In a recent study published in Applied and Environmental Microbiology, the authors set out to quantify cross-contamination between foods and a variety of common kitchen surfaces in a more scientific manner. To accomplish this, the authors prepared cultures of the non-pathogenic strain E. aerogenes and applied the cultures to surfaces such as stainless steel, laminate wood, and carpet. The transfer rates of the bacteria from inoculated surfaces to food products was then calculated. While transfer rates to moister foods was slightly quicker than others, the authors still observed microbial transfer for many food types and surfaces within a second.

So unless you have very quick reflexes, you may be better off leaving the dropped food where it is – or throwing it away.

Miranda et al. Longer Contact Times Increase Cross-Contamination of Enterobacter aerogenes from Surfaces to Food. Applied and Environmental Microbiology. 2016. DOI: 10.1128/AEM.01838-16

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Male muscle mass is partly influenced by exposure to viral proteins in the placenta

October 17, 2016

muscle mass Why do males have a tendency towards larger muscle mass compared to females? A recent study published in PLoS Genetics points to an interesting source – a virus. In this study, the authors traced this phenotype back to the expression of a retrovirus envelope gene, syncytin, which is commonly found in placental mammals. This protein, which is involved in muscle fiber formation and repair, was knocked out in mouse models to observe the impact on muscle development. Interestingly, when knocked out, mice had a >20% reduction in muscle mass, fiber area and nuclei per fiber – but it was only observed in male but not female mice. While more research will be needed to fully understand this sexual dimorphism, the study shows for the first time an interesting biological explanation between muscle mass in placental mammals.

Redelsperger et al. Genetic evidence that captured retroviral envelope syncytins contribute to myoblast fusion and muscle sexual dimorphism in mice. PLoS Genetics. 2016. DOI: 10.1371/journal.pgen.1006289

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New low cost plastic textile keeps you cooler than normal cotton

October 10, 2016

textile engineering If you are tired of sweating through your clothing during the hot summer, there may soon be a solution. A recent study published in Science describes a novel, nanoporous polyethylene-based textile that can reduce body temperature by 4oC. The textile, coined nanoPE, is porous enough to appear opaque (pore sizes range around 50-100 nm), but is actually transparent to mid-infrared body radiation. Also with cotton mesh integrated into the fabric, the material is still strong enough to wear.

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Hsu et al. Radiative human body cooling by nanoporous polyethylene textile. Science. 2016. DOI: 10.1126/science.aaf5471

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Tasmanian Devils are developing resistance to contagious cancer

October 3, 2016

contagious cancer The transmissible cancer, devil facial tumor disease (DFTD), is nearly 100% fatal and is responsible for a significant decline in the species' population. However, despite the persistence of this disease, Tasmanian Devils still continue to thrive. It turns out, as uncovered in a recent Nature Communications report, that resistance to this cancer is due in part to changes in seven genes involved either in immune system regulation, cell cycle regulation, or cancer. Such genes include proto-oncogenes (CBL-c), melanoma cell adhesion molecules (CD146 and MCAM), and TNF-related proteins (THY1 and CD90).

GenScript offers a variety of peptide services to accelerate the development of cancer therapeutics:

Epstein et al. Rapid evolutionary response to a transmissible cancer in Tasmanian Devils. Nature Communications. 2016. DOI: 10.1038/ncomms12684

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Zika affects neural progenitors in the adult brain and causes cell death

September 26, 2016

cartilage regeneration While the impact of the Zika virus (ZIKV) on normal development in babies has become better understood, the effect of the virus on the adult brain has been uncertain. In a recent Cell Stem Cell publication, the authors uncovered more information on how this virus affects the adult nervous system. In this publication, the authors observed that ZIKV can infect and kill adult neural progenitor cells in the brain, suggesting there may be long term consequences of this viral infection on cognition or behavior.

GenScript offers comprehensive peptide services to accelerate discovery of novel disease therapeutics:

Li et al. Zika Virus Infects Neural Progenitors in the Adult Mouse Brain and Alters Proliferation. Cell Stem Cell 2016. DOI: 10.1016/j.stem.2016.08.005

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Functional hip joint recreated with engineered stem cells and unique 3D template

August 22, 2016

cartilage regeneration Replacement of damaged, arthritic hip joints requires a difficult surgery, and is often avoided in younger patients as prosthetic joints do not last long. In an effort to improve the current replacement options, scientists have developed a novel, tissue engineered hip joint consisting of anatomically shaped, functional cartilage and adipose stem cells (ASC) engineered to produce the anticytokine, IL-1Ra. The joint was created using a 3D scaffold constructed from poly(ɛ-caprolactone), or PCL. The genetically modified ASCs were then cultured under chondrogenic conditions for 28 days to allow complete differentiation into functional chondrocytes. Upon induction with doxycycline, the ASC-derived chondrocytes secreted high levels of IL-1Ra, which in vivo could prevent MMP production which would ultimately impact construct stability.

GenScript offers a variety of peptide services to accelerate development of novel biomaterials for tissue regeneration:

Moutos et al. Anatomically shaped tissue-engineered cartilage with tunable and inducible anticytokine delivery for biological joint resurfacing. PNAS. 2016. DOI: 10.1073/pnas.1601639113

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Novel peptides found to reduce inflammation after traumatic brain injury

August 8, 2016

traumatic brain injury Traumatic Brain Injury can have lost-lasting physical and behavioral effects, and at its most severe can even be life-threatening. In an effort to identify potential therapeutics that would prevent inflammation and protect against negative side effects, scientists have recently synthesized novel theoredoxin-mimetic peptides (TXM-peptides) and examined whether they could inhibit MAPK-mediated inflammatory responses. In mouse models, following mild TBI, the authors demosntrated that TXM peptides could significantly relieve inflammation and ultimately cognitive performance after just 7 days.

For development of novel peptide therapeutics, GenScript offers a variety of peptide synthesis services:

Baratz-Goldstein et al. Thioredoxin-Mimetic-Peptides Protect Cognitive Function after Mild Traumatic Brain Injury (mTBI).
PLoS One. 2016. DOI:10.1371/journal.pone.0157064

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Immune modulation factor, MANF, improves retinal regeneration by eliminating pro-inflammatory immune cells

July 18, 2016

retinal regeneration Inflammation contributes to multiple disease pathologies that affect the eye, such as macular degeneration. While regenerative therapies hold a lot of promise in restoring vision to patients with this condition, retinal regeneration is inhibited by the excess of pro-inflammatory immune cells. However, a recent Science publication may have found a solution to this issue: a conserved factor involved in naturally occurring anti-inflammatory pathways, MANF, can improve regeneration by turning pro-inflammatory immune cells into anti-inflammatory cells.

To accelerate your regenerative medicine research, GenScript offers a variety of custom peptide services:

Neves et al. Immune modulation by MANF promotes tissue repair and regenerative success in the retina. Science. 2016. DOI: 10.1126/science.aaf3646.

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Amyloid beta peptides protect against microbial infection in Alzheimer's disease animal models

June 27, 2016

antimicrobial peptide Increased amyloid beta peptide concentrations, and subsequent deposition of amyloid plaques, are well understood to contribute to the pathogenesis of Alzheimer's Disease. While the negative implications of beta amyloid are clear, there has yet to be indication of the normal function of this peptide; however, new evidence may shed light on its role. A recent Science Translational Medicine report indicates that in fact amyloid beta has antimicrobial peptide function, and can protect against fungal and bacterial infection.

What is the mechanism for beta amyloid's antimicrobial activity?

In both in vitro and animal models, the authors demonstrated that amyloid beta oligomers bind to the microbial cell wall and mediate the agglutination and entrapment of microbes. In both the gut and brain, amyloid beta can protect further infection. This finding presents an interesting new twist in the development of therapeutics for Alzheimer's: how should we balance the protective activity of beta amyloid while minimizing the damaging role the peptide plays in the disease?

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Kumar et al. Amyloid-b peptide protects against microbial infection in mouse and worm models of Alzheimer's disease. Science Translational Medicine. 2016; 8 (340): 3410.

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Beads coated with zona pellucida peptides function as effective, reversible contraceptives

June 6, 2016

contraception There is a growing market for new and improved contraceptive devices, especially those that are long term but still reversible. The extracellular matrix of ovulated eggs, or the zona pellucida, is an ideal target for the development of contraceptives, as binding to peptides within this matrix is critical for sperm binding and subsequent fertilization. Given the significance of these zona pellucida peptides, specifically ZP2, scientists have come up with a creative approach to a new contraceptive: ZP2-coated agarose beads, when delivered into the uterus, will attract sperm and ultimately prevent against pregnancy.

How effective were the ZP2-coated beads?

In this study, the authors transcerviacally delivered the beads into mice, and monitored contraception over time. Over 10 estrus cycles, the contraceptive appeared to be effective. While initially reversible, over time the sperm become irreversibly bound to the beads and do not enter the uterotubal junction. While ideal to prevent pregnancy, it is feasible that the reversible nature could actually function in the assistance of reproduction.

Avella et al. ZP2 peptide beads select human sperm in vitro, decoy mouse sperm in vivo, and provide reversible contraception. Science Translational Medicine. 2016; 8(336). DOI: 10.1126/scitranslmed.aad9946

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New polysiloxane-based material improves skin's elasticity and eliminates wrinkles.

May 30, 2016

skin renewal The anti-aging market is estimated to be worth hundreds of billions of dollars, and there is a continuous search for effective products that prevent wrinkles and signs of age. As an alternative to traditional cosmetics, a recent Nature Materials report describes a new, wearable crosslinked polymer layer (XPL) that functions as a "second skin" and reduces the appearance of wrinkles.

How does it work?

The XPL-derived layer was applied topically to the under eye area of study participants. Its elasticity closely mimicked that of natural skin, and after 2 hours under-eye bags appeared significantly improved. The material was determined to be durable, comfortable and moisturizing – with the potential of being adequate for regular use. Natural looking, younger skin may be closer and easier than originally thought!

Peptide services to fast-track biomaterials and cosmetics development:

Yu et al. An elastic second skin. Nature Materials. 2016 May. DOI: 10.1038/nmat4635

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Resveratrol protects against cardiovascular disease by altering microbial activity in the gut

May 16, 2016

resveratrol Moderate amounts of red wine have been known to have a variety of health benefits, and these benefits have generally been attributed to the compound resveratrol. Heart disease, specifically artheroscleorsis, is one of the diseases that has appeared to be improved by resveratrol. The mechanism behind this has been generally unknown; however, a recent publication in mBio has uncovered a surprising mechanism: the benefits of resveratrol are in fact mediated by activity of the gut microbiome.

How do gut microbes facilitate the health benefits of resveratrol?

Trimethyl-N-oxide (TMAO) is a known risk factor for artherosclerosis. Interestingly, resveratrol increased levels of Lactobacillus and Bifidobacterium in the gut, and in turn these microbes inhibited the production of TMAO by altering production of the precursor molecule, TMA. So not only are the benefits of resveratrol confirmed, but in addition the gut microbiome has become an interesting new target in artherosclerosis prevention.

Chen et al. Resveratrol Attenuates Trimethylamine-N-Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota.
mBio. 2016; 7(2): e02210-15. DOI:10.1128/mBio.02210-15

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Optogenetics restores memory in Alzheimer's mouse models

May 2, 2016

Alzheimer's, optogenetics The progressive memory loss in individuals suffering from Alzheimer's can be especially difficult for both the patient and the family. However, is this memory loss truly permanent? A recent study published in Nature suggests that memory retrieval may be possible: using Alzheimer's mouse models, they showed that optogenetics can retrieve memories even after long-term amnesia.

How can optogenetics assist in memory retrieval?

Optogenetics, which is the process of using light to control cells in living tissue, was used in this study to stimulate cells in the hippocampus that are known to control memory. Mice were exposed to a fearful event prior to the onset of beta-amyloid plaque deposition. During Alzheimer's onset, they were exposed to optogenetic activation, and their ability to recollect earlier memory tests was analyzed. Both long-term memory and spine density was restored in the treated Alzheimer mouse models.

Roy et al. Memory retrieval by activating engram cells in mouse models of early Alzheimer's disease.
Nature. 2016; 531: 508-512. DOI: 10.1038/nature17172

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A bacterium that breaks down PET plastics has been discovered

April 25, 2016

biodegradation Increasing amounts of plastic products in the environment, such as poly(ethylene terephthalate) (PET), has serious impacts on pollution and energy usage. Recycling has become one of the primary methods to control the amount of plastic being consumed; however, there is ongoing concern regarding how to get rid of what is already out there. With this in mind, a group out of Kyoto Institute of Technology has identified a new bacterial species, named Ideonella sakaiensis, that can break down plastics like PET that would normally not degrade in nature.

How were these bacteria discovered?

In the recent Science publication, the authors collected PET-contaminated environmental samples and screened for microorganisms. Once identifying this novel species, they observed that I. sakaiensis could break down PET into smaller, non-toxic compounds, terephthalic acid and ethylene glycol using just two enzymes. While the process takes a while – 6 weeks to recycle a thumb-nail piece of plastic at 30℃ – this finding has the potential to revolutionize plastics recycling.

Yoshida et al. A bacterium that degrades and assimilates poly(ethylene terephthalate). Science. 2016 March 11; 351 (6278): 1196.

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Chronic consumption of a western diet increases Alzheimer's risk by increasing TREM2+ microglia in the brain

April 18, 2016

Alzheimer, western diet While there has been an established connection between diet and the chance of developing Alzheimer's, the mechanism behind this has been unclear until recently. In a recent Scientific Reports publication, scientists have finally confirmed how high protein, fat and sugar diets accelerate neurodegenerative disease, and it has to do with inflammation in the brain.

What is the mechanism?

In this study, the authors confirmed that prolonged consumption of a "western diet" has a variety of negative impacts on health, and was shown in Alzheimer's mouse models to increase risk for the disease by 25%. In turn, they also observed that mice on a western diet had a significant increase in microglia displaying TREM2 – indicative of increased immune activity and inflammation.

Learn more about how peptide synthesis services at GenScript accelerate Alzheimer's research.

Graham et al. Chronic consumption of a western diet induces robust glial activation in aging mice and in a mouse model of Alzheimer's disease. Scientific Reports. 2016; 6: 21568. DOI: 10.1038/srep21568

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Chronic stress accelerates cancer metastasis by remodeling lymph vasculature

April 11, 2016

cancer, tumor metastasis How can high stress levels accelerate tumor metastasis? While there has previously been evidence that chronic stress can impact health in general, including cancer survival rates, the mechanism behind this has not been known. In a recent Nature Communications paper, how stress impacts the spread of cancer has been elucidated.

How does cancer impact metastasis?

In this report, the authors demonstrate that high stress levels in mice actually restructures the lymph networks around tumors. This restructuring is partly the result of β-adrenergic signaling, and COX2 inflammatory signaling from macrophages. Restructuring of the networks increases tumor cell dissemination, and ultimately confirms the adverse impact that stress plays on cancer survival.

To accelerate cancer research, GenScript offers:

Le et al. Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination. Nature Communications. 2015; 7(10634). DOI: 10.1038/ncomms10634.

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A murine norovirus increases resistance against opportunistic bacteria in antibiotic-treated mice

April 6, 2016

antibiotic resistance, microbiota Gut microbes play an important role in protecting the host against harmful bacteria, such as Enterrococcus faecium; however, antibiotics can deplete these microbes. In an effort to increase resistance to infections, a recent Science Translational Medicine report presents new evidence that murine noroviruses can actually prevent E. faecium infections in antibiotic-treated mice.

How can this virus prevent infection?

When inoculations of the norovirus were delivered to antibiotic-treated mice, increased expression of TLR7 was observed – a protein involved in antiviral and antibacterial immunity. Activation of TLR7 led to increased synthesis of antimicrobial peptides, which accelerated depletion of E. faecium colonies in the gut. The authors also demonstrated that the norovirus mimic, Resiquimod (R848) could be used to deplete these harmful bacteria by inducing expression of IL-22 and IL-23. Ultimately the results of this study present a potentially new target to stimulate the immune system when antibiotics are needed.

Abt et al. TLR-7 activation enhances IL-22–mediated colonization resistance against vancomycin-resistant enterococcus.
Science Translational Medicine. 2016; 8(327): 327. DOI: 10.1126/scitranslmed.aad6663

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Eliminating senescent cells increases lifespan in mice

March 22, 2016

lifespan, cell senescence What's the secret to a long and healthy life? As we age, many of our health issues result from cell death: as cells die, or undergo senescence, they release molecules into tissues that contribute to age-related disease. So to improve lifespan, scientists have published a technique that selectively targets and destroys these senescent cells. Ultimately this technique can vastly improve lifespan and alleviate aging-related conditions.

How were senescent cells targeted?

In this study, a genetically modified mouse, INK-ATTAC, was used to model the physiological aspects of ageing. Senescent cells, which can be characterized by the expression of p16Ink4a, were targeted and induced into apoptosis. The controlled apoptosis drastically improved over all health, including reduced tumorigenesis, improved kidney function, and improved cardiac function. In turn, healthy lifespan was increased by 20-30%.

To accelerate your drug discovery research, GenScript offers:

Baker et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan.
Nature. 2016; 530: 184-189. DOI: 10.1038/nature16932

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Seasonal microbiota control metabolism in hibernating bears

March 14, 2016

microbiota, metabolism During the summer, bears consume a vast amount of food prior to hibernation during the winter; however, despite this weight gain, they do not have the same health side effects associated with obesity. A study published in Cell has shown light on this artifact, demonstrating that the population of gut microbiota alter between summer and winter, which impacts their metabolic status as seasons change. In fact, mice colonized with microbiota from "winter bears" show less weight gain compared to those colonized with "summer bear" bacteria.

To accelerate your research, GenScript offers:

Sommer et al. The gut microbiota modulates energy metabolism in the hibernating brown bear Ursus arctos.
Cell Reports. 2016; 14: 1-7. DOI: 10.1016/j.celrep.2016.01.026.

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New study links Neanderthal genes to risk for a variety of human clinical traits

March 7, 2016

human genome Family history can play a big role in our predisposition to develop a variety of health-related issues, from stress to heart disease. However, the results of a recent study published in Science suggests this predisposition can be linked even further back than our immediate family – they can be linked to Neanderthal DNA. After scanning the genomes of 28,000 Americans, the authors found that Neanderthal gene variants could be linked to increases risk for depression, blood clots, and nicotine addiction. They found that Europeans and Asians inherited approximately 1.5% of their genome from Neanderthals. So how come we've inherited such potentially deadly genes? The published study suggests that perhaps at one time these genes were in fact beneficial to Neanderthals, but over time due to a variety of reasons, ended up being detrimental to modern humans.

Would targeting Neanderthal genes help us fight these health issues? Learn more about how peptides and custom genes can be used to develop novel gene therapies.

Simonti et al. The phenotypic legacy of admixture between modern humans and Neanderthals.
Science. 2016 Feb 15; 351 (6274): 737-741. DOI: 10.1126/science.aad2149

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Early development of T regulatory cells improves food tolerance in children

March 1, 2016

food allergy Millions of people suffer from food allergies; however, why more children specifically suffer from these food intolerances has been unclear until recently. In a recent Science publication, the authors show that early exposure to new foods activates specific populations of T cells, specifically, regulatory T cells (Treg). Without early exposure, children become more likely to develop food intolerance as a result of less diverse T cell populations.

Kim et al. Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine.
Science. 2016; 351 (6275): 858-863.

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Functional, insulin-secreting pancreatic beta cells have been successfully generated from human skin cells

February 22, 2016

pancreatic beta cell The symptoms of diabetes result from the lack of adequate insulin secretion from pancreatic beta cells. Since there is no cure for the disease, attention has shifted towards the development of do novo insulin-producing stem cells from pluripotent stem cells. Generation of these cell types is particularly challenging, and requires a complicated, step-wise approach to guiding cells into endodermal and finally pancreatic cell fates. To improve upon current differentiation regimens, a recent study published in Nature describes a new cell conversion strategy which directly reprograms fibroblasts into endodermal progenitors – avoiding a true induced pluripotent phenotype.

How were insulin-derived cells generated?

In this study, skin fibroblasts were directly programmed into endodermal progenitor cells using a combination of pluripotency transcription factors (OCT4, SOX2, KLF4) along with lineage-specific soluble factor. This strategy directly converted the skin fibroblasts into definitive endodermal progenitor cells. From here, the progenitor cells were converted, step-wise, into insulin-producing beta cells. When transplanted into diabetic mouse-models, these cells could effectively secrete insulin in response to changing blood glucose levels.

Learn more about how custom peptides can accelerate stem cell differentiation research.

Zhu et al. Human pancreatic beta-like cells converted from fibroblasts.
Nature Communications. 2016; 7:10080. DOI: 10.1038/ncomms10080.

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New evidence shows that ApoE transcriptionally regulates expression of genes associated with Alzheimer's pathogenesis

February 16, 2016

Alzheimer's gene Apolipoprotein E ɛ4 (ApoE4) is one of the best genetic risk factors for Alzheimer's Disease, but what role it plays has been a mystery until now. In a recent Journal of Neuroscience publication, the authors show that ApoE4 actually functions as a transcription factor, and activates the expression of genes such associated with neurotrophins, programmed cell death, sirtuins and ageing. What could this finding mean for development of Alzheimer's therapeutics?

Theendakara et al. Direct transcriptional effects of apolipoprotein E.
J Neurosci. 2016 Jan 30; 36(3): 685-700. DOI: 10.1523/jneurosci.3562-15.2016.

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New algorithm helps structural biologists identify the most appropriate codons for synthesis of repetitive polypeptides

February 8, 2016

repetitive peptide Proteins with repeating units comprise many important molecules; however, designing transcripts encoding these peptide sequences can be time intensive and challenging. To address this, a group at Duke University developed a new codon-scrambling algorithm that helps identify the least repetitive genetic code to synthesize any protein of interest. The algorithm, which is made publically available at http://chilkotilab.oit.duke.edu, requires simply repeating sequence and number of repeats, and the optimal nucleotide sequence is reported. With this resource, protein design potentially can become much easier for any synthetic biology lab.

Interested in learning more about GenScript's gene synthesis services? Click here »

Tang et al. Combinatorial codon scrambling enables scalable gene synthesis and amplification of repetitive proteins.
Nature Materials. 2016 Jan 4. DOI: 10.1038/nmat4521

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Vaccination of cowpea mosaic virus-nanoparticles potently suppress metastatic cancer

February 1, 2016

cancer immunotherapy Cancer immunotherapy is one of the most promising strategies in the fight against cancer, and nanotherapy has the potential to contribute. Nanoparticles are nontoxic, stable and modifiable for a variety of medical applications, and in a recent Nature Nanotechnology publication, the authors. In this report, nanoparticles are coated with the shell of a plant virus and injected into tumors in mouse models. The viral particles trigger prolonged antigen-specific responses, and effectively reduce the volumes of skin and lung melanoma. In addition, the systemic responses were also effective in reducing metastatic cancer.

Lizotte et al. In situ vaccination with cowpea mosaic virus nanoparticles suppresses metastatic cancer.
Nature Nanotechnology. 2015. DOI: 10.1038/nnano.2015.292.

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New technique enables first-of-its–kind in toto imaging of mouse embryogenesis

January 25, 2016

embryogenesis, lineage mapping Early imaging and lineage mapping within a developing embryo has traditionally been difficult due to high light sensitivity and in vitro culture requirements. However, this bottleneck has recently been addressed in Nature Methods with the development of a new imaging technique called light-sheet microscopy. Here, excitation light is limited to a specific focal plane, which minimizes background and allows the embryo to remain in culture medium during imaging. Using this method, the authors were able to image complete development of a mouse embryo from zygote to blastocyst.

Watch the video

In turn, they also were able to determine when during embryogenesis cells become committed to specific lineage, such as trophoectoderm and inner cell mass.

Strnad et al. Inverted light-sheet microscope for imaging mouse pre-implantation development Nature Methods. 2015 June 24. DOI:10.1038/nmeth.3690.

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New insights into the link between sodium channel expression and endogenous opioids could help us live pain free

January 18, 2016

sodium channel, pain Individuals with congenital insensitivity to pain (CIP) are unable to feel pain; however, their ability to feel pressure and touch is not affected. A better understanding of the molecular basis behind this condition could potentially provide unique insights into pain management, and this was recently revealed in a Nature Communications publication.

What is the secret to a life without pain?

It has been well known that painlessness is contributed by non-functioning Nav1.7 sodium channels. In this study, the authors observed that individuals with CIP and mice that lack Nav1.7 have higher than normal levels of endogenous opioid peptides. In turn, if individuals with CIP were given the sodium channel blocker, naloxone, they felt pain for the first time. As a result, this study identified an important conclusion that both blocking Nav1.7 and opioid peptide supplementation could the recipe for effective pain management.

Minett et al. Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7. Nature Communications. 2015; 6(8967). DOI: 10.1038/ncomms9967.

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Amyloid-β burden has been linked to altered BRCA1 expression in Alzheimer's patients

January 12, 2016

BRCA1, Alzheimer's While BRCA1 has historically been primarily implicated in uncontrolled cell division, new evidence in mouse Alzheimer's models suggests that the BRCA1 gene may also have a role in regulating neuronal function. In fact, in this recent Nature Communications report, the authors observed that there were greatly reduced levels of BRCA1 in the brains of AD patients, and in vitro in mouse neural cell cultures.

What is the significance of BRCA1 depletion on learning and memory?

Based on the results of this study, the presence of amyloid-β interfered with proper BRCA1 expression. In turn, loss of BRCA1 appeared to contribute to increases in neuronal DSBs, neuronal shrinkage, as well as deficits in learning and memory. Ultimately, targeting BRCA1 expression as amyloid-β levels increase could be another therapeutic option for reversing the clinical effects of Alzheimer's.

Suberbielle et al. DNA report factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice. Nature Communications. 2015 Nov. DOI: 10.1038/ncomms9897.

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The skin microbiome is established during the first few weeks of life

December 14, 2015

skin microbiome Our skin is residence to a variety of microbes which play an important role in regulating immunity; but at what point did we develop tolerance to these microbes? In a recent Immunity publication, scientists have determined that tolerance is developed during a very specific window during development. The authors engineered S. epidermis, a prevalent microbe on skin, to express a fluorescently labeled peptide antigen 2W to track colonization at different time points in mouse development. They observed (1) that there is an accumulation of regulatory T cells in postnatal skin and (2) that this flux is critical for developing tolerance to these commensal bacteria. Together these results demonstrate that host-microbial relationships are developed early in life, and are critical for the development of adaptive immunity.

Scharschmidt et al. A wave of regulatory T cells into neonatal skin mediates tolerance to commensal microbes. Immunity. 2015;43:1011-1021. DOI: 10.1016/j.immuni.2015.10.016.

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The first oncolytic virus to treat advanced melanoma has been approved by the FDA

December 7, 2015

oncolytic virus For the first time, the FDA has approved an oncolytic virus to treat cancer. This virus, called talimogene laherparepvec (T-VEC) , which was engineered from the herpes simplex virus, has been shown in clinical trials to specifically target cancer cells and stimulate the immune system for their destruction.

How can this virus target melanoma?

To make the virus effective against cancer cells, multiple modifications that were introduced. To inhibit the virus' ability to cause herpes, key infection and antigen-presenting genes were deleted. To assist in immune cell stimulation, human GM-CSF was inserted. While T-VEC can enter normal cells, it will not reproduce; however following cancer cell infection by T-VEC, GM-CSF is released to stimulate elimination by T cells. Ultimately, in clinical trials, 16% of patients displayed a significant decrease in the size of their skin or lymph node lesions, compared to 2% of patients who did not receive the same treatment.

FDA News Release: FDA approves first-of-its-kind product for the treatment of melanoma

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New study reveals that amyloid-β-targeting antibodies worsen neural dysfunction in Alzheimer's models

November 30, 2015

Alzheimer's immunotherapy Amyloid β plays a central role in the pathology of Alzheimer's disease, and thus has been a primary target for immunotherapy and other therapeutics. Bapineuzumab, a β amyloid-targeting antibody, has shown the most potential in animal models and early clinical trials; however, the results of Phase 3 clinical trials have been less optimistic. In fact, bapineuzumab did not fully improve clinical outcomes in Alzheimer's patients, and actually led to various cognitive impairments and continued neuronal dysfunction (Salloway, 2014). So for the first time, a study published in Nature Neuroscience has uncovered the molecular basis behind these observations.

Why isn't Alzheimer's immunotherapy improving cognitive outcomes?

In this study, researchers used two-photon in vivo imaging to track calcium transients in Alzheimer's mouse models following treatment with the bapineuzumab equivalent, 3D6 antibody. While 3D6 successfully targeted and decreased amyloid β burden in PDAPP mice, there was no noticeable change in neuronal function. In fact, neuronal dysfunction, as a result of hyperactivity, worsened in Alzheimer's mouse models following treatment. This study thus presents an important new need to thoroughly investigate functional in vivo assays when developing successful immunotherapies for Alzheimer's.

Salloway et al. Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease. NEJM. 2014; 370: 322-333. DOI: 10.1056/NEJMoa1304839.

Busche et al. Decreased amyloid-β and increased neuronal hyperactivity by immunotherapy in Alzheimer's models. Nature Neuroscience. 2015; 18: 1725-1727. DOI: 10.1038/nn.4163.

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New study identifies why elephants stay cancer free

November 23, 2015

peto paradox, cancer While elephants have 100 times the number of cells human do, it has been noted that the chances they will have cancer does not increase proportionally. In fact, fewer than 5% of elephants die from cancer compared to 25% of humans. Known as the Peto Paradox, the reason behind this has confounded scientists until recently: a report in JAMA has finally identified the reason for why elephant cells respond differently to DNA damage.

What is the difference between elephant and human cells?

To identify the mechanism for why elephant cells are more resistant to cancer, the authors of the JAMA study compared responses of human cells, elephant cells, and cells from cancer-prone, Li-Fraumeni syndrome (LFS) patients to DNA damage by ionizing radiation. They found that elephant lymphocytes underwent p53-mediated apoptosis at a much higher frequency compared to human lymphocytes, and that this was attributed to the number of p53 copies in elephant cells. Elephant lymphocytes actually contain 40 copies of p53, the gene that controls apoptosis, compared to the one copy humans have.

What could these findings mean for cancer therapeutics?

The results of this study suggest that the extra copies of p53 enable elephants to kill off cancer cells before they become tumors. With this insight, it could be possible to make human cells more "elephant-like" by delivering extra copies of p53 to cells by gene therapy.

Abegglen et al. Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans. JAMA. 2015 Nov; 314(17): 1850-60. DOI: 10.1001/jama.2015.13134

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Bioadhesive nanoparticles make a longer lasting and more effective sunblock

November 9, 2015

bioadhesive nanoparticles, sunblock One of the most effective ways to prevent damage from UVA and UVB radiation is sunblock; however, there are disadvantages to those that are available currently. First of all, sunblock must be reapplied regularly to ensure optimum protection, and secondly, there is evidence that traces of the compounds found in sunblock, such as padmiate O, have been found in urine and breastmilk. So to improve the current option, researchers have turned to an unlikely material: bioadhesive nanoparticles.

How does this new sunscreen work?

In this Nature Materials publication, padimate O was encapsulated into bioadhesive nanoparticles. These nanoparticles, as well as conventional sunscreen, were applied topically to mice, and the mice were exposed to increasing doses of UV light. The authors found that even though the net weight of padimate O in nanoparticles was less than commercial formulations, these nanoparticles protected the mice from UV light more efficiently. Similarly, since these nanoparticles could be wiped from the skin, there is less risk for absorption into tissues.

Deng et al. A sunblock based on bioadhesive nanoparticles. Nature Materials. 2015. DOI: 10.1038/NMAT4422

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Individuals emit a unique microbial cloud

November 2, 2015

microbial cloud Increasing evidence suggests that each of us have a microbial signature: a population of microbes that is unique enough that it can distinguish between individuals. Previous studies have shown individuals can be identified simply from microbiota samples taken from different parts of the body. However, it turns out that we are actually surrounded by a cloud of microbes, which follows us wherever we go.

What is the significance of our microbe cloud?

In the study published in Peer J, researchers collected air samples of individuals during and after sitting in a sanitized chamber. At different time periods, the samples were collected and sequenced to analyze the microbial components. They found that the occupants could be detected by airborne bacterial emissions within 1.5-4 hours after leaving the room. Not only that, but in certain circumstances the samples were distinct enough between individuals to be identifiers. So for the first time, this study shows not only that part of our microbiome is airborne, but it is unique to each one of us.

Meadow et al. Humans differ in their personal microbial cloud. Peer J. 2015. 3:e1258, DOI: 10.7717/peerj.1258

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Late night consumption of caffeine extends your circadian rhythm

October 26, 2015

circadian rhythm For many people, drinking coffee at night can keep you awake for hours; however, a study recently published in Science Translational Medicine suggests that consumption of caffeine just before habitual bedtime can have even more lasting effects. According to this study, consumption of the equivalent of a double shot of espresso can actually extend your circadian clock – or the natural day-night cycle.

What is the biological impact of caffeine?

In this study, the effect of caffeine on circadian oscillations and melatonin levels were assessed in vitro and in vivo. In vivo, the authors observed that consumption of caffeine three hours before bedtime resulted in a 40 min delay in melatonin rhythm. As a result of this delay, the effects of caffeine would also be felt the next day: disruptions in melatonin rhythms and subsequent extension of the circadian clock will also affect bedtime the night after. The mechanism for this was confirmed by in vitro assays as well, demonstrating in U2OS cells that caffeine increases cAMP production.

Are there any benefits to regulating your circadian rhythm with coffee?

Timing caffeine consumption could have therapeutic benefits as well, especially in individuals with sleep-wake disorders or jetlag. For instance, when traveling west across time zones, coffee could help acclimation; however, further assessment will be required.

Burke et al. Effects of caffeine on the human circadian clock in vivo and in vitro. Science Translational Medicine. 2015; 7 (305): 305ra146. DOI: 10.1126/scitranslmed.aac5125

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New study demonstrates why wasp venom peptides have potent anticancer properties

October 12, 2015

wasp venom Peptides derived from venom can have multiple therapeutic benefits, and Polybia-MP1 (MP1) is an example of one of these peptides. MP1 is derived from wasp venom and has known antimicrobial properties; however, MP1 also displays specificity against cancer cells. The reason for this has been unclear up until recently, when a study published in the Biophysical Journal described the mechanism for how MP1 has anticancer potential.

How does MP1 specifically target cancer cells?

In this study, the authors found that the lipids phosphotidylserine (PS) and phosphatidylethanolamine (PE) are distributed differently on cancer cells compared to normal cells. In cancer cells, there are higher concentrations of both PE and PS distributed on the cell membrane. Both PS and PE play a synergistic role in promoting MP1 binding. For the former, MP1 binding is increased 7-8 fold, while PE lipids increase membrane susceptibility to permeabilization and also increase the size of the pores formed. Together, these findings confirm the potential MP1 has as a anticancer therapeutic.

Leite et al. PE and PS lipids synergistically enhance membrane poration by a peptide with anticancer properties. Biophysical Journal. 2015 September; 109: 936-947. DOI: 10.1016/j.bpj.2015.07.033.

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New scientific evidence confirms sleep duration is correlated with susceptibility to the common cold

October 8, 2015

rhinovirus It's no secret that getting a good nights rest has many benefits, from preventing weight gain to improving memory consolidation. A recent report published in Sleep has uncovered yet another benefit: sleep duration directly correlates with susceptibility to common colds.

How was the link made between sleep and risk for the common cold?

In this study, 164 healthy participants monitored their sleeping patterns by wrist actigraphy and sleep diaries over seven days. After this period, the volunteers were administered the rhinovirus via nasal drops, and monitored for another 5 days to see whether they displayed cold symptoms.

How much sleep do you need to stay healthy?

Based on the findings of this study, participants who slept less than 6 hours a night were significantly more likely to develop a cold: 30% of adults became sick if the slept less than 6 hours a night, compared to less than 20% if you sleep more than 7 hours. While the mechanism for how sleep affects the immune system is still unclear, this study confirms yet another reason to get a good nights sleep.

Prather et al. Behaviorally assessed sleep and susceptibility to the common cold. Sleep 2015; 38(9): 1353-1359. DOI: http://dx.doi.org/10.5665/sleep.4968

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The gene variant that triggers fat cells to burn energy has been identified

September 21, 2015

beige fat, obesity gene What makes a fat cell, or adipocyte, burn energy as opposed to storing it? It may not be just about hitting the gym for a few extra hours, and instead may be about genetics. Adipocytes, specifically beige adipocytes, burn energy in a process known as thermogenesis. In white, energy-storing adipocytes, this process is reduced. While previous studies have linked a gene called FTO to obesity, until now there was little understanding of the mechanism. Yet, a recent study published in the New England Journal of Medicine has finally determined how the allele inhibits thermogenesis.

How does the FTO allele impact adipocyte browning?

In this study, the authors analyzed epigenomic data, allelic expression, regulator expression, and gene expression patterns in both mouse models and adult patients to elucidate the association between FTO and obesity. They observed that variations in the FTO allele disrupt a motif for a repressor, ARID5B, which in turn increases the expression of two genes, irx3 and irx5. These genes become overexpressed during early adipocyte differentiation, ultimately decreasing thermogenesis seven-fold. To see if this process is reversible, the authors inhibited irx3 expression in mice, and found that body fat was reduced without any change in diet or exercise. Together, this report provides an interesting new target for weight loss strategies – suggesting that perhaps gene therapy may be another approach to combatting obesity.

Claussnitzer et al. FTO obesity variant circuitry and adipocyte browning in humans. New England Journal of Medicine. 2015; 373-895-907. DOI: 10.1056/NEJMoa1502214

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New viral nanocontainers deliver powerful snail peptide analgesics across the blood brain barrier

September 7, 2015

snail venom peptide Snail venom, while having paralytic effects on prey, has actually been found to have many beneficial clinical effects in humans. These neuropeptides have the potential to alleviate pain for a variety of conditions, from cancer to nerve damage. MVIIA, a neuropeptide commercially available as Prialt®, is derived from the cone snail Conus magus, but delivery of this 25 AA peptide has been a bottleneck for its clinical use. With improved delivery methods, this painkiller could have many of the benefits of opioids without the side effects.

How have delivery methods been improved for this drug?

Previously, the only effective method to deliver Prialt® was by intrathecal injection; however, the report recently published in Scientific Reports constructed a P22 virus like particle (VLP) that encapsulates the MVIIA peptide. In both in vitro and in vivo models, the conjugated VLPs were successfully endocytosed into endothelial cells, and when delivered intravenously into the tail vein of nude mice were able to pass through the blood brain barrier. By optimizing methods for peptide-drug delivery, this study opens up the opportunity to use other natural peptide products as pain killers.

Anand et al. Tailored delivery of analgesic ziconitide across a blood brain barrier model using viral nanocontainers. Scientific Reports. 2015 August. DOI: 10.1038/srep12497.

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New T-cell therapy treatment strategy shows promise for multiple myeloma

August 31, 2015

multiple myeloma Multiple myeloma remains a largely incurable form of cancer. While autologous stem cell transplants (ASCT) can improve prognosis, the lack of tumor-reactive T cells inhibits its efficacy. To solve this, scientists hypothesized that if T cells were genetically engineered to target specific molecules on cancerous plasma cells, the effects of ASCT would be boosted.

How are T cells engineered to specifically target myeloma?

In a previous study, the authors of the Nature Medicine paper identified two peptide antigens, NY-ESO-1 and LAGE-1, that are present on approximately 60% of myelomas. Patients' T cells were collected and the TCRs were engineered to recognize the peptide antigens. After transplanting these engineered T cells back into the patients, the authors observed increased T cell activity and a near complete response to the therapy in 70% of the patients tested. These Phase I/II clinical trial results suggest that TCR- engineered T cells may be the key to controlling multiple myeloma.

Rapoport et al. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma.

Nature Medicine. 2015; 21: 914-921.

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Targeting β2-microglobulin may reverse memory loss in aging adults

August 24, 2015

memory loss, anti-aging Memory loss as a result of aging is a significant impairment associated with many degenerative disorders, including Alzheimer's and dementia. Recently, however, researchers have found something interesting: adult rats that receive plasma from young rats perform better on memory tests than those that do not. So what blood-borne agent contributes to aging? In a recent study published in Nature Medicine, a pro-aging factor in the blood has been discovered and may be a therapeutic target.

What is this pro-aging factor?

B2-microglobulin (B2M), a component of MHC I, is known to regulate neurogenesis in the brain. In this study, the authors found that if B2M is applied exogenously to young mice, neurogenesis and cognitive function is inhibited. In addition, B2M -/- adult mice have significantly improved memory retention compared to adult WT mice, suggesting that inhibiting B2M could reverse memory loss in aging adults. Together, these results present B2M as a potential candidate for anti-aging therapeutics.

Smith et al. Β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis.

Nature Medicine. 6 July 2015; 21: 932-937. DOI: 10.1038/nm.3898.

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Markers on pancreatic cancer cell exosomes are the key to early detection

August 17, 2015

pancreatic cancer Pancreatic cancer remains one of the most deadly cancers: less than 4% of patients survive within five years of diagnosis. The poor prognosis is attributed to the difficulty in detecting the cancer before it spreads; however, a new study has identified an early detection method that can improve survival rates.

How can pancreatic cancer be detected?

In a recent study published in Nature, the authors identified a unique biomarker for pancreatic cancer. This marker, glypican-1 (GPC1), is a membrane bound protein that is over expressed in pancreatic cancer cell exosomes. These GPC1+ circulating exosomes (crExo) are detectable in serum by FACS analysis. The authors observed significantly higher levels of GPC1+ crExos in 100% of serum samples tested from pancreatic cancer patients. This test was also confirmed to detect pancreatic cancer at its earliest stages: GPC1+ crExos were detected at all stages (I-IV). So not only does this study identify a unique pancreatic cancer biomarker, but it presents a relatively simple blood test that could improve the chances of full recovery.

Melo et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature. 9 July 2015; 523: 177-182. DOI: 10.1038/nature14581

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Microbiota prevent allergic reactions by inducing T cells

August 11, 2015

allergic reactions Our predisposition for allergies largely has to do with exposure to pathogens: the earlier we are exposed, the less likely we will develop allergies to these pathogens in the future. Turns out, our microbiome also plays a hand in regulating allergic responses, but until recently how this occurs has been unclear. A recent study published in Science presents the mechanism for how our microbiome controls type 2 immunity.

How can our microbiome control allergic responses?

In this study, the authors found that T regulatory cells (Tregs) in the intestine express the nuclear hormone receptor, RORγt. In germ-free mice, there are significantly lower expression levels of these RORγt+Tregs as well as increased inflammation when challenged with compounds that can provoke allergic responses. Ultimately, by inducing RORγt+ Tregs, the microbiota can balance immune responses to allergens.

Ohnmacht et al. The microbiota regulates type 2 immunity through RORγt+ T cells. ScienceXpress. 9 July 2015. DOI:10.1126/science.aac4263.

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The link between deep sleep and Alzheimer's Disease progression has been confirmed

August 3, 2015

REM sleep, beta-amyloid A recent report published in Nature Neuroscience suggests a new therapeutic strategy to prevent Alzheimer's Disease progression: high quality sleep. In this study, the authors examined how β amyloid protein deposition in the prefrontal cortex affects sleep and the ability to perform memory-related tasks.

How does β amyloid impact sleep quality and memory?

It turns out there is a vicious cycle between the amount of quality sleep, in which memory consolidation occurs, and the presence of β amyloid protein. Adults with an elevated β amyloid burden in the medial prefrontal cortex get less NREM sleep and had a more difficult time remembering word-pairs that were provided to them the night before. There could be some hope though, as there has been mounting evidence that quality sleep can help eliminate β amyloid, ultimately improving memory. Together the results suggest that improving sleep quality could help stave off the symptoms of Alzheimer's.

Mander et al. β-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation. Nature Neuroscience. 2015 June 1; 18: 1057-1057. DOI: 10.1038/nn.4035.

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Circadian clock machinery has been successfully implanted into non-circadian microbes

July 27, 2015

microbe circadian clock Circadian rhythms, or processes that oscillate within a 24-hour time period, are observed in many species. These day-night variations have also been observed in cyanobacteria, and the machinery that regulates these processes has been well studied. Considering the significant role the gut microbiome plays in regulating health and behavior, a group at Harvard asked an interesting question: can circadian clock machinery be transplanted into bacteria that do not have diurnal cycles, such as E. coli?

To reconstruct the circadian oscillator in E. coli, the authors expressed the three proteins that comprise the circadian machinery in cyanobacteria, Kai A, Kai B and Kai C. In cyanobacteria, KaiC phosphorylation is regulated with 24 hour periodicity: during the day, Kai A phosphorylates Kai C, and at night Kai B inhibits Kai A, and Kai C is dephosphorylated. The same expression changes were also observed in the engineered E. coli. With this system, E. coli could be used for producing drugs in a time-dependent manner, or even be used to correct jetlag dysbiosis.

Chen et al. Transplantability of a circadian clock to a noncircadian organism. Science Advances. 2015; 9(5): e1500358. DOI: 10.1126/sciadv.1500358

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A new fate-mapping technique has identified regenerative cells in the heart

July 20, 2015

cardiomyocyte progenitor, cycling cardiomyocyte Cell therapy for the treatment of heart disease is one of the most promising therapeutic strategies to recover damaged tissue; however, identifying an adequate cell source has always been a bottleneck. While stem cells have received the most attention for their known proliferative potential, for some time scientists have known that there is a small population of heart cells, or cardiomyocytes, that do renew; however this percentage is very small (<1%) and their niche was uncertain (Bergmann 2009). In a recent Nature report, however, this population of cardiomyocytes has been successfully identified using a novel fate-mapping technique.

How were these cells identified?

To identify the proliferating cardiomyocytes, the authors developed a transgenic mouse line in which Hif-1α expressing cells were irreversibly labelled with the fluorescent marker, tdTomato. Hif-1α, which regulates the hypoxic stress response, is expressed by proliferating cardiomyocytes in the heart. Under the control of the cardiomyocyte-specific promoter, αMHC, the population of regenerating cardiomyocytes could be identified. Using this method, the authors were able to isolate the cells to specific niches in the ventricles and atria.

Kimura et al. Hypoxia fate mapping identified cycling cardiomyocytes in the adult heart. Nature. 2015 June 22. DOI: 10.1038/nature14582.

Bergmann et al. Evidence for cardiomyocyte renewal in humans. Science. 2009 April 9; 324(5923): 98-102. DOI: 10.1126/science.1164680.

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New test detects your entire viral history from a drop of blood

July 13, 2015

viral history, peptide library To date, there has not been an efficient way to identify an individual's viral history – information that could have significant impacts on health care. Rather than screening one pathogen at a time, the authors of a study published in Science developed a blood based assay that can detect the presence of thousands of antibodies from just 1 µl of blood.

How does this assay work?

To design the assay, the authors prepared a phage display peptide library encoding overlapping peptides that span the epitopes of over 108 antibodies. Blood samples from 569 donors across four continents were collected, and the blood was mixed with the library. Unbound antibodies were washed away, and PCR was performed to amplify the phage DNA to determine which peptides were bound. Not only could this test distinguish differences in viral history amongst individuals, but for only $25 a test, it could be a profound new point-of-care tool for the healthcare industry.

Xu et al. Comprehensive serological profiling of human populations using a synthetic human virome. Science. 2015 June 5; 348(6239): aaa0698-1. DOI: 10.1126/science.aaa0698

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Combining CRISPR and phages to target antibiotic-resistant bacteria

July 6, 2015

antibacterial resistance, bacteriophage Antibiotic and drug resistance in pathogens continues to plague the healthcare system, prompting both the identification of new antibiotics and methods to make bacteria more sensitive to the antibiotics that are currently available. A study recently published in PNAS took upon the latter, using bacteriophages to deliver a CRISPR-Cas gene editing system into the genome of antibiotic-resistant microbes.

How can bacteriophages confer antibiotic sensitivity to resistant bacteria?

In this study, CRISPR genes were amplified by PCR and inserted into the lambda phage genome by homologous recombination, which targeted genes for streptomycin resistance. Bacteria with antibiotic resistance were mixed with lysogenizing phages with the CRISPR-Cas system, resulting in destruction of the antibiotic resistance genes in transformants. Ultimately, this method has the potential to prevent the spread of antibiotic-resistance among bacteria, and may be included as part of disinfection protocols currently adopted by healthcare facilities.

Yosef et al. Temperate and lytic bacteriophages programmed to sensitize and kill antibiotic-resistant bacteria. PNAS. June 2015; 112 (23): 7267-7272. DOI: 10.1073/pnas.1500107112

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The feedback loop that controls tomato size has been identified

June 29, 2015

shoot meristem, arabinosyltransferase Understanding the genetic mechanisms behind fruit size in plants can have many implications for crop production and optimization. This mechanism has recently been elucidated in tomatoes and presented in a report published in Nature Genetics. In this study, the authors discovered that the feedback loop that controls stem cell proliferation in the meristem directly controls inflorescence in tomato plants, and that larger fruit size is indicative of a mutation or defect in arabinosyltransferase genes.

How does arabinosyltransferase affect tomato size?

Stem cell proliferation is directly influenced by a glycopeptide called CLV3. This peptide is modified by arabinose, the length of which is controlled by a cascade of arabinosyltransferases. Under normal conditions, modified CLV3 will bind to the CLV1 receptor and prevent overproliferation of stem cells in the meristem; however, defects in the arabinosyltransferase genes prevent proper arabinosylation of CLV3, which enlarges the meristem and stimulates production of extra flowers. This mechanism presents a novel target for studying the effects of genetic modifications on crop production.

Xu et al. A cascade of arabinosyltransferases controls shoot meristem size in tomato. Nature Genetics. May 2015. DOI: 10.1038/ng.3309.

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A novel CD4 mimetic exposes HIV to antibodies

June 23, 2015

HIV, antibody-dependent cell-mediated cytotoxicity Following infection, HIV downregulates CD4 and envelope (Env) expression to evade detection by the immune system. While this makes natural elimination difficult, the results of a recent PNAS publication take advantage mechanism to develop a new strategy to treat HIV-infected patients. In this study, the authors expose HIV by hijacking CD4 downregulation using a small molecule that mimics the function of native CD4 – otherwise known as a CD4 mimetic.

How do CD4 mimetics expose HIV to the immune system?

The CD4 mimetic, a small compound called JP-III-48, was incubated in vitro with sera from HIV-infected individuals, and the effect on native CD4 presentation was assessed. The authors found that the CD4 mimic effectively reversed downregulation of CD4 expression in infected cells, which ultimately increased the expression of Env protein on the cell surface. Exposure of Env enabled recognition of the virus by antibodies that mediate antibody dependent cell-mediated cytotoxicity. These results suggest that CD4 mimetics, such as JP-III-48, may be attractive options for the development of targeted HIV therapeutics.

Richard et al. CD4 mimetics sensitize HIV-1-infected cells to ADCC. PNAS. May 2015; 112(20):E2687-E2694.

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Can you be identified by your microbiome

June 15, 2015

gut microbiome, microbial fingerprint Increasing evidence supports that your microbiome can be altered by many external factors – from diet to wearing contacts. Considering the many factors that influence the diversity of a microbiome, a recent report in PNAS suggests that an individual's microbiome may be distinct enough to identify them within a population.

In this study, the authors defined specific metagenomic codes, or microbial taxa and genes, that were unique to different parts of the body and different individuals. After analyzing the microbial populations of individuals over 30-300 days, the results were striking: by the end of the testing period, approximately 30% of individuals tested could be identified just from the microbiota tested at a particular body site. The gut microbiome displayed the most specificity and stability, as 86% of those tested could be identified by this population alone. So while the microbiome may not replace genetic identification entirely, this study does highlight the potential of “microbial fingerprinting.”

Franzosa et al. Identifying personal microbiomes using metagenomic codes. PNAS. 2015; 112(22): E2930-E2938.

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A new type of pluripotent stem cell has been discovered

June 8, 2015

pluripotent stem cell, epiblast stem cell To date, there are two types of pluripotent stem cells (PSCs) derived from mouse embryos: embryonic stem cells (ESCs) from the inner cell mass and epiblast stem cells (EpiPSC) derived from the post-implantation epiblast. Their plasticity makes these stem cells ideal candidates for a variety of regenerative purposes; however, directed differentiation has continued to be a challenge. In a recent study published in Nature, authors describe a new type of stem cell – the region-selective PSC (rsPSC) – which have many advantages over previously identified PSCs.

What advantages do rsPSCs have over other pluripotent stem cells?

In this study, the authors optimized the culture conditions to take full advantage of the pluripotency of rsPSCs. Unlike ESCs, rsPSCs were more stable and proliferated more quickly. In addition, for the first time, these PSCs can also form all three germ layers in chimeric embryos: human rsPSCs could be efficiently integrated into mouse embryos. Together these results demonstrate that rsPSCs represent a novel stem cell type that can be used for both research and therapeutic purposes.

Wu et al. An alternative pluripotent state confers interspecies chimaeric competency. Nature. 06 May 2015; 521: 316-321.

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Neuropeptides mediate perineural invasion in head and neck cancer models

June 2, 2015

head and neck cancer, perineural invasion In cancers such as head and neck cancer, pancreatic cancer, and colon cancer, perineural invasion (PNI) is associated with a poor prognosis. The significant pain and discomfort is associated with cancer cell innervation into the nerves, but to date the mechanism of this event has been unclear. A recent manuscript, however, has shed new light on PNI, offering a mechanism to target for future therapeutics.

How is tumor spread mediated in head and neck cancer models?

In this article, the authors discovered that PNI results from cross-talk between cancer cells and nerves. Specifically, a neuropeptide called galanin (GAL) is released by nerves, resulting in a positive feedback loop which upregulates galanin receptor 2 (GALR2) on cancer cells. Not only does this process attract cancer cells to nerves, it also activates neuritogenesis and enhances PNI. This study highlights a new mechanism which can be targeted for anti-tumor immunotherapy.

Scanlon et al. Galanin modulates the neural niche to favour perineural invasion in head and neck cancer. Nature Communications. 2015; 6(6885): 7-13.

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Increased arginase activity contributes to the pathogenesis of Alzheimer's Disease

May 26, 2015

alzheimer's disease, arginase activity There has been increasing evidence that immunity plays a role in the progression of Alzheimer's Disease; however, what that role is has been under speculation. In a study recently published in the Journal of Neuroscience, the authors discovered that immunosuppressive CD11c+ microglia and increased arginase activity contribute to AD pathology.

How does arginase activity contribute to pathology?

In this study, the authors used a new AD mouse model, CVN-AD, to more accurately simulate the brain microenvironment. Unlike other models, the CVN-AD mouse model has reduced nitric oxide levels, mimicking those observed in human AD patients. They observed that CD11c+ microglia were present in areas of the brain with high amyloid beta levels, along with high extracellular arginase concentrations. The increased extracellular arginase activity decreased availability of arginine. Interestingly, when the arginine catabolism pathway was blocked, memory loss was reversed. Consequently, this study presents a new target – arginine metabolism – to reverse the effects of Alzheimer's.

Kan et al. Arginine Deprivation and Immune Suppression in a Mouse Model of Alzheimer's Disease. The Journal of Neuroscience. 2015 Apr 15; 35(15): 5969-5982.

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The link between height and heart disease risk has finally been confirmed by genetics

May 20, 2015

heart disease, height SNP For about 60 years, there has been anecdotal evidence that patients with a shorter than average height have a higher risk of heart disease. This was generally attributed to physiological differences associated with height, such as artery diameter; however, a new study published in the New England Journal of Medicine has confirmed that there is actually a genetic predisposition for this risk.

What is the genetic link between height and heart disease?

In this study, the authors used SNPs that corresponded to adult height, and compared these genetic variants with those that are associated with coronary artery disease. Based on a meta-analysis, they observed that there was a significant association between the height and heart disease SNPs. They also observed that these height-associated SNPs overlapped with biological pathways that control cardiogenesis, including BMP, TGF-ß, IGF-1 and STAT3 signaling pathways. Combined, the authors discovered that every 2.5 inch change in height affects coronary heart disease risk by 13.5%.

Nelson, CP et al. Genetically determined height and coronary artery disease. New England Journal of Medicine. 2015. DOI: 10.1056/NEJMoa1404881.

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You are as old as you look: a new study suggests facial characteristics are the most accurate aging biomarkers

May 12, 2015

aging biomarker, 3D facial morphogenesis While we think we are as old as we feel, science may tell us otherwise. Without a definitive aging-biomarker, physicians have found it difficult to develop individual treatment plans for patients. In response to this, a recent study published in Cell Research analyzed over 300 faces of individuals ranging from 17 to 77 to identify distinctive facial characteristics. They then created a composite map of these features, which enabled them to develop an algorithm that could quickly identify approximate age (within 6 years) from only a 3D facial image. The authors found that even when compared to blood markers, such as cholesterol for females and LDL in males, facial imaging was a more accurate predictor of age. This type of age analysis software can have significant implications on not only the development of anti-aging therapies, but also the development of targeted treatment strategies for fast- and slow-agers.

Chen et al. Three-dimensional human facial morphologies as robust aging markers. Cell Research. 2015; Mar 31. DOI: 10.1038/cr.2015.36.

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A new study combines light and magnets to decrease tumor volume in mice

May 4, 2015

blood-based assay; cancer detection An ongoing challenge in cancer treatment is the development of effective therapies that reduce tumors without affecting the surrounding tissue; however, a recent study in ACS Nano may have overcome this issue using nanomedicine. In this study, the authors describe a new liposome formulation containing magnetic nanoparticles and photosensitizers, which when delivered into tumors and activated reduce tumor volume in as little as 3 days.

How do these liposomes ablate tumors so quickly?

The advantages of liposomes is that they are readily taken up by cells and consequently are very useful for drug delivery. Yet instead of delivering drugs, these liposomes delivered a combination of magnetic nanoparticles and photosensitizers to tumor cells. After the liposomes were injected into tumors in mice and taken up by tumor cells, the magnetic nanoparticles localized to membrane-delimited compartments and the photosensitizers remained suspended in the cytosol. The liposome contents were the activated by exposing the mice to magnetic hyperthermia and photodynamic therapy (PDT) every 24 hours for three days. After exposure to magnets, the nanoparticles caused a localized increase in temperature, and PDT induced the release of ROS. Together, this treatment successfully induced apoptosis, ultimately ablating tumors without any negative side effects.

Corato et al. Combining magnetic hyperthermia and photodynamic therapy for tumor ablation with photoresponsive magnetic liposomes. ACS Nano. (2015) 9(3):2904-2916, DOI: 10.1021/nn506949t

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New evidence suggests tetracycline affects more than just gene expression

April 28, 2015

blood-based assay; cancer detection Tetracycline has been a popular choice as an inducible gene expression system since it can be applied to many experimental model systems. Yet while generally the research focus is on short term transcriptional control, there has not yet been any assessment of the negative long-term effects associated with tetracycline use. However, a study recently published in Cell Reports has verified that tetracycline does indeed have negative long term effects on eukaryotes by disrupting mitochondrial function.

What are the long-term effects of tetracycline?

The authors provided a low dose of tetracycline to multiple common eukaryotic models including the HeLa cell line, C.elegans, D. melanogaster, A. thaliana and C57BL/6J mice. They observed global repression of mitochondrial function in all models, which led to altered behavior. These behavioral changes included reduction or delay of growth, reduced oxygen consumption, reduced fertility and altered physiological fitness. Ultimately these results bring into question if antibiotics are confounding experimental outcomes.

Moullan et al. Tetracyclines disturb mitochondrial function across eukaryotic models: a call for caution in biomedical research. Cell Reports. 2015; 10: 1681-1691. DOI:10.1016/j.celrep.2015.02.034

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Can senolytic drugs slow the aging process

April 22, 2015

blood-based assay; cancer detection Of the characteristics associated with chronic diseases, the symptoms of aging remain the most difficult to treat. Part of the difficulty has been the lack of an age-specific biomarker to target; however, a new study may have a identified a population of cells that can directly impact healthy lifespan – senescent cells. As we age, the population of senescent cells increases, and clearing these cells has been observed to improve many age-related conditions.

How can targeting senescent cells improve healthy lifespan?

In this study, the authors identified the transcriptome of senescent cells and noticed that, similar to cancer cells, there was increased expression of anti-apoptotic gene sets. In fact, if expression of these genes (which include bcl-xl, PI3KCD, Pai-2, CDK inhibitor 1A, and ephrin ligands) is inhibited by siRNA, viability and survival of senescent cells is drastically reduced. Given this, the authors developed a combination of drugs that target senescent cells in order to improve aging-related symptoms and coined these as "senolytic drugs." In fact, when aging mice were given a single dose of these drugs (the anti-cancer drug dasatinib and anti-inflammatory quercetin) improvements were seen in cardiovascular function, physical endurance and healthy lifespan.

Zhu et al. The Achilles' Heel of Senescent Cells: From Transcriptome to Senolytic Drugs. Aging Cell. 2015 Mar. DOI: 10.1111/acel.12344

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A new blood-based assay can detect cancer at its earliest stages

April 13, 2015

senescent cells; anti-aging drug When it comes to treating cancer, the earlier the diagnosis the better. Unfortunately, there has yet to be an effective method to do so; however, a group at Stanford University has published a report describing a new, safe technology that may be able to detect cancer at its earliest stages with a simple blood-based assay. This assay uses DNA minicircles, which are similar to prokaryotic vectors except they lack the immunogenic features, encoding a secretable reporter gene driven by the tumor-specific promoter called Survivin.

How can these minicircles detect tumors?

When the authors injected the DNA minicircles along with a transfection agent into the mouse bloodstream, the Survivin promoter was activated by tumor cells. Survivin activation led to the expression of a secretable reporter, secreted embryonic alkaline phosphatase (SEAP), which can be detected in the bloodstream using an in vitro diagnostic test. As a result, the authors could distinguish between tumor-bearing and tumor-free mice. In the future, this diagnostic test could be applied to many different types of cancers by incorporating a tumor-specific promoter into the minicircle.

Ronald et al. Detecting cancers through tumor-activatable minicircles that lead to a detectable blood biomarker. Proc Natl Acad Sci USA. 2015; 112(10):3068-3073. DOI: 10.1073/pnas.1414156112

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High salt diets may have immune boosting effects

April 8, 2015

hypertonic environment, macrophage activation, antimicrobial activity High sodium generally has negative connotations in regards to health: high salt consumption has been attributed to cardiovascular disease, hypertension, edema and even stomach cancer. Yet in a new report published in Cell, authors describe an immunity boosting effect of high sodium levels in the skin.

How can salt boost the immune system?

Previously, reports have unveiled that there is a relatively higher concentration of sodium that is naturally stored in the skin, but the reason for this has been unclear. In the report in Cell Metabolism, a possible explanation was discovered: hypertonic environments actually stimulate macrophage activity by activating the transcription factor NFAT5 via the p38/MAPK signaling pathway. Once activated, nitric oxide (NO) production is stimulated, which ultimately promotes antibacterial activity. In addition, the authors found that if mice were fed a high-salt diet following infection by Leishmania major, skin salt levels increased and the cutaneous L.major infection improved more quickly than mice fed low sodium diets.

Jantsch et al. Cutaneous Na+ Storage Strengthens the Antimicrobial Barrier Function of the Skin and Boosts Macrophage-Driven Host Defense. Cell Metabolism. 2015 Mar 3; 21(3):493-501. doi: 10.1016/j.cmet.2015.02.003

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Better batteries inspired by biology

April 3, 2015

lithium battery, nanoscale material As our electronic devices become smaller and faster, the batteries that power them must also meet the same requirements. Nanoscale materials facilitate this design: because of their small size, nanostructured electrodes have more active sites for reactions to occur, allowing them to be lighter and more powerful than standard, bulk-material batteries. A bottleneck in nanoscale battery design is the nature of the materials – nanomaterials like lithium manganese nickel oxide (LMNO) and carbon nanotubes, the materials that compose lithium ion batteries, aggregate easily. To improve on current design, a group at the University of Maryland, Baltimore County is using snail shells as their muse.

How can snail shells inspire better battery design?

In mollusks, micro-patterning has been attributed to repetitive peptide sequences that bind to inorganic compounds such as calcium carbonate. Just as these peptides can pattern shells, the group at UMBC hypothesized that peptides could also organize other inorganic materials like LMNO. To find the peptide that sticks to LMNO, they added the metal oxide to a library of peptides containing different amino acid combinations. By doing so, they were able to identify candidates that could better organize the nanoparticles and ultimately improve their battery performance.

Barannikova and Allen. Solid-Binding Peptides as a Biotemplate for Li-Ion Battery Electrodes. Biophysical Journal. 2015; 108(2) Suppl 1: 634a.

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Engineered bone marrow can make functioning platelets

March 25, 2015

tissue engineered bone marrow, platelet differentiation For patients that suffer from traumatic events or have undergone cancer treatments, platelet replacement is critical and can be lifesaving. Currently, blood transfusions from donors are the only replacement options; however, a new report in the journal Blood describes how bone marrow engineered from silk can produce functioning platelets ex vivo.

In this study, the authors used silk from the silkworm Bombyx mori, a biomaterial that has been applied to many other tissue engineered devices, to recreate the bone marrow microenvironment. Within this niche, the authors produced gel-spun tubes to simulate the microvasculature in bone marrow. Interestingly, when culture medium supplemented with VEGF and VCAM-1 was perfused through the tissue-engineered device, megakaryocytes seeded within the device produced platelets. These platelets displayed characteristics of functional platelets (promotion of thrombus and clot formation) and these platelets were stable in transfusion bags for up to 4 days at room temperature. In addition, the tissue engineered bone marrow was demonstrated to be a unique disease model: megakaryocytes from patients with myelofibrosis were compared to healthy patients using the tissue engineered bone marrow, and the phenotypes of proplatelets were compared. Using this system, the authors were able to better understand the mechanisms behind platelet production in diseased and healthy conditions.

Di Buduo et al. Programmable 3D silk bone marrow niche for platelet generation ex vivo and modeling of megakaryopoiesis pathologies. Blood. Jan 2015. DOI: 10.1182/blood-2014-08-595561.

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New smartphone accessory can detect HIV and syphilis in 15 minutes

March 19, 2015

point-of-care, HIV detection, syphilis detection Smartphones are becoming increasingly popular for healthcare diagnostics, and because of their small size and decreasing cost they are being developed as diagnostic tools in developing countries. As the race continues to make even more cost effective and efficient accessories, a group at Columbia University has developed an immunoassay accessory, or dongle, that is powered by a smartphone. The dongle is the first of its kind to function as an ELISA to detect HIV and the presence of both treponemal-specific and non-treponemal antibodies for syphilis. With just a fingerprick, a positive or negative result can be provided in only 15 minutes.

Watch the video

There are many features of this dongle that make it particularly promising: firstly, the assay uses gold-labeled antibodies and silver enhancement that are stable for approximately 1 month at room temperature. In addition, the manufacturing cost is only $34 along with the cost of the smartphone, and $1.44 for each triplex immunoassay, making this device one of the least expensive of its kind.

Laksanasopin et al. A smartphone dongle for diagnosis of infectious diseases at the point of care. Science Translational Medicine. 2015; 7(273): 1-9. DOI: 10.1126/scitranslmed.aaa0056.

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Healing after a heart attack: a peptide improves cardiac nerve regeneration

March 10, 2015

heart attack therapy, cardiac regeneration Cardiovascular disease remains one of the deadliest diseases in developed countries, and heart attacks are a common manifestation of the disease. After a heart attack, scar tissue forms in the myocardium, preventing cardiac nerve regeneration. This is a particularly lethal event: 70% of heart attack survivors die as a result of heart arrhythmias due to inefficient nerve reinnervation. However, a report published in Nature Communications presents a potential solution using a peptide that has already been shown to help nerve regeneration following a spinal cord injury.

How can peptides improve recovery after a heart attack?

After a heart attack, chondroitin sulfate proteoglycans (CSPGs) present in the scar tissue prevent nerve regeneration into the myocardium. If the CSPG receptors, called protein tyrosine phosphatase (PTPσ) are blocked, then cardiac nerves can pass through the CSPG-rich cardiac scar. Based on this premise, the authors demonstrated that a new peptide called intracellular sigma peptide (ISP), the same peptide that helps SCI healing, binds to the PTPσ receptors and promotes reinnervation when delivered after a heart attack. These results present a potential new prophylactic treatment to prevent sudden cardiac death.

Gardner et al. Targeting protein tyrosine phosphatase σ after myocardial infarction restores cardiac sympathetic innervation and prevents arrhythmias. Nature Communications. 2015; 6(6235): 1-9. doi: 10.1038/ncomms7235.

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Redesigned nasal adenovirus vaccine has improved efficacy against the Ebola virus

March 6, 2015

ebola drug, nasal adenovirus vaccine, ebola virus February marked the one year anniversary of the Ebola outbreak, and clinical trials for Ebola vaccines have been accelerated over the past year. By the end of November 2014, a preliminary report of an adenovirus vector vaccine was published in the New England Journal of Medicine. While administration of the vaccine successfully increased the expression of anti-Ebola glycoprotein antibodies, the vaccine was noticeably ineffective in patients with previous exposure to the adenovirus.

In response to this, a new study published in Molecular Pharmaceutics has reported a systematic approach to improving the efficacy of the nasal adenovirus vaccine. The authors hypothesized that by conjugating amphiphilic polymers to the vector, residence time in the nasal cavity would be increased, which would improve bioavailability and ultimately vaccine potency. They found that by conjugating polyethylene glycol (PEG) to the vector, transduction was improved and immune responses increased even in mice with previous exposure to the adenovirus. These results demonstrate promising advancements towards developing an effective Ebola vaccine.

Ledgerwood et al. Chimpanzee Adenovirus Vector Ebola Vaccine – Preliminary Report. The New England Journal of Medicine. 2014; DOI: 10.1056/NEJMoa1410863.

Choi et al. Bolstering Components of the Immune Response Compromised by Prior Exposure to Adenovirus: Guided Formulation Development for a Nasal Ebola Vaccine. Molecular Pharmaceutics. 2015; DOI: 10.1021/mp5006454.

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A new antibiotic has been discovered with no detectable resistance

February 26, 2015

antibiotic resistance, soil bacteria As the threat of increased antibiotic resistance looms, there is a growing need to discover new and more powerful antibiotics. Previously, this was hindered by the ability to successfully culture bacteria: approximately 99% of bacteria grow in soil, and to date there has not been an effective method to culture them in a lab. This changed recently, however, when researchers teamed up with Novobiotic to develop a unique chamber for culturing soil bacteria.

This device, called the iChip, enabled the growth of bacteria that can only grow in soil. Following production of a colony, the bacteria can then be transferred to in vitro culture in a lab. Using this technique, the authors identified a new bacteria genus, Eleftheria terrae, which produces an antibiotic called teixobactin. Teixcobactin displayed excellent activity against gram positive bacteria, including Clostridium difficile and Bacillus anthracis, by inhibiting peptidoglycan synthesis.

Ling et al. A new antibiotic kills pathogens without detectable resistance. Nature. 2015; 517: 455-459. doi: 10.1038/nature14098.

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Detecting Alzheimer's disease early: a new technology combines amyloid beta oligomer detection with magnetic resonance imaging

February 20, 2015

alzheimer's disease, magnetic resonance imaging Alzheimer's disease affects one out of nine adults over the age of 65, and effective management of the disease is improved when patients can be diagnosed as early as possible. With increasing evidence that amyloid beta oligomers (AßO) are the earliest biomarkers for the disease, a group at Northwestern University has developed a non-invasive way to detect Alzheimer's.

How can Alzheimer's be detected non-invasively?

In this study, the authors conjugated magnetic nanoparticles to AßO antibodies and delivered the particles intranasally in 5xFAD Alzheimer's mouse models. The antibodies readily attached to AßO In the hippocampus, and the nanoparticles could be detected by MRI for at least 96 hours after delivery. These results present a potentially revolutionary therapeutic approach to diagnosing and treating Alzheimer's disease.

Viola et al. Towards non-invasive diagnostic imaging of early-stage Alzheimer's disease. Nature Nanotechnology. 2015; 10: 91-98. DOI: 10.1038/nnano.2014.254.

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Adhesive peptides in disguise: a new technology regulates how and when cells interact with biomaterials in vivo

February 11, 2015

adhesive peptide, RGD Adhesive peptides, such as RGD, improve cell attachment to biomaterials following implantation in vivo. Unfortunately, these adhesive peptides can also activate signaling pathways that regulate immune responses and tumorigenesis. Thus, temporal and spatial control over when and where cells interact with biomaterials would improve their potential in regenerative medicine, and a lab at Georgia Tech has developed a novel way to control the presentation of these bioligands using UV light.

How can UV light control RGD presentation?

In this study, RGD peptides were caged with a light-triggerable ester group, that upon exposure to UV light are released, exposing the RGD to cells. When these caged RGD peptides are immobilized to PEG-based hydrogels and implanted in vivo, there is initially little to no cell adhesion; however, upon activation by UV light, exposed RGD facilitates cell attachment. In addition, by timing UV exposure, fibrosis and vascularization can also be regulated.

Lee et al. Light-triggered in vivo activation of adhesive peptides regulates cell adhesion, inflammation and vascularization of biomaterials. Nature Materials. 2014; 1-9. DOI: 10.1038/nmat4157

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Injectable 3D vaccines: a new therapeutic strategy in the fight against cancer and infectious disease

February 6, 2015

3D vaccine, cancer treatment Part of the challenge with developing effective vaccines for cancer treatment and viral diseases is adequate immune system activation – if the host immune cells are not activated, then the therapeutic benefit of the vaccine is reduced. A recent study in Nature Biotechnology offers a novel strategy to overcome this challenge by combining biomaterials and adjuvant to elicit a more prolonged immune response.

How could 3D vaccines be more effective than normal vaccines?

In this study, silica nanorods are injected in vivo, and following injection they immediately form a 3D aggregate that is porous enough for cell encapsulation. If small inflammatory molecules are incorporated into the scaffold, the aggregate will attract and activate dendritic cells and stimulate antigen presentation. Ultimately the group showed that these 3D vaccines induce antibody titers two orders of magnitude higher than if a single, bolus dose of inflammatory molecules was injected. In addition, this vaccine demonstrated a variety of immunotherapy applications: silica nanorod aggregates containing inflammatory molecules suppressed early tumor growth in mice injected with lymphoma cells, and increased serum antibody levels following injection suggest applications for infectious disease.

Kim et al. Injectable, spontaneously assembling, inorganic scaffolds modulate immune cells in vivo and increase vaccine efficiency. Nature Biotechnology. 2015; 33, 64-72. DOI: 10.1038/nbt.3071.

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A cell surface protein is responsible for turning primitive cells into fat cells

January 30, 2015

fat cell, adipogenesis, peptide vaccine What exactly makes us develop fat tissue, and how is this process controlled? While most of our attention has focused on the behavioral components of weight gain, new data has uncovered a signaling cascade that appears to regulate the differentiation of fat cells, or adipocytes, from progenitor cells.

How is adipogenesis controlled?

A recent study published in the FASEB journal has observed that a cell surface protein on pre-adipocytes, Thy1, is lost during differentiation into adipocytes. The effect of Thy1 expression on weight gain was observed in Thy1-null mice: Thy1-knockout mice gained more weight and expressed higher serum levels of obesity markers when they were fed high-calorie diets compared to controls. The potential of Thy1 as a therapeutic target was also identified. Overexpression of Thy1 blocked adipogenesis by inhibiting activation of the transcription factor, PPAR-ϒ, which is crucial for expression adipocyte-specific genes. This discovery has made the potential of an obesity-prevention drug one step closer to realization.

Woeller et al. Thy1 (CD90) controls adipogenesis by regulating activity of the Src family kinase, Fyn. FASEB J. 2015; 29: 1-12. DOI: 10.1096/fj.14-257121

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A peptide in spider venom protects chondrocytes from mechanical stress

January 23, 2015

venom peptide, mechanosensory The chondrocytes in articular cartilage are exposed to extensive mechanical loads on a regular basis, and this can ultimately lead to irreversible damage. While the negative impact of high mechanical loads on chondrocytes has been known for a long time, the mechanism for how mechanical stress is sensed at a cellular level has not been well understood. Not only has a recent study elucidated this mechanism, the authors also may have identified a potential therapeutic target.

How can tarantula venom prevent cartilage damage?

In the recent study published in PNAS, the authors confirmed the expression of mechanosensory ion channels PIEZO1 and PIEZO 2 – calcium-permeable channels that have been known to be present in other sensory cells – in chondrocytes. After deforming the cells using a customized atomic force microscope (AFM), the authors noted an increase in Ca2+ influx, suggesting that these channels are partly involved in mechanotransduction. More surprisingly, low concentrations of a peptide derived from tarantula venom, GsMTx4, turned out to be chondroprotective. Specifically, the peptide blocks the PIEZO receptors, inhibiting deleterious spikes in Ca2+.

Lee et al. Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensory to articular cartilage. PNAS. 2014; 111(47): E5114-E5122. DOI:10.1073/pnas.1414298111

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New crystallography data identifies how parasites absorb hemoglobin for survival

January 16, 2015

parasite survival, sleeping sickness Many infectious diseases are difficult to both prevent and treat, and this is usually due an inadequate understanding of how parasites infect and remain viable in their host. This lack of knowledge has been a bottleneck for developing new, effective treatments for diseases that affect millions worldwide; however, new crystallography data of how parasites obtain nutrients from hosts may provide important information for developing novel drugs.

What makes these parasites so deadly?

A group from Aarhus University, led by Dr. Christian Andersen, has modeled how the Sleeping Sickness parasite Trypanosma brucei, which is transferred through the TseTse fly, acquires essential nutrients for survival. While it was previously understood that the parasite lives in the bloodstream and absorbs hemoglobin to survive, how it did this was unknown. The group was able to crystallize the interaction between the parasite haptoglobin-hemoglobin receptor (HpHbR) and host hemoglobin. By doing so they were able to identify the exact binding site of haptoglobin-hemoglobin with the parasitic receptor, highlighting a new target for developing more effective treatments.

Stokilde et al. Structural basis for trypanosomal haem acquisition and susceptibility to the host innate immune system. Nature Communications. 2014; 5(5487):1-8. doi:10.1038/ncomms6487

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The antimicrobial compound triclosan has been linked to liver cancer

January 9, 2015

triclosan, cancer, hepatocellular carcinoma The FDA has been scrutinizing the antimicrobial compound triclosan (TCS) for many years – and a recent study indicates that this has been for good reason. Researchers have shown that long-term exposure to TCS, the equivalent of 11 years in humans, can lead increased hepatocyte proliferation, increased oxidative stress, and ultimately tumor formation.

How does triclosan accelerate hepatocellular carcinoma development?

The mechanism behind tumorigenesis has been linked to impaired function of the nuclear receptor constitutive androstane receptor (CAR), a constitutively active receptor that senses the presence of xenobiotic substances and promotes their clearance. Researchers observed that CAR is indirectly activated in the presence of TCS, suggesting that TCS may be interfering with CAR's ability to promote toxin metabolism. As a result, TCS exposure led to increased hepatocyte proliferation, increased levels of superoxides and increased expression of fibrogenic proteins. Ultimately this had severe implications on liver tumorigenesis: more than 80% of mice developed tumors.

The commonly used antimicrobial additive triclosan is a liver tumor promoter. PNAS. (2014) Yueh M-F et al. DOI: 10.1073/pnas.1419119111

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How sunshine fights diabetes and obesity ••• without vitamin D

Dec 12, 2014

vitamin D treatment The health benefits of sunlight have long been correlated with increased vitamin D production. In fact, it has been suggested that metabolic ailments such as diabetes and obesity, which are characterized by decreased vitamin D levels could benefit vitamin D treatments via supplements or increased sun exposure. However, in several failed clinical studies, the administration of vitamin D could not reverse the effects of metabolic disease.

But now one group reports that exposure to UV light can suppress weight gain and insulin resistance in a new pathway unrelated to vitamin D production. The researchers found that the UV light induced the production of nitric oxide, a mediator of a number of metabolic pathways. The finding was further supported by the application of a nitric oxide cream to the mice, which also showed similar effects as shining the UV light.

Ultraviolet Radiation Suppresses Obesity and Symptoms of Metabolic Syndrome Independently of Vitamin D in Mice Fed a High-Fat Diet. Diabetes (2014) Geldenhuys S. et al. 63: 3759-3769.

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Study shows single kiss transfers 80 million microbes

Dec 5, 2014

oral microbiome In a recent study, researchers determined that individuals who frequently kiss share the content of their oral microbiomes. In fact, in just a single 10 second kiss over 80 million microbes are transferred from the one person to the next. The number of microbes transferred was determined by feeding a group of participants yogurt containing probiotic bacteria and having them kiss another group that did not eat the yogurt. The composition of microbes contained in the yogurt (namely Lactobacillus and Bifidobacteria) rose from a baseline 0.01% to 0.54% in the mouths or kiss recipients.

The study was published in the same month a another study of the gut microbiome that showed that microbes of the gut may help fight stomach viruses via flagella proteins that trigger the immune system.

Shaping the oral microbiota through intimate kissing. Microbiome (2014) Kort R. et al. doi/10.1074/jbc.M114.599878.

Prevention and cure of rotavirus infection via TLR5/NLRC4–mediated production of IL-22 and IL-18. Science (2014) Zhang B et al. 346: 861-86.

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New antimicrobial peptides cultivated from the horse dung

Nov 28, 2014

antimicrobial peptide, copsin The design of new antimicrobial drugs may call for inspiration from unusual sources. In a recent study, scientists isolated a new antimicrobial peptide, named copsin, from the mushroom, Coprinopsis cinerea, which makes its home in piles of horse dung and other herbivores. Researcher believe the unique structure of copsin may become a scaffold for the design of new types of antimicrobial drugs.

What are the unique characteristics of its structure?

The structure of copsin is stabilized by 6 disulfide bonds, an N-terminal pyroglumate and a C-terminal cysteine. The new antimicrobial peptide was able to retain activity at a temperature of 90°C and exhibited resistance to multiple proteases. Additionally, copsin was able to effectively kill a number of gram positive bacteria such as Enterococcus and L. monocytogenes by preventing the cell wall construction.

Copsin, a novel peptide-based fungal antibiotic interfering with the peptidoglycan synthesis. J Biol. Chem. (2014) Essig A. et al. doi/10.1074/jbc.M114.599878.

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New, interactive Human Protein Atlas Database launched

Nov 21, 2014

human proteome map, human protein atlas, proteomics On the heels of the Human Proteome Draft Map, which was published earlier this year, a new database detailing the diversity of the human proteome has been made available. The new Human Protein Atlas, is an interactive database containing 13 million maps of human proteins - dividing the proteins of the proteome into categories such as the druggable proteome, cancer proteome, and housekeeping proteome

Which organ houses the most diverse set of proteins?

In addition, the database features a section called the Organ Proteome which details the location and relative expression profiles of proteins in various organs such as the brain, heart, lung and kidney. Surprisingly the testes were found to house the largest number of diverse proteins - 999 to be exact. The database is poised to help researchers identify new drug targets based on new information about the dominance and location of proteins.

The Human Protein Atlas.

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Circadian clock of intestinal microbes influence metabolic disease

Nov 13, 2014

circadian clock, intestinal microbes, diurnal rhythm Circadian clocks synchronize the activities of both humans and microbes according to the time of day. Disruption of these clocks has been linked to diseases such as obesity, diabetes, and cancer. Normally these clocks receive cues from external signals of light and darkness. But what about the clocks of microbes living deep in your gut that are never exposed to light

How are the diurnal rhythms of intestinal microbiota controlled?

Now one group has determined how the circadian clocks of gut microbes are controlled, discovering that the feeding time of the host dictates intestinal microbe homeostasis. Moreover, de-synchronization of the circadian clocks of gut microbes to that of their human host could be pivotal to health and well-being.

In particular, the researchers discovered that the disruption of human circadian clocks via jet lag led to a disruption of microbial circadian clocks in their gut. The disruption altered the composition of the microbial community, resulting in the prominence of microbes associated obesity and metabolic disease.

Transkingdom Control of Microbiota Diurnal Oscillations Promotes Metabolic Homeostasis. Cell (2014) Thaiss CA. et al. 159: 514-529.

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700-year old viral genome reconstituted from ice

Nov 6, 2014

viral genome, viral DNA, reverse genetics As polar ice caps melt, ancient artifacts preserved for centuries will be uncovered. In a recent study, one group discovered a complete DNA viral sequence preserved for 700-years in frozen caribou fecal samples found in Northern Canada. The group used reverse genetic techniques to sequence, reconstitute, and study the virus, which was found to be able to replicate in the plant, Nicotiana benthamiana. The study suggested that although preservation of a complete intact virus is unlikely, viral DNA and viral particles could be preserved intact in artic permafrost and released into the environment as climate changes promote melting. However, whether or not these particles can retain their infectivity is unknown.

Preservation of viral genomes in 700-y-old caribou feces from a subarctic ice patch. PNAS (2014) Ng TFF. doi: 10.1073/pnas.1410429111

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First functional brain-like 3D model engineered

October 31, 2014

tissue engineered brain, 3D brain tissue The complexity and mystique of the brain and its functions have led it to be considered the final frontier by many. In a recent study, researchers built an modular, in vitro 3D brain tissue model using a silk protein scaffold, primary cortical neurons, and extracellular matrix components. The brain model was capable of simulating biochemical and electrophysiological responses of the cortical tissue, with results comparable to those observed in in vivo models . Responses included neurotransmitter release, cell damage, and electrophysical activity from stimuli such as mechanical damage or drugs.

Why build an in vitro brain model?

The 3D brain model overcomes a number of limitations of in vivo models. For instance, the model was viable for months in vitro, which is a significant improvement over traditional brain tissue models. In addition, the model allows for real-time studies of neuron functions in response to stiumuli –studies that can't be performed using mammalian models. The model also could be further develeoped to be potentially used in structure-function studies of the brain as well as to study neurological disease.

Bioengineered functional brain-like cortical tissue. PNAS (2014) Tang-Schomer MD. 111: 13811–13816.

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Universal Ebola peptide mimetics poised to aid viral drug discovery

October 24, 2014

ebola drug, GP2 protein, peptide mimetic In a recent study, researchers developed new tools for designing viral entry inhibitors against the Ebola virus. They designed peptide mimetics representing a region of Ebola's GP2 fusion protein intermediate, which facilitates entry of the virus into its host. The peptide mimetics can be used in high-throughput screening studies to identify inhibitors of GP2 that will prevent viral entry and proliferation. In addition, the mimetic design may be applicable in the design of other mimetics for viruses such as HIV.

Why are the mimetics considered universal?

The peptide mimetics stand out because their sequences are derived from a highly conserved region of the GP2 protein, which is 90% identical across all species of the Ebola virus. Because of their high conservation, these sequences could be used to design drugs that can inhibit all Ebola virus species, as well as inhibit potential mutated versions of the virus in the future.

Design and characterization of ebolavirus GP prehairpin intermediate mimics as drug targets. Protein Science (2014) Clinton TR. DOI: 10.1002/pro.2578.

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Fat-targeting peptide delivers new anti-obesity RNAi-based therapeutic

October 17, 2014

RNAi, fat cell, anti-obesity In a recent study, researchers utilize a peptide sequence that specifically targets adipose cells, ATS–9R, to deliver an RNAi-based anti-obesity therapeutic. The peptide specifically binds to a protein found in fat cell membranes called, prohibitin which is capable of entering the cell nucleus. Prohibitin is enriched in fat cells during the course of obesity. When injected into mice the peptide-vector conjugate decreased body fat by 20% and improved glucose tolerance as well as insulin sensitivity.

Oligopeptide complex for targeted non-viral gene delivery to adipocytes. Nature Materials (2014) Won Y-W. doi:10.1038/nmat4092.

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New kind of cysteine stabilizes peptide drugs

October 10, 2014

drug stability, dithiol amino acid, unnatural amino acid In a recent study published in Nature Chemistry, researchers designed a new kind of cysteine, called a dithiol amino acid, which makes it possible to create new tertiary structures in peptide drugs. The dithiol amino acid contains 2 R-group sulfhydryls a opposed to cysteine's one, allowing it participate in two disulfide bonds at a given time.

When natural cysteines in a known protease inhibitor were replaced by the newly designed cysteines, peptide stability increased and inhibitory activity increased by 40-fold. The properties of the new cysteine make it attractive for enhancing the potency of peptide and protein drugs designed rationally or via directed evolution.

Di-thiol amino acids can structurally shape and enhance the ligand-binding properties of polypeptides. Nature Chemistry. (2014) Chen S et al.DOI: 10.1038/nchem.2043

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Understanding S. aureus infection: 3 new proteins shed light on immune evasion

October 3, 2014

aureus virulence, immune evasion In a recent study, researchers discovered 3 new proteins secreted by Staphylococcus aureus that help the bacteria survive and proliferate in its host. The inhibitor proteins (Eap, EapH1, and EapH2), are secreted during bacterial infection and specifically bind to the neutrophil serine proteases neutrophil elastase (NE), proteinase 3, and cathepsin G.

While the proteins shed light on S. aureus virulence, they may also be used as a guide to develop neutrophil protease inhibitor drugs for the treatment of inflammation diseases caused by over-active proteases, since the proteins inhibit all 3 neutrophil serine proteases. Cystic fibrosis, chronic obstructive pulmonary disease, emphysema, and rheumatoid arthritis are all diseases for which drugs based on this new class of neutrophil protease inhibitors may someday be able to treat.

Staphylococcus aureus secretes a unique class of neutrophil serine protease inhibitors. PNAS (2014) Stapels D. A. C. et al. 111: 13187–13192.

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Accelerated wound healing: secrets from the salamander

September 25, 2014

wound healing, fibrosis Amphibians like the salamander are capable of healing incredibly fast from wounds that would cause mortality in humans such as severe limb, lung, spinal cord and even brain damage.

In a recent study, one group identified a unique peptide from the salamander called tylotoin that plays a key role in the cellular and molecular pathways of salamander wound healing. Identified in salamander skin, the peptide aids in the release of transforming growth factor β1 (TGF-β1) and interleukin 6 (IL-6) to increase keratinocyte, vascular endothelial cell, and fibroblast proliferation. The result is accelerated reepithelialization and granulation tissue formation at the site of the wound. The peptide may be the key to the development of future wound healing treatments for humans.

A potential wound-healing-promoting peptide from salamander skin. The FASEB Journal (2014) Mu L. et al. 28: 3919-3929

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How isolates from worms can treat autoimmune disease

September 18, 2014

helminthic therapy, autoimmune disease treatment Helminthic therapy is an alternative treatment for autoimmune diseases such as multiple sclerosis, celiac disease and Crohn's Disease. The therapy utilizes parasitic worms to infect patients, resulting in the suppression of autoimmune disease symptoms. In a recent study, scientists identified and characterized bioactive peptides isolated the hookworm Ancylostoma ceylanicum and Brugia malayi, named AcK1 and BmK1. In the study, the peptides were able to block the voltage-gated potassium (Kv) 1.3 channel in human T cells, as well as suppress CCR7−by human Tlymphocytes. The peptides resemble a peptide derived from a sea anemone that is currently in clinical trials for the treatment of multiple sclerosis.

Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: implications for autoimmune diseases. The FASEB Journal, 2014; DOI: 10.1096/fj.14-251967

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Novel biomaterial prevents tissue graft rejection

September 12, 2014

tissue graft rejection, immunosuppressant Following tissue graft transplants of a hand, doctors must administer systemic immunosuppressant drugs to prevent a patient's immune system from attacking the graft. However, immunosuppressant treatments often lead to undesirable side-effects.

In a recent study published in Science Translational Medicine, researchers developed a novel, self-assembled hydrogel, that when loaded with the immunosuppressant, tacrolimus, was capable of localized, controlled drug release. In graft models, a single dose of the hydrogel thwarted graft rejection for over 100 day, which was in stark contrast to the 35 days observed when traditional tacrolimus treatments were administered.

A single localized dose of enzyme-responsive hydrogel improves long-term survival of a vascularized composite allograft. Science Translational Medicine. (2014) T Gajanayake 10.1126/scitranslmed.3008778

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New gene may lead to therapy for jet lag

September 5, 2014

circadian clocks, suprachiamastic nucleus In a recent study, researchers described the identification of a gene that might spur future jet lag therapeutics. The gene was identified during a study of circadian clocks in mice. In particular, researchers studied the regulation of genes composing the suprachiamastic nucleus (SCN), a bundle of neurons in the brain that serves as a "master clock", telling us when to sleep and wake.

What role does the gene play in jet lag?

The researchers identified the gene, Lhx1, which encodes for a neuropeptide peptide of the same name, and was the only gene suppressed when over 200 transcripts were analyzed from mice subjected to phase-shift pulses of light following a period of constant darkness. Lhx1 was found to play a role in the synchronization of neurons of the suprachiasmatic nucleus. When subjected to jet-lag-like conditions, mice having little or no Lhx1 recovered faster than mice with more Lhx1. The study suggests that the decrease in Lhx1 and subsequent decrease in synchronization of the suprachiasmatic nucleus helped the mice adjust to their new time-schedule faster.

Lhx1 maintains synchrony among circadian oscillator neurons of the SCN. elife (2014) Hatori et al. DOI: http://dx.doi.org/10.7554/eLife.03357

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FDA reports antibiotic resistance decreasing for select drugs

Aug 29, 2014

antibiotic resistance, antimicrobial susceptibility A recent publication on the state of antibiotic resistance provides a glimmer of hope for those trying to thwart the epidemic. The National Antimicrobial Resistance Monitoring System (NARMS), which summarizes data reported by the FDA, CDC, and USDA has released its annual report in which antimicrobial susceptibility is tested in isolates from humans, retail meats, and food producing animals. The report cites a number of common antibiotics for which resistance is on the decline including the combined resistance to ampicillin, chloramphenicol, streptomycin, sulfonamide and tetracycline (ACSSuT) for salmonella in human isolates.

NARMS 2011 Executive Report

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Is bubblewrap the new 96-well plate

Aug 21, 2014

T cell assay, immunoassay Think before you pop – bubble wrap that is! In a recent study, Harvard researchers demonstrated that bubble wrap is not only an excellent packing material, but in its natural state it can also be used as cuvettes for fluorescent or absorbance assays, sterile culturing containers for E. coli and C. elegans, and for creating electrochemical cells.

Here are the top 5 properties of bubblewrap that make it excellent for bioassays

  • Its globally available, making it great for point-of-care applications
  • The bubbles are transparent and can be used for absorbance or fluorescent assays
  • The bubbles are sterile on the inside and can be used for cell culture
  • Its gas permeable, but not too gas permeable (it's sufficient for culturing E. coli as well as storing reagents, only 7% fluid loss     in volume due to evaporation per week)
  • It's extremely cheap (∼$0.6/m2; 1 m2 contains approximately 1000−5000 bubbles)

Adaptive Use of Bubble Wrap for Storing Liquid Samples and Performing Analytical Assays. (2014) Bwambok et al. doi: 10.1073/pnas.1409432111. Anal. Chem., 2014, 86 (15), pp 7478–7485. DOI: 10.1021/ac501206m.

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How do chaperones fold D-proteins

Aug 14, 2014

protein folding, chaperone protein Proteins containing D-amino acids are inherently proteolytic resistant compared to natural L-proteins. Hence, proteins containing D-amino acids have great potential value in drug development. But are mirror image proteins folded differently than natural proteins? In a recent study, researchers set out to determine if D-proteins had different folding requirements from L-proteins, by attempting to fold the L- and D- forms of a chaperone-dependent protein, DapA, using the chaperone, GroEL/ES.

The results of the study revealed that GroEL/ES is “ambidextrous”. The chaperone was able to fold both L- and D-forms of the protein through hydrophobic interactions. To facilitate the process the researchers chemically synthesized the L- and D- proteins, producing the longest chemically synthesized proteins on record – 312 residues long.

Synthesis and folding of a mirror-image enzyme reveals ambidextrous chaperone activity. (2014) Weinstock MT et al. doi: 10.1073/pnas.1410900111

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Multiplex early –stage cancer detection by universal "Immunosignature" platform

Aug 8, 2014

biomarker detection, cancer detection Early-stage biomarker detection is often a prerequisite for the successful treatment of a number of diseases. Now one group has published a study establishing a universal diagnostic test for the simultaneous detection of multiple early stage diseases. The so called immunosignature platform was used to identify different cancers in over 300 patient blood samples with an average accuracy of >98% (after training with ˃1000 samples). The platform is based on the use of 10,000 randomized peptides in an array which was incubated with diluted blood samples. Antibodies in the blood bind to the peptides in an array, “writing” a unique immunosignature that can be read and correlated to a specific disease. Notably the approach uses random peptides as opposed to known disease biomarkers, which allows for detection of numerous diseases.

Immunosignature system for diagnosis of cancer PNAS. (2014) Stafford et al. doi: 10.1073/pnas.1409432111.

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Human proteome map revisited: How many proteins are there

July 31, 2014

human proteome, proteomics, protein coding genes In late May, the two groups published landmark studies in Nature which presented drafts of the first human proteome map using high-resolution Fourier-transform mass spectrometry. These seminal studies presented a breakthrough in proteomics; in particular proteins encoded by 17,294 of human genes (approximately 84% of the total annotated protein-coding genes in humans) were identified.

But, now one group suggests that the number of protein coding genes may be overestimated. In a new publication, in which the first proteome drafts are analyzed, a quality test was carried out on data pertaining to the olfactory receptor family. The group asserts that since neither of the previous studies used nasal tissues to collect data, they should not have found evidence of 100 olfactory receptors. Their message for proteome map enthusiasts: proceed with caution.

Analyzing the First Drafts of the Human Proteome. Journal of Proteome Research. (2014) Ezkurdia I et al. DOI: 10.1021/pr500572z

Mass-spectrometry-based draft of the human proteome. Nature (2014) Wilhelm M, et al. doi: 10.1038/nature13319.

A draft map of the human proteome. Nature (2014) Kim MS, et al. doi: 10.1038/nature13319.

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Glioma vaccine selectively targets point-mutated protein

July 25, 2014

peptide vaccine, glioma therapy In a recent study researchers designed a vaccine to treat brain tumors, which elicited an immune response specific to a single point mutation in the target protein. The peptide vaccine was derived from the mutant protein, isocitrate dehydrogenase type 1 (IDH1), a mark of gliomas (slow growing brain tumors) and other tumors. The key ongongenic mutation in IDH1 is a point mutation resulting in an R to H amino acid change in the catalytic pocket of the protein.

The mutated IDH1 vaccine epitope was capable of eliciting CD4+ and TH1 cells that recognized the oncogenic protein. And, in mouse models, the vaccine elicited an immune response that was capable of controlling glioma growth, while the wild type peptide did not induce an immunogenic response.

A vaccine targeting mutant IDH1 induces antitumour immunity. Nature (2014) Schumacher T. et al. doi:10.1038/nature13387.

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Diabetes treated by iphone device: "bionic artificial pancreas"

July 19, 2014

type 1 diabetes, diabetes therapy In a recent study researchers developed and performed human trials using a bionic pancreas consisting of reservoirs for glucagon and insulin, 2 pumps, and an iphone 4s. The iphone, was key to the “bionic pancreas”, functioning as a receiver, processor, and transmitter of signals to dictate the amount of glucagon or insulin to be pumped to the patient, every 5 minutes. The phone included an app in which the patient could input what they ate, which helped calculate dosages. Motivation for the device stemmed from one of the researcher’s desire to help his teenage son, who has type 1 diabetes.

The device was tested on 52 patients, including adults and adolescents for a 5-day period. The system reduced hypoglycemic incidents in the patients by half in comparison to traditional pump devices. One-third of patients with type 1 diabetes use pumps to achieve nondiabetic levels of blood sugar, but traditional pumping systems only provide insulin, and not the glucagon, which helps prevent hypoglycemia.

Outpatient Glycemic Control with a Bionic Pancreas in Type 1 Diabetes. The New England Journal of Medicine (2014) Russell SJ. et al. doi: 10.1056/NEJMoa1314474

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Simple modification yields more stable peptide drugs and increases efficacy

July 11, 2014

pharmakokinetics, peptide stability, drug delivery Peptide drugs can be advantageous over small molecule drugs due to increased target specificity. However, the stability of peptide drugs in the bloodstream often pales in comparison to the stability of small molecule drugs due to their susceptibility to be degraded by proteases.

Researchers recently developed a method for enhancing the stability of peptide drugs in a recent study published in Nature Biotechnology, by replacing native α-amino acids with β3-amino acids in a model GPCR agonist, parathyroid hormone (PTH). PTH is a bioactive component of teriparatide, an osteoporosis drug. The incorporation of β3-amino acids altered the peptide backbone, but not the side chains, allowing the synthetic version of the peptide to retain its structure and activity.

By making 5 α → β3 placements of the pattern ααααβ in PTH, researchers were able to create a synthetic peptide sequence that mimicked the alpha helix of the natural peptide sequence. The amino acid replacement resulted in a 3 order of magnitude increase in the concentration of the PTH analogue in the bloodstream, which led to increased calcium levels, in comparison to the native peptide sequence. The results signified the enhanced effectiveness of the peptide as a GPCR agonist, which was attributed to its protease resistant design. Researchers believe the design strategy will be transferrable to other peptide therapeutics.

Backbone modification of a polypeptide drug alters duration of action in vivo. Nature (2014) Cheloha RW. et al. doi:10.1038/nbt.2920

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New target for gram-negative antibiotic drug development

July 3, 2014

gram-negative bacteria, antibiotic, drug development Antibiotic drugs act by inhibiting bacterial cell wall synthesis and integrity, or by targeting proteins crucial for cell metabolism. For gram-negative bacteria, this is especially challenging due to the nearly impenetrable outer cell membrane, which is composed of lipopolysaccharides (LPS). In addition, drugs that manage to gain entry into these bacteria can be pumped out by active efflux.

However, researchers in 2 independent studies published in Nature, solved the crystal structure of a new target for antibacterial drugs, the LptD-LptE complex. The complex , composed of the LptD, LptE proteins (2 of 7 total proteins in the LPS transporter) is responsible for the insertion of LPS into the outer cell membrane, which is critical for gram-negative bacteria survival. Previously, drugs developed against the LptD protein have shown antibacterial activity. With this new publication of the LptD-LptE complex, new drugs can be developed that do not need to enter the cell to exhibit antibacterial activity, and will add to the arsenal of drugs to help combat antibacterial resistance.

Structural basis for lipopolysaccharide insertion in the bacterial outer membrane. Qiao S. Nature 2014 doi:10.1038/nature13484.

Structural basis for outer membrane lipopolysaccharide insertion Nature. Dong H. Nature 2014 doi:10.1038/nature13464.

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"Sweet gel" for stem cell growth and differentiation

June 27, 2014

stem cell culture, self-assembling peptide Stem cells live in and interact with a complex environment that influences both cell growth and differentiation. Nearly half of the molecules in this environment contain sugar in the form of glycoproteins and proteoglycans, making them attractive for the development of biomaterials for stem cell culture. However, complex glycan synthesis chemistries make the development of glycobiomaterials difficult.

But in a recent study, researchers circumvented the synthesis of complex glycans by developing a novel glycoconjugate capable of self-assembly into glycan clusters that mimic larger glycans. The hydrogel was composed of the nucleotide, adenine, glucosamine, and the RGD peptide motif.

When assembled the gel stimulated mouse embryonic stem cell growth by doubling the number of cells. In addition, 84% of mouse zygotes differentiated into blastocysts in media containing the gel, compared to 31% without the gel.

Supramolecular assemblies of a conjugate of nucleobase, amino acids, and saccharide act as agonists for proliferation of embryonic stem cells and development of zygotes. Du X et al. (2014) Bioconjug Chem.125(6):1031-5.

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Making and erasing memories with light neuronal stimulation

June 20, 2014

synaptic plasticity, neurodegeneration Ever want to erase a bad memory? A recent study published in Nature, one group showed that they could erase and then restore a memory by using pulses of light to selectively strengthen and weaken synapses.

To create a memory of fear the group genetically engineered nerves in rat brains, making them sensitive to light. When the rat neurons were stimulated by light along with a simultaneous electrical shock to the rat's foot, a memory was created such that later on, light stimulation caused the rats to freeze in fear in the absence of the shock.

Then to erase the memory scientists subjected the rat brains to a low frequency train of optical pulses, upon which the rats no longer reacted to light stimulation. But all was not lost, as subsequently the erased memory could be recovered again by high-frequency train of electrical pulses, upon which the rats froze in fear in the absence of electrical shock again.

The results of study could be used for the treatment of neurodegenerative diseases such as Alzheimer's Disease, in which beta amyloid accumulates on neurons, weakening synapases. The study shows that the weakening of synapses can be reversed, suggesting that the effects of beta amyloid in Alzheimer's Disease patients could potentially be reversed as well, counteracting the neurodegenerative effects of the disease.

Engineering a memory with LTD and LTP. Nature, (2014) Nabavi, S. et al. doi:10.1038/nature13294

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Accelerating wound healing: peptide-based gel heals burns faster than standard-of-care dressing

June 12, 2014

wound healing peptide In a recent study published in Biomaterials, researchers developed a class of "smart" peptide hydrogels, that address 3 key requirements of burn treatments: infection prevention, skin hydration and necrotic tissue debridement. The treatment also addresses the lack of commercialized options for accelerated healing of 2nd and 3rd degree burns. The hydrogel was comprised of peptides which were aliphatic in structure and were non-toxic and non-immunogenic. The gel promoted faster epithelial and dermal regeneration than the current silicone-based standard of care, by acting as a scaffold to support the growth of skin cells. After 14 days, up to 93% of the burn wounds healed in response to the peptide gel, compared to 63% of burn wounds treated with Mepitel®, a silicone based dressing.

Ultrashort Peptide Nanofibrous Hydrogels for the Acceleration of Healing of Burn Wounds, Biomaterials, (2014) Loo, Y. et al. 35: 4805-4814.

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Dual-mimetic partially derived from scorpion toxin neutralizes HIV

June 6, 2014

antiviral peptide, HIV entry, viral entry In a recent study, researchers showcased the power of dual-action peptides in their development of an HIV inhibitor that effectively blocked HIV entry, neutralizing the virus. The inhibitor peptide was designed as a combination of a scorpion toxin-derived CD4 receptor mimetic, and a sulfopeptide mimetic of the amino-terminus of the co-receptor, CCR5. In recent years, peptides derived from scorpion venoms have emerged as potential HIV therapeutics having been shown to inhibit the chemokine receptors, CCR5 and CXCR4 and viral replication.

A double-mimetic peptide efficiently neutralizes HIV-1 by bridging the CD4- and coreceptor-binding sites of gp120 (2014) Journal of Virology Quinlan et al. 88: 3353-3358

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Contact lenses coated with antimicrobial peptides pass safety study

May 30, 2014

anionic peptide, antimicrobial, antibiotic peptide In a recent clinical trial study, contacts designed to prevent ocular inflammation and infection via microbial contamination were shown to be effective against microbial strains, as well as safe and comfortable to wear.

The contacts were coated with a cationic peptide, called melimine, through covalent attachment. Melimine is an antimicrobial peptide designed to incorporate the bioactive regions of protamine, a component of salmon sperm) and melittin (a component of bee venom). A day after they were worn by human volunteers the lenses were active against Pseudomonas and Staphylococcus bacteria. In addition, in both the human and animal component of the study no inflammation or toxic effects were observed from use of the contacts.

Biocompatibility of antimicrobial melimine lenses: rabbit and human studies (2014) Optometry and Vision Science Dutta D et al. 91:570-81

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Twins and TCRs: Study of identical twin T cell receptors shed light on diversity

May 18, 2014

T cell, adaptive immunity Influenced by environment and genetics, the mechanism of T cell receptor (TCR) repertoire generation and the role of parameters influencing the process are poorly understood. In a recent study published in PNAS, researchers studied how genetic factors impact TCR diversity by analyzing the TCR repertoires of 3 pairs of identical twins.

TCRs are composed of an α-chain and a β-chain. The gene encoding the β-chain contains 4 segments: variable (V), diversity (D), joining (J) and constant (C). The diversity of T cells is determined by gene rearrangement called, V(D)J recombination.

Although the researchers found that the overlap between the TCR repertoires of twins was similar to the overlap between non-related individual TCR repertoires, the researchers identified key processes in TCR repertoire generation for which genetics played key roles. In addition, they found that while J genes are selected randomly for recombination, selection in the thymus is preferential for αJ segments.

Zvyagin IV et al. Distinctive properties of identical twins' TCR repertoires revealed by high-throughput sequencing. (2014) PNAS. 111: 5980-5

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Somatic-cell nuclear transfer used to produce human embryonic stem cells from patient-specific stem cells for the first time

May 9, 2014

somatic-cell nuclear transfer, embryonic stem cells, induced pluripotent stem cells In two independent studies published in Cell Stem Cell and Nature, scientists report the derivation of diploid, pluriopontent human embryonic stem cell lines from human adult stem cells using somatic-cell nuclear transfer (SCNT) for the first time. In the Nature study, adult stem cell DNA from a type 1 diabetic, 32 year old woman was used to clone embryonic stem cells that were differentiated into insulin-producing cells. In the Cell stem Cell study the adult donors were 35 and 75 years of age.

The successful use of SCNT to clone the embryonic stem cells may have some advantages over induced pluripotent stem cells (iPSCs), which are produced by reprogramming adult stem cells to an embryonic state by adding genes. According to Nature News, embryonic stems cells cloned via SCNT may be less variable than iPSCs, and may be more likely to gain regulatory approval. In addition, the use of patient-specific adult stem cells to produce embryonic stem cells may lower the risk of transplant rejection.

Chung et al. Human Somatic Cell Nuclear Transfer Using Adult Cells Chung et al. (2014) Cell Stem Cell.http://dx.doi.org/10.1016/j.bbr.2011.03.031

Human oocytes reprogram adult somatic nuclei of a type 1 diabetic to diploid pluripotent stem cells Yamada et al. (2014) Nature. doi:10.1038/nature13287

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Charging a smartphone in 30 seconds… with peptides

May 2, 2014

nanomaterials; biomaterials, lithium battery According to recent reports, peptides could help usher in a new era in smartphone battery technology. A start-up company called StoreDot Ltd. demonstrated a new technology capable of fully charging a smartphone in 30 seconds. The company claims that the secret behind their battery design is the use of self-assembling peptides that assemble into nanocrystals (termed NanoDots), which form a super capacitor combined with layers of lithium. The design for the battery was based on the research of self-assembled biological nano-structures associated with Alzheimer's Disease. According to a recent press release, StoreDot aims to make peptide-based NanoDot technology available for use in 2015. So, are peptides the cure for short smartphone battery life? You decide.

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Wq Light-activated antimicrobials

April 25, 2014

light-activated peptide, antimicrobial As the race to develop new antimicrobial drugs to combat antibacterial resistance continues, researchers have developed a new light-controlled antibacterial drug and a surface in separate studies. The ability to turn the activity of antibacterial drugs on and off with light offers a number of potential advantages including local confinement of active drugs and reduction of active antimicrobial environmental build up. In one study, a peptidomimetic, whose backbone conformation could be altered by light, was designed based on the sequence for the antimicrobial peptide gramicidin S. In the second study, crystal violet, methylene blue, and gold nanoparticles were incorporated into medical grade silicone to create a light-activated antimicrobial surface that was active against E. coli and S. epidermis.


1Light-activated antimicrobial peptides kill on site

Scientists have developed an antimicrobial peptide that is only activated when exposed to UV light, allowing for localized treatment of bacterial infections.

2First-ever light activated antimicrobial surface?

A new bactericidal surface that incorporates common lab dyes and gold nanoparticles is an effective treatment against E. coli and S. epidermis when switched on by light.

1Controlling Biological Activity with Light: Diarylethene-Containing Cyclic Peptidomimetics (2014) Babii et al. 126: 3460–3463

2Light-activated antimicrobial surfaces with enhanced efficacy induced by a dark-activated mechanism (2014) Noimark S et al. DOI: 10.1039/C3SC53186D

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Peptide-based nasal spray developed for treatment of depression

April 18, 2014

antidepressant drug In a study published in Neuropsychopharmacology, researchers describe a novel treatment for Major Depressive Disorder, in the form of a peptide-based nasal spray. The treatment uses a pressurized olfactory device to deliver a peptide to the brain, effectively circumventing complications in getting the drug across the blood-brain barrier. The active peptide at the center of the treatment is an interfering peptide which disrupts D1-D2 dopamine receptor interactions. The development of the peptide drug and description of its target pathway was published in a 2010 Nature Medicine publication. The recently published intranasal spray delivery system was developed by Impel NeuroPharma.

Intranasal delivery of a peptide with antidepressant-like effect. Brown V, Liu F, Neuropsychopharmacology (2014) DOI: 10.1038/npp.2014.61.

Uncoupling the dopamine D1-D2 receptor complex exerts antidepressant-like effects. Lin Pei, Nature Medicine (2010) 16: 1393–1395.

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[Peptide power]2: p53-postive cancer treated by dual action stapled peptides

April 11, 2014

cancer therapy, cancer drug; p53 therapy A new treatment for p53-positive cancers has been developed in the form of stapled peptides. The stapled peptide, which was chemically synthesized as an alpha helix stabilized by the incorporation of a strategically placed hydrocarbon bond between two amino acids, was capable of inhibiting two inhibitors of p53, MDMX and MDM2. The administration of the stapled peptide led to the re-activation of p53 and inhibition of tumor growth in animal models. Read more about stapled peptides »

Stapled α−helical peptide drug development: A potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Chang YS et al. (2014) PNAS doi: 10.1073/pnas.1303002110

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Novel peptide enhances memory

April 4, 2014

alzheimer's disease, neuroscience receptor In a study published in Neuron, researchers not only characterize elements of a neuronal signal transduction pathway that plays a fundamental role in learning and memory, they also test the application of their findings by designing novel peptides whose action on the pathway results in memory and learning enhancement in aged mice.

Read the Publication See Video Abstract

The pathway involves the NDMA receptor complex, in particular, a subunit of that complex called NR2B. NR2B is involved in synaptic remodeling which results in memory formation. Researchers at the University of Texas Southwestern Medical Center hypothesized that interactions of NR2B with a cyclin dependent kinase, CDK5 controlled the release of NR2B to the surface of synapses, which results in memory formation. Read More »

Memory enhancement by targeting Cdk5 regulation of NR2B.Plattner et al. (2014) Neuron 81: 1070–1083.

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New "viral" video shows how a virus enters the cell

March 21, 2014

viral entry, viral infection In a study, published in Nature Nanotechnology, a 3D visualization movie was produced logging the approach and precise moment of entry of HIV-TAT coated nanoparticles to a cell surface. Researchers from Princeton University designed polystyrene and semi-conductor nanoparticles coated with HIV-TAT peptides to simulate HIV-1 viral particles, and employed a multi-resolution method to visualize the nanoparticle as it traversed the cell surface.

See the Movie Read the Publication

The study of how viruses or nanoparticles designed to deliver therapeutics behave requires knowledge of how a particle approaches and attaches to a cell membrane, enters the cell, and is subsequently trafficked within the cell. The video and study, sheds light on the interactions in the early stages of nanoparticle cellular uptake.

Multi-resolution 3D visualization of the early stages of cellular uptake of peptide-coated nanoparticles. K. Welsher and H. Yang (2014) Nature Nanotechnology doi:10.1038/nnano.2014.12.

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Could cancer detection be as easy as taking something similar to a pregnancy test

March 14, 2014

cancer diagnosis, cancer biomarker Researchers from Stanford University think so. In a recent PNAS publication, they described their development of a point-of-care diagnostic test capable of detecting colorectal cancer and thrombosis, a hallmark of cardiovascular disease. Utilizing peptide nanoparticle biomarkers, the test was developed to combat the rise in mortality from noncommunicable diseases, as well as address the unique challenges of developing countries, in which resources and revenue are limited. When administered to mice models, the assay was capable of detecting colorectal cancer and thrombosis biomarkers from unpurified urine. How did they develop it and how much did it cost? Read More »

Point-of-care diagnostics for noncommunicable diseases using synthetic urinary biomarkers and paper microfluidics. Warren, AD et al. (2014) PNAS doi: 10.1073/pnas.1314651111.


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