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The mechanics behind aging have been scrutinized over the last several year. Aging is a universal contributing factor to disease in both rodents and humans. One avenue of investigation is the manner at which diet has an impact on aging and whether or not certain diets can slow this process. For example, calorie restriction has been shown in multiple studies to slow the process of aging down. Another popular diet that has gained traction in recent years is the ketogenic diet. The idea behind a ketogenic diet is that when the body is starved of carbohydrates, it turns from using glucose to using fat as a main fuel source, resulting in the production of ketones as a main source of energy. The scientists in this study have found that this type of diet results in both an increase in longevity and physical strength.
Researchers involved in the study found that a ketogenic diet resulted in an increase in life span, memory function increases, and motor skill improvements in mice. Further proof of this increase was the lack of increase seen in markers of inflammation that normally increased due to aging.
Some of the specific targets and resulting positive effects include a positive impact on mTORC1 signaling pathway and acetylated p53.
This study shows that a diet with ketogenic qualities while maintaining healthy calorie counts can have major, positive impacts on quality of life when compared with just calorie restriction alone.
Roberts et al. A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice. Cell Metabolism, 2017; 26 (3):539. DOI: http://dx.doi.org/10.1016/j.cmet.2017.08.005
Preterm delivery, the birth of a baby at fewer than 37 weeks, is one of the leading causes of death and disease among children today. In an unprecedented study involving over 50,000 women of mainly European ancestry, scientists have identified a group of genes that regulate both gestational length and the chances of preterm delivery. Utilizing information from 23andMe, researchers were able to gather a large enough sample size to conduct an in-depth analysis of this nature.
According to researchers, there are 4 genes that were found to be linked to gestation length specifically. EBF1, EEFSEC, AGTR2, and WNT4 were all linked to gestational length based on the data from 23andMe. EBF1, EEFSEC, and AGTR2 were also found linked to preterm birth likelihood. Variants of two other genes, ADCY5 and RAP2C, were also found to be linked to gestation length.
These genes have previously been known to be involved in womb development and fetal nutrient supply, so their involvement in gestational length and preterm delivery is not a surprise. The identity of these genes could lead to further scientific breakthroughs, resulting in improved survival rates among children and a better understanding of gestational length.
Zhang et al. Genetic Associations with Gestational Duration and Spontaneous Preterm Birth. New England Journal of Medicines 2017; 377:1156-1167. DOI: http://dx.doi.org/10.1056/NEJMoa1612665
Human papillomavirus, known more commonly as HPV, is responsible for cervical cancer and a subset of other cancers in the head and neck areas. The interesting thing about this connection is the lack of a mechanism. For several cancers, such as skin and lung, we can link the source of their mutations to the cancers themselves. For skin, UV radiation would be the culprit and for lung, smoking would be the main cause for mutations. Scientists have now identified a novel mechanism that links infection by HPV with the aforementioned cervical, head, and neck cancers, and it involves a family of enzymes in our immune system that we believed to be beneficial to our survival: APOBEC3
APOBEC3A is the body's answer to the HPV virus, intended to target and scramble virus DNA to prevent infection by HPV. However, HPV has evolved so that now it has reduced the number of APOBEC3A target sequences in its genome. Researchers, by investigating the mutation signatures in the DNA of cancer cells, have found that many of the signatures match that of APOBEC3A, indicating that the enzyme has the unintended function of targeting human DNA and causing head and neck cancers.
Now that scientists can recognize cells mutated by APOBEC3, they can target these specific cells with immunotherapies to combat this new mutation source.
Warren et al. Roles of APOBEC3A and APOBEC3B in Human Papillomavirus Infection and Disease Progression Viruses 2017; 9(8): 233. 537-542. DOI: http://dx.doi.org/10.3390/v9080233
Both regulatory and convention T cells are vulnerable to exhaustion, which could compromise the overall effective function of the body's immune system. Regulatory T cells, the lymphocytes that maintain a state of equilibrium in the immune system, help to prevent disorders such as asthma, allergies, and autoimmune disorders. However, loss of liver kinase B1 resulted in regulatory T cells showing functional and molecular changes that are in accordance with functional exhaustion. This included a disruption in T cell survival and mitochondrial fitness/metabolism. It also resulted in aberrant expression of immune regulatory molecules, causing a disruption in the overall equilibrium of the immune system.
Scientists found that regulatory T cells use LKB1 signaling to their advantage to coordinate metabolic and immunological equilibriums, preventing functional exhaustion by regulating resting and active states of the regulatory T cells. In this way, LKB1 plays a key role in the balance between immunity and tolerance.
Any disruption in this balance can result a number of symptoms, ranging from minor effects such as allergies to more extreme and dire consequences, such as autoimmune disorders.
Yang et al. Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signaling Nature 2017; 548: 537-542. DOI: http://dx.doi.org/10.1038/nature23665
Scientists have discovered that a certain set of genes are crucial to whether or not immunotherapy for cancer treatment is successful. This shines a light on and offers an explanation as to why certain tumors don’t respond to immunotherapy as well as others. Understanding why certain patients respond very well to immunotherapy and why others don’t respond at all will help target treatment for the patients with more difficult cases of cancer.
Cancer immunotherapy depends heavily on the successful operation of T cells in the immune system. Using CRISPR as a tool to knockout every protein-encoding gene and then testing the resulting ability of these gene-modified melanoma cells to respond to immunotherapy, researchers were able to discover over 100 genes that could play a role in this cancer-fighting T cell function.
One gene in particular found is APLNR, the product of which encodes a protein known as the apelin receptor. This receptor has already been implicated in the developmental process of a variety of cancers, but this was the first indication of their role in t cell function.
This “master list” of genes could end up being an action plan for the study of tumor resistance to immunotherapy, specifically that reliant on T cell function.
Patel et al. Identification of essential genes for cancer
immunotherapy. Nature 2017; 548: 537-542.
The mammalian brain has the amazing skill of being able to adapt and learn at a rapid rate. However, like with the rest of the body's organs and systems, this ability deteriorates with age, resulting in decreases in the ability to learn and adapt. This ability is further hampered by brain injuries such as stroke or traumatic physical brain injuries. The way the brain changes and deteriorates over the course of a lifetime has been crucial in affecting how much humans can learn in certain stages of their lives. This gives a plausible explanation as to why certain ailments can be cured early in one's lifecycle but not later in life. This begs the question: can this plasticity be restored? Scientists now say yes.
Earlier research conducted by scientists linked a specific gene, known as Arc, to the ability of younger mice to have brain plasticity. Mice lacking this gene never have the ability to adapt to changing visual experiences, specifically in the visual cortex. Based of this information, scientists hypothesized that the expression of the Arc gene could be linked to determining the time period in which the brain experiences plasticity.
This new study finds that Arc rises and falls in conjunction with the mouse's visual plasticity. Both peak and drop suddenly during the middle years of a mouse's life cycle. Furthermore, when Arc was delivered via viruses to middle-aged mice, visual plasticity was equal that of younger mice.
Whether Arc is involved in other brain structures remains to be seen, but will be examined in future experiments.
Jenks et al. Arc restores juvenile plasticity in adult mouse visual
cortex. PNAS, 2017; 114 (34): 9182-9187.
Colon cancer is one of the most common cancers in the United States, affecting nearly 1.7 million individuals in 2016. There are many ways in which colon cancer can manifest in humans, one of which is through the formation of pre-cancerous polyps. This condition is more commonly known as familial adenomatous polyposis, a disease that results in the formation of polyps in the intestine at an early age, often developing into full-blown cancer later on. The research team decided to target the formation of the polyps by focusing on one gene in particular: CtBP.
Scientists were able to target CtBP with the HIPP drug (2-hydroxyl-imino phenylpyruvic acid) in mice. In targeting the drug, they were able to reduce polyp development by half and give a normal lifespan to mice born with a version of familial adenomatous polyposis. The mechanism behind how CtBP is an interesting one, as it is not mutated in colon cancer. It is, however, overexpressed in way that causes cancer to depend on its expression for growth and progression of disease. CtBP then represses cancer-preventing genes, allowing the disease to flourish unchecked through the regular apoptosis pathways.
Scientists hope that anti-CtBP gene therapies could eventually be used two-fold: to both control and cure colon cancer.
Sumner et al. Transforming activity and therapeutic targeting of
C-terminal-binding protein 2 in Apc-mutated neoplasia. Oncogene 2017:
Scientists have long be researching the idea of retinal regeneration. Many tissues of the human body can heal due to the nature of stem cells in these regions. These stems cells are able to differentiate into the corresponding type of cell that is needed to repair the damaged area. However, the limiting potential in retinal cells is the lack of these stem cells for differentiation and regeneration of vision-related cells. As a result, vision loss or damage is often permanent. However, scientists have now succeeded in regenerating retinal cells that work in adult mice. Their secret? Zebrafish.
Scientists were able to recreate a version of the gene responsible for retinal regeneration in zebrafish, Ascl1, and created a mouse with this gene. The gene was then subsequently turned on through the use of tamoxifen, a common treatment for breast cancer. However, this was not a new discovery. Earlier studies by the team had found that when the gene was activated, the Muller glia in the eye would differentiate into retinal cells and become active, working cells in contributing to eyesight. However, this activation only worked in the early stages of mice development, more specifically in the first two weeks of development. Scientists in this study were able to find that the reason activation of the gene did not work after two weeks was due to histone deacetylase inhibition. By using an additional drug that blocks this inhibition, the tamoxifen was once again able to activate Ascl1 and allow for retinal regeneration.
The team eventually hopes to be able to develop all different types of eye cells and also if this ability can be transferred to humans.
Chuang et al. Stimulation of functional neuronal regeneration from
Muller glia in adult mice. Nature 2017: 548:
Research involving the exploration of the cell cycle and, more specifically, cell growth has been studied for more than a century. Scientists first noticed a constant ratio of nucleus growth with respect to cell size over a century ago. This method in which cells maintain this constant ratio between nucleus size and overall cell size has not been well understood, until now. Scientists now find that the act of hoarding genetic materials in the nucleus allows it to increase in size and the control of this increase in genetic material is what allows the nucleus to maintain a ratio in conjunction with overall cell size.
Using the genome of fission yeast to search for cells related to nuclear size control, scientists were able to eliminate 2000 of the 5000 gene found in fission yeast that were already known to be essential for cell growth. The remaining 3000 genes were individually isolated and mutated and the phenotypes of the resulting mutant cell were analyzed under the microscope.
Scientists were able to uncover 14 genes who, when mutated, lead their respective cells to display an abnormal cell to nucleus ratio. Analysis into the genes showed that they were required for mRNA transport from within the nucleus to the outside of the cell’s cytoplasm. Furthermore, this nuclear swelling is dependent on lipid production. Scientists believe that this could be a precursor, causing cancer in the end.
Chuang et al. A systematic genomic screen implicates nucleocytoplasmic
transport and membrane growth in nuclear size control. PLOS Genetics,
2017; 13 (5):
Often times, the treatment for depression is uniform between men and women. Various treatments, ranging anywhere from therapy to antidepressants, are often prescribed to combat the symptoms associated with depression. Changes in sleep patterns, appetite levels, ability to focus, or self-esteem can signal depression. Extensive research has been done to study the varying risks of each sex in inheriting depression. However, what hasn’t been studied is the differences in how depression manifests in men and women.
Researchers recruited and studied adolescent volunteers and imaged their brains while exposing them to words that could be categorized as either happy, sad, or neutral. Researchers found that, through analysis of the MRI brain scans, that depression seemed to affect brain activity differently between the tested boys and girls. Specifically activity in the supramarginal gyrus and posterior cingulate were differentially activated between boys and girls experiencing depression.
These findings suggest that sex-specific treatment should be explored for men and women, due to the differences seen in brain activity.
Chuang et al. Adolescent Major Depressive Disorder: Neuroimaging
Evidence of Sex Difference during an affective Go/No-Go Task. Frontiers in
Most biology classes have taught us that each system within the body is responsible for a particular set of tasks. More specifically, the circulatory system is solely responsible for the pumping of blood throughout the body, while the digestive system is responsible for food maintenance. However, researchers have discovered a unique physiological method in sea spiders that involves the digestive system acting as the main component responsible for blood circulation. By injecting dye into sea spiders as a method to track the flow of blood, scientists were able to notice this unique function for the spiders' digestive systems.
First off, the dye injection allowed researchers to see that the hearts located within the sea spiders were beating weakly. However, they were able to see that the blood flow of the spiders was moving at the same rhythm as the waves of contraction associated with the digestive tract. In this sense, the contractions from the digestive tract were not only moving food throughout the body of the spider, but blood as well. Scientists are unclear as to how this behavior evolved, but the main theory is that the pairing of these two systems allows the spider to conserve valuable energy.
Gunter et al. Respiratory gut peristalsis by sea spiders.
Current Biololgy, 2017; 27 (13): R638.
Through a collaborative study between the Keck School of Medicine in California with the University of Hawaii Cancer Center, it was found that drinking coffee was associated with lower risk of death for a variety of ethnic groups. Some of the specific risks reduced for coffee drinkers include heart disease-related ailments, cancer, stroke, diabetes, and respiratory/kidney-related diseases. The study was focused on whites, Latinos, Japanese-Americans, and African-Americans. Some specific numbers include a 12 percent reduction in mortality for a cup of coffee a day drinkers and a 18 percent reduction for two to three cups a day drinkers. Previous studies have found an association between coffee consumption and reduced risk of several variations of cancer and liver disease. However, this study is the largest of its kind and includes a variety of different ethnicities.
The reduction in mortality was found with both caffeinated and decaffeinated coffee types, leading scientists to believe that the associated benefits are found due to the other intrinsic properties of coffee (antioxidants and phenolic compounds). Since this study includes four different ethnicities, the researchers involved in the studies were comfortable extending the results to apply to other groups.
Gunter et al. Coffee drinking and Mortality in 10 European Countries: A Multinational Cohort Study. Annals of Internal Medicine, 2017. DOI: http://dx.doi.org/10.7326/M16-2945
Park et al. Association of Coffee Consumption With Total and Cause-Specific Mortality Among Nonwhite Populations. Annals of Internal Medicine, 2017. DOI: http://dx.doi.org/10.7326/M16-2472
Traditional genetics has taught us that the offspring from a male and female pairing usually results in equal sharing of genetic material from the parents to produce viable offspring. However, an all-female lineage of salamanders has found a unique way to maintain genetic diversity. Researchers analyzed the genome of the all-female Ambystoma and found that the genetic profile represented from their sample contained genetic profile, in equal contributions, from three separate salamander species: Ambystoma tigrinum, Ambystoma texanum, and Ambystoma laterale.
The Ambystoma salamander still engages in sex but acquires genes in a different manner. After mating, the female keeps some of the male's genes while discarding the others. This process is known as kleptogenesis and allows the female to mate with multiple partners, selectively choosing which genes to keep and which genes to discard from each mating interaction. When the genome of the sample was studied, it was found that all three male partners contributed a total of 72% of the female's genome, with each of the genes from the partners being expressed equally. In other words, the three genomes representing the male partners are being expressed equally in this hybrid. Some future directions for this research include analyzing how the female chooses which genes to keep.
McElroy et al. Genome Expression Balance in a Triploid Trihybrid Vertebrate. Genome Biology and Evolution, 2017: 9(4) DOI: http://dx.doi.org/10.1093/gbe/evx059
Scientists have longed used a test to gauge how well a person can interpret emotions and thoughts from looking at another person's eyes alone. Through this testing over the past twenty years, it has been found that there is variation from person to person on how well they can interpret subtle clues from the eyes alone. Furthermore, on average, women have been shown to score better on this "Eyes Test" than men. Now, in a collaboration with the 23andMe genetics company, scientists have found that genes do influence performance on the Eyes Test.
Researchers found that specific variants on chromosome 3, in women only, were associated with their performance on the Eyes Test. One gene in particular that was closest to the discovered region is the LRRN1 (Leucine Rich Neuronal 1) gene, highly active in the striatum of the human brain. Interestingly enough, this region has been shown, in the past, to play a role in cognitive empathy. Furthermore, any associated genetic variants that increase the volume of the striatum also result in a higher score on the Eyes Test. Performance on the Eyes Test was not linked to the region on chromosome 3 and found to be linked elsewhere, showing a variety of influences on our ability to engage in cognitive empathy.
Warrier et al. Genome-wide meta-analysis of cognitive empathy:
heritability, and correlates with sex, neuropsychiatric conditions and cognition.
The way fungal and bacterial infections affect crops have long been an area of interest for scientists. Traditionally, the goal has been to minimalize the effect of the invading pathogen to prevent any damage to crops and the amount harvested from them for food production. However, the interaction between the two can actually end up producing a better end product. Scientists discovered just this when investigating the effect of powdery mildew and bunch rot fungus varieties on an assortment of grapes used to make wine.
Researchers evaluated the affected wines by forming a panel of 10 individuals who are expertly trained in identifying wine odorants. Thy also conducted Aroma Extract Dilution Analysis (AEDA) to compare the different wines. Researchers found that bunch rot infections positively affected all wine samples, increasing floral, fruity, and toasty aroma notes in all of the wine samples tested. The panel went as far as to rate the wine more positively than the healthy control samples. Through the AEDA, scientist found that the resulting positive change in aroma was caused by a grouped change in the presence and absence of aroma compounds. The bunch rot infection caused an increase in lactones, esters, alcohols, and vanillin when compared to the healthy samples of wine. Powdery mildew caused a largely subtle, but opposite change in aroma compounds. This caused the panel to rate wine samples that were affected by powdery mildew with lower aroma ratings when compared to healthy samples.
Pinar et al. Effects of Bunch Rot (Botrytis cinerea) and Powdery Mildew
(Erysiphe necator) Fungal Diseases on Wine Aroma. Frontiers in Chemistry,
Our human immune has evolved a variety of ways to effectively protect us from disease and infection in the real world. Everything from evolved responses in our T-cells to effective secondary responses in the form of accumulated antibodies, our bodies can tackle almost any invasive presence. However, much of this defense comes at a price, costing valuable energy to mount and maintain. Disease avoidance, however, is much more energy efficient. By preventing and sending signals to the brain to identify disease individuals, the body can effectively save the energy that would be normally used to fight off infection and reallocate that energy elsewhere.
Researchers injected subjects with enough bacteria to give the test patients classic, recognizable symptoms of disease, such as fever and tiredness, and took photograph and samples of their odor from them. They then asked a group of subjects/participants to evaluate the attraction towards these individuals and whether or not they would start a conversation/interaction with them. Researchers found that both smell and the visual appearance of disease caused participants to rate those individuals as less attractive and caused them to engage in disease avoidance by indicating that they were less likely to interaect with them as well. This gives confirmation to the idea that survival from infection also includes disease avoidance in the form of picking up these cues in social settings and engaging in disease avoidance.
Regenbogen et al. Behavioral and neural correlates to multisensory detection of sick humans. PNAS, 2017; 201617357. Link: http://dx.doi.org/10.1073/pnas.1617357114
The way our brains processes objects in the real world is a complex but quick process, taking only milliseconds to complete. Almost all of this visual processing of our environment occurs in the ventral-temporal complex, dubbed the visual brain for its ability to quickly create recognition out of light input from our eyes. Does this development pathway in the brain require learning in terms of the visual input we receive over time or is this an innate ability of the brain? The answer lies in examining those who were born blind.
Researchers examined a group of individuals who were born blind to see how their brains would respond to auditory input representing a variety of categories: faces, body parts, scenery, and objects. The resulting brain activity measured also occurred in the same area and in the same way as those who were born with sight and visual input. This means that blind individuals are also able to build and use a visual map in the ventral-temporal complex even without sight. Furthermore, the map itself is relatively the same as that of sighted individuals, meaning that both auditory and visual input can be used to activate the visual brain.
This raises one final question for future studies: what exactly are people using the visual brain for?
Hurk et al. Development of visual category selectivity in ventral visual
cortex does not require visual experience PNAS, 2017;
Sex determination in most mammals is determined by the sex chromosomes, with females having two X chromosomes and males having one X and one Y chromosome. However, in a unique case in the animal kingdom, Amami spiny rats carry just a single X chromosome in their development process, making it an interesting subject to investigate the method of sex determination in animals. Scientists found that when they used fibroblasts from the female spiny rats' tails, they were able to derive iPSCs that had the ability of creating both male and female germ cells.
When the iPSCs from the tail are planted in a mouse-spiny rat chimera host, both male and female germ cells could be created in the body. Using a fluorescent marker, the researchers were able to trace what percentage of the developing cells in the surrogate mouse mothers were a result of the injected iPSCs. Their results found iPSCs in several tissues (i.e. patches of brown spiny rat skin and fur). Amazingly, the iPSCs were also contributing to spermatids and oocytes, but at a much lower rate.
Future research will be focused on the viability of these germ cells and if viable, whether or not this could possibly represent a m ethod of conservation for this species.
Honda et al. Flexible adaptation of male germ cells from
female iPSCs of endangered Tokudaia osimensis Science Advances,
Scientists have successfully combined living cells and technology to deliver a system that successfully regulates insulin levels in mice. Diabetes is one of the most widespread disease in the world, with the number of those affected reaching 415 million worldwide and climbing. One of the key treatments for those afflicted with diabetes is to adequately monitor and regulate blood sugar levels, aiming to keep them within what is considered a normal range for healthy living. Shao's team of scientists has now been able to regulate insulin levels in mice at the touch of a button in mice.
Researchers were able to create cells that produced and released insulin when exposed to far-red light. These cells were then added to a sheath that contains red LED lights that can be controlled by external electromagnetic fields (HydrogeLEDs). Once the sheath was implanted in the skin of the mice, the researchers were then able to administer insulin by turning on the lights through their smartphone devices, thereby activating the production and release of insulin from the custom created cells. The researchers were also able to engineer the cells to prevent any unwanted communication between their artificial cellular process and any native celluar signaling processes.
Shao et al. Smartphone-controlled optogenetically
engineered cells enable semiautomatic glucose homeostasis in diabetic mice.
Medicine, 2017; 9 (387): eaal2298.
Myostatin, in pervious research studies, has long been known as a skeletal muscle growth inhibitor. As a result, a buildup of myostatin results in situations where pateints have less muscle mass and vice versa resulting in more muscle mass. Patients experiencing obesity have overproduction of myostatin, which affects them two-fold. The excess myostatin makes it both harder to exercise and difficulty building muscle mass, resulting in a cycle of inactivity. What happens when an obese mouse has inhibited myostatin production?
The researchers divided their mice into four groups: lean and obese mice with both uninhibited and inhibited myostatin production. The mice groups that were inhibited in their myostatin production showed higher muscle mass than those with normal myostatin production levels. However, the obese mice with inhibited myostatin production remained obese, even with higher muscle masses. The differences between the two inhibited myostatin groups were found in their markers of cardiovascular and metabolic health. The obese mice with inhibited myostatin production showed levels of cardiovascular and metabolic health that was similar to those of their lean counterparts and significantly better than the obese mice group with normal myostatin production.
This gives the idea that a pill could be created in the feature that mimics the cardiovascular and metabolic health benefits of exercise, protecting against obesity. This could also aid in muscle dystrophy instances as well.
Butcher et al. Augmented Muscle Mass as a Novel Buffer against Obesity-Derived
FASEB Journal, 2017; 31 (1): 1011.7.
A cell's most undifferentiated form, a stem cell, is capable of forming other kinds of cells through the process of differentiation. As a result, they are often thought of as the "purest" form of cells. There has a been much debate about what leads to variation in stem cells, a long-standing question in the field regarding stem cells and their expression differences. Previous studies have shown that induced pluripotent stem cells made from the cells of identical twins are even capable of showing important differences in their epigenetic profiles. Scientists have now discovered the primary driver of what causes these differences between not only iPSCs, but stem cells as a whole.
Scientists found that even though identical twins have the same genes as each other, making them ideal for this type of study, the collection of methyl marks on their DNA, otherwise known as their epigenomes, increased in variation over time. One reason for this variation is due to environmental factors. While reprogramming skin cells, for example, from their adult state back to their native embryonic state removed most of these variations between twins, some key differences still remained between the twins when comparing embryonic stem cells to these induced pluripotent stem cells.
Once the scientists looked at the similarities between the remaining differences, it became clear that the variation in methyl marks appeared to land near known binding sites for MYC, a regulatory protein. It was through this method that scientists discovered the differences between stem cells lies in the control of methylation by the MYC protein.
Panopoulos et al. Aberrant DNA Methylation in Human iPSCs Associates with
MYC-Binding Motifs in a Clone-Specific Manner Independent of Genetics. Cell Stem Cell,
Researchers, in previous studies, have identified Xist as the mechanism in which the silencing of X chromosomes occurs. Xist, an abbreviation for X-inactive specific transcript is located on the X chromosome itself and controls production of the associated protein that causes silencing of the X chromosome during embryonic development in females. This causes genes to inactive, effectively silencing the X chromosome. One thing researchers have struggled to explain is how in certain triploidy conditions, two copies of the X chromosome remain active.
The location of the gene responsible for the repression of Xist has yet to be discovered, let alone the specific identity/function of the gene itself. Researchers in this article have been able to identify the region through a specific set of techniques.
They first started by looking at autosomal trisomies, since having two active X chromosomes is lethal in the early stages of development. The results showed identifiable trisomies in all chromosomes except for chromosome 1 and chromosome 19, indicating that the possible location of this repressor could be on one of these chromosomes., since none of the embryos survived long enough to be identifiable. Combining the information from two genetic databases, researchers searched on chromosomes 1 and 19 for areas of the chromosomes that were hypothesized to make proteins that could successfully interact with Xist. Only one section between the two chromosomes fit this criteria, the stretch of DNA on the short arm of chromosome 19, leading researchers to believe that the repressor gene must be located there.
Migeon et al. Embryonic loss of human females with partial trisomy 19 identifies
region critical for the single active X. PLOS ONE, 2017; 12 (4): e0170403
The field of synthetic biology continues to expand, with synthetic biologists constantly trying to improve the engineering of living cells, transforming them into circuits that can be programmed and controlled. The main hurdle when reprogramming cell behavior is to control both the input of information into the cell and also the output, or the way the cell responds to the input. Once both are controlled, the cell's signaling behavior becomes predictable, allowing it to function within a genetic circuit. Scientists in this paper have been engineered a new method, termed "BLADE" or "Boolean logic and arithmetic through DNA excision", that allows for a more efficient way to program mammalian cells as genetic circuits.
Classic engineering of genetic circuits involves the use of transcription factors to create them, modeling the way electronic circuit design was constructed. The methodology behind this technique was tricky and hard to work with since the conversion of DNA to RNA and the control of this conversion was hard to predict. Furthermore, mammalian themselves are much more complex than prokaryotes, requiring something much more complex than electronic circuits to model themselves after in order to be successfully reprogrammed.
"BLADE" involves the use of DNA recombinases and their enzymatic cut and paste behavior that can alter specific DNA sequences. The fact that the DNA recombinases are more specific allows them to be more easily customized in field. This lets researchers obtain specific results using this one design. "BLADE" allows researchers to use a variety of input sources/methods, alter those signals, and control the endpoints or output behaviors of the cells.
Weinberg et al. Large-scale design of robust genetic circuits with multiple
inputs and outputs for mammalian cells. Nature Biotechnology, 2017.
Congenital blindness, a symptom where there is a lack of vision that is present from birth, can be caused by a variety of factors. One such specific disease is known as Leber Congenital Amaurosis (LCA). This disease is recessive, with the phenotype being inherited when the child has two copies of the mutated gene, one from each parent. This syndrome accounts for nearly 5% of vision deficiencies/impairments and is one of the leading causes of blindness in children worldwide. Even though this disease is a leading cause of congenital blindness, the mechanisms behind how the disease manifests itself in children is not well understood. Researchers have no found a similar syndrome in zebrafish, allowing them to study the disease and its progression in a model organisms. Scientists hope to use the zebrafish as a model to unravel the actions of the syndrome to better understand its progression in humans, ultimately coming to a successful treatment for human LCA.
Researchers found that the mutant DNA sequence in zebrafish that resembled the LCA phenotype was Aipl1b. This gene is active in the cones of zebrafish and subsequent mutations in the gene result in deformed cones and inactive cone photoreceptors. This degeneration only affects cones, as rods did not show any affliction from the mutation itself. Aip1 was also found to be crucial to the stability of cGMP-phosphodiesterase 6 and guanylate cyclase, two key components in the phototransduction process. Without the activity and regulation from these enzymes, the zebrafish will not be able to perceive and light stimulus due to the lack of transmission of information to the brain.
Iribarne et al. Aipl1 is required for cone photoreceptor function and survival
through the stability of Pde6c and Gc3 in zebrafish. Scientific Reports, 2017; 7:
Bone defects have often been difficult to treat. Treatment options all have their own associated complications. One common technique used to enhance bone repair is bioceramics. The main limitation with the use of bioceramics, such as hydroxyapatite, is that the materials themselves, when used as scaffolds, tend to be brittle. This can result in pieces of the original scaffolding breaking off, resulting in inflammation in the surrounding soft tissue. Biological materials, or materials derived from natural sources, have shown more success. Sea urchin spines, in particular, show promise as scaffolding for bones due to their strength and simultaneous porosity.
Researchers were able to extract and convert sea urchin spines from their native state to a biodegradable version that was based on magnesium-substituted tricalcium phosphate. This was done through a hydrothermal reaction, allowing the scaffolding to be created. Due to the structural stability and strength, the scaffolding derived from sea urchin spines could also be both cut and drilled to fit specific sizes. The porosity of the spines also allowed for the exchange and flow of bone cells and nutrients, allowing vascularity to form when bone growth began. After the new growth occurs, since the sea urchin spines are biodegradable, the only thing left after time is the newly formed bone.
Cao et al. Lightweight Open-Cell Scaffolds from Sea Urchin Spines with Superior
Material Properties for Bone Defect Repair. ACS Applied Materials & Interfaces,
Megakaryocytes, normally found in bone marrow, are responsible for the production blood thrombocytes, otherwise known as platelets. Platelets themselves are a vital component of blood, since they are a key component necessary for blood clotting. Although megakaryocytes have been discovered in the lung before, the majority of their blood-producing behavior was thought the occur in the bone marrow. Scientists in this research study have found otherwise, discovering a large population of megakaryocytes and blood stem cells that resided in the lungs of mice.
Scientists were able to discover the new population of megakaryocytes in the lung through the use of a variation of an imaging technique known as two-photon intravital imaging. Through this technique, the scientists involved in the study were able to view the path and behavior of individual cells locked within the blood vessels of a mouse lung. Researchers not only found the megakaryocytes living in mouse lungs, but also discovered that the megakaryocyte cells themselves in the lungs were able to produce more than 10 million platelets per hour, accounting for a little more than half of a mouse's total platelet count. This suggests a substantial role for these megakaryocytes in blood platelet production overall.
Blood stem cells were also found in the lung through the same altered imaging technique. It was found, through a series of lung transplant studies, that these blood stem cells were able to restore and aid bone marrow function in the instance of damaged bone marrow. Both of these studies have important implications in the study and treatment of platelet diseases and blood diseases as a whole.
Lefrancais et al. The lung is a site of platelet biogenesis and a reservoir for
haematopoietic progenitors. Nature, 2017.
It has long been known that elasmobranch fishes (sharks, rays, skates, etc.) use electrosensory organs to detect environmental electric fields and their minute fluctuations. It is through the detection of these fluctuations that allows these fish to locate and hunt prey, among other things. The mechanism behind this detection, however, has been a mystery to scientists, until now. Scientists have now discovered two channels, one voltage-gated and one calcium-activated, that act through a coupling mechanism to regulate the electrosensation of cell membrane voltage oscillations. These oscillations, in turn, are important to the detection of weak electrical signals, such as the fluctuations that can be seen with small prey.
The researchers in the study focused on the skate ampullary organs, isolating electrosensory cells from these organs first. After performing sensitivity recordings, researchers were able to identify two separate ionic currents, one that is a voltage-sensitive calcium current and one that is a calcium-sensitive potassium current. These currents, based off their natures, are able to interact with each other to set up an electrical oscillation within the cell membranes that allows them to be sensitive to electrical fields in the environment and any associated disturbances.
Researchers also used gene expression experiments to confirm the specific subtype of calcium and potassium channels involved, CaV1.3 and BK channels respectively. Researchers, in one particular experiment, were able to make mutations within ion channel genes in the rat genome, making them more similar to the ion channels seen in skates. This resulted in the rat channels behaving like those found in the electrosensory cells of skates.
Finally, to show the associated behavior of hunting is affecting by these electrosensory cells and, more specifically, these ion channels, researchers were able to block these key ion channels through the use of drugs. This, in turn, eliminated the skates' ability to hunt for their prey.
Bellono et al. Molecular basis of ancestral vertebrate electroreception.
Last year, an enzyme called NMNAT2 was discovered by scientists. The enzyme, found in the brain, was found to play two key roles in preventing dementia. The first role involves a more protective function, guarding neurons from degradation as a result of stress. The second role was found to be that of a chaperone role, helping to prevent misfolded proteins, otherwise known as tau, from accumulating in the brain. This in turn prevents plaques from forming and, as a result, preserves brain function. Scientists set out to find what substances have the potential to alter the levels of NMNAT2 enzyme in the brain. Their study included both new and existing drugs/compounds, with over 1,280 being investigated as potential influences on levels of NMNAT2 enzyme in the brain.
One of the main substances found to increase production of NMNAT2 was caffeine. Caffeine has been shown to increase memory the memory abilities of transgenic mice who have been altered to produced more misfolded tau proteins. Furthermore, these transgenic mice were also found to have lower levels of NMNAT2, linking the increase of misfolded tau proteins to the absence of NMNAT2. Researchers took these findings a step further to confirm the effect that caffeine has on NMNAT2 levels. Transgenic mice altered to produce lower levels of NMNAT2 were able to recover normal enzyme levels with the addition of caffeine. One of the other compounds discovered to boost NMNAT2 levels in a comparable manner was rolipram. Research into these compounds and the other 22 compounds could help us better identify the pathways in the brain responsible for these mental disorders.
Ali et al. Screening with an NMNAT2-MSD platform identifies small molecules that modulate
levels in cortical neurons. Scientific Reports, 2017; 7: 43846.
Enterobacteria, a group of gram-negative bacteria that can thrive in the digestive tract of animals, includes both harmless and pathogenic types of bacteria. Some of the more familiar pathogens within this group of bacteria include Salmonella and E. coli. While it has been clear that these enteropathogenic bacteria prefer the optimal conditions within our gut, the manner in which they establish themselves and proliferate is not well understood. Scientists, in a new article publish in Science, have now discovered that pathogens not only sense their host, but further tailor their gene expression profiles to better infect and colonize their host.
The pathogens themselves are able to initiate the type III secretion system and related proteins through contact induced expression of NleA. Scientists discovered, through GFP-tagged NleA, that only cells attached to the intestinal wall were able to express the contact-induced version of NleA. Furthermore, it was found that the T3SS mechanism (type III secretion system) was able to inject a group of effector proteins that made the host cell and environment more susceptible to infection. It is through these two key mechanisms caused by the T3SS mechanism that allows enterobacteria to better infect their hosts and cause possible pathogenic effect on their hosts.
Katsowich et al. Host cell attachment elicits posttranscriptional regulation in infecting
enteropathogenic bacteria. Science, 2017; 355 (6326): 735. Neuron, 2017.
One of the fundamental rules of genetics is under assault: the idea that our body treats each copy of DNA instructions, one from each parent, equally. Scientists have discovered that the main culprits challenging this convention are the cells analyzed in the brain, specifically the ones associated with the dorsal raphe nucleus in newborn mice. Researchers have found that it is actually not uncommon for a developing mouse brain to differentially activate one copy over the other in certain instances.
The scientists in the study screened thousands of genes to quantify levels of activation for each copy to see if there was a discrepancy. Scientists at the University of Utah School of Medicine have found that in the dorsal raphe nucleus of neonatal mouse brains, 85% of genes differentially activate their gene copies. This region is primarily known for secreting serotonin, which is responsible for the feelings associated with well-being and happiness. In juvenile brains, the phenomenon still occurs, but at a smaller percentage, with the percentage falling to 10% of genes that are differentially activated. This genetic imbalance may help us understand brain disorders and irregularities in the future. It could not only explain susceptibility to certain disease, but also explain why certain individuals are not prone to them as well.
Huang et al. Diverse Non-genetic, Allele-Specific Expression Effects Shape Genetic
Cellular Level in the Mammalian Brain. Neuron, 2017.
There are a variety of different types of bacteria that are capable of many different functions. One type of bacteria that falls within this category are electrogenic bacteria. This specific type of bacteria is able to produce electricity as part of their metabolism, occurring as a substitute for the lack of oxygen in their environment. One example of a type of bacteria that is able to do this is Shewanella oneidensis. As a result, it has to use metal minerals and electrodes, instead of oxygen, to run its metabolism. This is primarily done via proteins in their cell membranes that are able to conduct electricity/current. Scientists have now not only discovered the method in which they are able to produce electricity, but have also been able to transfer this ability to non-electrogenic bacteria.
Since the electrogenic ability of S. oneidensis is conferred through these specific conducting membrane proteins, scientists decided to try a variety of molecular membrane additives to non-electrogenic bacteria, in hopes of adding the electrogenic skill. In the case of the S. oneidensis bacteria, researchers were able to synthesis a molecule called DFSO+. DFSO+ contains an iron atom within its core, while being designed to be translocated into the bacteria's cell membranes. Once integrated, the molecule itself is able to conduct current through its iron core and a new method of transporting electrons between cell membranes is created.
The applications for this sort of groundbreaking technology include wastewater treatment and sustainable/renewable generation of electricity. It also has the potential to be much more cost ffective than genetically engineered bacteria, since the additional of the synthetic molecule itself should be relatively cheap. In this study, the DFSO+ molecule was integrated into the membrane by simply dissolving DFSO+ in water and adding that to the bacteria.
Kirchhofer and Rengert et al. A Ferrocene-Based Conjugated Oligoelectrolyte Catalyzes
Electrode Respiration. Chem, 2017.
Memory formation in humans can be considered a complicated process. There are many factors that go into the development of short term and long term memories. However, the formation of fear memories from traumatic events is a separate entity entirely. Scientists have found how a particular gene, known as fkbp5, is directly involved in the formation of memories, specifically those that occur from traumatic events. This phenomenon is a process known as "fear extinction". Those individuals and animals suffering from PTSD lack in their ability to successfully undergo "fear extinction", which cause them to form fearful memories. Furthermore, treatment with dexamethasone prevents formation of these fearful memories. Dexamethasone is a steroid that is normally used to treat inflammation.
The study found that the interaction between dexamethasone and fkbp5 enhanced fear extinction in mice that were put through fear extinction training. This only occurred when a high enough dose was given for the drug to entire the brain. The high dose of dexamethasone causes an increase in fkbp5 expression in the amygdala, allowing for fear extinction to occur. Looking at fkbp5's influence in humans found that variants of the fkbp5 gene caused differences in fear extinction learning. Researchers hypothesize that if dexamethasone can work in humans, it could eventually be used to prevent PTSD and other fearful memories caused by traumatic events.
Galatzer-Levy et al. A cross species study of heterogeneity in fear extinction learning
FKBP5 variation and expression: Implications for the acute treatment of posttraumatic stress
Neuropharmacology 2017; 116:188
The extent to which animals behave in a rational manner has not be studied extensively. Humans have often displayed the ability to behave irrationally, especially with regard to mate choice. Rational choice, in terms of mating behavior, is seen as choosing the mate that will lead to a higher probability of success in producing healthy, advantageous offspring. Humans will often differ from rational choices based on the availability of alternative choices for irrelevant reasons, leading to disadvantageous choices in variety of scenarios. But do non-human animals act rationally when it comes to mate choice?
In the experiment conducted by researchers, male fruit flies were given two potential female mates. The male flies were found to be making a consistent choice between the two females, selecting the mate that would produce more offspring on a consistent basis, 70 to 100 percent of the time. Furthermore, when given a choice between the lesser of the two females from the first experiment and a 3rd lesser choice in terms of offspring numbers, the hierarchy of mate selection was still followed by the male fruit flies. These results show that fruit flies are able to perform, to some degree, the cognitive process of making rational mate choices, something often thought of as a very human characteristic behavior. While it is still unclear what female characteristics or phenotypes are being selected for during these decisions, it is clear that the male flies are able to distinguish female reproductivity based off some cues.
Arbuthnott et al. Mate choice in fruit flies is rational and adaptive. Nature
2017. 8: 13953.
The body uses a variety of weapons in its fight against bacteria and, in particular, infectious bacteria. One of its key defenses against MRSA and the types of bacteria that causes it, such as Staphylococcus aureus, is the one-two punch known to involve nutritional starvation followed by an oxidative burst. The body first starves the bacteria of manganese, and then uses the oxidative burst as a kind of finishing blow, eliminating the bacteria and preventing infection. The scientists associated with this study discovered that the reason why S. aureus is so good at turning into MRSA is because of its possession of two SOD enzymes.
SOD enzymes give bacteria production against the second part of the body's one-two punch immune system, the oxidative burst. By starving the enzyme of manganese, the main nutrient the SOD enzyme needs to function properly, it leaves the bacteria exposed to the oxidative burst. The second SOD enzyme found in S. aureus can function not only with manganese as its crucial nutrient, but also with iron. It is this dual identity that allows it to function even in the presence of manganese starvation, ensuring that the bacterial defensive barrier remained active. Thus, the S. aureus is given enough time to develop into MRSA.
Gracia et al. A Superoxide Dismutase Capable of Functioning with Iron or Manganese
Resistance of Staphylococcus aureus to Calprotectin and Nutritional Immunity. PLOS
The function of astrocytes are much more complex than initially thought. Not only do they act as a sort of "scaffold", holding neurons in place, they also are critical in supporting and guiding neurons. The astrocytes themselves enhance the survival of these neurons and their connections. There are also two different types of astrocytes, resting astrocytes and reactive astrocytes. It is these reactive astrocytes that are further divided into two subsets, A1 and A2. A2s have long been known to support neuron health, being the astrocytes that help neurons cover from oxygen deprivation, such as that found during strokes. A1s, on the hand, are known to produce large amounts of substances that can cause inflammation, resulting in an adverse effect on neuron health. Scientists have known about the toxicity of these A1 reactive astrocytes, but how exactly are they formed and what exactly do they do once formed?
Researchers were able to discover that the A1 astrocytes were formed by a combination of exposure to pro-inflammatory factors secreted by microglia, specifically, IL-1-alpha, TNF-alpha, and C1q. Through a series of experiments, researchers were also able to show that A1 astrocytes resulted in fewer synapses and lack of efficient pruning of synapses, causing inefficient brain function as well. A1s also have been linked to neurodegenerative diseases, having been shown to cluster in areas of the brain where the neurodegenerative diseases are most active. A1 astrocytes are able to accomplish all of this destruction through the release of a neurotoxin, the identity of which is currently under research. The goal of these scientists is to be able to anticipate and prevent disease when possible in healthy, as well as treatment for the affected.
Liddelow et al. Neurotoxic reactive astrocytes are induced by activated microglia.
Telomeres are known to be repetitive nucleotide sequences found at the end of chromosomes. They are important for promoting chromosome stability, protecting the ends of the chromosome from degradation. As a result, through several studies, they have also been implicated and shown to be involved in regulating cellular aging. Furthermore, longer telomeres and known to prolong cellular lifespans. However, the complete mechanism regulating telomere length has long been a mystery. Scientists have now discovered a protein specific to telomeres, TZAP (telomeric zinc finger-associated protein) which binds to long telomeres, at the same time competing with TRF1 and TRF2. TZAP is able to control telomere length and as a result cellular aging.
The binding of TZAP to telomeres triggers a cellular process now known as "telomere trimming". This process causes the rapid deletion of telomeric repeats, thereby shortening the telomere and regulating telomere length. The binding of TZAP itself to the ends of telomeres is triggered by a lowered concentration of shelterin complex at longer telomeres. This binding can be thought of as a molecular switch, helping set the limits on telomere length. This study helps shed light on lifespan as well as cancer propagation models in mammals.
Li et al. TZAP: A telomere-associated protein involved in telomere length control.
One of the most promising strategies in regenerative medicine is stem cell therapy. This method, which involves the use of stem cells or pluripotent stem cells to treat any disease or abnormal condition. One of the most common stem cell therapies in use today involves bone marrow transplants. Stem cell therapies are able to work by promoting repair through the body's natural pathways. This is done by secreting paracrine factors, of which include proteins and genetic materials. However, this process is not without fault, with many stem cell therapies encountering risks of tumor growth, immune rejection, and also natural fragility. Stem cells themselves require careful storage and characterization before they can be used in stem cell therapies. Scientists have now developed a synthetic cardiac stem cell that can be used for the same applications as natural stem cells, but without many of the same complications listed above.
Chen and scientists involved in the study were able to create a stem cell-like molecule from PLGA, a degradable polymer. This cell-mimicking microparticle was then given growth factor proteins that were harvested from previously cultured human cardiac stem cells. The final step then involved coating this newly created CMMP with a cardiac stem cell membrane.
When tested, the synthetic CMMP stem cell and cardiac stem cell were able to both initiate and promote the growth of cardiac stem cells, to comparable levels of effectiveness. Furthermore, due to the CMMP nature and structure, the lack of replication reduces any risk of tumor formation resulting from the introduction of the artificial stem cell. The CMMP structure also allows the synthetic stem cell to be much more durable than natural human stem cells and can be manufactured to fit use with any type of stem cell in the human body. This could be the first step towards a stem cell product that lacks any of the disadvantages of stem cell therapies seen today.
Tang et al. Therapeutic microparticles functionalized with biomimetic cardiac stem cell membranes and secretome. Nature Communications, 2017; 8:13724. DOI: http://dx.doi.org/10.1038/ncomms13724
Plants use a variety of different defense mechanisms to fend off dangers posed by the environment, thereby increasing their survival and reproduction capability. Almost all of this defense is coordinated and carried out through the use of a wide variety of enzymes. However, scientists have long tried to explain how these variety of enzymes worked together with high efficiency to initiate plant defense. This is where the theory of metabolons came in and which, until now, were a myth. Metabolons are described as a cluster of enzymes that come together to perform a common goal. Their ability to dissemble and assemble at the drop of a hat is what makes them both beneficial and almost impossible to analyze. However, scientists have now confirmed their existence through the use of fluorescent fusion proteins, filming their formation and movement in live cells along the ER in sorghum during the formation of dhurrin, a defense metabolite.
The metabolon used to form dhurrin was reconstituted in liposomes, allowing for the gathering of CYP79A1 and CYP71E1 to form homooligomers and hetero-oligomers. These in turn allow for the recruitment of UGT85B1. The formation of this structure allows for dhurrin pathway to be formed and broken down on an as-needed basis. Dhurrin is used in the plant to form cyanide, which is needed when the cell wall is broken to deter any herbivores from eating the plant.
Understanding how metabolons are formed and regulated offers a golden opportunity to further isolate and optimize synthetic biology approaches to better suit industrial uses, resulting in the efficient industrialization and production of needed products in a variety of hosts. Metabolons represent yet another customizable step in the metabolic pathway to form desired products.
Laursen et al. Characterization of a dynamic metabolon producing the defense compound dhurrin in sorghum. Science, 2016; 354 (6314): 890. DOI: http://dx.doi.org/10.1126/science.aag2347
Sunlight has long been known to have beneficial effects on an individual's health. Studies have shown sunlight to improve mental health, directly improving an individual's mood, as well as improving physical health, with documented increases in vitamin D in the body associated with exposure to sunlight. Researchers have now found a new way that vitamin D affects human health, by way of the immune system. Through a series of experiments involving exposure to low levels of blue light, scientists discovered that exposure to sunlight increases T cell movement, resulting in a improved immunity response.
One of the keys that allows sunlight to affect T cell movement is hydrogen peroxide. Hydrogen peroxide has previously been known to drive T cell movement when released by white blood cells. When an infection occurs, white blood cells will release hydrogen peroxide and instigate T cells, among other immune cells, to respond to and eliminate the bacteria. Sunlight, through a pathway separate from its effect on vitamin D production, also makes hydrogen peroxide in T cells. This production also in turn allows T cells increased movement through the same pathway initiated by white blood cells. This research suggests that some light therapy could be a way to improve immune responses to infection.
Phan et al. Intrinsic Photosensitivity Enhances Motility of T Lymphocytes. Scientific Reports 2016; 6: 39479. DOI: http://dx.doi.org/10.1038/srep39479
Autism spectrum disorder is diagnosed and characterized by a person's inability to engage in social interaction or communication. Over the course of several years of studies, several hundred genes have been found to contribute to autism. In this study, researchers found an additional set of genes that originally belonged to the "essential genes" group. These group of genes, which traditionally are known to have a strong effect on survival and fitness, were found to have an affect on a person's risk for ASD.
A previous study carried on mouse models showed that a third of genes, known as essential genes, are necessary for life and related to human disease. This new study takes this finding a step further by investigating the link between essential genes and ASD. Researchers studied siblings and found that children with ASD had a significantly higher number of mutations in essential genes when compared to their siblings who were unaffected by ASD. This further substantiates the idea that ASD is caused by a background of mutations vs. one particular gene. Researchers were able to analyze close to 9,000 genes total, coming up with a list of 29 essential genes that are considered high-priority in relation to ASD. These findings suggest that ASD is caused by an aggregate effect of mutated essential genes that end up, through a combinatory effect, causing the symptoms seen with ASD. Researchers believe that ASD can be classified as polygenic disease.
Ji et al. Increased
burden of deleterious variants in essential genes in autism spectrum
PNAS 113:52 15054-15059 (2016). DOI: http://dx.doi.org/10.1073/pnas.1613195113
Cancer dormancy has remained an issue that has puzzled researchers and doctors alike in the quest for an effective cancer treatment. Conceptually speaking, it gives a plausible explanation to the recurrence rate and latency period between successful eradication of primary tumors and the appearance of secondary, life-threatening tumor. These relapses can occur both locally, in the initial area, or systemically, in other areas of the body. Furthermore, these reappearances can often be even more threatening than the initial tumor cells.
Researchers have now found that the dormant tumor cells in breast cancers could have become latent due to the cannibalization of nearby stem cells.
How can the cannibalization of stem cells lead to dormancy and protection against cancer treatments?
The breast cancer cells, after engulfing the stem cells, went dormant. This dormancy in turn caused the cancer cells to be much more difficult to kill. These specific cell types, cancer cell that have engaged in cannibalism, are resistant to normal forms of cancer treatment, such as chemotherapy and nutrient starvation. Furthermore, because only a few cancer cells engage in this type of behavior, when dormant, they are difficult to detect using remission scanning methods.
Now that there is a possible explanation for recurrence and the dormant behavior of cancer cells, a targeted treatment that addresses the cannibalism itself or the dormancy behavior could be an effective way to treat cancer in the future.
Bartosh et al. Cancer cells enter dormancy after cannibalizing mesenchymal stem/stromal cells (MSCs). PNAS 113:42, 6447-6456 (2016). DOI: http://dx.doi.org/10.1073/pnas.1612290113
Most children's hair can generally be tamed with a comb and some patience. However, there are some specific cases where even patience and skill with a comb can't save a child from messy hair. In the case of a phenomenon known as "uncombable hair syndrome", even repeated combing and styling of a child's hair does not help fix or dress the hair into an aesthetically pleasing style. Those who are affected by this syndrome have the characteristic symptoms of frizzy, dry hair with a characteristic shine. Usually, with time, the symptoms will ease into adulthood, where the hair can then be styled normally. Scientists have now discovered mutations in three genes that are involved in the forming of hair which cause uncombable hair syndrome.
What are the functions of the genes associated with uncombable hair syndrome?
The study found that three genes, PADI3, TGM3, and TCHH, are involved in the development of the uncombable hair syndrome. PADI3 and TGM3 are known to produce enzymes involved in hair formation. The third gene, TCHH, produces a protein that is normally responsible for the formation of the structure and general shape of the hair. The three proteins interplay with each other, with PADI3 enzyme using the TCHH protein as a substrate to change the way it is structured, allowing keratin filaments to join to it. TGM3 enzyme finishes the process by linking the keratin to the TCHH protein. It is in this way that the hair shape and structured are formed. If there is any mutation in any one of these three functions, then the formation of hair is affected, resulted in uncombable hair syndrome. These mutations will help lead to further studies into the mechanisms involved in the formation of hair and why certain hair disorders can occur.
Basmanav et al. Mutations in Three Genes Encoding Proteins Involved in Hair Shaft Formation Cause Uncombable Hair Syndrome AJHG 99:6, 1292-1304 (2016). http://dx.doi.org/10.1016/j.ajhg.2016.10.004
Family planning and human reproductive behavior has largely thought to be controlled by voluntary actions. Decisions such as the number of children we have over the course of our life and the age at which we have our first child are all included in the "voluntary" decisions we make regarding our family dynamics. However, in a research article co-authored by over 250 scientists, have identified twelve areas of the DNA sequence that correlate with the number of children we have in our family and the age at which we first conceive a child.
What are the functions of the genes associated with these variants?
The study shows that the twelve areas of DNA and their variants that are linked with the age at which we first conceive a child are also associated with other reproduction and sexual development characteristics. Some of these characteristics include the age at which girls have their first period, when voice breaks begins to occur in boys, and age of menopause. One thing to stress, according to first author Nicola Barban, is that our genes do not solely determine our reproductive behavior, but we have identified parts of it that will influence it. A total of 24 genes were identified, from the 12 DNA variants. While some of these genes were already previously studied and known to influence infertility, a number of others have not yet been studied, such as LINCO1104 and U73166.2. Improvement in our understanding of all of the associated genes in this study could lead to improved infertility treatments in the future.
Mills et al. Genome-wide analysis identifies 12 loci influencing human
Nature Genetics 48 1462-1472 (2016). http://dx.doi.org/10.1038/ng.3698
With global warming and climate change becoming of increasing concern in the world, alternative sources of energy has been thrust into the spotlight. One well known alternative to traditional methods of energy production is solar energy. While traditional methods of harvesting solar energy have steadily been improving, the issues of efficient harvesting in low levels of light continue to be an issue hampering the advancement of this energy source. Researchers at the Universities of Bristol and Essex have discovered a special form of nanotechnology, known as photonics, in commonly grown houseplants called begonias. This nanotechnology allow the begonia to create alternate forms of chloroplasts called iridoplasts in their leaves. The formation of the iridoplasts in the leaves causes the blue sheen commonly seen in begonia.
How do iridoplasts function in begonia and how does it relate to energy harvest?
The blue sheen was initially hypothesized to act as either a deterrent for predators or as protection from too much light. Researchers actually found that the leaves only developed the blue sheen when In dark conditions. After exposure to light, the sheen would slowly disappear.
Using electron microscopy, a difference between the 'blue' chloroplasts, otherwise known as iridoplasts, were found when compared to chloroplasts in other plants. The inner structure had almost changed completely, resulting in thin, uniform layers nanometers in thickness. While this structuring allows the leaves to reflect all of the blue light, resulting in the blue sheen seen, it in turn absorbs more green light than the traditional chloroplast. This is beneficial to the begonia because in their natural environment, under a forest canopy, the upper canopy trees are absorbing most of the blue light, leaving only green light filtering to the begonia below. The iridoplasts allow the begonia to scavenge this remaining green light to efficiently conduct photosynthesis. Researchers further demonstrated this by finding that the iridoplasts performed better than normal chloroplasts in low light levels. Researchers hope that this discovery can result in better artificial electronics and energy harvesting, as well as improved crop yields.
Jacobs et al. Photonic multilayer
structure of Begonia
chloroplasts enhances photosynthetic
Nature Plants 2: 16162 (2016). DOI: http://dx.doi.org/10.1038/nplants.2016.162
Mosquitos have long been a nuisance and a public health threat for a long time now. Mosquito-transmitted diseases, such as malaria, cause an estimated 450,000 deaths a year worldwide and affecting 214 million people total. One key to preventing the spread of malaria and other diseases is by controlling the rate in which mosquitos will bite humans. A main factor that controls whether or not a mosquito bites a human is the variety of unique smells each human gives off, with certain ones being attractive to mosquitos. To better understand how mosquitoes process sensory information, scientists used a powerful Q-system genetic technique to target specific olfactory neurons. The resulting data showed that regions in the brain associated with smell were connected to OR neurons rom the antennae and maxillary palps. However, researchers were surprised to find those same neurons also connected to regions of the brain associated with taste.
How is taste involved in mosquito target acquisition?
The genetic system designed by scientists consists of two parts and allowed them to generate glowing neurons. This will allow scientists to target other specific neurons in the future. In this particular case, scientists can see which neurons light up in response to a specific smell.
While the OR neurons connecting the maxillary palps and antennae to the antennal lobes in the brain were associated with smell, researchers also found that OR neurons from the labella were connected to the region of the brain known as the subesophageal zone. This area of the brain has historically only been associated with the sense of taste in flies studied. This discovery implies that mosquitoes not only have a preference for certain smells, but also certain flavors. Potter, a researcher involved in the study, hypothesizes that this could be a result of our skin emitting odorants that are picked up by the labella and cause an influence of taste towards the mosquito, especially when the insect is searching for a location to bite. This could influence further mosquito control techniques by offering one additional way to repel mosquitos.
Riabinina et al. Organization of olfactory centres
malaria mosquito Anopheles
Nature Comm. 7: 13010 (2016). DOI: http://dx.doi.org/10.1038/ncomms13010
One key question facing scientists investigating the origins of life and evolution as a whole: How did genetic code or precursors to today's genetic code first replicate before enzymes were available to catalyze the process? Present day replication of genetic code is impossible without a variety of enzymes, such as DNA polymerase III and ligase enzymes. For the past 50 years, the scientists that have been searching for an answer have been performing experiments in water. However, researchers Christine He and Isaac Gallego added an off-the-shelf solvent, increasing the viscosity of the solution and resulting in spontaneous replication.
How does the addition of solvent aid in replication?
Researchers found that these types of experiments should be focused on producing a process that is easily reproduced in a variety of environments and conditions. The main issue facing doing these experiments in water is the rapid cooling experienced after the liquid is heated. In water alone, the cooling of the solution after being heated by the sun would cause the chains to rapidly snap back together. Normally, with the aid of proteins and enzymes, the replication fork would be held open long enough to allow replication to occur in these situations. However, without the aid of enzymes, the rapid cooling would not allow replication to occur. Increasing the viscosity with a solvent, as the researchers did, would allow time for the short nucleotides to pair with the long strand, before the chains snap back together. "In that solution, it gives the short nucleotides, which move faster, time to jump onto the long strand and piece together a duplicate of the long strand," researcher He said. Furthermore, in the experiments conducted, the DNA and RNA strands were able to fold onto themselves spontaneously to produce hairpins, further keeping them open for the pairing process.
He et al. A viscous solvent enables information transfer from gene-length nucleic acids in a model prebiotic replication cycle. Nature Chemistry, 2016 DOI: http://dx.doi.org/10.1038/nchem.2628
The mammalian brain's ability to adapt and mold itself over time in response to external stimuli is one of its most intriguing abilities during memory formation and learning. All of the experiences that a person undergoes causes a response in our brain by modifying the activity and organizational network of neurons in specific circuits. This, in turn, results in a change in feelings, thoughts, and behavior experienced and exhibited by the individual. This experience and resulting change in brain circuitry is known as synaptic plasticity. Researchers have now discovered that synaptic plasticity is controlled by a signaling pathway involving the protein BDNF and its receptor TrkB, and GTPase proteins Rac1, Cdc42, and RhoA.
Harward and Hedrick et. al., in their first publication, were able to identify an autocrine signaling system within dendritic spines. The autocrine signaling system within the dendritic spines functions when the protein BDNF is release from the spine and interacts with TrkB receptors on the same spine. This same cell interaction further activates signaling inside the spine, eventually leading to spine enlargement.
In the second publication, Hedrick and Harward et. al., researchers were able to elucidate the mechanism signaling proteins activated by the BDNF-TrkB autocrine signaling system. This signaling leads to activation of GTPase proteins Rac1, Cdc42, and RhoA. These proteins are known to regulate the shape of dendritic spines, but the method in which they worked together to control the structure of spines was unknown, until now. Researchers found that all three of these GTPase proteins were activated simultaneously, but differed in where the proteins spread to. Rac1 and RhoA spread to the surrounding dendrite, affecting the plasticity of the originating spine and surrounding spines as well. Cdc42 activity, on the other hand, was restricting to only the originating spine, producing spine-specific plasticity.
Harward and Hedrick et al. Autocrine BDNF –
signaling within a single dendritic spine. Nature, 2016, 538: 99-103
Harward and Hedrick et al. Rho
complementation underlies BDNF-dependent homo- and heterosynaptic plasticity. Nature,
Acne is reported to affect millions of people globally. Its target demographic is mostly the adolescent population, affecting anywhere from 80% to 90% of teenagers in the western population. The association with acne, a non-threatening disease, is often negative, with the resulting appearance associated with clogged hair follicles often leading to a reduction in self-esteem and increase in anxiety. However, scientists have now found a possible benefit of having acne: protection against aging. Through a series of studies investigating the length of white blood cell telomeres in twins, it was found that those twins suffering from acne were found to have longer telomere length in their white blood cells. Furthermore, one of the genes involved with dictating telomere length was found to be associated with acne.
While some caution needs to be given, in that this result only shows an association, and no sort of causation directly linking acne with protection against aging. For many years, many dermatologists have noted the link between the skin of acne sufferers and slower aging (wrinkles and skin thinning). The longer telomeres could result in protection against aging, by giving the white blood cells of acne sufferers more room in their chromosomes to deal with the natural deterioration seen with aging. In addition to a gene associated with telomere length being found to be linked with acne sufferers, researchers also found a gene pathway that regulates cell death to be less expressed in acne sufferers (p53 pathway). The p53 pathway is known to regulate programmed cell death. Further investigation is needed to directly link these two genes to acne sufferers and protection against aging.
Ribero and Sanna et al. Acne
length. A new spectrum between senescence and apoptosis pathways. Journal of
The many physical benefits of endurance training has already been extensively studied and documented. Endurance training itself can be used to prevent a variety of diseases, such as cardiovascular disease, as well as being used as a weapon in the fight against the obesity epidemic currently plaguing the US. However, little research has been done into the molecular basis of the benefits seen in those participating in endurance training. Researchers have now analyzed the RNA in muscle tissue, using RNA-seq technology, before and after participants engaged in endurance training. The resulting data showed that over 2600 genes were affected by the endurance training. Furthermore, these 2600 genes were shown to produce around 3400 RNA variants, meaning that genes can not only modulate expression levels in response to endurance exercise, but also change function as a result of increased physical activity.
What are the genetic impacts behind the benefits seen with endurance training?
Some genes that showed variation in their splicing events and expression levels are very biologically relevant to health. One of the genes that showed variation in isoforms was the SPARC gene, which is responsible for preventing myofiber atrophy. Five different isoforms of the SPARC gene increased from 1.5 to 3 fold in expression levels. Another affected gene involved in myogenesis is HIC-5, which was shown to be induced over 3 fold with training. Overall, over 3,000 isoforms were significantly affected by training. This type of research can help optimize training for specific individuals Furthermore, it can also help with the development of new drugs, which can help people who are physically unable to exercise themselves reap the benefits of training.
Lindholm et al. The Impact of Endurance Training on Human Skeletal Muscle Memory, Global Isoform Expression and Novel Transcripts. PLoS Genet 2016, 12(9): e1006294. DOI: http://dx.doi.org/10.1371/journal.pgen.1006294
One of the more controversial science topics discussed in the general public today is the creation and commercialization of transgenic plants, otherwise known as genetically modified plants or crops. While much of the controversy surrounds the safety of creating such organisms for consumption, transgenic plants are also extensively used in scientific research, allowing researchers to explore the role of a gene. One group of crops that have been difficult to transform, up until this point, is grain crops. This is due to the fact that Agrobacterium, the prime method in transforming plant tissue, is only effective in a few grain cultivars. A team of researchers from DuPont have made the transformation of grain crops with agrobacterium much more efficient with a new technique that involves morphogenic genes.
How were morphogenic genes used to increase the transformation efficiency of grain crops?
Researchers from DuPont added certain morphogenic genes, specifically Bbm and Wus2, to the other genes being transformed with agrobacterium. Morphogenic genes are known to promote the production and growth of embryonic tissue. One of the main issues facing agrobacterium-mediated transformation of grain crops is the fact that grain croups are recalcitrant to regeneration. The addition of the morphogenic genes not only increased the transformation rates of existing grain cultivars, but also widened the selection of transformable grain crops. This technique was also shown to be efficient in rice, sugarcane, and sorghum.
Wrobel et al. Morphogenic Regulators Baby boom and Wuschel Improve Monocot Transformation. The Plant Cell, 2016: 28: 9, 1998-2015. DOI: http://dx.doi.org/10.1105/tpc.16.00124
Much of breast cancer research has been focused on discovering new targets for treatments to disrupt or prevent the formation of tumors. However, not much focus has been given to research focused on increasing the effectiveness of current treatments, such as tamoxifen. Tamoxifen is commonly used to treat estrogen receptor-positive breast cancer cases (70% of all clinical cases of breast cancer) by blocking the binding process of estrogen to a protein that grows in response to estrogen. However, there are some cases in which patents develop endocrine resistance and do not respond to the drug. Researchers have now shown that by inhibiting XPO1, a nuclear transport gene, the endocrine resistance seen in these cases can be reversed and the subsequent effectiveness of tamoxifen increased.
How were scientists able to safely target XPO1-mediated nuclear transport?
This current study used information from previous research that identified the kinase ERK5 as the protein that is activated by estrogen. This protein causes a signaling cascade that results in cell proliferation and metastasis. Based of this information, scientists in this study theorized that by blocking nuclear transport genes, such as XPO1, we could prevent the export of ERK5 from cells' nuclei, preventing the activation of this signal. By using the XPO1 inhibitor selinexor in combination with tamoxifen in mice, scientists were able to completely block tumor regression. Even in the weeks following treatment, no tumor recurrence was seen in the mice. Selinexor, which is already in trials for treatment of leukemia and prostate cancer, can open new doors to effective breast cancer treatment.
Wrobel et al. ERα-XPO1 crosstalk controls tamoxifen sensitivity in tumors by altering ERK5 cellular localization. Molecular Endocrinology, 2016; me.2016-1101. DOI: http://dx.doi.org/10.1210/me.2016-1101
Treatments for alcoholism are limited but in dire need, as alcohol-related deaths are approaching 3.3 million worldwide annually. One of the main theories as to what causes addiction and alcoholism is the overactivation of specific neural pathways related to compulsive drinking, located mainly in the amygdala. This continued overactivation eventually increases the negative emotional states experienced during alcohol withdrawal. In this study, lead by Dr. Guglielmo and his team of researchers, this alcohol dependence seen can be completely reversed in rats by targeting a specific neural pathway in the amygdala.
How were scientists able to target a specific pathway to reverse alcoholism?
Previous studies have shown that alcoholism can activate a specific neural circuit, a shortcut between alcohol and associated feelings of reward. In this study, the specific neural circuit associated with alcoholism in the amygdala was targeted in rats by using Fos LacZ transgenic rats and the Daun02 inactivation procedure. B-gal is induced only in activated Fos+ neurons. When these rats are subsequently injected with Daun02, the B-gal is able to convert Daun02 into daunorubicin. Daunorubicin leads to reduced neuronal activity and then eventually cell death. This technique, while not applicable to humans, shows that focusing on the amygdala and associated neural pathways could lead to a better understanding of alcoholism and improved treatments/medication.
Guglielmo et al. Recruitment of a Neuronal Ensemble in the Central Nucleus of the Amygdala is Required for Alcohol Dependence, 2016. The Journal of Neuroscience, 36(36): 9446-9453. DOI: http://dx.doi.org/10.1523/JNEUROSCI.1395-16.2016
As the spread of electronic devices and our dependence on them increases, advances in nanotechnology become increasingly crucial to meeting this demand. However, issues with conductivity at such a small scale coupled with the harsh chemical techniques used to create conductive, nano-sized materials impedes progress in this field. Dr. Lovley and his team at the University of Massachusetts Amherst have discovered a way to produce renewable engineered wires from a bacteria known as Geobacter.
How were scientists able to use Geobacter to form useable nanowires?
Geobacter natural form hair-like protein filaments that can be used as microbial nanowires. It uses these filaments to make connections with iron oxides in the ground of the surrounding environment, helping support its growth. This natural electrical current formed is enough for its own survival, but is not conductive enough for human use. This is where Dr. Lovley and his team come into play. Lovely's team engineered the bacteria by replacing two crucial amino acids with tryptophan. This replacement increased the conductivity of the nanowires by 2,000x when compared to their natural counterpart. Furthermore, the replacement also caused them to become more durable and considerable smaller, coming in with a diameter of around 1.5 nm. These nanowires could have numerous applications in the field of nanotechnology and could pave the future for creation of tools through the use of renewable resources.
Tan et al. Synthetic Biological Protein Nanowires with High Conductivity, 2016. Small, 12: 4481-4485. DOI: http://dx.doi.org/10.1002/smll.201601112
Stem cells have unlimited potential in that they have the ability to differentiate into several different cell types. However, the differentiation of stem cells is usually regulated by the cell's surrounding environment (neighboring cells, extrinsic factors). Stem cells that are found in the lungs will differentiate into lungs, controlled by the organ that they are located in. However, researchers from Biomedicine at the University of Basel have discovered that adult hippocampal stem cells are controlled by two mechanisms, one being through local niche influences and the other through the Drosha enzyme.
How does Drosha operate to control hippocampal stem cell fate?
Drosha is an enzyme that is able to degrade the mRNA for NFIB in hippocampal stem cells. This prevents the transcription factor from being translated. NFIB is a critical protein in oligodendrocyte formation and its degradation in hippocampal stem cells biases them towards differentiating into neurons. It is through intrinsic regulation of Drosha that these stem cells in the hippocampal region are able to direct differentiation away from oligodendrocyte formation. Research is still ongoing to see if these stem cells are able to modify the amount of Drosha to satisfy body needs.
Rolando et al. Multipotency of Adult Hippocampal NSCs In Vivo Is Restricted by Drosha/NFIB 2016. Cell Stem Cell 19, 1-10. DOI: http://dx.doi.org/10.1016/j.stem.2016.07.003
Researchers have long known about the variation seen between organs in terms of cancer prevalence. Malignant tumors are known to be much more common in the colon and breast than in the brain and heart. Furthermore, certain organs, such as the uterus, will commonly develop benign fibroid tumors, but the occurrence of malignant uterine cancers is rare. Researchers are now proposing that this difference can be explained, at least in part, by the natural selection pressures seen on certain organs. Organs that are smaller or are more central to survival, such as the heart or brain, may have evolved more mechanisms to defend against cancerous cells. Furthermore, humans may have naturally pushed out any genes that may have caused a prevalence in critical organ tumors through natural selection. The lesser selective pressure on lungs, which can also be considered a critical organ, is the fact that it is a paired organ and also much larger than the heart. Researchers are currently working to test their hypothesis through a complete analysis that takes into account all possible confounding factors.
Thomas et al. Evolutionary Ecology of Organs: A Missing Link in Cancer Development? 2016. Cell: Trends in Cancer. Vol. 2, 8:409-415. DOI: http://dx.doi.org/10.1016/j.trecan.2016.06.009
Olfcatory receptors have long been thought to be exclusively expressed within the nasal passage, limited to the olfactory epithelium. However, more recent research has identified other human tissues where olfactory receptors can be found, with some regulating essential physiological functions. In an article published in Frontiers of Physiology, researchers have found two additional olfactory receptors, OR2AG1 and OR1D2, in human airway smooth muscle cells located in the bronchi of lungs. OR2AG1 is activated by amyl butyrate, which in turn inhibited contraction of the smooth muscle cells. OR1D2 is activated by bourgeonal, leading to an increase in contraction.
Knowing what causes human airway smooth muscle cells to contract could lead to new therapeutic targets. One such strategy could involve blocking these specific olfactory receptors, OR2AG1 and OR1D2, to effectively reduce instances of contraction in patients with chronic inflammatory lung diseases.
Kalbe et al. Olfactory Receptors Modulate Physiological Processes in Human Airway Smooth Muscle Cells, 2016. Frontiers in Physiology. 7:339. DOI: http://dx.doi.org/10.3389/fphys.2016.00339
The flu vaccine is updated each year to protect against the strains that researchers believe will be most prevalent in the upcoming season. The process of having to track and update the influenza vaccine is costly and is not always effective in predicting the most prevalent strains for the upcoming year. However, a team of scientists headed by project lead Dr. Joyce at the Vaccine Research Center at NIH recently published in Cell the discovery of vaccine-induced antibodies that can eliminate multiple strains of influenza virus. Subjects that were enrolled in the VRC 310 trial (H5N1 DNA/MIV-prime-boost influenza vaccine trial) were found to have cross-reactive memory B cells. The B cells were found to encode 3 major classes of antibodies that were able to neutralize a variety of influenza subtypes.
How are these B cells able to react to various subtypes of the influenza virus?
The antibodies for the B cells were found to target the stem region of the virus, specifically reacting with the protein hemagglutinin, recognizing overlapping epitopes in the hemagglutinin stem. The stem itself is highly conserved among strains, allowing for the antibodies to recognize multiple strains of influenza. This could ultimately lead to the successful development of a universal influenza vaccine that is able to elicit broadly-neutralizing antibodies.
GenScript has a variety of services available to help you with your antibody studies:
Joyce et al. Vaccine-Induced Antibodies that Neutralize Group 1 and Group 2 Influenza A Viruses. 2016, Cell 166, 609-623. DOI: http://dx.doi.org/10.1016/j.cell.2016.06.043
Scientists and researchers alike are constantly looking for innovative ways to tackle cancer therapy. One method to attack cancer is through the use of immunotherapy. However, one of the recurring issues with immunotherapy is the immune system's inability to distinguish between cancer cells and healthy cells, decreasing their effectiveness in identifying which cells to attack. In more recent years, the use of a non-reproducing strain of Toxoplasma gondii to target solid tumors has gained popularity. In a new study published in PLOS Genetics, scientists have identified which of the parasite proteins are required to allow the immune system to target cancer cells. Through a series of deletions in parasite secreted effector proteins, the list of candidates were narrowed down to ROP5, ROP 17, ROP 18, ROP 35, and ROP 38 rhoptry proteins and GRA2, GRA12, and GRA 24 dense granule proteins as the activators of antitumor immunity seen in host responses.
How will this affect the future of cancer and tumor immunotherapy?
This research shows that specific proteins from parasites, and not the act of invasion itself, control host antitumor responses. It also further adds evidence to the effectiveness of using of either nonreplicating infectious organisms or their secreted proteins to combat tumors. By identifying which pathways are being affected by these proteins, scientists can further develop more efficient therapies against cancer.
GenScript has the expertise to help you in your pathogen-related studies. Let us help you build your constructs quickly so you can get to the research that matters!
Fox et al. Secretion of Rhoptry and Dense Granule Effector Proteins by Nonreplicating Toxoplasma gondii Uracil Auxotrophs Controls the Development of Antitumor Immunity 2016, PLOS Genetics 12(7): e1006189.
The antibiotic era is one that has given a plethora of positive advancements in the history of medicine. Their use has lead to a significant decline in human mortality and morbidity. Unfortunately, the frequency of pathogens that are resistant to antibiotics has increased over recent years. A variety last-resort antibiotics, such as polymyxin antibiotics, have been reserved to combat these resistant pathogens. However, pathogens can develop resistance to these last-resort antibiotics as well. In a recent article in Antimicrobial Agents and Chemotherapy, researchers have identified a new resistance gene, mcr-1.2 in the multidrug-resistant pathogen Klebsiella pneumonia. The bacterium was found from a rectal swab of a child with leukemia. The odd antibiotic profile of the bacterium caused the researchers in the study to further analyze the genome of the bacterium, resulting in the discovery of mcr-1.2.
What advantage does the mcr-1.2 gene give to Klebsiella pneumonia?
The mcr-1.2 gene gives Klebsiella pneumonia resistance to the last-resort antibiotic colistin. Furthermore, this gene variant is located on a plasmid, meaning that the resistance to colistin can be transferred between bacterium. These facts are alarmign because this is the first time an mcr gene has been found on Klebsiella pneumoniae and only a few cases of human infections that have caused by K. pneumoniae have been reported.
As a leader in gene synthesis with over 600,000 completed gene synthesis projects, GenScript has the expertise to help you in your pathogen-related studies. Let us help you get your constructs completely quickly, all with our industry-leading quality control:
Pilato et al. MCR-1.2: a new MCR variant encoded by a transferable plasmid from a colistin-resistant KPC carbapenemase-producing Klebsiella pneumoniae of sequence type 512 2016, AAC. DOI: http://dx.doi.org/10.1128/AAC.01075-16
One of the key indicators of Parkinson's disease is the accumulation of α-synuclein, resulting in the formation of both Lewy bodies and neurites. One of the key goals of researchers is to understand the specific mechanisms that result in this α-synuclein accumulation, which has long been poorly understood, until now. In an article published in The Journal of Clinical Investigation, researchers have discovered that abnormal hyperactivity of tyrosine kinase c-Abl critically regulates α-synuclein, causing an increase in both the amount of α-synuclein and the aggregation of α-synuclein.
Plants communicate with each other in a number of different ways, one of them being through electric signals. Much like how the human body uses electrical signals to communicate throughout the body, leaves also send electrical signals to other areas of the plant. However, the molecular tools used to receive such signals have long been a mystery, until now. In a recent article published in Plant Biology, researchers have identified the exact part of TPC1, a cation channel, responsible for acting as a sensor for electric fields. A 3-D model of the TPC1 protein was created , showing that the TPC1 protein is made of two interconnected protein units. Subsequent evolutionary analysis identified the second unit of TPC1 as a strong candidate since it has been highly conserved across all organisms over millions of years. Mutational analysis provided the final clue, showing that plants that carried the mutation in that subunit lost their ability to respond to electric fields.
How does TPC1 and its voltage sensor activity tie into Ebola Research?
It was recently found that the Ebola virus requires both TPC1 and TPC2 during host cell entry. This discovery has lead to the idea that the TPC proteins could be an effective target for therapy. With this new information how TPC1 functions in plants, researchers are hopeful that it will lead to new insights into the infection path of Ebola and a possible way to interfere with the infections path, through TPC1.
GenScript provides over 2 million ORF cDNAs in our CloneEZ™ ORF cDNA clone collection, including TPC1, to help accelerate this process so you can get your constructs fast, all with our industry-leading quality control:
Jaślan et al. Gating
cation channel AtTPC1 in the plant vacuole is based
on a single voltage-sensing domain.
2016, Plant Biol. 18(5): 750-60 DOI: http://dx.doi.org/10.1111/plb.12478
One of the key indicators of Parkinson's disease is the accumulation of α-synuclein, resulting in the formation of both Lewy bodies and neurites. One of the key goals of researchers is to understand the specific mechanisms that result in this α-synuclein accumulation, which has long been poorly understood, until now. In an article published in The Journal of Clinical Investigation, researchers have discovered that abnormal hyperactivity of tyrosine kinase c-Abl critically regulates α-synuclein, causing an increase in both the amount of α-synuclein and the aggregation of α-synuclein.
What causes the α-synuclein to aggregate in Parkinson's disease?
The phosphorylation of α-synuclein has been investigated extensively as a possible marker of Parkinson's disease pathology. Phosphoserine 129 α-synuclein has long been thought of as a contributor to the pathology of Parkinson's Disease. However, it appears that the phosphorylation of phosphotyrosine 39 by c-Abl kinase drives the accumulation of α-synuclein in Lewy bodies. This leads to phosphotyrosine 39 as a possible progression marker for Parkinson's Disease.
Scientists in this study used cloning and mutagenesis kits to manually construct the full-length WT human α-synuclein plasmid and the human α-synuclein mutant plasmids. GenScript offers a variety of cloning and mutagenesis options to help accelerate this process so you can get your constructs fast, all with our industry-leading quality control:
Brahmachari et al. Activation of tyrosine kinase
2016, The Journal of Clinical Investigation. DOI: http://dx.doi.org/10.1172/JCI85456
The inflammation associated with mosquito bites occurs as a result of chemicals and proteins in the mosquito saliva, specifically the anticoagulants that prevent blood from clotting. This evokes the commonly known response of itching and swelling localized to the area of the bite. However, the resulting inflammation can also aid in virus replication. In a recent article published in Cell: Immunity, researchers have discovered that the inflammation resulting from a mosquito's saliva not only helps arbovirus establish an infection, but also helps to propagate the arbovirus throughout the body.
How do arboviruses use myeloid cells to replicate?
According to the scientists in the study, the virus is retained at the site of the bite by the swelling. An inflammatory influx of neutrophils follows, which then eventually results in the recruitment of myeloid cells to the area of inflammation. It is these myeloid cells that get inadvertently infected by the invading virus. Researchers further proved the association by limiting the ability of the spread of the virus by suppressing inflammation through neutrophil depletion and blockade of inflammasome activity. Future treatments could focus on the mosquito bite site as a target to prevent virus infection.
In this study, scientists used cDNA clones of SFV virus when electroporating into BHK cells. GenScript offers a variety of services, from gene synthesis to express cloning, to make generating cDNA clones easy:
Pengen et al. Host
Response to Mosquito Bites Enhances the Severity of Arbovirus Infection.
2016, Cell: Immunity 44, 1455-1469 DOI: http://dx.doi.org/10.1016/j.immuni.2016.06.002
Tobacco smoking and its many negative health effects have been documented for years now. Lung diseases alone induced by smoking include emphysema, chronic bronchitis, and lung cancer. In come e-cigarettes in 2006, which many viewed as the healthy alternative to tobacco smoking. Dubbed the safer alternative to cigarettes, e-cigarettes have exploded in popularity in the years following their introduction. However, in a recent article published in the American Journal of Physiology – Lung Cellular and Molecular Physiology, researchers discovered that e-cigarette use actually suppressed more immune response genes in nasal epithelial cells than traditional smoking did. In this article, a clinical study involving the analysis of nasal scrape biopsies, nasal lavage, urine, and serum from 3 groups (nonsmokers, cigarette smokers, and e-cigarette users) were conducted to look for differential changes in gene expression profiles, specifically genes relating to the immune system. It was found that all genes that showed decreased expression in cigarette smokers, when compared to nonsmokers, were also decreased in e-cigarette smokers (n = 53) and to a greater degree. Furthermore, vaping was also associated with suppression of an additional 305 unique genes.
Does this mean e-cigarettes are worse than cigarettes?
The authors caution against making this comparison between the two. Vapor inhalation and smoke inhalation are two different processes. As a result, while there will be some similarities in the health effects seen, vaping could result in a different set of biological effects and resulting respiratory complications.
In this study, scientists identified over 300 genes that were suppressed in association with e-cigarette use. GenScript offers a variety of molecular biology services to accelerate your downstream research:
Martin et al. E-cigarette use results in suppression of immune and inflammatory-response genes in nasal epithelial cells similar to cigarette smoke 2016, American Journal of Physiology – Lung Cellular and Molecular Physiology 311.1, 135-144. DOI: http://dx.doi.org/10.1152/ajplung.00170.2016
Multiple sclerosis is a neurodegenerative disease where the immune system malfunctions and begins attacking the myelin surrounding nerve fibers. This causes disconnects in the way information flows between the brain and body, affecting more than 2 million people around the world. MS has long been known to have a hereditary component to it. However, the exact genetic link as to how it is passed from generation to generation remained elusive, until now. Researchers in a recent Cell: Neuron article have identified a gene, NR1H3, that when mutated, can result in a loss of function of its gene product, the LXRA protein. Mutant LXRA results in altered gene expression profiles, which results in MS pathogenesis. Mutant LXRA also resulted in an inability to form WT dimers, giving an explanation as to why altered expression profiles were seen.
How might this information help in treatments for MS?
This new information should help in the fight against MS by allowing researchers to develop models for MS in animals that are similar physiologically to the form of the disease seen in humans. In the end, this information will allow researchers a new method for studying the mechanisms causing the disease and, as a result, new drugs to target those specific mechanisms.
In studying used both a WT form of LXRA and a mutant form. GenScript has a variety of services available to help maximize the efficiency of your mutagenesis experiments:
Wang et al. Nuclear Receptor NR1H3 in Familial Multiple Sclerosis. 2016, Neuron 90, 948-954. DOI: http://dx.doi.org/10.1016/j.neuron.2016.04.039
The search for a vaccine for HIV has been an unsolvable riddle in the science field for the past few decades. Vaccine efforts have primarily focused on developing antibodies to the HIV envelope proteins, gp120 and gp41. While these efforts have successfully produced HIV-reactive antibodies, HIV's ability to evade vaccine-induced immunity continues to pose a challenge. Headed by project lead Dr. Stewart-Jones in Dr. Kwong's group, a team of scientists at NIH-NIAID-VRC recently published atomic-level details of the glycan shields surrounding the HIV-1 Env trimers from clades A, B, and G.
How might this information help in the search for a vaccine for HIV?
In this research report, Dr. Guillaume Stewart-Jones and the team of scientists were able to crystallize fully glycosylated HIV-1 envelope trimers from 3 separate clades: A, B, and G. It was found, among other things, there were a variety of glycan conformations and glycan-glycan interactions. Knowing the specific structures and the distributions of the glycans within the glycan shields could ultimately aid scientists in designing vaccines that will be able to take into account not only the shape of the protein trimers, but the glycan shields surrounding them. Antibodies should, as a result, be able to bind more efficiently to their targets, leading to a more effective immune response.
GenScript has a variety of services available to help you with your crystallography/antibody studies:
Stewart-Jones et al. Trimeric HIV-1-Env Structures Define Glycan Shields from Clades A, B, and G. 2016, Cell 165, 1–14. DOI: http://dx.doi.org/10.1016/j.cell.2016.04.010
The mitochondrion has long been considered to be an essential organelle for all eukaryotes, functioning as the power supply for cells. However, a recent report in Current Biology challenges this notion with the discovery of a eukaryotic organism, Monocercomonoides sp, which lacks any mitochondrial genes or proteins.
How can this eukaryote exist without mitochondria?
In this study, the authors discovered that this particular species in fact did have mitochondria at one point; however, the mitochondria were eventually lost. In its place, the microbe acquired, by lateral gene transfer, a sulfur mobilization system to replace the Fe-S cluster forming pathways. Ultimately this paper reveals how far certain eukaryotes, from underexplored environments, have adapted and evolved.
GenScript offers a variety of services to support important microbial discoveries:
Karnkowska et al. A eukaryote without a mitochondrial organelle. Current Biology. 2016; 26(10): 1274-1284. DOI: 10.1016/j.cub.2016.03.053
Oct4 gene expression is a hallmark of pluripotency, and expression is typically lost as pluripotent cells differentiate; however, Oct4 expression in somatic cells has also been reported. While the significance of this has been largely unclear, a recent study published in Nature Medicine has uncovered, for the first time, a functional role for OCT4 in somatic cells.
How does OCT4 prevent against athersclerosis?
In this report, the authors used ApoE-/- mouse models to study the impact of Oct4 expression on smooth muscle cells (SMC), which dedifferentiate during the development of atherosclerosis. In Oct4- KO mice, plaque pathogenesis was exacerbated and SMC migration was impaired, which are both indicators of worsening atherosclerosis. Could targeting Oct4 be a new approach to improving the pathogenesis of this disease?
Cherepanova et al. Activation of the pluripotency factor OCT4 in smooth muscle cells is atheroprotective. Nature Medicine. 2016. DOI:10.1038/nm.4109
How much of your sense of wellbeing can be attributed to genetics? A recent GWAS study has revealed that there likely is a genetic predisposition to a variety of psychological traits – from happiness to depression. Using publically available data, the authors identified multiple genes that appeared to be linked to subjective wellbeing, depression and neuroticism. They found that there were genetic variants linked to each trait: 3 SNPs were linked to wellbeing, 2 were associated with depression, and 11 were associated with neuroticism. Interestingly, they were also able to genetically link neuropsychiatric phenotypes and health indicators with some of these variants. For instance, they found that those suffering from anxiety had the largest genetic correlation with depression and neuroticism variants, but not with subjective wellbeing.
To accelerate your research, GenScript offers:
Okbay et al. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analysis. Nature Genetics. 2016 April. DOI: 10.1038/ng.3552
How many genes does an organism really need to sustain life? This has been a question Craig Venter, a synthetic biologist and founder of the J. Craig Venter Institute in La Jolla, CA, has been trying to answer. In a recent Science report, Venter's team has described the synthesis of a synthetic cell, coined JCVI-syn3.0, with a 531 kbp genome consisting of 473 genes.
What can we learn from this minimal cell?
From this minimal genome, the authors were able to dissect which genes were essential and which were nonessential. Using Tn5 mutagenesis, they identified 4 major gene functional groups: of the 473 genes, 48% were involved with expression or preservation of genome information, 17% were involved with cytosolic metabolism, and 18% expressed proteins associated with the cell membrane. Interestingly, 17% of the genome still had unknown function. Overall, this simply cell can play a significant role in exploring genome function.
GenScript's services accelerate exploration of genome function:
Hutchison et al. Design and
synthesis of a
minimal bacterial genome.
Science. 2016; 351:aad6253. DOI: 10.1126/science.aad6253
There are a variety of diseases that are in part caused by dysfunctional trafficking of RNA from the nucleus for translation. To enable RNA tracking within a live cell, and to get more insight into how trafficking dysfunction accelerates disease, a group out of UCSD has turned to the revolutionary gene editing tool, CRISPR/Cas9. To difference is though, that the group altered the Cas9 protein to specifically target RNA as opposed to DNA.
How can CRISPR track RNA in living cells?
In this report published in Cell, the RNA-targeting Cas9 (RCas9) recognizes an RNA-specific PAM sequence (PAMmer) to enable localization to RNA. With GFP fused to the RCas9, the authors could visualize GAPDH, ACTB, TFRC and CCNA2 mRNA movement within the cell.
Nelles et al. Programmable RNA Tracking in Live Cells with CRISPR/Cas9. Cell. 2016; 165: 488-496.
The spread of the Zika virus remains a global health concern, with outbreaks reported in multiple countries in the Americas and Africa. While typically symptoms are mild and last only a few days, there have been reports that babies born to infected mothers are more likely to develop microcephaly. A recent report in Cell Stem Cell has confirmed this link by identifying a potential mechanism for how Zika influences normal brain development.
In this study, the authors examined (1) the potential for Zika to infect human embryonic cortical neural progenitor cells (hNPCs) and (2) how infection by the virus influences cell growth. They found that not only could Zika infect hNPCs with high efficiency, but infected hNPCs secrete the Zika particles themselves to infect surrounding cells. In addition, Zika infection increases cell death and causes cell cycle dysregulation, which demonstrates how the virus causes abnormal brain development. In addition, Zika's ability to so efficiently infect neural progenitor cells also brings into question what this virus could do to adult neural function.
Tang et al. Zika virus
human cortical neural progenitors and attenuates their growth.
Cell Stem Cell. 2016; 18 : 1-4. DOI: 10.1016/j.stem.2016.02.016
The genes that are associated with a variety of hair traits – from beard texture to unibrows and greying hair – have finally been identified through a genome-wide screen in over 6,000 Latin Americans. The results of this study were recently published in Nature Communications, and the findings include:
Could gene therapy be the trick to preventing grey hair?
To accelerate your research, GenScript offers:
Adhikari et al. A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features. Nature Communications. 2016; 7(10815). DOI: 10.1038/ncomms10815.
Detecting cell death can be an indicator for progression of cancer or graft failure; however, the source of this cell-free circulating DNA (cfDNA) until recently has been unidentifiable. In a recent PNAS publication, scientists sought to find an efficient way to quickly identify where the DNA was coming from in order to advance treatment.
How can cfDNA be identified?
In this report, the authors developed a blood-based diagnostic test based on the principles that (1) dying cells release fragmented DNA into the bloodstream and (2) that each tissue contains DNA with a unique methylation pattern. Based on these unique methylation patterns, plasma samples were collected from healthy patients and those with multiple sclerosis, acute brain damage and pancreatic cancer. In all cases, oligodendocyte-specifc, brain-specific or pancreatic-specific DNA could be detected in plasma samples for each disease, respectively. Ultimately this quick test could revolutionize the detection and treatment of potentially lethal disease.
To accelerate your research, GenScript offers:
Lehmann-Werman et al. Identification of
death using methylation patterns of circulating DNA.
PNAS. 2016; 1-9. DOI: 10.1073/pnas.1519286113
Glioblastoma, one of the most lethal brain tumors, is associated with a mean survival rate of only 14.6 months, with a 5-year survival rate of less than 10% even after chemotherapy or radiation. Immunotherapy is emerging as an alternative to these common therapeutics, and CAR-T cells have the potential to sufficiently boost the immune system to target and kill tumor cells. In a recent Cancer Immunology Research publication, the authors describe a new CAR-T strategy to target glioblastoma.
How were these CAR-T cells designed?
In this study, CAR-T were constructed with CD28, 4-1BB and CD3ζ intracellular domains to target podoplanin (PDPN), which is highly upregulated in lymphatic epithelium. The engineered CAR-T cells were highly specific, and injection of these T cells into immundeficient mice decreased tumor growth by 60% compared to controls. These results confirm the potential of immunotherapy in the treatment of brain tumors.
Resources supporting CAR-T therapy research:
Shiina et al. CAR T cells targeting
orthotopic glioblastomas in mouse
Cancer Immunol Res. 2016 Mar; 4(3): 259-68. DOI: 10.1158/2326-6066.
How might individuals that share similar genetic traits, such as identical twins, have different weights? While obesity, or weight gain in general, is typically the result of environmental factors, there is increasing evidence of how genetics can play a role in determining weight. Specifically, a recent study published in Cell reveals that predisposition to weight gain is in part determined by epigenetic regulation.
How does epigenetics contribute to obesity?
Previously, it had been observed that genetically identical mice with a single copy of Trim28, which encodes for a chromatin-interacting regulatory protein, had significant differences in weight. In fact, happloinsufficiency led to more obese phenotypes in children. The lower Twin28 activity was in turn linked to decreased activity of obesity-associated imprinted gene networks that include Nnat, Peg3, Cdkn1c and Plagl1. Ultimately, this study demonstrates how complex genetic traits, such as obesity, can be.
To accelerate your research, GenScript offers:
Dalgaard et al. Trim28 Happloinsufficiency
Bi-Stable Epigenetic Obesity.
Cell. 2016; 164: 353-364. DOI: 10.1016/j.cell.2015.12.025.
Why do we crave sweet foods, and what turns it off? A recent study published in Cell Metabolism has uncovered the mechanism behind our sugar appetite, and it starts in the liver. The authors found that carbohydrate intake activates the expression of fibroblast growth factor 21 (FGF21). Once we've gotten our fix, FGF21 acts on the hypothalamus to turn off the craving. What might this finding mean for treatment of obesity and type 2 diabetes?
To accelerate your research, GenScript offers:
Von Holstein-Rathlou et al. FGF21 mediates endocrine control of
and sweet taste preference by the liver.
Cell Metabolism. 2016; 23: 1-9. DOI: 10.1016/j.cmet.2015.12.003
Schizophrenia is an heritable psychiatric disorder with unknown pathogenic mechanisms; however, a recent Nature publication has unveiled a surprising, new genetic association. In this paper, the authors found that variations of the complement component 4 (C4) gene, which is commonly involved in maintaining immunity, was involved in adolescent synaptic pruning, ultimately leading to development of schizophrenia. Could targeting C4 be an option for gene therapy?
Sekar et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016 Feb 11; 530: 177-183.
As the ancient remains of Ötzi, a 5,300-year old Iceman discovered in the Alps in 1991, are studied, interesting clues into his descent and overall health have been revealed. In a recent Science report, scientists have sequenced the gut microbiota and discovered the presence of H. pylori, a microbe that has evolved into multiple strains over time. Even more interesting, the H.pylori genome indicated the microbe was of Asian and not European origin. What does this mean about the history of human migration?
Maixner et al. The
pylori genome of the Iceman.
Science. 2016 Jan 8; 351 (6269): 162-165. DOI: 10.1126/science.aad2545.
The Zika virus, which is carried by infected mosquitos of the Aedes genus, has been spreading aggressively over the past 9 months. Following the first report in Brazil in May 2015, the virus has now spread to at least 25 countries. While symptoms for the virus are relatively mild, the risk to unborn children is more severe, and can lead to significant birth defects. Interestingly, the virus had gone years without an outbreak of this proportion, so why the sudden change? A recent report, currently under peer review, suggests that mutations to the viral genome may have contributed to its ability to infect cells so easily. Specifically, NS1 codon usage adaptation may have enabled viral replication in human cells.
Learn more about how GenScript's services enable vaccine design and discovery:
Molecular Biology services:
Freire et al. Spread of the pandemic Zika virus lineage is associated with NS1 codon usage adaptation in humans. 2015. DOI: 10.1101/032839
Until recently, studying the direct relationship between epigenetics and gene expression within a single cell has been difficult to address; however, a recent publication in Nature Methods describes a new approach to do so. This method, called scM&T seq (single cell genome and transcriptome sequencing) allows direct association DNA methylation and transcription without impacting the transcriptome itself. As a proof of concept, the authors investigated the relationship between methylation and maintenance of pluripotency in embryonic stem cells (ESCs). From these studies, they identified important mechanistic controls that regulate pluripotency in the presence or absence of serum.
To accelerate your research, GenScript offers:
Angermueller et al. Parallel
single-cell sequencing links transcriptional and epigenetic
Nature Methods. 2016 Jan 11. DOI: 10.1038/nmeth.3728
Which genes control human intelligence? To address this question, a group out of the Imperial College of London used a systems genetics approach to find out how genetics regulates cognition. In doing so they identified two networks, M1 and M3, that contain genetic variants which play a role in cognitive abilities such as memory. Further, the authors elucidated that genes within the M3 network are associated with neurodevelopmental conditions including autism, epilepsy and schizophrenia.
Johnson et al. Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease. Nature Neuroscience. 2015 Sep 08. DOI: 10.1038/nn.4205
The predatory bacterium Bdellovibrio bacteriovorus attacks other bacteria by loosening their cell walls with enzymes called DD-endopeptidases. Once the cell walls are loosened, B.bacteriovorus enters the infected cell and metabolizes the intracellular components. DD-endopeptidases function by targeting peptidoglycan, and so the question is how B.bacteriovorus remains unaffected by the weapons it releases. Turns out there is a gene responsible for neutralizing the toxin, protecting the bacterium from its own attack.
How does this "self-protection" work?
In this study, the authors identified for the first time a self-protection ankyrin protein, Bd3460, which prevents DD-endopeptidase from complexing with B.bacteriovorus' peptidoglycan as it is released from the cell Consequently, the predator's cell wall remains intact, allowing the bacterium to target and attack prey bacteria. By identifying the genes that promote bacterial resistance, this could open doors to target antibiotic-resistant bacteria.
Lambert et al. Ankyrin-mediated self-protection during cell invasion by the bacterial predator Bdellovibrio bacteriovorus. Nature Communications. 2015; 6:8884. DOI: 10.1038/ncomms9884.
Heart failure (HF) affects millions of individuals worldwide, and with a lack of molecular markers for the disease the development of targeted therapeutics has been hindered. In an effort to find gene variants associated with HF, a systems genomics approach was used to dissect gene expression patterns in patients with heart failure.
Is there a gene that is linked to heart failure?
From this study, the authors identified a gene variant, HCRTR2, that was associated with regulating cardiac function. This gene encodes a receptor that binds neuropeptides, specifically orexin, which regulate sleep. Specifically, mutations to HCRTR2 have been previously shown to cause epilepsy. So while HCRTR2 agonists may have a potential therapeutic balance, future therapeutics may require a balance between sleep regulation and heart function.
Perez et al. Systems genomics identifies a key role for hypocretin/orexin receptor-2 in human heart failure. J Am Coll Cardiol. 2015 Dec; 66(22): 2522-33. DOI: 10.1016/j.jacc.2015.09.061
The secret to a long and healthy life may in fact be in your genes. In an effort to uncover gene transcripts that are involved in ageing, samples from C. elegans, zebrafish and mice were collected and compared between different developmental timepoints. From this screen, the authors identified 12 genes that when inhibited using RNAi, could increase lifespan by 5%. Specifically, inhibition of one gene in particular, bcat-1, extended mean lifespan in C.elegans by 25%. Upon further investigation, they found that impaired bcat-1 expression led to an accumulation of branched-chain amino acids in tissues. Interestingly, when nematodes were fed supplements of these amino acids, there was a similar effect on lifespan, suggesting a potential new target to reverse physiological ageing.
Mansfeld et al. Branched-chain amino acid catabolism is a conserved regulator of physiological ageing. Nature Communications. 2015; 6: 10043. DOI: 10.1038/ncomms10043
A new study in PNAS presents a revolutionary new approach to fight malaria with the help of synthetic biology. Two single-chain antibodies that target the critical Plasmodium faciparum proteins Chitinase 1 and CSP can be expressed in mosquitoes to render them incapable of transmitting parasites to humans. This new study characterizes a CRISPR-Cas9-mediated gene-drive system that may be used to safely and efficiently introduce these genes into wild mosquito populations to support global malaria eradication efforts.
To accelerate your research, GenScript offers:
Gantz et al. Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi. PNAS 2015; published ahead of print November 23, 2015, doi:10.1073/pnas.1521077112. Read the Full Text »
The freshwater cnidarian Hydra is known for its unique ability to reform a complete individual from any fragment of its body, a tremendous feat of regeneration. A new study sheds light on how epithelial cells in Hydra respond to the loss of all neural cells and the stem cells that give rise to them; the epithelial cells themselves radically shift their transcriptional programs to upregulate over a dozen genes associated with neurogenesis and neurotransmission.
Understanding how epithelial cells can acquire neuron-like sensing and signaling capabilities may lead to new strategies for regenerative medicine, for example to compensate for neuronal cell death in neurodegenerative disease.
To accelerate your research, GenScript offers:
Wenger et al. Loss of neurogenesis in Hydra leads to compensatory regulation of neurogenic and neurotransmission genes in epithelial cells. Phil. Trans. R. Soc. B 2016 371 20150040; DOI: 10.1098/rstb.2015.0040. Published 23 November 2015. Read the Full Text »
A new study in Nature Communications sheds light on how male fruit flies decide to mate and how effectively they compete with rival males. The study finds that the fatty acid elongase gene named james bond is vital to sex pheremone biosynthesis. Comparative analysis across Drosophila species paints a picture of how evolution uses modifications to cis-regulatory elements as a mechanism to expand pheremone diversity.
This study used gene synthesis servies from GenScript to generate plasmids used to construct transgenic lines of fruit flies. To accelerate your research, GenScript offers:
Ng et al. The fatty acid elongase Bond is essential for Drosophila sex pheromone synthesis and male fertility. Nat Commun. 2015 Sep 15;6:8263. doi: 10.1038/ncomms9263. Read the Full Text »
A major breakthrough in understanding how pathogenic microbes develop resistance to antibiotic drugs has been reported in Nature Communications. By examining combinations of seven mutations in dihydrofolate reductase that microbes can acquire to gain trimetoprim resistance, researchers found that evolution toward proceeds along less direct paths than might be expected, as cells range through a multipeaked adaptive landscape and delay commitment to a single genotypic fate.
What does this mean for efforts to predict and counteract the emergence of antibiotic-resistant pathogens? It's bad news for researchers, as it reveals that microbes keep their options open to many different possible indirect paths toward collecting a set of mutations whose epistatic interactions generate the ability to survive the onslaught of modern medicine's best antimicrobial weapons.
As the arms race between humans and pathogenic microbes continues, GenScript is here to help accelerate your research by offering molecular biology services including:
Palmer AC et al. Delayed commitment to evolutionary fate in antibiotic resistance fitness landscapes. Nat Commun. 2015 Jun 10;6:7385. Read the Full Text »
West Nile Virus, the potentially deadly mosquito-borne pathogen that has spread through the US since 1999, causes neuropathology and death in a small percentage of infected individuals. To discover how WNV causes neuronal cell death, researchers turned to genome-wide screening, and chose a CRISPR-mediated knockout approach as a more powerful tool compared to older RNAi-based screening technology.
As a result of this screen, seven essential genes were found link WNV to neuronal cell death: EMC2, EMC3, SEL1L, DERL2, UBE2G2, UBE2J1, and HRD1. Importantly, all of these genes are members of the endoplasmic reticulum-associated protein degradation (ERAD) pathway, suggesting the robustness of the screening results and highlighting this pathway as a prime target for further basic research and therapeutic development.
To accelerate your research on the genetic and molecular mechanisms of viral diseases, GenScript offers:
Ma H. et al. A CRISPR-based screen identifies genes essential for West Nile virus-induced cell death. Cell Rep. 2015 Jul 28;12(4):673-83. doi: 10.1016/j.celrep.2015.06.049. Read the Full Text »
A study recently published in Nature provides new evidence that gut microbes influence the immune system – in this case, by causing neutrophils to enter a pro-inflammatory "aged" state that exacerbates sickle cell disease and septic shock. Clinical studies of children with SCD revealed that daily penicillin – normally prescribed to control infection – also reduced the number of aged neutrophils in circulation, which could prevent sickle-cell crisis and chronic tissue damage.
How does the gut microbiome influence circulating neutrophils? Gut microbes secrete signals that pass through the intestinal lining into the bloodstream and activate neurophils via signaling pathways that include toll-like receptor and myeloid differentiation factor 88. These neutrophils take on a "aged" phenotype that includes enhanced αMβ2 integrin activation and enhanced pro-inflammatory activity that promotes tissue pathology.
GenScript offers molecular biology services to accelerate your research:
Zhang D. et al. Neutrophil ageing is regulated by the microbiome. Nature. 2015 Sep 24;525(7570):528-32. doi: 10.1038/nature15367. Read the Full Text »
On October 7, 2015, Australia's High Court ruled invalid the BRCA1 gene patent held by Myriad Genetics, finding that naturally-occurring DNA sequences – including mutations associated with disease – cannot be patented. This new ruling is consistent with a 2013 decision by the US Supreme Court and suggests the end of gene patents on a global scale. Researchers, biotech leaders, and patient advocacy groups are all weighing in on how this legal decision will affect the development of, and patient access to, new diagnostics that screen for genetic risk factors for disease.
The US Supreme Court's 2013 decision notes that "Patent protection strikes a delicate balance between creating "incentives that lead to creation, invention, and discovery" and "imped[ing] the flow of information that might permit, indeed spur, invention." They find that, while Myriad did discover the precise location and genetic sequence of BRCA1 and BRCA2, there was no "new and useful composition of matter" to fulfill the requirements of patent eligibility.
The NIH and numerous professional organizations have issued statements supporting the US Supreme Court's 2013 ruling on gene patents; as NIH Director Francis Collins writes, "The right to control exclusively the use of a patient's genes could have made it more difficult to access new tests and treatments." In contrast, a statement from the Biotech Industry Organization notes that "companies that research, develop and use modern biotechnology to produce products ranging from life-saving medicines and vaccines to renewable fuels, industrial enzymes and disease-or pest-resistant crops…have long relied on patents on preparations of DNA molecules and other biological chemicals in order to bring innovative, socially beneficial products to the marketplace."
While patent protection undoubtedly spurs biotechnology business investment, narrowing the scope of patents may avoid the risk that patents can stifle innovation. A recent analysis of gene patents published in Nature Biotechnology discusses differences in the uses of patented gene sequences in medicine versus crop-based agriculture, and show that patented human gene sequences map to homologous regions in diverse plant species extremely frequently, highlighting the need to narrow the scope of gene patentability, among other efforts to stimulate biological innovation across different industries and fields of study.
To accelerate your research on the human disease genetics or synthetic biology for any application, GenScript offers:
Gene Patent Practice across plant and human genomes. Jefferson et al. Nature Biotechnology 33, 1033–1038 (2015) doi:10.1038/nbt.3364
A new technique reported in Nature Communications may make it easier and safer to activate neuronal activity in deep brain regions for both research and therapeutic uses. The approach is somewhat similar to optogenetics, which uses light to stimulate photo-activatable receptors. But by employing low-frequency ultrasound, which can travel through the body without any scattering, sonogenetics allows greater precision and deeper tissue penetration from a non-invasive stimulus.
The TRP-4 channel in C. elegans was used as a proof-of-principle to demonstrate the power of sonogenetics. This mechanosensory ion channel is normally unaffected by ultrasound, but the researchers were able to use gas-filled microbubbles to transduce the ultrasound waves and make TRP-4 channels respond to them. Then, by expressing TRP-4 in neurons that don't normally express it, researchers were able to activate both sensory neurons and interneurons with low-pressure ultrasound. Sonogenetics could be used for diverse applications – potentially even for medical applications, since ultrasound is already widely used for medical sonography.
Ibsen et al. Sonogenetics is a non-invasive approach to activating neurons in Caenorhabditis elegans. Nature Communications, 2015; 6: 8264 DOI: 10.1038/ncomms9264 Read the Full Text »
A new study in Nature Communications shines a spotlight on the earliest stages of human development – from fertilized oocyte to zygote and then to day 3 embryos containing up to 10 cells. Using novel techniques for single-cell sequencing, researchers created a precise inventory of mRNA transcripts at different developmental stages. To their surprise, they found that a majority of highly upregulated transcripts in the early transition from oocyte to four-cell embyro actually map not to known coding regions but to unannotated genomic regions – which are hot new candidates for novel factors that could be extremely valuable to stem cell research going forward.
They also deduced from studying the far 5' end of transcripts that the master regulators that guide gene expression changes critical for embryogenesis are Alu elements and PRD-like homeobox genes.
These findings will inform future research on embryogenesis and infertility, as well as basic stem cell research and clinical applications such as reprogramming iPS cells for regenerative medicine. GenScript offers molecular biology services to accelerate your research:
Töhönen et al. Novel PRD-like homeodomain transcription factors and retrotransposon elements in early human development. Nat Commun. 2015 Sep 11;6:8207. doi: 10.1038/ncomms9207. Read the Full Text »
A new study finds that polyphenols that occur naturally in wild blueberry plants can inhibit the growth of bacteria that cause gum disease. F. nucleatum proliferates and forms biofilms in our mouths – what we know as dental plaque – which can lead to gingivitis and periodontitis. Polyphenol-rich wild blueberry extract acts not only as an antibacterial, but also quells the inflammatory response that makes gum disease so painful. Researchers are working to develop a method to deliver these antibacterial, anti-inflammatory polyphenols to the gum in between dental cleanings in order to avoid the development of periodontitis. Since periodontitis is typically treated with conventional antibiotics, this new move could reduce antibiotic use, which helps prevent the development of antibiotic resistance among the bacterial communities that make up our oral microbiome.
GenScript offers molecular biology services to accelerate your research:
Ben Lagha et al. Wild Blueberry (Vaccinium angustifolium Ait.) Polyphenols Target Fusobacterium nucleatum and the Host Inflammatory Response: Potential Innovative Molecules for Treating Periodontal Diseases. J Agric Food Chem. 2015 Aug 12;63(31):6999-7008. doi: 10.1021/acs.jafc.5b01525. Read the Full Text »
A systematic review and meta-analysis published in the Lancet finds that people who work 55 hours or more per week have a 33% higher stroke incidence, and 13% increase in relative risk of coronary heart disease, compared to those who work a standard 35-40 hour work week.
This study has already sparked heated discussion in the popular media and among scientists. While many feel that the expansive dataset from over 600,000 patients from across the world presents a strong case that these effects are real, others caution, as always, that correlation does not equal causation. And while some insist this study indicates a dire need for better public health measures to spread awareness of vascular risk factors in the workforce, others think policy impact will be negligible as long work hours have become a cultural norm in many competitive professional fields that are exempt from labor regulations.
To help you get more out of each hour you spend in the lab, GenScript offers molecular biology services to accelerate your research:
Kivimäki et al. Long working hours and risk of coronary heart disease and stroke: a systematic review and meta-analysis of published and unpublished data for 603 838 individuals. Lancet. 2015 Aug 19. pii: S0140-6736(15)60295-1. doi: 10.1016/S0140-6736(15)60295-1 Read the Full Text »
A new paper published in Science shows how a single mammalian-specific exon-skipping event drives widespread changes in splicing that drive neurogenesis in big-brained mammals like humans.
A remarkable cache of over 1,500 fossils in a South African cave has revealed a new member of the hominin family.
Although most moles on our skin are benign, these common bumps sometimes transform into melanoma, one of the deadliest forms of cancer. A recent study in Cancer Discovery identifies the critical gene that keeps the common oncogenic BRAF(V600E) mutation in check in moles: the CDKN2B gene encodes the p15 tumor suppressor protein, which can halt cell proliferation via TGFβ. The paper also demonstrates a new in vivo melanoma model, derived from human skin grafts, that accurately reproduces the 3D tissue architecture of moles.
GenScript offers molecular biology services to help you uncover molecular mechanisms of cancer biology in your research:
McNeal et al. CDKN2B loss promotes progression from benign melanocytic nevus to melanoma. Cancer Discov. 2015 Jul 16. pii: CD-15-0196. Read the Full Text
New research shows for the first time in humans that white adipose tissue can undergo a change to resemble brown fat, which burns calories. The paper published in Cell Metabolism found that adrenergic stress in burn patients led to fat "browning" as measured by enriched UCP1, mitochondrial density, and metabolic rate. These molecular mechanisms may be harnessed to develop drugs that help prevent and treat obesity and metabolic disease.
GenScript offers molecular biology services to help you uncover molecular mechanisms of disease in your research:
Sidossis et al. Browning of Subcutaneous White Adipose Tissue in Humans after Severe Adrenergic Stress. Cell Metab. 2015 Aug 4;22(2):219-27. Read the Full Text
A CRISPR-based research tool has identified dozens of genes that enable cancer drug resistance – including both known genes such as EGFR and new GPCRs. The dCas9-based Synergistic Activation Mediator (SAM) complex robustly activates transcription of endogenous genes using guide RNA to target the complex to any genomic locus of interest. A genome-wide library of guides enabled SAM to perform unbiased screening of genes whose activation gives rise to a phenotype of interest such as drug resistance.
SAM offers several advantages compared to a traditional approach of overexpression from cDNA. First, SAM activates endogenous gene transcription, which better allows it to capture mutations/variants in the specific primary cell or cell line in hand, as well as the complexity of transcript isoform variance. In addition, SAM avoid the difficulty of cloning large cDNA sequences into size-limited expression vectors, as well as the cost and complexity of synthesizing and using pooled cDNA libraries. And compared to previously reported CRISPR-based transcription activators, SAM shows more consistent, robust activation of genes and has been validated not only for a small subset of genes but in fact across the entire human genome.
To aid your research, GenScript offers:
*GenScript's CRISPR reagents are designed by Feng Zhang's laboratory and offered through a license with the Broad Institute.
Konermann et al. Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex. Nat Methods. 2014 Aug;11(8):783-4. Read the Full Text
Chronic kidney disease affects 26 million Americans, and when it progresses to renal fibrosis it requires dialysis or kidney transplantation. A new study in Nature Medicine reports that the expression of just two genes involved in epithelial-to-mesenchymal transition, Twist1 and Snai1, can recapitulate the fibrotic disease state of tubular epithelial cells; even more exciting, inhibiting Twist1 and Snai1 reverses chronic renal injury in mouse models of renal fibrosis.
To help you discover and characterize genes that drive kidney disease phenotypes and that may be game-changing therapeutic targets, GenScript offers:
To assist your genome editing efforts, GenScript offers CRISPR reagents designed by Feng Zhang’s laboratory and offered through a license with the Broad Institute:
*GenScript's CRISPR reagents are designed by Feng Zhang's laboratory and offered through a license with the Broad Institute.
Lovisa et al. Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nat Med. 2015 Aug 3. doi: 10.1038/nm.3902. Read the Full Text
After years of backcrossing your transgenic mice, is it possible that the phenotypic effects you're studying are artifacts of strain differences and not truly caused by your gene of interest? A new study in Immunity asserts that passenger mutations that are conserved throughout backcrossing confound interpretation of all genetically modified congenic mice.
Fortunately, there’s a faster and more foolproof way to manipulate mouse genomes: CRISPR genome editing is now a mature technology with hundreds of peer-reviewed studies demonstrating its use to create heritable, homozygous knock-out or knock-in mice within a single generation. Best of all, CRISPR shows unprecedented specificity and efficiency, with no need to back-cross, allowing you to start using fully-validated new transgenic mouse strains within weeks instead of years.
To assist your genome editing efforts, GenScript offers CRISPR reagents designed by Feng Zhang’s laboratory and offered through a license with the Broad Institute:
Vanden Berghe et al. Passenger Mutations Confound Interpretation of All Genetically Modified Congenic Mice. Immunity. 2015 Jul 21;43(1):200-9. doi: 10.1016/j.immuni.2015.06.011.Read the Full Text
Biomedical research is expensive – making it all the more important to carefully design and execute experiments that yield reproducible results. A recent study published in PLoS Biology found that half of all preclinical research spending in the US – over $28.2 billion/year – is lost to unreproducible studies that delay the discovery of life-saving therapies.
The study identified four primary sources of error, the most common of which is faulty biological reagents and reference materials. The authors recommend best practices to improve the efficiency of biomedical research spending, such as having funders and publishers require PIs to document reagent validation.
GenScript makes it easy to obtain reliable, validated bioreagents with ISO 9001 quality assurance certification. All DNA constructs from GenScript are sequence-verified with 100% accuracy guaranteed, and accompanied by sequence chromatograms, plasmid maps, and COA documentation to prove it.
Freedman LP, Cockburn IM, and Simcoe TS. The Economics of Reproducibility in Preclinical Research. PLoS Biology June 2015. DOI: 10.1371/journal.pbio.1002165 Read the Full Text
A new paper in the Journal of Clinical Investigation shows that a single dose of an aerosolized Ebola vaccine protects against subsequent lethal challenge with the Ebola virus in rhesus macaques. If these results hold up in human clinical trials, it could be a boon for people living in the remote areas such as those where last year's Ebola epidemic originated, as inhaled vaccines can be administered without the medical training required for injectable vaccines.
This is the first time an aerosolized vaccine has been designed to target a filovirus; the vaccine itself consists of an Ebola glycoprotein packaged in a human parainfluenza viral vector. To support research to characterize viral antigens and design vaccines, GenScript offers Gene Synthesis services to provide the custom DNA constructs you need with 100% sequence accuracy.
Meyer et al. Aerosolized Ebola vaccine protects primates and elicits lung-resident T cell responses. J Clin Invest. 2015. doi:10.1172/JCI81532. Read Full Text
Cornell students participating in the international Genetically Engineered Machine (iGEM) competition are bringing underprivileged youth into the world of science research and showing the public how synthetic biology solves real-world problems.
Inside the lab, the Cornell iGEM team is developing bacterial probiotics to keep fisheries healthy. Outside the lab, they volunteer as mentors to get children exited about biology and teach a hands-on synthetic biology crash course to high school students. While the team's reagent costs have been covered by sponsorship from GenScript and other supporters, they're now seeking crowd-funding to cover remaining project costs.
GenScript is proud to sponsor iGEM teams from around the globe for the 7th year in a row. Read about the projects and awards of GenScript-Sponsored teams » GenScript's molecular biology services enable iGEM teams to create new biological building blocks and to recombine modular genetic parts into optimized synthetic gene circuits.
As pathogenic bacteria acquire resistance to common antibiotics, researchers are racing to discover or engineer new drugs. A recent paper in Science Advances reveals the power of modular engineering of biosynthetic pathways to create valuable new compounds. By assembling different combinations of tailoring enzymes, they created 42 new analogs of erythromycin, 3 of which are effective against erythromycin-resistant bacteria.
To support your metabolic engineering projects, GenScript offers:
Zhang G et al. Tailoring pathway modularity in the biosynthesis of erythromycin analogs heterologously engineered in E. coli. Science Advances 2015 May; 1(4):e1500077 Read the Full Text
As we learn more about the human microbiome, evidence keeps mounting that the 'Gut-Brain Axis' enables our intestinal bacteria to influence our mood and mental health:
To support your studies of genes – human or microbial – and their influence on human health and disease, GenScript offers molecular biology services including Gene Synthesis and CRISPR genome editing.
Christian et al. Gut microbiome composition is associated with temperament during early childhood. Brain, Behavior, and Immunity, 2015; 45: 118 DOI: Read the Full Text
Keightley et al. Pathways in gut-brain communication: evidence for distinct gut-to-brain and brain-to-gut syndromes. Aust N Z J Psychiatry. 2015 Mar;49(3):207-14. Read the Full Text
Partty et al. A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood: a randomized trial. Pediatr Res. 2015 Jun;77(6):823-8. doi: 10.1038/pr.2015.51. Read the Full Text
A new method for analyzing genomes to identify marks of positive, negative, and balancing selection that occurred over the past 500,000 years have filled in new details in the story of human evolution. The genes that underwent positive selection around the time that modern humans diverged from Neanderthals are primarily involved in brain function, including several genes involved in Alzheimer's disease pathology, such as SPON1, MAPT, SORL1, ELAVL4, SNCA and SHC3. The authors speculate that natural selection favoring enhanced cognitive abilities – as these positively-selected alleles enhanced synaptic connectivity and functional plasticity – may have come at the price of vulnerability to neurodegenerative disease in aging brains, which is uniquely observed among modern humans and not other primate relatives.
To support your studies of genes and signaling pathways involved in nervous system development, physiology, and disease, GenScript offers molecular biology services including Gene Synthesis and CRISPR genome editing.
Zhou H D et al. A Chronological Atlas of Natural Selection in the Human Genome during the Past Half-million Years. bioRxiv. 2015 May http://dx.doi.org/10.1101/018929. Read the Free Full Text
CRISPR/Cas9-mediated genome editing is not only an efficient way to create gene KO & KI, but is a uniquely powerful tool to functionally characterize the >98% of the genome that does not encode protein. A new study demonstrates how CRISPR can be used to systematically validate putative regulatory elements described by the ENCODE and EPIGENOME projects: even in a repeat-rich genomic region, a genomic insulator upstream of mouse tyrosinase was efficiently deleted or inverted, with no significant off-target effects and high efficiency in vivo, demonstrating a functional role for this noncoding region in regulating tyrosinase gene expression and mouse coat pigmentation.
GenScript makes it easy for your lab to start using CRISPR to create transgenic animals or isogenic cell lines. Our license with the Broad Institute and our extensive in-house experience making CRISPR-edited mammalian cell lines enable us to make your transition to CRISPR seamless:
Seruggia D et al. Functional validation of mouse tyrosinase non-coding regulatory DNA elements by CRISPR–Cas9-mediated mutagenesis. Nucleic Acids Res. 2015 May 26;43(10):4855-67. Read the Free Full Text
It’s well-established that being a ‘morning person’ or a ‘night owl’ is more than a simple preference – “chronotype” or diurnal preference has a biological basis, and it carries consequences for risk of diabetes, depression, insomnia and other diseases.
Humans aren't the only animals who show chronotype diversity: a recent study comparing early vs late chronotype fruit flies identified 152 differentially expressed genes that cluster into highly evolutionarily conserved pathways such as MAPK and Hedgehog, suggesting that the circadian clock may control cascades of gene expression that set larks and owls on distinct developmental trajectories.
To support your research needs, GenScript offers Gene Synthesis services to allow you to study the function of genes in isolation or in complex signaling pathways that underlie neurodevelopment, circadian physiology, behavior, and disease risk.
Pegoraro M. et al. Gene expression associated with early and late chronotypes in Drosophila melanogaster. Front. Neurol. (2015) Read Free Full Text
With the first oncolytic virus poised for FDA approval, and several more in pharma pipelines, the arsenal of cancer therapeutics may soon gain a powerful new tool: viruses that seek & destroy tumor cells and that stimulate anti-tumor immune responses. An oncolytic HSV-based therapy has shown impressive efficacy in advanced melanoma, and may be even more potent when combined with antibody immunotherapies or cell therapies.
Engineering oncolytic viruses and therapeutic antibodies relies upon cutting-edge molecular biology. As a pioneer in gene synthesis, GenScript accelerates research to develop novel cancer therapeutics and uncover basic mechanisms of tumor biology.
Dolgin E. Oncolytic viruses get a boost with first FDA-approval recommendation. Nature Reviews Drug Discovery 14, 369–371 (2015) Read Full Text
Antibody engineering is a critical strategy for developing next-generation IgG1-based therapeutics for cancer and inflammatory diseases. But a recent study in J. Immunology provides clear new evidence of the challenge of optimizing one feature of a rAb without disrupting other clinically vital functions.
To extend the half-life of therapeutic IgG, this study used Gene Synthesis to generate a panel of novel Fc mutants designed to optimize the pH-dependent FcRn–IgG1 interaction. The engineered Fc variants showed either enhanced or reduced Fc-mediated effector functions, as shown by binding to C1q and FcγRs as well as downstream cellular processes measured by ADCC and other cell-based assays.
To support your research needs for therapeutic protein engineering or any area of biomedical research, GenScript offers:
Grevys et al. Fc Engineering of Human IgG1 for Altered Binding to the Neonatal Fc Receptor Affects Fc Effector Functions. J Immunol. 2015 Jun 1;194(11):5497-508. doi: 10.4049/jimmunol.1401218. Read Full Text
For the many people who strive to reduce sugar intake, it can be tough to choose between natural sugars, artificial low-calorie sweeteners, or denying the craving for sweets. Proteins may offer a better solution: did you know that some naturally-occurring proteins taste hundreds of times sweeter than sugar? Plants native to West Africa naturally produce sweet proteins, such as monellin, isolated from the “serendipity berry” Dioscoreophyllum cumminsii and miraculin, isolated from the “miracle fruit” Synsepalum dulcificum.
A recent paper shows how structure-guided protein engineering enabled the design of new protein-based low-calorie sweeteners that could be used in food – potentially offering a powerful tool to combat increasing rates of diabetes and obesity.
To support your research needs, GenScript offers Gene Synthesis services to accelerate protein engineering, structural and biochemical studies, or characterizing novel variants in vitro or in vivo.
Rega et al. Design of sweet protein based sweeteners: Hints from structure–function relationships. Food Chem. 2015 Apr 15;173:1179-86. doi: 10.1016/j.foodchem.2014.10.151. Read Full Text
Do you know that dozens of different species of bacteria, yeast, and other microbes work together to make cheese? Surface-ripened cheese microbial communities came under the meta-omics microscope in a recent paper published in PLoS ONE, producing a vivid picture of the metabolic activities and cross-talk between different organisms that takes place over the month-long process of cheese maturation. For example, they showed that robust growth of two yeast strains early in the process causes an increase in pH in cheese curds, which promotes later growth of acid-sensitive bacteria. The study also revealed the species and metabolic pathways primarily responsible for lactose degradation that allows cheese to be enjoyed by many of us who are lactose-intolerant. Most exciting, meta-transcriptomics analysis identified new gene biomarkers that could be used in the future to monitor and improve the efficiency and safety of food fermentation – with delicious results.
To support your research needs, GenScript offers Gene Synthesis services to allow you to study gene function and to engineer novel enzymes and metabolic pathways.
Dugat-Bony et al. Overview of a Surface-Ripened Cheese Community Functioning by Meta-Omics Analyses. PLoS One. 2015 Apr 13;10(4):e0124360. Read Full Text
Small regulatory RNAs abound in nature, and they're proving to be a versatile tool for programming novel synthetic gene networks to precisely control gene expression. Naturally-occurring sRNAs can repress or enhance translation by interacting with ribosome binding sites (RBSs), and can repress transcription by binding intrinsic terminator hairpins. However, there are no known naturally-occurring sRNAs that could activate transcription, which limits the ways in which synthetic gene regulatory circuits can be designed.
A recent paper in Nature Chemical Biology reports on the development of small RNA transcriptional activators (STARs), a newly-engineered functional class of small RNA that expands the capabilities for RNA-only logic gates. In addition to designing sRNAs with potent transcriptional activation (up to 94-fold enhancement), they systematically deduced design rules to allow other researchers to create customized sRNAs for any application in the future.
GenScript offers Gene Synthesis and library design and construction services to allow you to apply synthetic biology tools to any research project.
The arms race between pathogenic microbes and the antibiotics we used to control them continues to rage: few new drug candidates are in the pipeline to tackle enterobacter and MRSA, and new reports show that diverse bacteria trade the genes that confer antibiotic resistance more easily than previously imagined.
Overuse of antibiotics is often considered to be the primary selective pressure that prompts bacteria to acquire, maintain, and spread genes conferring antibiotic resistance, but a new study suggests that these genes pre-date the emergence of modern medicine. The microbiota of people living in an isolated Venezuelan tribe (that had never been exposed to antibiotics) carry genes conferring antibiotic resistance, suggesting ancient roots to a very modern problem.
To support your research needs, GenScript offers Gene Synthesis services to provide the custom DNA constructs you need with 100% sequence accuracy.
Clemente et al. The microbiome of uncontacted Amerindians. Science Advances 01 Apr 2015: Vol. 1 no. 3 e1500183. DOI: 10.1126/sciadv.1500183 Read Full Text
Traits like height, which seem to vary in an intractably complex quantitative manner, may actually be regulated in a very straightforward way by simple epigenetic mechanisms. A new study published in Nature Communications reports that global DNA methylation levels determine body size in carpenter ants. The degree of methylation of the Egfr gene was identified as the critical regulator of ant body size, consistent with EGFR's role as a transcriptional regulator for many genes involved in growth signaling. Other polygenic traits may similarly be coordinated by master regulators whose expression can be quantitatively tuned by epigenetic modification in response to environmental conditions.
To accelerate your studies of epigenetics and gene variation, GenScript offers Gene Synthesis services to provide the custom DNA constructs you need with 100% sequence accuracy.
Alvarado et al. Epigenetic variation in the Egfr gene generates quantitative variation in a complex trait in ants. Nat Commun. 2015 Mar 11;6:6513. Read Full Text
Although protein coding regions are highly conserved across evolution, regulatory regions differ greatly between species, which enables diverse gene expression patterns that allow flies and humans to develop into very different animals. Transcription factor proteins in different species might be expected to differ somewhat in how they bind DNA, but a new systematic comparison of drosophila, mouse, and human finds that TF binding specificity is almost perfectly conserved through 600 million years of divergent evolution. This surprising result, that transcription factors have not evolved to recognize even subtly different DNA motifs, implies that gene expression is regulated by a single universal "DNA regulatory code" that governs protein-DNA interactions.
To generate a collection of 760 DNA-binding domains for systematically assaying drosophila transcription factor binding specificity, these researchers used codon-optimized gene synthesis from GenScript. GenScript offers Gene Synthesis services to provide the custom DNA constructs you need with 100% sequence accuracy.
To support your research needs, GenScript offers Gene Synthesis services to provide the custom DNA constructs you need with 100% sequence accuracy.
Nitta et al. Conservation of transcription factor binding specificities across 600 million years of bilateria evolution. Elife 2015 Mar 17;4. Read Full Text
Although we inherit DNA from two parents in equal proportions, a new report in Nature Genetics reveals a pervasive bias in gene expression favoring paternal alleles. Genetic imprinting and parent-of-origin effects have been observed before, but this study identifies hundreds of new genes that show allelic imbalance, highlighting the importance of heritable variation in regulatory regions of the genome.
This finding was made possible by crossing highly divergent mouse strains through a breeding experiment called the Collaborative Cross. This project aims to expand genetic diversity in mouse models to more closely resemble the degree of genetic variation found within the human population, in order to gain more insight into the genetics of human diseases.
To support your research needs, GenScript offers Gene Synthesis services to provide the custom DNA constructs you need with 100% sequence accuracy.
Crowley et al. Analyses of allele-specific gene expression in highly divergent mouse crosses identifies pervasive allelic imbalance. Nat Genet. 2015 Apr;47(4):353-60. Read Full Text
A new study published in Science tackles the mystery of the genetic basis for ALS, a motor neuron disease in which 90% of cases are sporadic and the vast majority of those show no mutations in genes known to cause familial ALS. Through whole-exome sequencing of thousands of ALS patients and controls, researchers were able to identify a new ALS-causing gene, TBK1, and to show that disruptions to the autophagy pathway play a more important role in ALS than previously recognized.
As next-generation sequencing expands access to collections of new gene variants associated with disease such as the ALS and control exome sequence banks created in this study, a critical next step for developing diagnostics and therapeutics is to characterize how these mutations contribute to disease processes.
To support your research needs for customized DNA constructs encoding novel gene variants, GenScript offers Gene Synthesis services to create any gene sequence in any vector, with 100% sequence accuracy – because you have more important things to do than routine cloning.
Cirulli et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science. 2015 Mar 27;347(6229):1436-41. Read Full Text
A new study published in Nature provides striking new evidence that an immunoadhesin gene therapy approach could provide effective, long-term protection against HIV-1 – perhaps sooner and better than a conventionally-developed vaccine. Unlike traditional vaccines, which introduce an immunogen in order to stimulate a person's immune system to produce antibodies in response, this approach essentially replaces the need for an immune system response to HIV. Instead, it involves stably expressing an immunoadhesin, which acts similarly to a monoclonal antibody in binding and neutralizing a pathogen. CD4-Ig immunoadhesins have been used in HIV research for several years, but this new study finds that fusing CD4-Ig to a small CCR5-mimetic sulfopeptide allows it to bind the HIV-1 envelope glycoprotein Env far more potently than CD4-Ig alone or any of the best broadly neutralizing antibodies studied to date. Furthermore, this study shows that AAV-expressed eCD4-Ig provided longstanding protection against SIV challenges in rhesus macaques and is a promising candidate for safely and effectively protecting human populations from HIV.
To support your research needs for customized DNA constructs for vaccine research, therapeutic antibody engineering, and immunology, GenScript offers Gene Synthesis services to provide the custom DNA constructs you need with 100% sequence accuracy.
Gardner et al. AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges. Nature. 2015 Mar 5;519(7541):87-91. Read Full Text
Plant genetics researchers are now racing to map the genomes of many varietal strains of cannabis in order to better understand the genetic variations underlying widely varying levels of THC and CBD. These efforts aim to address the need for reliable dosing and quality control in cannabis plants grown for medicinal use and may also help bring the power of personalized medicine to cannabinoid-based therapies.
Amid continued controversy over medical marijuana policies – for example, The New England Journal of Medicine just published a perspective on the public health risks – researchers are discovering more potential therapeutic uses for cannabis-derived compounds. In addition to its wide use for pain relief and anti-emesis, new reports show cannabis-based drugs can kill tumor cells, and in a mouse model of Alzheimer 's disease they decrease Aβ42 levels and protect against cognitive decline.
To support your research needs for customized DNA constructs for disease research and comparative genomics, GenScript offers Gene Synthesis services to provide the custom DNA constructs you need with 100% sequence accuracy.
Aso et al. Cannabis-Based Medicine Reduces Multiple Pathological Processes in AβPP/PS1 Mice. J Alzheimers Dis. 2015;43(3):977-91. Read Full Text
Scott et al. The combination of cannabidiol and Δ9-tetrahydrocannabinol enhances the anticancer effects of radiation in an orthotopic murine glioma model. Mol Cancer Ther. 2014 Dec;13(12):2955-67. Read Full Text
Hernandez D. How genetics is reshaping the marijuana industry. Fusion 4 Feb 2015. Read Full Text
Ghosh et al. Medical Marijuana's Public Health Lessons — Implications for Retail Marijuana in Colorado. N Engl J Med 2015 Mar 12;372(11):991-3. Read Full Text
Nelson B. Medical marijuana: Hints of headway? Despite a conflicted regulatory landscape, support for medical marijuana is growing amid increasing evidence of potential benefits. Cancer Cytopathol. 2015 Feb;123(2):67-8. Read Full Text
A new study in PNAS reports the development of a safe, reliable, and sensitive method for earlier cancer detection. Rather than looking for endogenous cancer biomarkers that may be present in the blood, researchers engineered a novel, genetically-encoded biomarker: the tumor-specific PSurv promoter drives tumor-specific expression of human SEAP, a secretable reporter gene that can be easily detected. Using mice, they found that their engineered biomarker accurately distinguished between tumor-bearing and tumor-free individuals, and even quantitatively reported on tumor burden. In order to facilitate use of this diagnostic tool in humans, they selected an unusual but uniquely safe vector: DNA minicircles.
DNA minicircles are safer than other types of vectors for gene delivery for several reasons. First, they avoid the many safety concerns of viral vectors such as replication competence, immune reactions, and insertional mutagenesis inciting pathology such as oncogenesis. Even compared to traditional nonviral plasmid vectors, minicircles are less immunogenic because they completely lack antibiotic resistance genes or a prokaryotic backbone that may be recognized as foreign by the human immune system. Furthermore, minicircles have higher gene transfer rates and longer-lived expression profiles than other non-viral vectors, making them a highly effective vehicle as well. MCs have recently become much faster and less expensive to produce, making them a promising vehicle for future gene therapy efforts.
To support your research needs for customized DNA constructs to engineer novel biomarkers, to deliver tumor-targeted gene therapy, or to study cancer signaling pathways, GenScript offers Gene Synthesis services to provide the custom DNA constructs you need with 100% sequence accuracy.
Ronald et al. Detecting cancers through tumor-activatable minicircles that lead to a detectable blood biomarker. Proc Natl Acad Sci U S A. 2015 Mar 10;112(10):3068-73. Read Full Text
A new study by researchers at Johns Hopkins reports stunning results for curing glioma in rats, using a new method likely to be safe and effective in humans. In order to make the pro-drug ganciclovir effective at killing glioma cells in the brain, DNA encoding HSVtk must be delivered to the brain, ideally without using viral vectors for gene delivery. Instead, they selected biodegradable nanoparticles which they showed could permeate through the brain via intracranial convection-enhanced delivery. This is the first time that nanoparticle-delivered therapeutics have effectively killed brain cancer cells and extended survival in animals.
To support your studies of molecular and cellular features of neuropsychiatric diseases, GenScript offers Gene Synthesis services to provide the custom DNA constructs you need with 100% sequence accuracy.
Mangraviti et al. Polymeric Nanoparticles for Non-Viral Gene Therapy Extend Brain Tumor Survival In Vivo. ACS Nano. 2015 Feb 24;9(2):1236-49. Read Full Text
A new study in Biological Psychiatry finds hallmarks of cellular aging in people who have experienced early life stress, depression, anxiety, or substance abuse. The relationship seen between psychopathology and shortened telomeres confirmed earlier reports, and this paper presents the first evidence of altered mitochondrial biogenesis, including increased mtDNA copy number, in people with early life stress, anxiety, or substance use disorders.
To support your studies of molecular and cellular features of neuropsychiatric diseases, GenScript offers Gene Synthesis services to provide the custom DNA constructs you need with 100% sequence accuracy.
Tyrka et al. Alterations of Mitochondrial DNA Copy
Number and Telomere Length with Early Adversity and Psychopathology.
Biological Psychiatry. Article in Press; Published Online: January 16, 2015. DOI: http://dx.doi.org/10.1016/j.biopsych.2014.12.025 Read Full Text
Bird genomes tend to be considerably smaller than the genomes of other vertebrates, and a new Science paper from the avian genome consortium sheds light on the mystery of how and why bird genomes became so trim.
Not only have avian lineages lost transposable elements (<10% of bird genomes are repeats, compared to 34-53% in mammals), but even their protein coding regions show shorter introns and intergenic regions. This genomic contraction is also seen in bats, the only group of mammals that fly -- a case of convergent evolution suggesting that flight creates a selective pressure on genomes to shrink.
Some have proposed that the sheer mass of so many copies of junk DNA in all the body's cells, and the energetic demand of maintaining it, was too costly for flyers to maintain. Phylogenetically controlled correlations have been observed between genome size and relative flight muscle size as well as other morphologic features, suggesting that the metabolic intensity of powered flight has driven genome size reductions in birds (Wright et al. 2014). Others have suggested that introns, which play a role in regulating gene expression, may shrink in flying birds due to a need for more rapid gene regulation in response to the intense energetic demands of powered flight (Zhang et al. 2014). On the other hand, some researchers suggest that small genomes first evolved in the saurischian dinosaur lineage long before avian flight appeared, casting doubt on flying behavior as a driver of genome size (Organ et al. 2007).
To support your studies of genes, intergenic regions, and genome structure in any species, GenScript offers Gene Synthesis services to provide the custom DNA constructs you need with 100% sequence accuracy.
Zhang et al. Comparative genomics reveals insights
into avian genome evolution and adaptation.
Science. 2014 Jul;46(7):748-52. Read Full Text
Wright et al. Metabolic 'engines' of flight drive genome size reduction in birds. Proc Biol Sci. 2014 Jan 29;281(1779):20132780. Read Full Text
Organ et al. Origin of avian genome size and
structure in non-avian dinosaurs. Nature. 2007 Mar 8;446(7132):180-4.
Read Full Text
On the search for gene variants underlying psychopathology, a recent article in the Harvard Review of Psychiatry discusses the lack of success of GWAS and GxE studies to pinpoint genetic determinants of depression. But new findings reveal that our gut microbes are critical players in determining susceptibility to depression, anxiety, and other psychiatric disorders; for example, numerous publications report that antibiotics and probiotics influence CNS disease symptoms. Ongoing studies like the crowd-sourced American Gut project aim to gather meta-genomic data on microbiome populations – opening new frontiers to study the biological basis of mental illness.
To support your studies of gene variants and gene-environment interactions in health and disease, GenScript offers Gene Synthesis services to provide the custom DNA constructs you need with 100% sequence accuracy.
Wang & Caspar. The role of microbiome in central nervous
system disorders. Brain Behav Immun. 2014 May;38:1-12.
Read Full Text
Dunn et al. Genetic determinants of depression: recent findings and future directions. 2015 Jan-Feb;23(1):1-18. 2014 May;38:1-12. Read Full Text
Did you learn long ago that every cell in your body contains an identical copy of your DNA? In fact, a growing body of evidence shows that mosaicism occurs more frequently than we thought – and new technology is making it possible to detect de novo mutations in specific cell lineages and understand how they impact our health.
A study in Neuron reports a new method for single-cell whole-genome sequencing to identify somatic mutations and map their mosaic patterns in the brain. And, as a Nature Genetics paper reports, searching for somatic mutations can help identify the cause of, and potential treatments for, certain elusive diseases; learn how novel mutations in KCNH1 were identified as the cause of a rare seizure disorder in children whose mothers were healthy mosaic carriers.
To support your studies of gene variants and their functions in health and disease, GenScript offers Gene Synthesis services to provide the custom clones you need with 100% sequence accuracy, starting at just $0.23/bp.
Studies recently published in Science reveal that songbirds learn to sing using largely the same set of genes and brain pathways used in humans speech – a remarkable new account of convergent evolution in two quite distant lineages. Further work on the classic model songbird, the zebra finch, fleshes out the story of two-way communication between genes and singing behavior, showing that 10% of the avian genome is regulated by singing behaviors via activity-dependent transcription factors and epigenetic modifications. This rich new understanding of the molecular, anatomical, and functional basis of songbird vocalization was made possible by recent publication of 45 new bird genome sequences, which will open new frontiers for future studies in comparative genetics.
Pfenning et al. Convergent transcriptional specializations in the brains of humans and song-learning birds. Science. 2014 Dec 12;346(6215):1256846. Read Full Text
Whitney et al. Core and region-enriched networks of behaviorally regulated genes and the singing genome. Science. 2014 Dec 12;346(6215):1256780. Read Full Text
Although blonde hair color clearly runs in families, the genetic variant that gives rise to platinum locks has only recently been discovered. A study published in Nature Genetics follows up on previous GWAS findings to identify the critical SNP and how it functions. A single base pair change in the enhancer region of the KITLG gene reduces binding by the transcription factor LEF1, which alters growth factor signaling in developing keratinocytes – and lightens fur color in mice harboring the human variant.
As you work to uncover the genetic basis of phenotypic variation, GenScript is here to provide custom gene synthesis to accelerate studies of gene function and regulation of gene expression.
Guenther et al. A molecular basis for classic blond hair color in Europeans. Nat Genet. 2014 Jul;46(7):748-52. Read Full Text
A recent paper in PLoS ONE reports that the building blocks of life can remain biologically functional after a trip to space and back. Plasmid DNA applied to the outside of a sounding rocket survived the microgravity of space and the intense heat (exceeding 128℃ ) and pressure (hypergravity of 17.6 g) during atmospheric re-entry. This suggests that DNA, or other biomolecular markers of extraterrestrial life, could survive entry through Earth's atmosphere embedded in meteorites. This has huge implications for life on Earth and elsewhere in the universe; traces of DNA left by humans on "space junk" could complexify our search for signs of life elsewhere in the universe.
To support your studies of life here on Earth, GenScript offers Gene Synthesis services with the unmatched expertise to create any gene in any vector – even difficult DNA sequences containing high or low GC content, repeats, or secondary structures.
Thiel et al. Functional Activity of Plasmid DNA after Entry into the Atmosphere of Earth Investigated by a New Biomarker Stability Assay for Ballistic Spaceflight Experiments PLoS One. 2014 Nov 26;9(11):e112979. Read Full Text
A recent paper in Nature Communications reports success with a clever technique to make CRISPR-mediated genome editing easier in human cells. Compared to the commonly-used U6 promoter, driving guide RNA expression from the H1 promoter more than doubles the number of targetable sites within the genomes of humans and other eukaryotes.
Why is H1 more versatile than U6? The U6 promoter initiates transcription from a guanosine (G) nucleotide, while the H1 promoter can initiate transcription from A or G. In designing a gRNA sequence, the requirement for the protospacer adjacent motif (PAM) sequence "NGG" at the end of a 20-mer means that U6-driven gRNA must fit the pattern GN19NGG. But H1-driven gRNAs can also target sequences of the form AN19NGG, which occur 15% more frequently than GN19NGG within the human genome.
To support your genome editing efforts, GenScript offers:
Ranganathan et al. Expansion of the CRISPR–Cas9 genome targeting space through the use of H1 promoter-expressed guide RNAs. Nat Commun. 2014 Aug 8;5:4516. Read Full Text
A recent paper in Nature Communications reports a breakthrough that could make T-cell therapeutics much faster and easier to develop: in vitro-directed evolution of T-cell receptors enable researchers to change the peptide specificity of T-cells without having to isolate T-cell clones. Starting with predictions regarding key residues within the complementarity determining regions (CDRs), researchers generated and screened mutant libraries to identify a novel TCR protein variant that recognizes a cancer peptide of interest, MART1/HLA-A2.
GenScript offers comprehensive services to support your protein engineering efforts, from gene synthesis to High-throughput Protein Variant expression and purification, Antibody Library & Phage Display and Functional Assay Validation.
Smith et al. Changing the peptide specificity of a human T-cell receptor by directed evolution. Nat Commun. 2014 Nov 7;5:5223. Read Full Text
A recent paper in Science reports a revolutionary method to enable E. coli to create robust, rewriteable records of biological events through precise dynamic genome editing. A programmable module called SCRIBE translates input signals into ssDNA fragments that can be inserted into genomic DNA and securely stored until it is read, edited, or erased later on. This new breakthrough in synthetic biology effectively harnesses the stable, high-capacity information reservoir represented by the genome to serve as flexible, analog storage for any customized use.
To help you generate novel DNA modules or synthetic genes, GenScript offers leading gene synthesis technologies and unparalleled services that all deliver 100% sequence-perfect plasmid DNA clones:
Farzadfard F, Lu TK. Genomically encoded analog memory with precise in vivo DNA writing in living cell populations. Science. 2014 Nov 14;346(6211):1256272. Read Full Text
Efforts are ongoing to develop new crop varieties that produce greater yields when grown without chemical pesticides, which can harm the environment and are expensive for farmers to purchase and apply. A recent paper in Plant Science reports that rice plants' natural defenses against pests can gain a boost from a scorpion peptide to keep leafroller pests at bay.
Codon-optimized gene synthesis can promote the efficient expression of transgenes in plants for both basic and applied research. For example, a Dec 2014 paper in Plant Science reports that rice plants' natural defenses against pests can gain a boost from a scorpion peptide to keep leafroller pests at bay. This study used codon-optimized gene synthesis services from GenScript to express the scorpion peptide gene LqhIT2 in rice plants in order to study how it affected the plant and its lepidopteran pests in both the lab and the field. In addition to direct species-selective toxicity, LqhIT2 boosted jasmonate-mediated phenylpropanoid biosynthesis in the rice plants, which produces lignin and flavonoids that are critical components in plant defense. This finding could lead to the development of new rice varieties that produce greater yields when grown without chemical pesticides.
GenScript offers free codon optimization with our patented OptimumGene algorithm to help you improve soluble protein expression in your experiments. Our gene synthesis services allow you to get 100-% sequence-verified expression clones containing any custom-made DNA sequence starting at $0.23/bp, with cloning into any vector starting at $49.
Tianpei et al. Scorpion peptide LqhIT2 activates phenylpropanoid pathways via jasmonate to increase rice resistance to rice leafrollers. Plant Sci. 2014 Dec (1-11); 2014-12. Read Full Text
As HCV-related liver disease claims hundreds of thousands of lives each year, Hepatitis C Virus research has thus far been hampered by a lack of infectious cell-culture systems to support basic and translational research including vaccine development. A new paper in J.Virology reports a breakthrough in developing in vitro infectious clones for the most common HCV strains. These researchers synthesized HCV-1 and H77 prototype genomes containing specific mutations that enable infectious particle production in cell culture.
To make viral genome synthesis faster and more affordable, GenScript's new GenBrick™ synthesis service leverages efficient one-step assembly technology.
Li et al. Efficient infectious cell culture systems of the hepatitis C virus prototype strains HCV-1 and H77. J Virol. 2014 Oct 29. pii: JVI.02877-14. Read Full Text
A new paper in Nature Neuroscience sounds like science fiction: humans can control protein expression from "designer cell" implants with only their thoughts. An EEG reads brain wave patterns associated with certain mental states, and a brain-computer interface wirelessly transmits a signal to cell cultures or to cells implanted in lab animals. This study used synthetic gene circuits to create a light-inducible orthogonal signal transduction pathway leading to tunable expression of a target protein. This application of synthetic biology holds great promise for gene and cell therapies that could revolutionize patient care.
Optogenetics and other types of synthetic gene circuits are increasingly used in neuroscience research. GenScript's gene synthesis services provides any DNA construct you need with 100% sequence accuracy. Our new GenBrick™ synthesis service makes it easier than ever to get sequence-perfect long genes or entire genetic circuits.
Folcher et al. Mind-controlled transgene expression by a wireless-powered optogenetic designer cell implant. Nature Communications. 2014 Nov 11;5:5392. Read Full Text
A new paper in Cell reports a breakthrough technique to bring synthetic biology out of the lab. By freeze-drying biological components and embedding them in paper, researchers can rapidly create new cell-free transcription-based detectors that can be used anywhere, without relying on laboratories with sterile cell culture facilities. As a proof-of-principle, they developed a paper-based Ebola virus detector in a single day.
To enable studies requiring custom-made genetic circuits or synthetic genomes, GenScript's new GenBrick™ synthesis service leverages efficient one-step assembly technology to produce 8-15kb long DNA building blocks for synthetic biology, offering 100% sequence-perfect clones in just 23 business days for $0.45/bp. Compared to the time-consuming and error-prone process of assembling oligos and screening for mutation-free clones in your own lab, GenScript's GenBrick™ synthesis service saves you time, money, and hassles.
Pardee et al. Paper-Based Synthetic Gene Networks Cell. 2014 Nov 6. 159(4):940–954. Read Full Text
After a 1953 paper revealed that guinea pig serum could kill tumor cells through L-asparaginase activity, several bacterial L-asparaginases were developed as FDA-approved drugs to treat acute lymphoblastic leukemia (ALL) and other cancers. However, side effects persist, likely due to off-target glutaminase activity and immunogenicity. The first problem could be addressed by identifying or engineering an enzyme with better substrate specificity, while immune reactions against the bacterial enzymes may be circumvented by using a mammalian enzyme. So researchers recently went back to the original source: the guinea pig. 60 years after that first report, they've now characterized a guinea pig enzyme they say could potentially replace currently used cancer drugs. They report the first crystal structures for gpASNase1, both ligand-free and in complex, which help explain the lack of off-target L-glutaminase activity in this enzyme compared to bacterial homologs currently in therapeutic use. They also determined that the guinea pig enzyme has superior kinetic properties compared to the human enzyme; while the kinetics have made the human enzyme a poor candidate for therapeutic use, the guinea pig enzyme has favorable kinetic properties similar to those of bacterial homologs currently in use clinically.
In order to express and purify bacterial and mammalian L-asparaginases for enzymatic and structural assays, these researchers ordered codon-optimized gene synthesis from GenScript. See how GenScript can accelerate your research:
Schalk AM, Nguyen HA, Rigouin C, Lavie A. Identification and Structural Analysis of an L-asparaginase Enzyme from Guinea Pig with Putative Tumor Cell-killing Properties. J Biol Chem. 2014 Oct 15. pii: jbc.M114.609552. Read Full Text
The dentate gyrus within the hippocampus is thought to be involved in age-related memory decline. A new study in Nature Neuroscience reports that healthy older adults who consumed a high-flavanol diet for three months showed improved function in both fMRI scans and DG-specific cognitive tests.
In order to study the mechanisms of age-related memory decline and the neuroprotective effects of flavanols, GenScript's gene synthesis service makes it easy to obtain 100% sequence-verified DNA constructs. For example, Codon-optimized gene synthesis is routinely used to create optogenetic reporters for noninvasive imaging of synaptic networks even in deep brain regions such as the dentate gyrus.
Brickman AM et al. Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults. Nature Neuroscience, 2014 Oct 26. doi: 10.1038/nn.3850. Read full publication
It's been well established that a high-sugar diet can lead to fat accumulation and weight gain. A new study finds this effect disappears when there's a loss of function in alh-6, a mitochondrial enzyme involved in proline metabolism.1 Alh-6 deficiency activates SKN-1/Nrf2, which induces fatty acid oxidation genes – the first demonstrated link between amino acid metabolism and lipid metabolism, and one that is conserved from worms to humans.
This enhanced fat-burning tendency isn't always good – for example, in C. elegans under conditions of nutrient deprivation, alh-6 mutants lost weight quickly and didn't survive as well. And the harms of a high-sugar diet may extend beyond weight gain to accelerating cellular senescence, according to a recent study that showed shortened telomeres in humans after sugary soda consumption.2 However, this new finding does holds promise for preventing or treating metabolic diseases such as obesity and type II diabetes, especially because Nrf2 activators are already in development for safe use in humans as cytoprotective agents under electrophilic stress.
To study the physiological effects of altering the expression of key metabolic enzymes and transcription factors regulating broad, conserved homeostatic programs, GenScript's gene synthesis service makes it easy to obtain 100% sequence-verified plasmids encoding WT ORFs or any mutation or fusion construct you can design. We offer:
1. Pang S et al. SKN-1 and Nrf2 couples proline catabolism with lipid metabolism during nutrient deprivation. Nat Commun. 2014 Oct 6;5:5048.
2. Leung CW et al. Soda and Cell Aging: Associations Between Sugar-Sweetened Beverage Consumption and Leukocyte Telomere Length in Healthy Adults From the National Health and Nutrition Examination Surveys. American Journal of Public Health. 2014 Oct 16:e1-e7.
In addition to its familiar function of encoding genetic information, DNA is a valuable biomaterial for fabricating customized nanostructures. DNA's ability to self-assemble into precise 3-D structures used in applications from drug delivery to electronic components. A new study reports the creation of scaffolded DNA origami structures far larger than previously described, thanks to two major technological improvements: the use of longer DNA scaffolds and the use of a new chip-based platform for inexpensive synthesis of 1600 DNA sequences serving as staples.
GenScript has developed chip-based DNA synthesis technology to power our GenPlus High-Throughput Gene Synthesis service. As the global leader in gene synthesis, with over 13 years of R&D innovation and customer satisfaction, our technologies can deliver any custom DNA sequences you can imagine, of any length & complexity, with 100% sequence accuracy guaranteed starting at just $0.23/bp.
Marchi et al. Toward larger DNA origami. Nano Lett. 2014 Oct 8;14(10):5740-7. Read Full Text
In addition to providing a much-loved beverage, the coffee plant is emerging as a valuable model organism for research on the evolution of biosynthetic pathways and genome structure. A recent Science publication presents the newly-sequenced coffee genome and a stimulating case of convergent evolution: caffeine biosynthesis evolved independently in coffee, tea, and cacao.
This study also examined the coffee genome structure and found a unique pattern of gene family expansions among N-methyltransferases (NMTs) involved in multiple biosynthetic pathways. New versions of old genes appear to have arisen through tandem sequential duplication, unlike in other members of the asteroid angiosperm lineage which have experienced whole-genome triplication. This unique feature of coffee sheds new light on the mechanisms by which enzyme function diversification occurs.
To study novel genes and non-coding regions that are discovered in newly-sequenced genomes, GenScript's gene synthesis service makes it easy to obtain 100% sequence-verified plasmids and other custom molecular biology reagents. We offer:
The WHO has released new projections that the death-toll for the current Ebola outbreak will reach 20,000 by November, bringing increased attention to the need to contain the spread of this epidemic and to reduce the 70% death rate. Prevention efforts are focused on public health campaigns to reduce transmission rates, and two Ebola vaccine candidates are poised to enter clinical trials soon. Several patients diagnosed with Ebola appear to have benefitted from treatment with the siRNA-based drug TKM-Ebola, in addition to other therapies such as blood transfusions from Ebola survivors and supportive care. TKM-Ebola made two major steps forward this week:
Tekmira is developing the RNAi-based therapeutics that can be delivered using lipid nanoparticle (LNP) delivery technology. Preclinical studies of TKM-Ebola were published in The Lancet in 2010. Read the Full Publication » Lipid-encapsulated siRNA delivery has also shown promise for treating Marburg Virus infection (J. Infect. Dis. 2013)
Work continues to develop new therapeutic strategies for Ebola and other deadly viruses. CDC researchers recently developed a new system for identifying antiviral agents that are effective against Marburg and Ebola viruses, using codon-optimized Ebola virus genes synthesized by GenScript. Read the free full text of the paper »
Photosynthesis is such a fundamentally important process that you might think plants are highly efficient at it. However, scientists working to improve crop yields have noticed that one enzyme, Rubisco, represents a weak link in the photosynthetic pathway due to its poor oxygenase activity and slow turnover. A recent paper in Nature reports that plants can be engineered to use a better Rubisco enzyme from cyanobacteria, which increases carbon fixation rates. Tobacco plans whose native Rubisco gene was completely knocked out were able to grow by using transgenic cyanobacterial Rubisco, which successfully assembled into active enzyme to support autotrophic photosynthesis. The next step will be to introduce the remaining components of the cyanobacterial CO2 concentrating mechanism, including inorganic carbon transporters and carboxysome shell proteins, to recapitulate a complete and functional CCM in plants. If this strategy is successful in increasing total photosynthesis rates and thus improving crop yields, it could be a major breakthrough for sustainable farming and global food security.
Plant biologists are increasingly turning to CRISPR-mediated genome editing to create knock-in and knock-out strains, for several reasons. CRISPR is highly efficient with very low risk of off-target effects. It is easy to use in any lab, and compatible with widely-used methods for creating transgenic strains through agrobacterium-mediated transformation. However, CRISPR technology does not leave a “transgenic” footprint if the Cas9 and gRNA constructs are transiently expressed or are backcrossed out. Therefore there are hopes that new plant strains created using CRISPR/Cas9 genome editing technology may escape being labeled as GM strains which may increase their acceptance as food crops. Learn more about how gene synthesis and genome editing are being used in plant biology research applications.
GenScript is the global leader in gene synthesis to accelerate genetic engineering, CRISPR-mediated genome editing, recombinant enzyme expression, biosynthetic pathway engineering, and gene functional studies. We offer:
Lin MT, Occhialini A, Andralojc PJ, Parry MA, Hanson MR. A faster Rubisco with potential to increase photosynthesis in crops. Nature. 2014 Sep 25;513(7519):547-50. Read Full Text
In addition to serving as a model organism for basic biology research, such as in the cutting edge work being done by the synthetic yeast genome project, yeast are increasingly being adapted through metabolic engineering to be used for industrial applications. A recent paper in Nature Chemical Biology reports the successful biosynthesis in yeast of medically important opioids.1 To reproduce part of the complex alkaloid metabolic pathway in yeast, the researchers had to engineer yeast to express multiple biosynthetic enzymes that naturally occur in poppy and bacteria. Their first efforts were thwarted by low product yields owing to undesired side reactions that diverted intermediates away from the intended biosynthetic pathway. Fortunately they developed a clever solution: by localizing certain enzymes to the ER, they were able to compartmentalize key reactions within the cell. Their persistence paid off, leading to yields of up to 131 mg/L of opioid products, the highest yield of desired metabolite ever reported from genetically engineered micro-organism.
Other studies of metabolic engineering inyeast and alkaloid biosynthesis have employed codon-optimizedsynthetic genes from GenScript. GenScript is the global leader in genesynthesis to accelerate recombinant proteinexpression, metabolic engineering, or any projects requiring gene over-expressionor genetic modification.
Thodey K et al. A microbial biomanufacturing platform for natural and semisynthetic opioids Nature Chemical Biology 2014 Oct;10(10):837-44. Read Full Text
A recent paper in Nucleic Acids Research reports the discovery of a new class of Type II DNA topoisomerase enzymes, found in archaeal and bacterial genomes as well as bacterial plasmids. As their name suggests, topoisomerases help to solve topological problems that arise when complementary DNA strand separate to allow transcription, replication, or some forms of DNA repair.
This study used computational techniques to mine genomic data in order to identify novel genes containing domains with high similarity to previously-known topoisomerase-encoding genes. They identified never-before-seen genes that encode type IIB enzymes in which the A and B subunits are fused into a single polypeptide, forming the smallest known type IIB enzymes. This monophyletic group of newly discovered enzymes differs substantially from other archaeal and eukaryotic type IIB enzymes, prompting a proposal to classify them into a new subfamily called DNA topoisomerase VIII. Functionally, they show diverse DNA relaxation, decatenation and cleavage activity, meriting further characterization.
In the puzzling story of how topoisomerase enzymes originated and diversified over evolutionary history, this study provides new evidence that topoisomerases diversified in the Viral/Plasmid world before entering the three domains of living cells, and independently entered multiple bacterial, archaeal, and eukaryotic lineages on different occasions – and may still be doing so. The current pool of “mobile elements” represent potential reservoirs of novel proteins involved in DNA metabolism that could be harnessed by efforts toward protein engineering for biomedical and synthetic biology purposes. Furthermore, the Paenibacillus host in which one of the new topoisomerase genes was found may be a promising source for novel topoisomerase inhibitors that could be therapeutic candidates for cancer.
To biochemically characterize these novel enzymes, these researchers used GenScript's gene synthesis service to obtain 100% sequence-verified plasmids for recombinant protein expression and purification. GenScript offers custom molecular biology services to accelerate your research:
Each cell in the human body contains only two copies of genes stored in nuclear DNA, but can contain thousands of copies of genes found in mitochondrial DNA (mtDNA). Mutations in mtDNA can accumulate over your lifespan and contribute to diverse pathologies including neurodegenerative disease, cancer, and diseases associated with aging. A new study employing deep sequencing of 1,000 human genomes reports that healthy humans harbor mutations in their mitochondrial DNA at a surprisingly high rate: 90% of healthy individuals carry at least 1 mtDNA heteroplasmy, and 20% of apparently healthy people carry known pathogenic mtDNA mutations.1
How many copies of a pathogenic mtDNA mutation are needed to tip the scales from health to disease? The consensus seems to be that about 60% of all mitochondria in a cell must harbor a mutation before deleterious phenotypes can be observed. In most cases, a mutation causes a loss of function that can be compensated for by the remaining normal copies of the gene. However, some gain of function mutations may cause problems at much lower doses.
Can mtDNA mutations be corrected to prevent disease? A recent study in EMBO Mol Med. reports a new techniques for correcting mtDNA mutations utilizing mitochondrially-targeted zinc finger nucleases.2 If developed for clinical use, techniques like this may provide a way to intervene to remove potentially harmful mtDNA heteroplasmies before disease onset. Other gene therapy strategies such as codon-optimized gene delivery or genome editing with CRISPR/Cas9 technology are being used extensively for basic and translational research.
GenScript offers gene synthesis of customized DNA constructs – giving you ultimate flexibility to design mutants, promoter-reporters, fusion proteins, or any other constructs you can imagine to help you study pathogenic mutations and the function of genes and pathways involved in mitochondrial disease etiology & progression.
Long-standing controversy surrounds the question of how much of the human genome is functional and how much can rightly be dismissed as “Junk DNA.” A recent publication in PLoS Genetics sheds new light on the composition of the human genome, and demonstrates that different classes of genomic elements show different rates of change.
By comparing modern genomes of different species, scientists observe that some portions of the human genome have accumulated mutations at a much slower than expected rate. This suggests that when mutations have occured, they've had a negative effect on fitness and been purged from the population. A new study shows that ~8.2% of the human genome appears to be currently subject to purifying selection, and therefore serving some function that contributes to fitness.1
To put this number in context, it is much smaller than the 80% of the genome has been annotated by the ENCyclopedia Of DNA Elements (ENCODE) consortium as having some biochemical activity2. However, it is almost 8 times the amount of the human genome that encodes protein, and more than 3x larger than the amount of evolutionarily constrained human genome shared with mouse. This is consistent with the observation that certain classes of genomic sequences, especially long non-coding RNA (lncRNA), have high ‘turnover’ rates, meaning that they have likely gained and lost function relatively rapidly throughout the human lineage, compared to low-turnover observed within protein-coding regions.3
Why does it matter? Portions of the genome that bear signatures of purifying selection but whose functions are not yet understood may represent fields ripe for exploration to discover novel genes or novel elements that regulate gene expression, chromosomal stability, or other key biological processes. Conversely, portions of the genome that appear to be non-functional relics of evolution could be candidates for omission in efforts to create sleeker synthetic genomes in cells engineered for industrial/biomedical applications, as is being done through the Sc2.0 synthetic yeast genome project.
To help your research into the mysteries of the genome, GenScript offers:
Global nutrition and food security are major concerns as human population rises and the land area devoted to agriculture shrinks. Biotechnology has accelerated the development of improved food crops that can address these issues in order to boost the economic productivity of farms and improve human health. However, genetically modified food crops have met with consumer resistance and increasing regulation due in part to concerns over the long-term safety and environmental effects of transgenes being introduced into plants. One way in which the scientific community is responding is to identify new technologies that can achieve the nutrition and food security goal of prior genetic engineering efforts while avoiding the use of transgenes and the “GM” label that is controversial among consumers.
“Superbananas” have made news headlines as a biofortified crop containing enhanced levels of vitamin A to counteract widespread vitamin A deficiencies in certain parts of the world. A new “Science & Society” paper in Trends in Biotechnology presents the argument that luxury items such as fruit crops may find more consumer acceptance for bioengineering than do staple crops such as grain and rice, and discusses the possibility that new technologies such as CRISPR-mediated genome editing may elude the regulatory designation as “GMOs” since they contain no foreign DNA.1 Successful CRISPR-mediated genome editing has been demonstrated in citrus fruits2 and a variety of other food crops and diverse plant species3.
GenScript offers gRNA constructs for CRISPR-mediated genome editing, including expert gRNA design for any species.
Why are viral diseases like AIDS still incurable? Although antiretroviral drugs can effectively control viral load in many patients, the permanent integration of viral DNA into a host genome means that patients remain vulnerable to re-activation of a latent virus. Exciting new research now shows that CRISPR technology can remove HIV DNA that has integrated into the host genome in human cells, re-igniting our hopes for developing a true cure for AIDS.
CRISPR-mediated genome editing is revolutionizing biomedical research due to its precise targeting, high efficiency, and ease of use in any cell type or experimental system. CRISPR has been used to create new transgenic animal models for basic and translational research, and it holds promise for use in gene therapy and other medical applications.
GenScript's new GenCRISPR™ gRNA construct service makes it easy to perform CRISPR/Cas9-mediated genome editing in your own lab.
Researchers recently discovered that switching on the expression of Pax5, a tumor suppressor gene commonly mutated in childhood leukemia patients, was sufficient to reverse leukemia.1 As published by Liu et al. in Genes & Development, re-engaging the transcriptional program seen in normal B-cell differentiation, Pax5 restoration achieved durable disease remission despite the continued presence of other oncogenic mutations.
Numerous genes other than Pax5 are frequently mutated in leukemia and other cancers, including GSTT12, CEPBA, RUNX1, and GATA2.3 The increasing use of whole-genome sequencing of biopsied tissue from individual patients is shedding light on new gene targets every day. Given the increasing incidence of cancers worldwide, despite the advances in therapeutic modalities such as antibodies for immuno-oncology, genetic approaches to modulate gene expression levels through gene switches, or to replace mutated genes with healthy ones through gene therapy, could provide valuable additions to our anticancer arsenal.
To study gene expression and gene function, thousands of researchers around the world turn to GenScript for gene synthesis to generate custom DNA constructs encoding newly discovered genes, disease-associated gene variants, somatic and inherited mutations, and even large gene cassettes of 50kb or longer.
Stop codons made the news in May when Science published findings about stop codons reassignments in the wild – that is, the recoding of typical stop codons to encode specific amino acids, which occurs in viral genes involved in phage-host interactions.1
Now a new study in Nucleic Acids Research addresses stop codon read-through in mammalian cells – where chromosomal genes can be expressed with C-terminal extensions that may contain functional domains.2
To study gene expression, thousands of researchers around the world turn to GenScript for gene synthesis, including the synthesis of newly discovered genes, gene variants, mutant sequences, and even entire genetic circuits of 50kb or longer.
The small molecule BASI showed potent anti-cancer effects in a high-throughput screen for glioblastoma multiforme (GBM), the most common type of adult brain tumor. Now a new study reveals that BASI inhibits glioma proliferation, invasion, and migration in vitro and in vivo by altering levels of several micro-RNAs, which form a coordinated, multi-level blockade of the Wnt / β-catenin signaling pathway. Building upon prior work that elucidated the role of several of these miRs in regulating Wnt signaling, this study provided novel characterization of the role of miR-181d, and reported on the ability of the small molecule BASI to simultaneously target the entire suite of miRNAs that regulate β-catenin through diverse mechanisms. Because Wnt is implicated in the growth of multiple tumor types, BASI and the miRs it regulates are promising subjects for further basic and translational research.
To study the effect of miR-181d on the β-catenin pathway, these researchers ordered custom-cloned CTNNB1 and CREBBP reporter plasmids from GenScript. With GenEZ™ Molecular Cloning, it's easy to get customized ORF clones or even completely custom genes in expression-ready plasmids.
Mother Nature offers a gold-mine of information about how common problems have been solved across evolutionary time. Although we tend to rely on only a few model organisms in the lab, searching the genomes of other species provides valuable insights.
The International Institute for Species Exploration released its “Top 10 New Species” list on May 23rd, to celebrate the birthday of Carolus Linnaeus, the “Father of Taxonomy.” Learn more about the 10 most intriguing life-forms identified in the last year on the IISE website.
How can newly discovered species help your research?
Everyday biomedical researchers are:
Studying genes found in a variety of species can provide key insights into gene regulation, protein function, metabolic pathways, and more. Whatever your research focus, GenScript has the tools you need.
A recent study published in Nature circles around to a jackpot by shifting from a drug screen to molecular target and back – and delivers a major advance for cancer drug discovery by combining chemical proteomics, pharmacology, and genetic approaches.
Starting with a small molecule that blocks Ras-dependent cancer cell proliferation, researchers discovered an attractive new target for anticancer therapies: MTH1 (Nudt1). They used codon-optimized gene synthesis from GenScript to express Nudt1 for enzymatic assays and crystallization studies, and identified (S)-crizotinib as a highly specific, low-nanomolar MTH1 inhibitor.
How does MTH1 help cancer cells grow?
A nucleotide pool sanitizing enzyme, MTH1 helps avoid the incorporation of oxidized nucleotides during DNA damage repair and DNA replication. This is useful for all cells to protect the integrity of their DNA – but it's especially important for cancer cells due to their fast proliferation rates and high levels of intracellular reactive oxygen species. Similar to currently used chemotherapy agents that target rapidly dividing cells, drugs that inhibit MTH1 could make cancer cells selectively vulnerable to oxidative damage-induced cell death.
Why is (S)-crizotinib well-positioned for drug development?
(S)-crizotinib was discovered as a contaminant in a preparation of the (R)-enantiomer of crizotinib, which is already FDA approved for clinical use. Since the two compounds differ in only one chiral center, it is likely that (S)-crizotinib will be a safe drug with favorable pharmacokinetic and pharmacodynamic properties. Further, the chemical proteomics experiments in this study demonstrate that, while (R)-crizotinib binds to many different protein kinases, MTH1 as the only common high-significance interactor of (S)-crizotinib, and showed nanomolar potency for (S)-crizotinib to block cancer cell proliferation. This high degree of specificity and potency also increase the chance that (S)-crizotinib will pass safety and efficacy benchmarks in clinical trials.
As the most cited Biology CRO worldwide, GenScript is the ideal partner to accelerate your research by synthesizing the customized DNA constructs your experiments require. As a pioneer in Gene Synthesis technology, GenScript now offers GenEZ™ Next-Gen Molecular Cloning, the easiest way to get expression-ready, sequence-verified clones in your choice of vector, containing either ORF RefSeqs or gene insert sequences of your own design.
Successful neurotrophin gene therapy in a guinea pig model of sensorineural deafness could soon be translated to humans. A report in Science Translational Medicine finds that electroporation of BDNF cDNA into mesenchymal cells of the ear stimulates spiral ganglion neurite regeneration, which improves sensitivity to electrical signals transmitted by cochlear implants.
Gene delivery, whether for therapeutic or basic research use, requires high-quality customized DNA constructs. Gene synthesis enables the construction of more efficient vectors and cargos for gene delivery. As a pioneer in Gene Synthesis technology, GenScript now offers GenEZ™ Next-Gen Molecular Cloning, the easiest way to get expression-ready, sequence-verified clones in your choice of vector.
A critical regulator of osmotic homeostasis has finally been identified: SWELL1, a ubiquitous membrane-bound protein, has been identified as an essential component of the volume-regulated anion channel.
How do cells maintain a constant volume despite fluctuations in
As we know, water diffuses freely across the semi-permeable plasma membrane of all cells, and tends to move from areas of lower solute concentration to areas of higher osmolarity. Therefore, any time intracellular osmolarity increases or extracellular osmolarity decreases, cells should swell – with disastrous consequences. But they don’t – instead, they do a remarkable job of maintaining constant cell volume, presumably by exporting ions whenever they sense their volume increasing. Scientists inferred the presence of a volume-regulated anion channel (VRAC) through which chloride ions leave swollen cells in order to restore homeostasis. Further studies characterized the pharmacological and electrophysiological properties of VRACs, but their molecular composition has remained elusive – until now.
A recent study published in Cell reports on a genome-wide RNAi screen using a cell-based ﬂuorescence assay to identify VRAC components. The authors discovered that the ubiquitously expressed gene LRRC8A (now renamed SWELL1) encodes a transmembrane protein required for hypotonicity-induced ion flux. Expressing an RNAi-insensitive SWELL1 cDNA clone completely restored channel function, and several point mutants modulated the volume-sensitive ionic currents.
Synaptic plasticity is known to underlie learning and memory, but we're still discovering the molecular mechanisms by which synaptic activity leads to changes in synapse morphology and function. A recent Nature Neuroscience paper reports a new post-translational modification that is required to coordinate the changes involved in memory formation: after enhanced synaptic activity, DHHC5 palmitoylates δ-catenin, increasing its binding to synaptic cadherin both in vitro and in the hippocampus of fear-conditioned rodents. These researchers used a synthetic δ-catenin gene, in which the palmitoylated cysteine residues were mutated to serine, to demonstrate that δ-catenin palmitoylation is required for numerous facets of activity-induced synaptic plasticity, including N-cadherin stabilization at synapses, postsynaptic spine enlargement, insertion of GluA1 and GluA2 into the synaptic membrane, and increased mEPSC amplitude.
CRISPR/Cas9 technology for precise gene editing has already proven successful in mice, C. elegans, Xenopus tropicalis, and plants. Now CRISPR has been used the silkmoth Bombyx mori, an important insect model organism.
Ma et al. used CRISPR to disrupt the Bmku70 gene, which is required for non-homologous end joining (NHEJ) and plays a role in telomere length maintenance, subtelomeric gene silencing and antigen diversity. Bmku70 knockouts exhibit an increased frequency of homologous recombination and thus can provide a powerful new model for future studies on the fundamental mechanisms of DNA repair.
Why is CRISPR more efficient than TALEN or ZFN for insect models?
Ma et al. report that numerous prior attempts at site-directed insertion of recombinant DNA
mori genome have failed. These earlier experiments used ZFN or TALEN techniques, which
effectively generated transgenic strains of many species through targeted homologous recombination (HR).
insect cells show a preference for the nonhomologous end joining (NHEJ) pathway rather than the HR
repair of double strand breaks (DSBs), making the efficiency of HR-based genome editing very low.
While both zinc-finger nucleases (ZFN) and TAL effector nucleases (TALEN) can be engineering to target a locus of interest, they rely upon protein-DNA interaction; in contrast, CRISPR uses an RNA-DNA pairing to determine the specificity and activity of the nuclease. RNA-DNA interactions are generally much more stable than protein-DNA interactions, yielding higher efficiency of success. In addition, CRISPR is much simpler and faster for researchers to use.
The CRISPR method relies upon customized gene constructs that encode a codon-optimized Cas9 nuclease and a synthetic guide RNA for precise targeting. GenScript's gene synthesis service can prepare the constructs you need for CRISPR/Cas9-based genome editing.
Magnetotactic bacteria (MTB) are diverse group of gram-negative bacteria that contain specialized organelles called magnetosomes. Magnetosomes produce uniform crystals of magnetic iron compounds such as magnetite (Fe3O4) or greigite (Fe3S4), and align in chains that form a permanent magnetic dipole within the cell.
Naturally occurring MTBs are difficult to grow in the lab, so scientists sought to express magnetosomes in a more tractable model organism. However, recapitulating an entire functioning organelle isn't as simple as expressing a single transgene, especially since all the elements involved in magnetosome biogenesis and function have not been identified. Magnetosome formation and function requires numerous genes that work together to direct 1) invagination of the cytoplasmic membrane to form free-standing vesicles that will become the magnetosome organelles; 2) the uptake of iron into the new magnetosome; 3) the redox-controlled biomineralization of magenetite crystals; and 4) the self-assembly of crystals into nanochains along a dedicated cytoskeletal structure.
In a new Nature Nanotechnology paper, Kolinko et al. identify a minimal gene cassette (containing up to 29 unique genes) that can induce magnetosome biosynthesis within R. rubrum, a bacterial strain commonly used for biotechnology. Building upon earlier work by several other groups (Zurkiya et al.; Nakamura et al.; Goldhawk et al. and Benoit et al.) expressing the MagA gene in E. coli or mammalian cells and using magnetotectic bacteria in cancer imaging, this new report of engineering R. rubrum to generate magnetosomes represents an advance toward large-scale biotech and medical applications.
Why do bacteria have magnetosomes? (What's the advantage of carrying around a magnet?)
Magnetosomes give MTBs a unique ability to sense electromagnetic fields, which helps them orient and migrate by either passively aligning or actively swimming along geomagnetic field lines. These cells may also be able to harness magnetic force to swim faster than other microbes: some MTBs have been observed to swim at speeds nearly twice that of E. coli cells in spite of being larger in size and in spite of having less flagellar proteins.
How can magnetosomes treat tumors?
Magnetosomes can be taken up by cancer cells and then exposed to a magnetic field, causing hyperthermia that slows cancer cell proliferation and eradicates tumor xenografts in mice. Magnetosomes can also serve as efficient delivery vehicles for gene vaccines and may be used to improve MRI technology by enhancing magnetic resonance contrast for medical imaging. This is only the latest example of how genetic engineering brings new advances in the prevention, diagnosis, and cure of human disease.
"Optogenetics" allow researchers to stimulate synaptic activity in specific neurons that are made to express light-sensitive ion channels (channelrhodopsins). Despite the variety of opsins with different peak wavelength sensitivities, until now it has not been possible to independently activate two distinct neural populations without significant cross-talk or losing temporal resolution. Researchers at MIT reported in Nature on two new opsins with non-overlapping excitation spectra, Chronos and Chrimson, that allow independent optical excitation of distinct neural populations in mouse brain slices. These tools open the door to explore how multiple synaptic pathways interact to encode information in the brain.
Opsin genes occur naturally in microbial algae. In order to efficiently express these genes in mammalian cells, these researchers turned to GenScript for codon optimization and gene synthesis. Codon optimization overcomes codon usage bias, secondary structures, and other sequence features that can inhibit heterologous gene expression. GenScript has developed the leading codon-optimization algorithm: OptimumGene, patented in 2012 and continuously improved based upon the latest research findings.
Scientists are striving to understand how genetic variants predispose individuals to overweight and weight-related diseases such as type 2 diabetes, which are becoming more prevalent. Many genetic variants have been identified that seem to be associated with obesity – but a critical next step is to elucidate the mechanisms by which these 'mutant' sequences actually alter gene expression or protein function.
Breaking news: FTO, the first "obesity gene" to be identified and still to date the strongest genetic determinant of obesity risk, has now been shown to influence obesity only indirectly by housing regulatory elements for the true actor: the homeobox gene IRX3.
The first "obesity gene," FTO, was discovered by three unique genome wide association studies published in 2007 1, 2, 3. However, a new study published in Nature on March 20, 2014 reveals that obesity-related variants located within FTO introns have no effect on FTO gene expression or function, but instead regulate the expression of IRX3, a gene several hundred thousand base pairs away. Mechanistic studies employing both human brain tissue and transgenic mice show that IRX3 expression in the hypothalamus controls basal metabolic rate and body mass and composition.
This reversal of FTO' s reputation highlights the importance of investigating the functional roles of new genetic variants as soon as they are identified. In order to characterize the functional roles of naturally-occurring DNA mutations, researchers often need to generate variant constructs for experiments such as reporter gene assays. GenScript's mutagenesis service offers a time-saving and cost-efficient option to get the constructs you need.
With advances in genome sequencing and personalized medicine, it's more critical than ever to understand how genetic variants actually influence physiology and disease etiology. GenScript is the leading provider of custom molecular biology services including gene synthesis, which can deliver the precise DNA constructs you need, without the limitations and headaches of traditional PCR-based manipulation of pre-existing templates.
A recent Science paper reports that the presence of AT-rich rare codons in the N-terminal region enhances protein expression by reducing RNA secondary structure in bacteria. This is great news for all researchers whose experiments have suffered from low levels of heterologous protein expression. By taking advantage of the degeneracy of the genetic code, you can alter your nucleotide sequence to favor efficient protein expression while preserving the amino acid sequence you need – a technique called codon optimization.
It's been known for some time that codon usage bias among different species. As a consequence, when researchers want to express a gene in a different organism in order to study it – for example, expressing a human allele associated with disease in a model organism such as a mouse – the gene may be poorly expressed because a scarcity of tRNAs can cause translation to stall. One solution to this problem is to over-express the desired tRNA species – but this introduces the confound of altering the stoichiometry governing translation for every protein in the cell. A better solution is to replace codons that are rare in the host organism with more common ones. Many codon optimization algorithms have been developed upon this basis.
However, these latest results published in Science suggest that eliminating rare codons may not always be beneficial: as with real estate, it's all about location, location, location. At the N-terminus of a protein, some rare codons actually increase protein expression levels. It turns out that the key here is not tRNA abundance, but rather the fact that AT-rich codons tend to reduce the formation of mRNA secondary structures that can prevent the mRNA from progressing smoothly through the ribosome – throwing a wrench into the gears of the translation machinery.
GenScript has developed the leading codon-optimization algorithm: OptimumGene, patented in 2012 and continuously improved based upon the latest research findings. Consistent with this study in Science, OptimumGene accounts for the secondary structure of mRNA and allows rarer codons at the N-terminus. GenScript's algorithm considers dozens of additional factors known to affect transcription, mRNA stability, translation, and protein folding, and generates up to 100-fold increases in protein expression.
Crystallography has afforded scientists a chance to see sub-microscopic details of protein structures for a full century now. While we may take this technique for granted, it's still revealing secrets that can revolutionize our understanding of protein folding, enzyme activity, and evolution – with very real implications for protein engineering efforts that hold immense promise for applications such as biomedicine and alternative energy.
For example, in a recent paper published in Nature Chemical Biology, crystal structures reveal important features of QueE, a key enzyme in purine biosynthesis. By crystallizing QueE in complex with the catalyst AdoMet and substrates CPH4, 6CP, and CDH, they discovered that QueE contains a modified core fold unlike any other AdoMet radical enzyme. After locating the active site and characterizing its intricate hydrogen bonding network, they discovered that substrate binding generates a metal-binding site.
These crystal structures were obtained using codon-optimized gene synthesis of the QueE gene.GenScript has the expertise to rapidly synthesize codon-optimized gene constructs for the efficient expression of proteins you need for crystallography.
As reported in Nature, scientists have generated the first monkeys harboring specific mutations, through the use of CRISPR-mediated gene editing.
This breakthrough promises to produce better models for studying human disease. CRISPR/Cas9 technology for precise gene editing has already proven successful in other species including in mice, C. elegans, Xenopus tropicalis, and plants.
Why is CRISPR an important breakthrough for creating transgenic monkeys?
Most traditional methods for gene targeting require the introduction of a transgene cassette via homologous recombination. Recombination occurs rarely, so these methods typically use many individual animals – which is challenging to accomplish with non-human primates…
TALENs aren't just for single-gene targeting anymore: researchers recently created TALEN constructs for 18,740 unique protein-coding human genes. In a pilot test of 124 genes, all TALENS were active and disrupted their target genes at high frequencies.
A library of TAL effector nucleases spanning the human genome, Kim et al. Nature Biotechnology 2013 Mar; 31 (3); 251-8.
To construct their gene library, these researchers ordered custom gene synthesis from GenScript of TALE plasmids containing all possible combinations of four repeat variable di-residue (RVD) DNA sequence modules. GenScript's Combinatorial Assembly Library service can cost-effectively generate gene libraries for high-throughput genome editing, synthetic biology, and other applications. Read More
Tyrosine Kinase Inhibitors (TKIs) have already revolutionized the treatment of cancer. But much remains to be learned about how specific receptor tyrosine kinases (RTKs) contribute to cancer, inflammation, and neuropathic pain and how they can be most effectively targeted to alleviate these diseases. These two recent papers use disease-relevant cellular and animal models to characterize new drug candidates and reveal new secrets of cancer biology:
The RTK inhibitor GTx-186 has a unique kinase profile, with activity against TRK-A/B/C, RET, ROS1, NF KB, AP-1, and ALK, conferring the power to quell cancer cell growth in vitro, tumor growth in vivo, and inflammation in disease-relevant cell-based assays and animal models.
Lenvatinib, currently in clinical trials cancer therapnny as a known VEGFR2/3 inhibitor, was just shown to have antitumor activity RET gene-fusion tumor models. Most exciting, this study suggests there may be synergy between lenvatinib's distinct roles in suppressing angiogenesis and in slowing transformed cell growth – spurring new research on the fundamental oncogenic mechanisms of commonly-observed RET gene fusions.