Culture

New Orleans, LA - Research led by Nicolas Bazan, MD, Ph.D., Boyd Professor and Director of the Neuroscience Center of Excellence at LSU Health New Orleans School of Medicine, has discovered unique patterns of genetic activity that may lead to the development of blinding retinal diseases. The results are published online in the Federation of American Societies for Experimental Biology (FASEB) journal, BioAdvances.

"A central question to understand blinding retinal diseases is how key genes are expressed to sustain retinal function and how retina building blocks participate," notes Dr. Bazan, who also holds the Ernest C. and Yvette C. Villere Chair of Retinal Degenerative Diseases Research at LSU Health New Orleans.
Bazan's research team investigated retina structure and function using rodent models where two potentially strategic proteins were deleted. They used sensitive and specific molecular imaging to map the spatial arrangement of the building blocks where the retina cells that sense light (photoreceptors) are constructed. They used a multidisciplinary approach that includes Optical Coherence Tomography imaging (a procedure used clinically to see the integrity of retina noninvasively) and electroretinogram to decide about function.

They report the discovery of novel gene signatures leading to mutations in two proteins - MFRP, which participates in cell fate and development, and Adipor1, whose absence in the retina results in the inability to take up and incorporate the building block docosahexaenoic acid (DHA 22:6) and the onset of retinal degeneration. A single amino acid mutation of Adipor1 occurs in a high proportion of retinitis pigmentosa patients. Different forms of this receptor mutation have been found in age-related macular degeneration (AMD), as well as in other forms of retinal degeneration.

The researchers found that the absence of 22:6 leads to modifications, which then trigger an increase in proinflammatory genes and a decrease of genes that are critical for visual system function.

The study demonstrates that the MFRP mutation resembles the ADIPOR1 mutation on multiple levels. Deletion of these proteins leads to flecked retina and slow cell death onset. Functionally, the mutations express the same degree of functional attenuation. Both mutants clearly demonstrate the inability to take up and incorporate building blocks, which results in remarkable changes in the retina.

"Although the gene signature shows that both mutants are activated by signals involving proinflammatory cytokines, we found that each of these pathways has distinct features," Bazan says.

"Moreover, our results highlight the critical role of MFRP and ADIPOR1 in preserving retinal function. Our findings demonstrate that the maintenance of retinal function relies on two proteins MFRP and ADIPOR1, acting to ensure proper acquisition and distribution of key building blocks molecules necessary to sustain protection against age-related Macular degeneration and other retinal degenerative deceases."

A new clinical guideline from the American Society for Radiation Oncology (ASTRO) provides recommendations on the use of radiation therapy to treat patients diagnosed with the most common types of skin cancers. The guideline details when radiation treatments are appropriate as stand-alone therapy or following surgery for basal and cutaneous squamous cell carcinomas (BCC, cSCC), and it suggests dosing and fractionation for these treatments. The executive summary and full-text version of ASTRO's first guideline for skin cancer are published online in Practical Radiation Oncology.

Skin cancer is the most prevalent cancer in the United States, with more than 5 million cases diagnosed each year. More than 95% of these diagnoses are BCC or cSCC, which, in contrast to melanomas, respond well to radiation therapy if treated promptly and properly. Although surgery to remove the lesion is considered the primary approach for definitive/curative treatment of these non-melanoma skin cancers, radiation therapy can play an integral role in both the curative and post-operative settings.

ASTRO developed the new guideline to provide clarity about treatment options. "There is significant variation in practice about when and how radiation should be used for non-melanoma skin cancers, largely because few randomized studies have compared modern treatment options head-to-head," explained Phillip Devlin, MD, FASTRO, chair of the guideline task force and a radiation oncologist at Brigham and Women's Hospital in Boston.

"For this guideline, we drew on the consensus of a multidisciplinary group of leading experts, as well as a systematic review of the evidence, to help physicians understand when radiation is most likely to benefit their patients and to encourage informed discussion about treatment options," added Anna Likhacheva, MD, MPH, vice chair of the guideline task force and a radiation oncologist with Sutter Medical Group in Sacramento.

Recommendations for Radiation Therapy for BCC and cSCC

The guideline first defines appropriate indications for radiation therapy (1) as definitive/curative treatment for BCC and cSCC, (2) as adjuvant treatment following surgery and (3) as definitive or adjuvant treatment for disease that has spread to a patient's regional lymph nodes. Recommendations are as follows:

In the definitive/curative setting, radiation is strongly recommended for patients with BCC or cSCC who cannot undergo or decline surgical resection. It is conditionally recommended for patients with BCC or cSCC located in anatomically sensitive areas such as the nose or lips, where surgery could compromise function or cosmetic outcomes. Definitive radiation therapy is discouraged, however, for patients with genetic conditions that predispose them to be more sensitive to radiation.

In the adjuvant/post-operative setting, radiation following surgery is recommended for patients at high risk of cancer recurrence, including a strong recommendation when there is evidence that BCC or cSCC has spread to a patient's nerves. Post-operative radiation is also recommended for patients at high risk of recurrence following surgical resection, including strong recommendations for high-risk patients with cSCC and conditional recommendations for high-risk patients with the relatively less aggressive BCC. Recommendations also outline prognostic features that indicate which patients are at greater risk for recurrence and spread.

For patients with BCC or cSCC that has spread to regional lymph nodes, surgical removal of the affected lymph nodes followed by radiation is strongly recommended for both BCC and cSCC, although not for patients with one small involved lymph node without extracapsular spread. The guideline also strongly recommends definitive radiation for patients with regional cSCC spread who cannot undergo surgery.

Recommendations address technical aspects of radiation therapy, suggest dosing and fractionation schedules and include a brief discussion of the different types of radiation delivery methods. The task force concluded that the appropriate use of any of the major radiation modalities results in similar cancer control and cosmetic outcomes. The guideline also considers the use of drug therapies such as chemotherapy, biologic and immunotherapy agents in combination with radiation.

About the Guideline

The guideline was based on a systematic literature review which produced more than 1,500 articles, of which 143 (published from May 1988 through June 2018) were then carefully evaluated. The task force included a multidisciplinary team of radiation, medical and surgical oncologists, a radiation oncology resident, medical physicist, dermatologist and dermatopathologists. The guideline was developed in collaboration with the American Society of Clinical Oncology (ASCO) and the Society of Surgical Oncology (SSO), who provided representatives and peer reviewers.

ASTRO's clinical guidelines are intended as tools to promote appropriately individualized, shared decision-making between physicians and patients. None should be construed as strict or superseding the appropriately informed and considered judgments of individual physicians and patients.

ITHACA, N.Y. - Female grape berry moths are the biggest insect threat to wine grapes in the eastern U.S. The moths lay their eggs on grapes and, once hatched, the larvae penetrate the skin, then eat and damage the fruit. But no one is quite sure how the moths home in on berries from the wider landscape.

A new study, published Nov. 21 in the Journal of Chemical Ecology, investigates how these pests find their target amid a sea of other plants in the landscape.

The researchers originally hypothesized that grapes might have a unique profile of volatile compounds that the moths recognize, and perhaps other neighboring plants have volatile organic compound profiles that deter moths.

They created a study design that gauged the attraction of female grape berry moths to volatile organic compounds emitted from grape vines, the moths' natural host plant, as well as to nearby gray dogwood and apple trees.

"Chemical cues, signals, are used by almost all insects to locate resources in their habitat, such as mates or host plants," said Charles Linn, a senior research associate at Cornell, now retired, and the senior author on the paper.

"Grape plants produce maybe hundreds of compounds, but the insects are really only detecting a subset with their antennae," said Greg Loeb, professor of entomology at Cornell AgriTech and a co-author of the paper.

Michael Wolfin, Ph.D. '17, a postdoctoral researcher at Penn State, is the paper's first author.

The researchers ran gas chromatography, electro-antennal detection and mass spectrometry analyses coupled with behavioral tests in a wind tunnel and identified 11 volatile organic compounds emitted by grapes that the moths detected. Though these compounds appear in particular ratios in grapes, they are common and are shared by most plants, including gray dogwood and apples.

When the study's authors used the grape vine odors to lure the moths into traps, the method worked, but ineffectively.

In wind tunnel tests, the researchers found the moths flew upwind at the same rates toward both plant clippings and extracts of volatiles from grapes, dogwood or apples.

"The berry moth wasn't showing clear evidence of discrimination based on these compounds" over long distances, Loeb said. "We suggest that maybe plant-eating arthropods are using these common volatiles to find the correct habitat, and then using other cues to zero in on where they are going to lay their eggs."

"These results support a model that is in marked contrast to others in the literature and should provide a new hypothesis for future testing," Linn said.

More study is needed to determine what cues the moths use to find berries. A preliminary study using artificial wax grapes showed that berry moths would not lay eggs on bare wax, but when a grape skin was laid over the wax, the females did lay eggs, suggesting there is something on the skin's surface they recognize.

Though no deterring volatiles were found, the research offers clues for breeders to perhaps develop varieties with tweaked ratios of volatiles to throw insects off scent.

Researchers at the University of São Paulo (USP) in Brazil have described a system present in a species of opportunistic bacterium found in hospital environments that injects a cocktail of toxins into competing bacteria and completely eliminates them. This discovery can be used in the future development of new antimicrobial compounds.

The study was supported by São Paulo Research Foundation - FAPESP and published in PLOS Pathogens by researchers affiliated with USP's Chemistry Institute (IQ) and Biomedical Sciences Institute (ICB).

The researchers discovered that Stenotrophomonas maltophilia uses a secretion system that produces a cocktail of toxins and injects them into other microorganisms with which it competes for space and food. In addition, the researchers characterized one of 12 proteins in the cocktail - Smlt3024 - and observed that this molecule alone can considerably reduce the rate at which other bacteria replicate.

"We believe these toxins can be explored as a form of treatment in the future. Just as antibiotics can come from other bacteria, we are exploring this arsenal used by bacteria themselves to kill other species of pathogen," said Ethel Bayer-Santos, a researcher at ICB-USP.

The study was part of her postdoctoral project at IQ-USP, which was also supported by FAPESP. She currently has a Young Investigator grant from FAPESP.

Bacterial secretion systems are protein complexes present on the cell membranes of bacteria for the secretion of substances. These systems are used by pathogenic bacteria to secrete virulence factors and invade host cells.

"The Type IV secretion system [T4SS], as it is known, secretes proteins and DNA into other cells or the extracellular medium. We recently showed that it is present in Xanthomonas citri, the pathogen that causes citrus canker. We have now found it in this bacterium [S. maltophilia], which is frequently isolated from water and soil but can become an opportunistic pathogen in hospital environments," said Shaker Chuck Farah, a professor in IQ-USP and principal investigator for the study.

The research is linked to two Thematic Projects funded by FAPESP: "Cyclic di-GMP signaling and the Type IV macromolecule secretion system in Xanthomonas citri" and "Structure and function of bacterial secretion systems".

The group's discovery of the secretion system in X. citri was reported in a paper published in Nature Communications. Another article by the same group, published in 2018 in Nature Microbiology, describes the atomic structure of much of the secretion system using cryogenic electron microscopy (cryo-EM), an imaging technique that enables scientists to observe the 3D structure of biomolecules as they move and interact.

Bacterial warfare

Competition between microorganisms determines which species will dominate or be eradicated from a specific habitat. Bacteria have several mechanisms that can reduce the multiplication of competitors or even kill them. One is T4SS, which itself consists of more than 100 components originating from 12 different proteins present on the surface of their cells.

The researchers found that the secretion systems in X. citri and S. maltophilia contain antidotes to the toxins they secrete. These antidotes are required to protect the microorganisms from their own weapons. On approaching another species of bacterium, the attackers inject the toxins into the competitor by mere contact or using a pilus, a microscopic filament that functions like a harpoon.

To test the action of the system, the researchers performed several experiments involving competition between bacteria. In one experiment, they placed specimens of S. maltophilia and Escherichia coli, a species widely used in the laboratory, in the same medium. E. coli had barely begun to multiply when S. maltophilia approached and eliminated its rivals. The same effect was observed against Klebsiella pneumoniae and Salmonella typhi, as well as Pseudomonas aeruginosa, a bacterium that infects cystic fibrosis patients.

Another experiment consisted of testing the effect of Smlt3024 alone. Specimens of E. coli that expressed the toxin in the cytoplasm exhibited no growth alterations. However, when, in addition to the gene for Smlt3024, they also had a signal sequence - a set of certain amino acids that changes the location of the protein - the toxin was directed to the periplasm (the space between the inner and outer membranes in bacteria), exactly as the original system does in S. maltophilia and X. citri. In this case, cell division in E. coli was considerably reduced, demonstrating the effect of the protein.

Although both S. maltophilia and X. citri have the same system, they can kill each other using T4SSs, as another experiment showed. Experiments also showed that key components of one system can be replaced by homologues from another and that the T4SS in one bacterium can secrete the toxins of another.

All this is evidence of similarities in the structures that can be studied in the future to explore similar T4SSs (homologues) identified in tens of other bacterial species.
New studies may allow other researchers to develop molecules that inhibit the action of this system for use in the discovery of new drugs.

"We can screen drugs capable of binding to this system and inhibiting some important stages in the transfer of toxins from one cell to another. This could reduce the survival of these bacteria in some environments," Farah said.

"The toxin itself could be used as an antimicrobial agent, but other studies need to be done to test this possibility," Bayer-Santos said.

The study also has three other authors supported by FAPESP, and all are affiliated with IQ-USP: Bruno Yasui Matsuyama, who has a postdoctoral scholarship from FAPESP; Gabriel Umaji Oka, who also has a postdoctoral scholarship from FAPESP; and William Cenens, whose postdoctoral scholarship ended in May 2019.

A team of researchers from the Georgia Institute of Technology and The Ohio State University has developed a soft polymer material, called magnetic shape memory polymer, that uses magnetic fields to transform into a variety of shapes. The material could enable a range of new applications from antennas that change frequencies on the fly to gripper arms for delicate or heavy objects.

The material is a mixture of three different ingredients, all with unique characteristics: two types of magnetic particles, one for inductive heat and one with strong magnetic attraction, and shape-memory polymers to help lock various shape changes into place.

"This is the first material that combines the strengths of all of these individual components into a single system capable of rapid and reprogrammable shape changes that are lockable and reversible," said Jerry Qi, a professor in the George W. Woodruff School of Mechanical Engineering at Georgia Tech.

The research, which was reported Dec. 9 in the journal Advanced Materials, was sponsored by the National Foundation of Science, the Air Force Office of Scientific Research, and the Department of Energy.

To make the material, the researchers began by distributing particles of neodymium iron boron (NdFeB) and iron oxide into a mixture of shape memory polymers. Once the particles were fully incorporated, the researchers then molded that mixture into various objects designed to evaluate how the material performed in a series of applications.

For example, the team made a gripper claw from a t-shaped mold of the magnetic shape memory polymer mixture. Applying a high-frequency, oscillating magnetic field to the object caused the iron oxide particles to heat up through induction and warm the entire gripper. That temperature rise, in turn, caused the shape memory polymer matrix to soften and become pliable. A second magnetic field was then applied to the gripper, causing its claws to open and close. Once the shape memory polymers cool back down, they remain locked in that position.

The shape-changing process takes only a few seconds from start to finish, and the strength of the material at its locked state allowed the gripper to lift objects up to 1,000 times its own weight.

"We envision this material being useful for situations where a robotic arm would need to lift a very delicate object without damaging it, such as in the food industry or for chemical or biomedical applications," Qi said.

The new material builds on earlier research that outlined actuation mechanisms for soft robotics and active materials and evaluated the limitations in current technologies.

"The degree of freedom is limited in conventional robotics" said Ruike (Renee) Zhao, an assistant professor in the Department of Mechanical and Aerospace Engineering at Ohio State. "With soft materials, that degree of freedom is unlimited."

The researchers also tested other applications, where coil-shaped objects made from the new material expanded and retracted - simulating how an antenna could potentially change frequencies when actuated by the magnetic fields.

"This process requires us to use of magnetic fields only during the actuation phase," Zhao said. "So, once an object has reached its new shape, it can be locked there without constantly consuming energy."

Federal disability benefits can lead to increases in other support for beneficiaries, such as in-kind assistance from adult children, according to a new RAND Corporation study.

Receipt of federal disability insurance also increases the likelihood that children are paid for their in-kind assistance and enables children who provide that assistance to reduce the amount that they work.

These findings, published online by the Journal of Health Economics, suggest that disability recipients are using disability benefits to provide financial compensation to their adult children caregivers.

"These findings provide new evidence that family shares in the burden of disability and that the impact of disability benefits extends beyond the beneficiary to the entire family," said Stephanie Rennane, the study's author and an associate economist at RAND, a nonprofit research organization. "Receipt of federal disability benefits allows a family to reoptimize how they support one another."

While prior work has studied the various sources of income and insurance for individuals who experience a disability, less research has examined how family support mechanisms interact and change over the evolution of a disability, and how they interact with federal disability benefits.

In order to examine trends in income, benefits and family assistance, Rennane used the Health and Retirement Study to analyze information about informal caregiving provided to survey respondents, and matched these details to disability benefit records from the Social Security Administration. The experiences of about 3,000 people were analyzed.

The study compared informal care provided to respondents who had received benefits through either the Social Security Disability Insurance program or Supplemental Security Income program with care to respondents who applied for the benefits, but were denied. The analysis adjusted for differences in health and income between accepted and denied applicants.

The analysis found that the receipt of federal disability payments leads to a 9 percentage point increase in the likelihood of receiving assistance from their children.

Receipt of federal disability payments also more than doubles the likelihood that children are paid for their help and leads to a 50% decline in the probability that the assisting children work full time.

The effects are particularly strong among lower income beneficiaries who receive Supplemental Security Income and among those who recently lost a spouse. Social Security Disability Insurance disability payments also decrease the likelihood that a spouse works.

"The benefits of federal disability payments are shared in complementary ways within the family, enabling a more-holistic network of both formal and informal caregiving," Rennane said. "The resources from disability insurance allow children to reallocate their time to care for their parents."

Cystic fibrosis is caused by an inherited mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Due to this mutation, the CFTR protein doesn't embed in cell membranes to form a channel for chlorine ions the way it should. As a result, mucus-producing cells secrete a thicker-than-normal mucus that can create blockages in the lungs and digestive system. In the lungs, this thicker mucus can help bacteria thrive, making lung infections a serious and chronic problem for many people living with cystic fibrosis.

Yet some people with cystic fibrosis don't develop lung infections as early or as frequently as others. Researchers at University of California San Diego School of Medicine recently discovered that genetic variations dampening expression of another gene, called RNF5, offer a likely explanation.

In the study, published December 10, 2019 in eLife, the team found that individuals with cystic fibrosis who carry specific genetic variants lowering expression of RNF5 have more mutant CFTR protein on their cell surfaces. Even if the CFTR protein isn't totally functional, it's likely better than having none at all, the researchers said.

Cystic fibrosis symptoms can be significantly improved with relatively new medications that boost CTFR function. But there are two caveats: The drugs are extremely expensive and they don't work for everyone.

"The cystic fibrosis field is trying to figure out what are the modifiers across the genome that increase or decrease the probability that an individual patient will respond to these expensive drugs," said senior author Kelly A. Frazer, PhD, professor of pediatrics and director of the Institute for Genomic Medicine at UC San Diego School of Medicine. "RNF5 may be one of these modifier genes."

The RNF5 gene is located in the Major Histocompatibility Complex (MHC). Genes in this region encode molecules that are displayed on the surface of most cells in the body. They play an important role in how the body responds to infections. Scientists have long known that everyone has their own set of MHC gene variations, and that they make people more or less susceptible to infections or autoimmune diseases. But because the genes present in the MHC region are so dense with variations, they have not been well-studied for their direct link to diseases.

Frazer and colleagues took a new approach to analyzing MHC gene variants by grouping them. That allowed the team to more easily identify associations between genetic variation, gene expression levels and their effects on complex diseases. The researchers applied this approach with whole genome sequencing of induced pluripotent stem cells derived from 419 people. That translated into investigating more than 4,000 traits, from which they identified 180 associated with variants in the MHC region.

"We've known there's an association between MHC genes and bacterial colonization in patients with cystic fibrosis, but no one knew why," Frazer said. "We assumed it was due to MHC's involvement in the immune system. But now we know that's likely not the only mechanism -- different expression levels of RNF5 may also play an important role."

"This study uncovered a new aspect of cystic fibrosis -- one that could lead to new drug design and development, and allow clinicians to better tailor treatments," said first author Matteo D'Antonio, PhD, a project scientist in Frazer's lab. "But that's just one example of how we might employ this new genetic analysis technique. Now we have a road map, and we can apply it to other diseases and cell types."

Dec. 11, 2019 - A decision aid developed to support patients undergoing genomic sequencing can reduce the amount of time patients spend speaking with overburdened genetic counselors while helping them were more knowledgeable about the benefits of sequencing, suggests a study from St. Michael's Hospital.

Published in Genetics in Medicine, the official journal of the American College of Medical Genetics and Genomics (ACMG), the study evaluated the effectiveness of the Genomics ADvISER, an interactive online decision aid designed to guide patients who have had their genome sequenced and are being offered additional medical information revealed by the sequencing.

Generally, patients undergo genomic sequencing to learn about a particular condition they may have -- but the test also reveals secondary or incidental findings, a slew of other data that may or may not present troubling news about a person's risk to develop additional health issues.

For example, a person could have their genome sequenced to evaluate heart disease and uncover that they have a neuromuscular disease as well as a high risk for heart issues. Another might have their genome sequenced as part of a study on Cystic Fibrosis - a genetic lung disease - and find out they also have alterations in a gene that influences cancer.

"When you start to open the Pandora's box to find one thing you did want to know about your genome, you might find more than you bargained for," said Dr. Yvonne Bombard, a scientist at the Li Ka Shing Knowledge Institute of St. Michael's Hospital, who has led the creation of the Genomics ADvISER.

"Clinical guidelines recommend that clinicians engage in shared decision-making with patients about receiving secondary findings before sequencing. With existing constraints on genetic counselors' time, there is a need for less resource-intense ways to provide education and decision-making support."

Dr. Bombard's study found that patients who used the Genomics ADvISER needed to spend 24 minutes less speaking with a genetic counselor than those who did not access the tool. Those who used the Genomics ADvISER also said they were more knowledgeable about the benefits of sequencing.

This is the first known randomized controlled trial to evaluate a decision aid that guides adult patients' selection of secondary findings from genomic sequencing. One hundred and thirty three patients were randomized. The intervention arm used the Genomics ADvISER to select the categories of secondary findings they wished to receive, whereas control participants spoke to a genetic counselor to make their selection.

While the decision aid did not decrease decisional conflict compared with genetic counseling alone, it did result in shorter conversations with counselors and a higher knowledge of sequencing benefits.

"With this study, we have evidence that our decision aid has the potential to address a critical gap that exists in genomic sequencing," Dr. Bombard said.

"As genomic sequencing becomes more popular in a variety of specialties, achieving improved genomics knowledge with fewer resources and significantly less time spent with genetic counselors is a crucial benefit the Genomics ADvISER provides."

Dr. Bombard and her team have started to look at ways to develop tailored methods to support patient needs during and after genomic sequencing. They are working on the 2.0 version of the Genomics ADvISER, which will transform aid into an adaptable, interactive, patient-centered digital decision support tool using artificial intelligence to customize it based on patient preferences, values, health literacy and experiences.

Diseases of the gut are often notoriously difficult to diagnose, nevermind understand, which is where a network-based approach comes in. Rather than trying to understand individual symptoms, or the role of individual genes, we can use computational methods to get that deeper understanding - looking at how genes work together in complex systems, and how these fail in a disease.

The Korcsmaros Group at EI and QIB have therefore pioneered a combined experimental and computational pipeline that tells us what genes are the important 'master regulators' in the gut, and which of these genes overlap with those associated with IBD, suggesting new angles to research in the future.

Much of this requires us to look at the cells in the gut. Paneth cells release antimicrobial peptides to protect the gut from pathogens and goblet cells release mucus to create a protective barrier. Dysregulation of their function is implicated in diseases such as IBD.

A promising method of understanding the role of these cells has recently been introduced. Known as organoids, stem cells can be cultured from mice models or from patients to make a small model of a human gut, and the effects of different treatments can then be explored, opening avenues for precision medicine, among others.

These organoids can also be modified to study the relative importance of different cell types within the system, and to explore interactions between different genes in healthy or diseased cells. One question that scientists have had is whether this 'enrichment' of organoids, to give us more Paneth cells or goblet cells for example, gives us a realistic model.

The good news, according to PhD student Agatha Treveil of EI, who first authored the paper, is that: "Based on our transcriptomics analysis, we see clear increases in targeted cell types as we expected from using the organoid enrichment methods."

The pipeline, published in Molecular Omics, allows us to compare gene expression in organoids that are enriched for Paneth cells or goblet cells with those that are not. These can then be compared with a growing database of known gene interactions.

Essentially, we can tag the genes which regulate others - highlighting in particular those that regulate lots of processes and are important for goblet and Paneth cell function. The finding that many of these genes overlap with inflammatory processes and IBD both confirms the important role of Paneth cells in IBD, and opens another route to understanding this range of costly illnesses.

Agatha Treveil continues, "this is a pioneering step forward in establishing a pipeline to better understand the gene networks at play in the gut. It enables us to design new experiments to explore IBD-related processes further."

Dr Tamas Korcsmaros, the leader of the project, said, "This project nicely represents the collaborative environment we have at the Norwich Research Park, with UEA, EI and QIB focusing on new experimental models, transcriptomics and computational approaches, and then applying them in translational projects with clinical researchers of the Norfolk and Norwich University Hospital. Now, we have a pipeline that we can use to investigate organoids generated from IBD patients, and analyse drug compound or probiotic effects on these key cell types."

Aging adults are more likely to have - and die from - cardiovascular disease than their younger counterparts. New basic science research finds reason to link biological aging to the development of narrowed, hardened arteries, independent of other risk factors like high cholesterol.

Senior author Daniel Goldstein, M.D., of Michigan Medicine's Frankel Cardiovascular Center, says his team's new Circulation Research paper is the first to dissect the biological effect of aging from hyperlipidemia on atherogenesis.

"We identify a novel pathway within the aorta by which mitochondrial dysfunction and the pro inflammatory cytokine IL-6 co-exist in a positive feedback loop with aging to promote atherosclerosis," Goldstein says of the team's work using mouse models of cardiovascular disease and aging.

The researchers report aged mice had more severe atherogenesis than young mice, even when both groups had similar cholesterol levels for the same time period.

Future research, then, might investigate therapies to mitigate against the effects of vascular aging before high cholesterol becomes a problem, with the goal of reducing the development of atherogenesis in the first place, Goldstein and colleagues say.

LA JOLLA--(December 10, 2019) In mouse models of Alzheimer's disease, the investigational drug candidates known as CMS121 and J147 improve memory and slow the degeneration of brain cells. Now, Salk researchers have shown how these compounds can also slow aging in healthy older mice, blocking the damage to brain cells that normally occurs during aging and restoring the levels of specific molecules to those seen in younger brains.

The research, published last month in the journal eLife, suggests that the drug candidates may be useful for treating a broader array of conditions and points out a new pathway that links normal aging to Alzheimer's disease.

"This study further validated these two compounds not only as Alzheimer's drug candidates but also as potentially more widely useful for their anti-aging effects," says Pamela Maher, a senior staff scientist at Salk and a co-corresponding author of the new paper.

Old age is the biggest risk factor for Alzheimer's disease--above the age of 65, a person's risk of developing the disease doubles about every five years. However, at a molecular level, scientists aren't sure what occurs in the brain with aging that contributes to Alzheimer's.

"The contribution of old age-associated detrimental processes to the disease has been largely neglected in Alzheimer's disease drug discovery," says Antonio Currais, a Salk staff scientist and first author of the new paper.

Maher and David Schubert, the head of Salk's Cellular Neurobiology Lab, previously developed CMS121 and J147, variants of plant compounds with medicinal properties. Both compounds tested positive for their ability to keep neurons alive when exposed to cellular forms of stress related to aging and Alzheimer's disease. Since then, the researchers have used the drug candidates to treat Alzheimer's in animal models of the disease. But experiments revealing exactly how the compounds work suggested that they were targeting molecular pathways also known to be important in longevity and aging.

In the new research, Maher, Currais and their colleagues turned to a strain of mice that ages unusually fast. A subset of these mice was given CMS121 or J147 beginning at nine months old--the equivalent of late middle age in humans. After four months, the team tested the memory and behavior of the animals and analyzed genetic and molecular markers in their brains.

Not only did the animals given either of the drug candidates perform better on memory tests than mice that hadn't received any treatment, but their brains showed differences at the cellular and molecular levels. In particular, expression of genes associated with the cell's energy-generating structures called mitochondria was preserved by CMS121 and J147 with aging.

"The bottom line was that these two compounds prevent molecular changes that are associated with aging," says Maher.

More detailed experiments showed that both drugs affected mitochondria by increasing levels of the chemical acetyl-coenzyme A (acetyl-coA). In isolated brain cells, when the researchers blocked an enzyme that normally breaks down acetyl-CoA, or when they added extra amounts of an acetyl-coA precursor, they saw the same beneficial effect on mitochondria and energy generation. The brain cells became protected against the normal molecular changes associated with aging.

"There was already some data from human studies that the function of mitochondria is negatively impacted in aging and that it's worse in the context of Alzheimer's," says Maher. "This helps solidify that link."

Maher and Currais are planning future experiments to test the effects of CMS121 and J147 on how other organs age. They also hope to use the new results to inform the development of new Alzheimer's drugs; targeting other molecules in the acetyl-coA pathway may help treat the disease, they hypothesize.

"We are now using a variety of animal models to investigate how this neuroprotective pathway regulates specific molecular aspects of mitochondrial biology, and their effects on aging and Alzheimer's," says Currais.

Using a targeted gene epigenome editing approach in the developing mouse brain, Johns Hopkins Medicine researchers reversed one gene mutation that leads to the genetic disorder WAGR syndrome, which causes intellectual disability and obesity in people. This specific editing was unique in that it changed the epigenome -- how the genes are regulated -- without changing the actual genetic code of the gene being regulated.

The researchers found that this gene, C11orf46, is an important regulator during brain development. Specifically, it turns on and off the direction-sensing proteins that help guide the long fibers growing out of newly formed neurons responsible for sending electrical messages, helping them form into a bundle, which connects the two hemispheres of the brain. Failure to properly form this bundled structure, known as the corpus callosum, can lead to conditions such as intellectual disability, autism or other brain developmental disorders.

"Although this work is early, these findings suggest that we may be able to develop future epigenome editing therapies that could help reshape the neural connections in the brain, and perhaps prevent developmental disorders of the brain from occurring," says Atsushi Kamiya, M.D., Ph.D., associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine.

The study was published online in the September 11 issue of Nature Communications.

WAGR syndrome is also known as chromosome 11p13 deletion syndrome, which can result when some or all of the gene located in the region of chromosome 11p13 that includes C11orf46 is deleted by chance. The researchers used a genetic tool, short hairpin RNA, to cause less of the C11orf46 protein to be made in the brains of mice. The fibers of the neurons in the mouse brains with less of the C11orf46 protein failed to form the neuron bundled corpus callosum, as is found in WAGR syndrome.

The gene that makes Semaphorin 6a, a direction-sensing protein, was turned on higher in mice with lower C11orf46. By using a modified CRISPR genome editing system, the researchers were able to edit a portion of the regulatory region of the gene for Semaphorin. This editing of the epigenome allowed C11orf46 to bind and turn down the gene in the brains of these mice, which then restored the neuron fiber bundling to that found in normal brains.

London: As opposed to making you happy, eating ice cream may cause you a headache. Cephalalgia, the official journal of the International Headache Society, published the article entitled "Prevalence and characteristics of headache attributed to ingestion or inhalation of a cold stimulus (HICS): A cross-sectional study", by Torsten Kraya and colleagues from the Department of Neurology, at Martin-Luther-University Halle-Wittenberg, and St. Georg Hospital, Leipzig, Germany.

The authors investigated 618 adults, students and staff from the university, who filled a questionnaire about headaches. Half of the population had a headache after the ingestion of a cold stimulus, regardless of having a diagnosis of migraine or tension-type headache.

The pain was referred to as moderate, lasted less than 30 seconds and occurred in frontal and temporal areas in most individuals. Associated symptoms happened in half of the headaches (tearing, seeing flashing light dots, eye redness, and running nose).

The pleasure of eating ice cream or drinking a cold drink may be decreased by a painful headache.

PITTSBURGH--Carnegie Mellon University computer scientists have taken a deep learning method that has revolutionized face recognition and other image-based applications in recent years and redirected its power to explore the relationship between genes.

The trick, they say, is to transform massive amounts of gene expression data into something more image-like. Convolutional neural networks (CNNs), which are adept at analyzing visual imagery, can then infer which genes are interacting with each other. The CNNs outperform existing methods at this task.

The researchers' report on how CNNs can help identify disease-related genes and developmental and genetic pathways that might be targets for drugs is being published today in the Proceedings of the National Academy of Science. But Ziv Bar-Joseph, professor of computational biology and machine learning, said the applications for the new method, called CNNC, could go far beyond gene interactions.

The new insight described in the paper suggests that CNNC could be similarly deployed to investigate causality in a wide variety of phenomena, including financial data and social networking, said Bar-Joseph, who co-authored the paper with Ye Yuan, a post-doctoral researcher in CMU's Machine Learning Department.

"CNNs, which were developed a decade ago, are revolutionary," Bar-Joseph said. "I'm still in awe of Google Photos, which uses them for facial recognition," he added as he scrolled through photos on his smartphone, showing how the app could identify his son at different ages, or identify his father based on an image of the rear right side of his head. "We sometimes take this technology for granted because we use it all the time. But it's incredibly powerful and is not restricted to images. It's all a matter of how you represent your data."

In this case, he and Yuan were looking at gene relationships. The approximately 20,000 genes in humans work in concert, so it's necessary to know how genes work together in complexes or networks to understand human development or diseases.

One way to infer these relationships is to look at gene expression -- which represents the activity levels of genes in cells. Generally, if gene A is active at the same time gene B is active, that's a clue that the two are interacting, Yuan said. Still, it's possible that this is a coincidence or that both are activated by a third gene C. Several previous methods have been developed to tease out these relationships.

To employ CNNs to help analyze gene relationships, Yuan and Bar-Joseph used single-cell expression data -- experiments that can determine the level of every gene in a single cell. The results of hundreds of thousands of these single-cell analyses were then arranged in the form of a matrix or histogram so that each cell of the matrix represented a different level of co-expression for a pair of genes.

Presenting the data in this way added a spatial aspect that made the data more image-like and, thus, more accessible to CNNs. By using data from genes whose interactions already had been established, the researchers were able to train the CNNs to recognize which genes were interacting and which weren't based on the visual patterns in the data matrix, Yuan said.

"It's very, very hard to distinguish between causality and correlation," Yuan said, but the CNNC method proved statistically more accurate than existing methods. He and Bar-Joseph anticipate CNNC will be one of several techniques that researchers will eventually deploy in analyzing large datasets.

"This is a very general method that could be applied to a number of analyses," Bar-Joseph said. The main limitation is data -- the more data there is, the better CNNs work. Cell biology is well-suited for using CNNC, as a typical experiment can involve tens of thousands of cells and generate a massive amount of data.

ITHACA, N.Y.- Some problems are best solved with new tech or a flashy app. But sometimes adapting existing technology works best of all.

A new system developed by Cornell Tech researchers will allow thousands of patients of community health care workers in rural Africa to use a basic tool on their mobile phones - one that doesn't even require an internet connection - to provide feedback on their care anonymously, easily and inexpensively.

"Technological interventions, when designed in the right way, can help address some of the complex health problems we have in the world," said Fabian Okeke, doctoral student in information science at Cornell Tech and first author of "Including the Voice of Health Care Recipients in Community Health Feedback Loops in Rural Kenya," presented at the Association for Computing Machinery Conference on Computer-Supported Cooperative Work and Social Computing, Nov. 9-13 in Austin, Texas.

The system showed promising results in a recent study and will soon be expanded by Medic Mobile, a nonprofit health tech company that collaborated on the research and works with more than 20,000 health care workers across 14 African countries.

In remote areas in Africa and India, where a single doctor might serve 10,000 people, many rely on community health care workers, who visit their homes and act as intermediaries between doctors and care recipients. While this model is considered effective and has been adopted around the world, there have been cases of mistreatment. A 2016 study found that 70% of women who gave birth at a referral hospital in Tanzania experienced one form of abuse or disrespect.

Until now, efforts to improve care and accountability have focused on collecting data from caregivers. In this study, the researchers sought to create a system allowing care recipients to offer feedback of their own.

"If you're providing services for a pregnant mother in rural Kenya, how is the pregnant mother going to say whether the service is helping her?" Okeke said. "We wanted to somehow bridge this gap - not just in the research literature but in community health. So we started thinking about ways to integrate the voices of care recipients and to do it in a way that is scalable."

The researchers chose an unstructured supplementary service data (USSD) system - commonly used by owners of prepaid mobile phones to check their balances. They chose USSD because it offered anonymity, unlike short message service texting; and because it is far less expensive than a call-based system.

With USSD, users enter a series of numbers into their phones, prompting questions about their experiences at the health care centers. Since most Kenyans already own mobile phones and are familiar with USSD, it was easy for them to adopt, the researchers said.

"Often when people think about interventions in developing nations, they think, 'Let's go build an app from scratch or a completely new tool,' but many times you can go back and tap into existing infrastructures," Okeke said. "People are already used to placing calls and texting - I think the innovation here is that you can go back to those mundane technologies and transform them into something else."

The researchers deployed the tool for seven weeks, training five care workers who, in turn, trained care recipients. For example, users who were visited by health care workers could dial *384*888# on their phones to provide feedback, which took less than two minutes. Users who visited community health care centers could dial a different series of numbers to offer feedback.

Users dialed in to answer a series of questions 495 times, with an error rate of less than 1%. Around 70% of the responses were positive, 17% negative and 13% neutral.

The researchers also conducted focus groups with patients and caregivers to gauge their opinions.

"We found that people were pretty enthusiastic about using USSD for providing feedback," Okeke said. "It was a way to empower them to communicate how they felt about the services they received."

Even the health care workers - who at first feared the feedback could be used maliciously against them - seemed pleased with the results, the researchers found.

"Initially, when we started the design process, health workers said this could be a tool that becomes a punishment," Okeke said. "But most of the feedback was positive, so it's validating the hard work that they're doing, but it's also holding them accountable. We heard things from care workers like, 'Now it's on me to combine both the positive and the negative to understand where I can improve my services.'"

Medic Mobile is in the process of incorporating the USSD system into its software toolkit, which is used by health care organizations across Africa. "The potential impact is thrilling," Okeke said.