Culture

Neurons control blood flow in tiny vessels in the brain, but researchers know little about this relationship. Now a team of Penn State engineers has found a connection between nitric oxide expressing neurons and changes in arterial diameters in mice, which may shed light on brain function and aging.

"The brain has many types of neurons," said Patrick J. Drew, Huck Distinguished Associate Professor of Engineering Science and Mechanics, Neurosurgery and Biomedical Engineering. "People have observed that blood flow and neural activity go together, and we wanted to measure the blood flow and activity in specific subtypes of neurons."

The researchers looked for a way to turn neurons off and on so that they could determine which neurons dilated the blood vessels.

"We knew that when animals run, all the neurons become more active and this causes the blood vessels to react," said Drew. "There are excitatory and inhibitory neurons and there is some evidence that if you stimulate inhibitory neurons you get vasodilation, but there are lots of inhibitory neuron types. We wanted to find out which ones were responsible."

The researchers used two-photon microscopy to look at the surface and deep arteries in the somatosensory cortex of mice while the mice were awake. They were able to make multiple observations of the same arteries in the same animals over a series of different neural perturbations, so they could compare results in individuals rather than across individuals. They reported their results in eLife.

"Thirty years ago people realized that nitric oxide is a vasodilator," said Drew. "Other researchers have seen an enzyme of nitric oxide stimulate a subset of neurons giving us a hint that this could help locate the responsible neurons."

Drew and his team showed that with an increase or decrease of the nitric oxide enzyme there was a change in dilation without there being a change in electrical activity. According to Drew, the brain is oversupplied with oxygen, so an increase in dilation when running or for other reasons is not necessarily to increase oxygen supply.

"The changes do not seem to be linked with need," said Drew. "It is a mystery why it happens."

Because the researchers could track changes in the same blood vessel over time and with different stimuli, they could compare these changes to the baseline in the individual animals. They could also inhibit certain groups of neurons for various lengths of time.

"Our results suggest a model where approximately half of the dynamic range in the basal and evoked blood arterial diameter is controlled by a small group of neurons and the rest is controlled by other neurons and astrocytes," the researchers report. "Any damage to or dysfunction of nNOS neurons (producing nitric oxide enzymes) could result in decreased basal blood flow, regardless of the metabolic need."

The researchers also noted that changes in the diameter of blood vessels affects the amplitude of fmri signals. Because fmri is used to image blood vessels in animals and humans, this can produce signals not related to neural activity.

"This tells us that fmri signals may not represent overall activity," said Drew. "It suggests that if these neurons die, it might cause the development of dementia."

The researchers would like to know what happens if these neurons are shut down for a long time. They would also like to know what happens if these same neurons are stimulated for a long time. Another goal is to understand what drives these neurons, what modulatory input do they receive and in what other parts of the brain do they function?

As humans evolve, cancer also evolves in parallel, making the race for finding efficient treatment methods for cancer patients challenging and constant. In addition to designing drugs for treatment, the delivery of these drugs to targeted organs is also a major challenge faced by the cancer research community.

Many research groups have tried to develop techniques to efficiently deliver anti-cancer drugs to tumors. An interesting way utilizes a distinct group of cells in our body, the mesenchymal stem cells (MSCs), which have a special ability to find and move towards tumors. This means that theoretically, we can load these "tumor-homing" MSCs with anti-cancer drugs and use them to hinder cancer progression. However, pilot studies show that the anti-cancer drug loading capacity of MSCs is limited, and they tend to lose their ability to target and reach tumor cells upon drug loading.

In a recent study published in Journal of Controlled Release, researchers from Japan, led by Dr. Kosuke Kusamori and Professor Makiya Nishikawa from Tokyo University of Science, sought to find out how to modify MSCs to bypass these problems. Dr. Kusamori, Assistant Professor in the University's Department of Pharmacy says, "We wondered if the answer to our dilemma of modifying mesenchymal stem cells with an anticancer drug was to exploit the property of mesenchymal stem cells to accumulate in tumor tissues."

Using the well-known "avidin-biotin complex" (ABC) method, the researchers used liposomes--cellular lipid bags popularly used as drug delivery systems--to carry the anti-cancer drug doxorubicin (DOX) to the surface of specific mouse MSCs. They named these lipid bags carrying DOX "DOX-Lips."

The researchers found that the MSCs loaded with DOX-Lips could carry and selectively target mouse colon cancer cells growing in artificial cultures in the lab. These modified MSCs could not only carry a significant amount of the drug, but also efficiently deliver it inside the target cancer cells. To test if this feature is replicated in a living system, they used a mouse model with skin and lung cancer. They found that in both cases, DOX-Lips were able to efficiently reach cancer cells and release the drug into the cytoplasm of the cancer cells. The researchers concluded that the modified MSCs could completely suppress tumor growth in mouse models.

There are several advantages to this new method. First, the process is relatively faster than previously known methods. As Yukiya Takayama, a doctoral student in Professor Nishikawa's lab and a co-author of the study observes, "The relatively short duration of the ABC method made it possible to quickly modify the cell surface with DOX-Lips and avoid cell damage." Second, this method did not affect the process of cell attachment to cancer cells, thereby ensuring maximum efficiency in drug delivery. Third, contrary to previous observations that lipid bags of only a certain size can be used to deliver drugs, this new study suggests that the size of the lipid bags very likely does not affect drug delivery; this finding can be exploited to deliver many different doses of drugs as well.

The combination of the ABC method and the use of Lips thus seems to be the answer to the researchers' dilemma. Professor Nishikawa is excited about these results. "We have succeeded in developing a new targeted cancer therapy," he observes. "Mesenchymal stem cells can migrate to brain tumors and minute cancer lesions that are otherwise inaccessible to conventional drug delivery systems. Our method may thus be effective against intractable cancers," Nishikawa says.

This study is thus a promising advancement in the field of cancer research; the new method identified by the researchers may prove to be the answer on how to send the treating drug to cancer's doorstep.

With nearly 2 million Americans battling type 1 diabetes, it is no surprise that clinical therapies for the disease are constantly evolving and improving. In type 1 diabetes mellitus, the body's immune system attacks and destroys insulin-producing β-cells. As a result, people living with type 1 diabetes lose insulin secretion and encounter difficulty regulating glucose levels -- especially after meals. Drugs developed to proliferate β-cells often are inefficient and have off-target effects that can dysregulate other cell types and pancreatic hormone production. To address these issues, researchers at Brigham and Women's Hospital and the Broad Institute teamed up to design next-generation β-cell-targeting proliferators: zinc-binding prodrugs (ZnPD). To achieve this, the researchers engineered a new screening platform, the Disque Platform, to better represent β-cells in the lab. Utilizing the Disque Platform, researchers identified a ZnPD drug which exhibited a 2.4-fold increase in β-cell numbers in culture, out-performing its native drug, harmine, and avoiding off-target effects. Results are published in Science Advances.

"We exploited a unique feature of β-cells, which contain at least a million-fold more intracellular zinc ions than other cell types for insulin processing," said Amit Choudhary, PhD, a member of the Brigham's divisions of Renal Medicine and Engineering in Medicine and an associate member of the Broad Institute. "The ZnPD leverages principles in chemical biology to switch on the proliferators specifically in β-cells, preventing unwanted proliferation in other cell types and systemic cytotoxicity while promoting sustained β-cell proliferation."

With no durable and effective treatments for β-cell loss, researchers capitalized on this high zinc concentration in β-cells to guide their drug development. "Our novel drug type attaches an inactive β-cell proliferator to both a molecule with high affinity for zinc, known as a chelator, and a linker molecule, whose job is to stabilize the overall chemical structure," said Kisuk Yang, PhD, a postdoctoral fellow in the Karp Lab. Upon zinc binding to the chelator, the β-cell proliferator is released and begins promoting the proliferation of β-cells. However, another challenge faced by the researchers when testing the safety and efficacy of ZnPDs was the lack of accurate screening method.

Conventional screening platforms cannot reproduce the exceptionally high levels of zinc ions found in β-cells, which was essential in the design of ZnPDs. Alternatively, 3D culture systems preserve morphological and biological complexity, but are expensive and complex, and thus impractical for use in drug screening.

"To overcome these challenges, we engineered the Disque Platform: a new screening platform which combines 2D simplicity with 3D architecture. In this platform, cells are shaped into thin discs, which can accommodate both conventional 2D well plates and 3D bioreactors," said Peter Jones, a previous graduate student at Karp Lab and co-first author.

In developing the ZnPD mechanism of action, researchers looked to harmine, a type 1 diabetes drug recently found to induce β-cell proliferation but with toxic effects. Using the Disque Platform, the researchers screened multiple ZnPDs and identified a novel hit that exhibited a 2.4-fold increase in the generation of β-cells compared to harmine. Importantly, this ZnPD did not exhibit off-target effects and toxicities. The ZnPD represents a novel, chemical-biology-based drug carrier for targeted cell delivery.

"The Disque Platform can support rapid and cost-effective production of disc-shaped pseudo-islets in vitro that can be used to discover more effective drugs, and to advance a long-term cell transplantation strategy for diabetic therapy," said Jeff Karp, PhD, head of The Karp Lab and member of the Brigham's Department of Anesthesiology and Perioperative Pain Medicine. Karp is also an associate member of the Broad Institute. "In the future, the Disque Platform may be adapted to culturing other islet types or small-scale organoids for reliable drug screening applications. The implications for both this novel ZnPD and the Disque Platform are widespread, spanning beyond diabetes research."

DARIEN, IL - The American Academy of Sleep Medicine has published a new clinical practice guideline establishing recommendations for the use of behavioral and psychological treatments for chronic insomnia disorder in adults.

The guideline includes one strong recommendation -- which is one that clinicians should follow under most circumstances -- for the use of cognitive behavioral therapy for insomnia. CBT-I combines one or more cognitive therapy strategies with education about sleep regulation plus behavioral strategies such as stimulus control instructions and sleep restriction therapy. Treatment typically involves four to eight sessions.

"This is the first systematic review to use the GRADE system to evaluate behavioral insomnia therapies," said lead author Jack Edinger, who has a doctorate in clinical psychology and is a professor in the section of sleep medicine at National Jewish Health in Denver. "The multicomponent treatment, cognitive behavioral therapy for insomnia, is the most supported therapy."

Published online as an accepted paper in the Journal of Clinical Sleep Medicine, the guideline updates the AASM's 2006 practice parameters. It was developed by an expert task force and approved by the AASM board of directors. The process included a systematic literature review, meta-analyses, and assessment of the evidence using the GRADE methodology. A draft of the guideline was made available for public comment.

"There have been significant advancements in behavioral and psychological treatments for chronic insomnia, which affects millions of American adults," said AASM President Dr. Kannan Ramar. "The AASM guideline will help optimize patient-centered care by providing actionable recommendations for clinicians and patients."

The guideline includes several conditional recommendations -- which require the clinician to use clinical knowledge and experience while considering the patient's values and preferences -- suggesting that clinicians use multi-component brief therapies and three single-component therapies: stimulus control, sleep restriction therapy, and relaxation therapy. The guideline also suggests that sleep hygiene should not be used as a single-component treatment for chronic insomnia disorder in adults.

"Although sleep hygiene practices are often suggested and well-understood by patients, sleep hygiene recommendation do not constitute an effective stand-alone therapy," said Edinger.

Insomnia involves difficulty falling asleep or staying asleep, or regularly waking up earlier than desired, despite allowing enough time in bed for sleep. Daytime symptoms include fatigue or sleepiness; feeling dissatisfied with sleep; having trouble concentrating; feeling depressed, anxious, or irritable; and having low motivation or energy. Chronic insomnia disorder, which affects about 10 percent of the adult population, is distinguished by a sleep disturbance with associated daytime symptoms occurring at least three times per week for at least three months.

The AASM's previously published clinical practice guideline for the pharmacologic treatment of chronic insomnia also emphasizes that medications for chronic insomnia disorder should be considered mainly in patients who are unable to participate in CBT-I, patients who still have symptoms after this therapy, or those who require a temporary adjunct to CBT-I.

BIRMINGHAM, Ala. - The bacteria Streptococcus pneumoniae colonizes the nasopharynx and can cause pneumonia. Then, it can spread from the lungs to the bloodstream and cause organ damage. This opportunistic pathogen commonly infects young children, those who are immunocompromised and the elderly. In 2015, S. pneumoniae infections worldwide killed an estimated 192,000 to 366,000 children under age 5.

To understand how this pathogen adapts to different locations in the body, and also how the host responds to the invading microbe, researchers at the University of Alabama at Birmingham, the University of Maryland School of Medicine and Yale University School of Medicine measured bacterial and host gene expression at five different sites in a mouse model -- the nasopharynx, lungs, blood, heart and kidneys -- using three genetically different strains of S. pneumoniae.

Their resulting in vivo atlas of host-pathogen interactions at disease-relevant anatomical sites is now published in Proceeding of the National Academy of Sciences. The researchers identified shared and organ-specific transcriptomes of S. pneumoniae, and they showed that the bacterial and host gene expression profiles are highly distinct during asymptomatic colonization versus disease-causing infection.

This means the bacterium behaves differently, depending on which site it infects, and that the mouse organs, in turn, also respond differently to the presence of bacteria. Additionally, certain S. pneumoniae genes were found to always be highly expressed by all three strains of bacteria at all anatomical sites, which makes them ideal targets for new vaccines or therapies.

This was the first time that gene expression profiles during colonization and at multiple host infection sites were mapped from both the host and the pathogen perspectives.

"We believe that the atlas of transcriptional responses during host-pathogen interactions presented here," the authors wrote, "will constitute an essential resource for the pneumococcal and microbial pathogenesis research communities and serve as a foundation for identification and validation of key host and pneumococcal therapeutic targets in future studies."

Carlos J. Orihuela, Ph.D., professor in the UAB Department of Microbiology, and Hervé Tettelin, Ph.D., professor in the University of Maryland School of Medicine Department of Microbiology and Immunology, are co-senior authors.

Besides a descriptive analysis of the transcriptomes, researchers confirmed their findings using bacterial mutants, in vivo challenge experiments and host treatments. In challenge experiments, the researchers found that an interferon beta anti-inflammatory treatment prevented the bacteria from invading vital organs and promoted host survival. This finding offers potentially new therapeutic avenues.

Symptoms of pneumococcal infection include fever, cough, shortness of breath, chest pain, stiff neck, confusion, increased sensitivity to light, joint pain, chills, ear pain, sleeplessness and irritability. While advances in antibiotics and the use of pneumococcal conjugate vaccines since 2000 have lowered deaths attributable to S. pneumoniae, the pathogen continues to show an increase in antibiotic resistance, and it also can switch to capsule types that are not covered by the current United States Food and Drug Administration-approved vaccines. Thus, pneumococcal infections continue to be a significant cause of illness and death.

Research has shown that human milk is the optimal nutrition source for neonates and infants. It confers protection against both immediately life-threatening infant diseases such as necrotizing enterocolitis, as well as later onset diseases in adults, like obesity, diabetes and inflammatory bowel disease. Scientific evidence suggests that what a mother eats while she is breastfeeding can modulate the beneficial composition of the mother's milk, but the underlying mechanisms involved have not been elucidated.

In a new study published in Nature Scientific Reports, researchers from Baylor College of Medicine, Texas Children's Hospital and other institutions describe a natural mechanism that can modify the benefits of maternal milk. They report the first evidence that the mother's diet while breastfeeding can shape the profile of human milk oligosaccharides (HMO), a type of complex carbohydrate in the mother's milk. Changing the HMOs, which are food and fodder for healthy microbes, in turn modifies the functional abilities of the milk microbiome. It has been proposed that the establishment of a healthy microbiome in the newborn and infant influences lifelong metabolic health.

"In previous work in both humans and primates, we found that what a pregnant woman eats during pregnancy has the capacity to affect her child's lifelong metabolic health. In the current study we present the first evidence showing that the diet of a breastfeeding mother can directly affect the milk's HMO composition," said senior and corresponding author Dr. Kjersti Aagaard, Henry and Emma Meyer Chair in Obstetrics and Gynecology and professor of molecular and human genetics at Baylor.

"This was particularly exciting, since HMOs are basically inert substances to a mother or her baby. However, they exert their health benefits by acting as food or fodder to microbes -- both bacteria and some viruses. This appears to be a very interesting example where what we eat affects our microbes via an intermediate (the HMOs), which we make but don't directly benefit from. It gives us a fascinating glimpse into what we and others believe is a natural co-evolution process," Aagaard said.

Working with Dr. Morey Haymond, professor of pediatrics-nutrition at Baylor, the team of researchers supplied breastfeeding mothers with all their meals in a controlled setting at the USDA Children's Nutrition Research Center. The mothers consumed a particular diet for 30 to 70 hours. After a two-week washout period, the same woman ate a different diet also provided by the researchers.

The researchers carefully collected milk samples from each subject at these different time points including the diet "switches." In this way, each woman could serve as her own control, something referred to as a "cross-over" trial design. This helped the researchers to control for the possibility of how individual women may vary one to the next in the amount of HMOs made, as well as the possibility of confusing microbes in the milk with environmental contaminants. The team analyzed the HMO and microbiome composition of the milk and gleaned clues as to the effect of the mothers' diet.

"We found that distinct maternal carbohydrate and energy sources in the diets we provided preferentially altered the milk concentrations of HMOs, and this was accompanied by changes in the metabolic capacity of the milk microbiome," said first author Dr. Maxim Seferovic, instructor of obstetrics and gynecology at Baylor working in the Aagaard lab. "It is not that the maternal diet itself is directly affecting the microbes, but that the diet affects the microbes' food, the HMOs, which in turn shape the functional capacity of the community of microbes in the milk that will be consumed by the baby. Interestingly, the changes in HMO occurred quickly, in a matter of 2 to 3 days, after the mothers changed their diet."

The researchers propose that the findings can have implications not only for the baby but also for the mother.

"We propose that our findings can have potential effects on baby's health and development, including the potential for promoting healthy gut integrity at the mucosal surface. HMOs feed certain microbial communities, and it has been suggested that the establishment of those microbial communities is probably important for neonatal development of brain function," said co-author Dr. Melinda Engevik, postdoctoral fellow in pathology and immunology at Baylor. "We speculate that having certain HMOs promotes the growth of certain microbes in the milk, which then pass to the baby and may promote healthy development."

"One other exciting aspect of our study is the suggestion that HMOs seem to preferentially affect the growth potential of microbes that may also impart health risk or benefit for the mother. For instance, by shaping the community of microbes in the milk in ways that may favor the growth of certain beneficial microbes via the simultaneous exclusion of those that cause mastitis during breastfeeding," Aagaard said.

If not treated with antibiotics, mastitis, or the painful inflammation of breast tissue that typically involves an infection, prevents breastfeeding and can become a serious condition.

HMOs also can potentially prompt a healthy microbiome in other ways. For example, by feeding the good microbes, acting as a decoy that attracts and sequesters potentially dangerous microbes and by breaking down HMOs and producing nutrients that may benefit other microbes.

A group of proteins called 4E-BPs, involved in memory formation, is the key to unlocking the antidepressant effect of ketamine in the brain, according to researchers from three Canadian universities. The discovery could lead to better and safer treatments for certain patients suffering from major depression.

Because more than 30% of patients are resistant to selective serotonin reuptake inhibitors (SSRI), the most commonly-prescribed antidepressants, finding an effective treatment for major depressive disorder is challenging.

Initially, ketamine was approved for anesthesia and pain relief. Since its discovery, researchers have been studying new uses for this drug, and ketamine was approved last year for patients with major depression who are treatment-resistant. Unlike standard antidepressants, which can take several weeks to have an effect, ketamine works within hours. Until now, little was known about the molecular mechanism that triggers the antidepressant effect of ketamine on the brain.

In the study published in Nature, researchers from McGill University, Université de Montréal, and Carleton University investigated the effect of ketamine on behaviour and neuronal activity in mice. Using genetic tools to remove proteins from specific brain cells, the team found that when 4E-BPs are absent in the brain, specifically in neurons, ketamine cannot produce its antidepressant effect. 4E-BPs act as a switch to turn on or off the process of protein synthesis - an essential component of memory formation.

"This is yet another prime example of how basic research, in this case the control of protein synthesis, leads to major discoveries in understanding disease, and the hope of curing it," says co-author Nahum Sonenberg, a professor at the Department of Biochemistry at McGill University.

The researchers examined the role of 4E-BPs on ketamine's effect in two major types of neurons: excitatory neurons, which make up most of the neurons in certain parts of the brain, and inhibitory neurons, which control excitatory neurons and have important effects on behaviour.

"We were expecting that 4E-BPs would only be important in excitatory cells, but surprisingly, removing 4E-BPs from inhibitory cells was sufficient to block the effect of ketamine," says co-author Jean-Claude Lacaille, a professor at the Department of Neurosciences at Université de Montréal.

Medicine is not one size fits all

The discovery and approval of ketamine for treatment-resistant patients was considered a major advance in modern psychiatry. Despite its promise, ketamine remains a less-than-perfect therapy because it can be addictive. The researchers hope that their findings will pave the way for better and safer antidepressant therapies for patients with major depressive disorder.

"Too many decisions continue to be made by a trial-and-error approach that can prolong the suffering of patients and affect their quality of life," says co-author Aguilar-Valles, a former research associate at McGill University and now an assistant professor at Carleton University. "Our discovery has the potential to bring us closer to find a safer alternative to ketamine, and ultimately to a personalized medicine approach, where medical treatments are tailored to the individual characteristics of each patient."

The study also involved a clinician-researcher, Dr. Gabriella Gobbi, from the Department of Psychiatry at McGill University, who works with individuals affected with depression and other psychiatric illnesses.

As next steps, the researchers will examine whether males and females have different responses to ketamine. This could have important implications for treatment for people with depressive disorders, among which women are significantly overrepresented.

LA JOLLA--(December 16, 2020) Getting computers to "think" like humans is the holy grail of artificial intelligence, but human brains turn out to be tough acts to follow. The human brain is a master of applying previously learned knowledge to new situations and constantly refining what's been learned. This ability to be adaptive has been hard to replicate in machines.

Now, Salk researchers have used a computational model of brain activity to simulate this process more accurately than ever before. The new model mimics how the brain's prefrontal cortex uses a phenomenon known as "gating" to control the flow of information between different areas of neurons. It not only sheds light on the human brain, but could also inform the design of new artificial intelligence programs.

"If we can scale this model up to be used in more complex artificial intelligence systems, it might allow these systems to learn things faster or find new solutions to problems," says Terrence Sejnowski, head of Salk's Computational Neurobiology Laboratory and senior author of the new work, published on November 24, 2020, in Proceedings of the National Academy of Sciences.

The brains of humans and other mammals are known for their ability to quickly process stimuli--sights and sounds, for instance--and integrate any new information into things the brain already knows. This flexibility to apply knowledge to new situations and continuously learn over a lifetime has long been a goal of researchers designing machine learning programs or artificial brains. Historically, when a machine is taught to do one task, it's difficult for the machine to learn how to adapt that knowledge to a similar task; instead each related process has to be taught individually.

In the current study, Sejnowski's group designed a new computational modeling framework to replicate how neurons in the prefrontal cortex--the brain area responsible for decision-making and working memory--behave during a cognitive test known as the Wisconsin Card Sorting Test. In this task, participants have to sort cards by color, symbol or number--and constantly adapt their answers as the card-sorting rule changes. This test is used clinically to diagnose dementia and psychiatric illnesses but is also used by artificial intelligence researchers to gauge how well their computational models of the brain can replicate human behavior.

Previous models of the prefrontal cortex performed poorly on this task. The Sejnowski team's framework, however, integrated how neurons control the flow of information throughout the entire prefrontal cortex via gating, delegating different pieces of information to different subregions of the network. Gating was thought to be important at a small scale--in controlling the flow of information within small clusters of similar cells--but the idea had never been integrated into models through the whole network.

The new network not only performed as reliably as humans on the Wisconsin Card Sorting Task, but also mimicked the mistakes seen in some patients. When sections of the model were removed, the system showed the same errors seen in patients with prefrontal cortex damage, such as that caused by trauma or dementia.

"I think one of the most exciting parts of this is that, using this sort of modeling framework, we're getting a better idea of how the brain is organized," says Ben Tsuda, a Salk graduate student and first author of the new paper. "That has implications for both machine learning and gaining a better understanding of some of these diseases that affect the prefrontal cortex."

If researchers have a better understanding of how regions of the prefrontal cortex work together, he adds, that will help guide interventions to treat brain injury. It could suggest areas to target with deep brain stimulation, for instance.

"When you think about the ways in which the brain still surpasses state-of-the-art deep learning networks, one of those ways is versatility and generalizability across tasks with different rules," says study coauthor Kay Tye, a professor in Salk's Systems Neurobiology Laboratory and the Wylie Vale Chair. "In this new work, we show how gating of information can power our new and improved model of the prefrontal cortex."

The team next wants to scale up the network to perform more complex tasks than the card-sorting test and determine whether the network-wide gating gives the artificial prefrontal cortex a better working memory in all situations. If the new approach works under broad learning scenarios, they suspect that it will lead to improved artificial intelligence systems that can be more adaptable to new situations.

PHOENIX, Ariz. -- Dec. 15, 2020 -- The Translational Genomics Research Institute (TGen), an affiliate of City of Hope, has identified a specific genetic target that could help explain the tremendous variation in how sick those infected with COVID-19 become.

The study results, recently published in the journal mSphere, describe a molecule made from DNA -- miR1307 -- as a potential dimmer switch that may influence the severity of the disease; why some infected with SARS-CoV-2, the virus that causes COVID-19, have mild or even no symptoms, while others become seriously ill or die.

Led by Nicholas Schork, Ph.D., a Distinguished Professor and Director of TGen's Quantitative Medicine and Systems Biology Division, researchers identified miR1307 by comparing the genetic elements of SARS-Cov-2 with seven other human coronaviruses, some of which merely cause common colds. In addition, they examined the genomes of coronavirus strains known to infect bats, pigs, pangolins, ferrets, civets and chickens.

"We pursued a systematic gene-by-gene comparative analysis, investigating how and to what extent the SARS-CoV-2 genome sequence differs from other well-characterized human and animal coronavirus genomes," Dr. Schork said. "Our study results will allow the development of models of how the virus and its hosts interact, enhancing our understanding of the disease-causing mechanisms of SARS-CoV-2 and how to exploit both viral and host therapeutic targets."

Study results suggest that miR1307 serves as a switch that turns various genes within the virus on or off, potentially making the disease more or less harmful to patients by regulating, for example, how fast or slow the virus replicates. In past studies, miR1307 has been found to affect the severity of several types of cancer, lung disease and the flu, specifically the H1N1 influenza virus that caused a 2009 pandemic. It was first discovered as a key regulatory agent in the Epstein-Barr virus, best known as the cause of infectious mononucleosis.

According to Dr. Schork, the study results also provide the basis for additional investigations, such as designing vaccines based on proteins or RNA, developing specific genetic markers for community disease monitoring, and tracing COVID-19 from one species to another.

COLUMBUS, Ohio -- A new study offers strong evidence that kids who use e-cigarettes are more likely to take up smoking or smokeless tobacco, researchers say.

Teen boys who vaped were almost three times as likely to start smoking as other teen boys with similar risk profiles and more than two times as likely to try smokeless tobacco, the study from The Ohio State University found. The research was published online this week in the journal Addictive Behaviors.

Unlike most previous research suggesting a link between vaping and tobacco, this study didn't simply follow young people over time to make a connection between the two behaviors. That's important, because some have questioned the validity of those longitudinal studies, arguing that kids who took up smoking might have done so whether they vaped or not, said lead researcher Brittney Keller-Hamilton, who completed the study as a graduate student and program manager in Ohio State's College of Public Health.

"For an ideal study, from a purely scientific perspective, we'd give everybody an e-cigarette, follow them for a few years and see if they start smoking, then rewind the clock and don't give them an e-cigarette. Or we'd randomly assign kids to vape or not to vape," she said. "We can't do either of those things, obviously."

So they looked to an advanced statistical approach -- "causal inference" -- in which they compared users and non-users of e-cigarettes who started the study with similar known risk factors for vaping based on a variety of factors, including alcohol use, marijuana use, impulsivity and their parents' education levels and tobacco history.

"We identified two groups of young people who were equally likely to start vaping based on a number of factors, and then we compared the outcomes over the course of the study. We found that e-cigarette users were 2.7 times as likely to try smoking," said Keller-Hamilton, who currently works as a research scientist in the Center for Tobacco Research at Ohio State's Comprehensive Cancer Center.

Study co-author Bo Lu, a biostatistics professor at Ohio State, said the approach leads to more robust scientific findings, and brings researchers closer to a true estimate of the causal effect of vaping on cigarette smoking in young people.

"I hope that our findings provide policymakers and others stronger evidence of the connection between e-cigarette use and tobacco use and that this will lead to positive impacts on more thoughtful designs in health policy research," Lu said.

This research is part of the Buckeye Teen Health Study, which followed more than 1,200 boys from urban Franklin County and nine rural Appalachian counties in Ohio for two years. They were 11 to 16 years old when they entered the study.

The new findings support continued efforts to restrict access to tobacco products to those 21 and older and actions to discourage vaping among kids, including measures that make e-cigarettes harder to obtain and less appealing, Keller-Hamilton said.

The data for this study was collected before federal restrictions were imposed on certain types of vaping products that appeal to young people, including those with flavors.

"But for all of these policies there are loopholes that the tobacco industry quickly identifies and works around, so it is important to remain vigilant in seeking strategies and policies to prevent teens from starting habits that pose a threat to their health, particularly when they serve as a stepping-stone to more harmful tobacco products," Keller-Hamilton said.

BOSTON - (December 16, 2020) - Intensive interventions to reduce blood glucose and blood pressure levels in type 2 diabetes reduce the risk of developing cardiovascular autonomic neuropathy (CAN), a frequent but underdiagnosed complication of diabetes that can be life-threatening.

In a study led by Alessandro Doria, MD, PhD, MPH, from the Joslin Diabetes Center and Harvard Medical School, and Rodica Pop Busui, MD, PhD, of the University of Michigan, published online in Diabetes Care, researchers found that intensive glycemic control reduced CAN risk by 17%, while intensive blood pressure control reduced risks by 22%.

They also found that intensive control of blood glucose was more effective in individuals with no history of cardiovascular disease (CVD) and that blood pressure lowering was more effective in individuals older than 65 years, suggesting that some degree of personalization of risk reduction might be possible.

They add that any benefits with the approach should be weighed against risks and costs, particularly because excess mortality has been observed in a trial, following intensification of treatment for glycemia.

The analysis focuses on the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which originally investigated the effects of intensive glycemic, blood pressure control and lipid interventions on cardiovascular events in individuals with type 2 diabetes and high CVD risks.

For their analysis the authors included participants that had an evaluation for CAN at baseline and at least one more assessment after randomization (~7000 individuals). Specifically, they looked at the effects on CAN of intensive glucose treatment, intensive blood pressure treatment and fenofibrate (a lipid lowering agent), compared to standard treatments.

None of the interventions (intensive and standard care) involved the newer drugs class of SGLT2 inhibitors and only few participants received GLP1-receptor agonists towards the end of trial, as the overall trial ran from early 2001 through to 2010 when these drugs were not widely used in clinical practice. The average follow-up was about five years.

They found that intensive treatment to reduce HbA1c (a measure of blood glucose levels) to near normal levels resulted in a 17% reduced risk for CAN (odds ratio: 0.83; confidence interval 0.74-0.93; p=0.002) compared to standard treatment, and that was after adjusting the risk model for a very broad spectrum of confounding factors, including all traditional CAN and cardiovascular disease risk factors.

The same direction of effect was evident for the intensive treatment of raised blood pressure. That approach resulted in a 22% reduced risk for CAN compared to standard treatment approaches (odds ratio: 0.78; CI 0.65-0.92; p=0.004) after adjusting for confounding factors. Treatment with fenofibrate and a statin compared to placebo and a statin was not as successful, with no significant difference between the interventions.

Additional analyses based on subgrouping showed that the protective effects of intensive treatment of glycemia on CAN risk was only found in individuals without a history of cardiovascular disease events but not in individuals with such a history. Blood pressure interventions was especially evident in older adults over the age of 65 years where CAN risk was reduced by 34%.

Notably, intensive glycemic control applied on top of intensive blood pressure control did not appear to reduce CAN risk more than intensive blood pressure lowering on its own. Taken together, the authors suggest these observations point towards the possible personalization of risk reduction strategies, but that more research will be needed to confirm the usefulness of these approaches.

While concluding that intensive glycemic and blood pressure control is likely to benefit patients in terms of CAN risk reduction, they do urge caution with respect to risks and costs. This is particularly from the perspective that the original ACCORD trial showed that after three and half years of follow-up, intensive glucose-lowering did result in reduced non-fatal cardiovascular events but paradoxically also an increase in overall mortality.

Commenting further on the research, senior co-author Dr Alessandro Doria said:

"Based on previous smaller studies, we thought that intensive glycemic and blood pressure control would probably work, but these results provide us with definitive proof that these treatments can be used to prevent this serious complication of diabetes."

Co-author Prof Rodica Pop Busui added:

"These findings have high clinical care relevance, as we have previously demonstrated that CAN, even in earlier stages, independently predicts cardiovascular and all-cause mortality in type 2 diabetes, and major cardiovascular events and heart failure in type 1 diabetes."

Natural variations in ultraviolet radiation influence the spread of COVID-19, but the influence is modest compared to preventive measures such as physical distancing, mask wearing, and quarantine, according to new research from Harvard University.

"Understanding the potential seasonality of COVID-19 transmission could help inform our response to the pandemic in the coming months," said Jonathan Proctor, a postdoctoral fellow at the Harvard Data Science Initiative and the Harvard Center for the Environment. "These findings suggest that the incidence of COVID-19 may have a seasonal pattern, spreading faster in the winter when it's darker than in the summer."

Analyzing daily COVID-19 and weather data from over 3,000 administrative regions in more than 170 countries, Proctor, together with co-authors Peter Huybers, also at Harvard University, Tamma Carleton and Kyle Meng from the University of California Santa Barbara and Jules Cornetet at France's École Normale Supérieure Paris-Saclay, found that the spread of COVID-19 through a population tended to be lower in the weeks following higher UV exposure. Findings were published in the Proceedings of the National Academy of Sciences.

The seasonality of COVID-19 has been a mystery since the disease first emerged one year ago, though there have been some clues that UV could play a role. Related species of coronaviruses such as SARS and MERS were found to be sensitive to UV radiation and recent laboratory studies show that UV inactivates SARS-CoV-2, the virus that causes COVID-19, on surfaces.

Attempts to understand the influence of UV in the real world, however, have been limited by scarce data and the difficulty of isolating climate variables from other drivers of transmission. To test for an environmental signal within the noise of the pandemic, the team compiled and cleaned data from statistical agencies around the world. To avoid potentially confounding factors that differ across regions, such as healthcare infrastructure or population density, the team examined how transmission within a particular population changed according to variations in sunlight, temperature, precipitation and humidity experienced by that same population.

"We basically ask whether daily fluctuations in environmental conditions experienced by a population affect new COVID-19 cases up to two weeks later," Meng explained.

The researchers diagnosed the relationship between UV and COVID-19 using data from the beginning of the pandemic and then used that relationship to simulate how seasonal changes might influence the spread of COVID-19. They found that changes in UV between winter and summer led to a 7-percentage point decrease in the COVID-19 growth rate on average across the Northern Hemisphere, which is about half the average daily growth rate at the beginning of the pandemic. While this research shows that COVID-19 exhibits a seasonal pattern due to changes in UV, the full seasonality of COVID-19 remains unclear because of uncertain influences from other environmental factors such as temperature and humidity.

"We are confident of the UV effect, but this is only one piece of the full seasonality picture," Carleton said.

The team noted that environmental influences are just one of many determinants of COVID-19 transmission, and that the estimated effects of UV seasonality in the Northern and Southern Hemispheres are a fraction of the size of previously estimated effects of anti-contagion policies including quarantines and travel bans.

"As we saw in the U.S. this summer, UV exposure alone is unlikely to stop the spread of the virus without strong social distancing policies," said Proctor. "Regardless of the weather, additional measures appear to be necessary to substantially slow the spread."

The team analyzed the data in multiple ways and consistently found that the higher the UV, the lower the spread of COVID-19, but it remains unclear what mechanism is driving that effect. It may be that UV destroys the virus on surfaces or in aerosols, or that on sunny days people go outside more where there is less transmission. It is even possible that UV reduces susceptibility to COVID-19 by stimulating production of vitamin D and boosting the immune system.

"There's still so much that we don't know about how environmental factors both directly and indirectly, though human behavior, influence the spread of the virus," said Huybers. "But a better understanding of the environmental influences on COVID-19 could allow for seasonal adjustment of containment policies and may help inform vaccination strategies.

Groundbreaking research led by a team of scientists including a University of Massachusetts Amherst biostatistician shows that oral hormone therapy (HT) significantly alters the metabolome of postmenopausal women. This finding, which examined blood specimens from the landmark Women's Health Initiative (WHI) study, may help explain the disease risks and protective effects associated with different regimens of hormone therapy.

"This is the first analysis of the metabolomic effects of hormone therapy conducted within the framework of a randomized clinical trial," says Raji Balasubramanian, associate professor in the School of Public Health and Health Sciences, whose research connects biostatistics, molecular epidemiology and women's health.

Balasubramanian, in collaboration with Dr. Kathryn M. Rexrode at Brigham and Women's Hospital, a teaching affiliate of Harvard Medical School, and colleagues at the Broad Institute of Harvard and MIT, Harvard's T.H. Chan School of Public Health, Brown University and several institutions in Spain, wanted to study whether hormone therapy alters the universe of small molecule metabolites. "The answer was a resounding yes," says Balasubramanian, lead author of the paper published in Circulation: Genomic and Precision Medicine.

The WHI's hormone therapy trials in the 1990s examined the effects on coronary heart disease (CHD), breast cancer and other conditions of two hormone therapies - estrogen alone and a combination of estrogen and progestin. The combination therapy was found to significantly increase CHD risk by 29%; estrogen alone was found to decrease CHD risk by 9%, although this effect was not statistically significant.

"Our focus was on cardiovascular disease and understanding at a molecular level why these two hormone therapy regimens had disparate effects in regard to cardiovascular disease," Balasubramanian says.

Using liquid chromatography mass spectrometry (LC-MS) techniques, researchers at the Broad Institute measured 481 metabolites in blood specimens from the WHI hormone therapy trial participants: 503 from women in the estrogen-only group, half of whom were on placebo; and 431 in the estrogen plus progestin group, with half on placebo. The research team recorded measurements obtained right before hormone therapy began and one year later, when the women were still on active treatment or placebo.

The findings revealed "profound changes in the metabolome, spanning a wide range of classes including lipids, amino acids and other small molecule metabolites," Balasubramanian says. In fact, 62% of metabolites were significantly changed with estrogen-alone therapy, and 52% with estrogen plus progestin.

While most of the changes in metabolites were consistent with each type of hormone therapy, 22 metabolites were identified that had discordant effects. Twelve of those were associated with CHD risk in an evaluation of an independent WHI dataset.

With estrogen-alone treatment, the changes in all 12 metabolites provided a protective CHD effect. With estrogen plus progestin, 11 metabolites were unchanged. The amino acid lysine was significantly altered by both hormone therapies, but in the opposite direction. Estrogen-alone therapy increased lysine levels, providing a protective effect, and estrogen plus progestin decreased lysine levels, elevating CHD risk.

"Getting a handle on what subset of metabolites had differential changes between the two drugs related to cardiovascular diseases might point to the molecular underpinnings of the difference in risk between the two treatments," Balasubramanian explains.

UMass Amherst 2020 graduate Ryan Sheehan contributed to the data analytic aspects of the study and continues to work in Balasubramanian's lab as a research associate. Taking part in the study was "the best experience a student could have," he says. "Not only was I able to contribute my own skills and knowledge to this important paper, but also I was able to learn so much about the processes that go on with professional research. The amount of time and attention to detail that went into each step is something I will try to mimic in my own work as I progress in my professional career."

The study also lays the groundwork for identifying other hormone therapy-related metabolomic changes in a broader age group of women and how those changes are associated with differential risks for other health conditions, such as breast cancer, depending on the hormone regimen.

"We're excited to contribute to advancing research in women's health," Balasubramanian says.

CAMBRIDGE, MA--December 16, 2020--In 2019, the National Academies of Science, Engineering, and Medicine (NASEM) published a consensus report for the US Congress--Reproducibility and Replicability in Science--which addressed a major methodological crisis in the sciences: The fact that many experiments and results are difficult or impossible to reproduce. The conversation about this report and this vital topic continues in a special, twelve-article feature in issue 2:4 of the Harvard Data Science Review (HDSR), publishing today.

Growing awareness of the replication crisis has rocked the fields of medicine and psychology, in particular, where famous experiments and influential findings have been cast into doubt. But these issues affect researchers in a wide range of disciplines--from economics to particle physics to climate science--and addressing them requires an interdisciplinary approach.

"The overall aim of reproducibility and replicability is to ensure that our research findings are reliable," states HDSR Editor-in-Chief Xiao-li Meng in his editorial. "Reliability does not imply absolute truth--which is an epistemologically debatable notion to start with--but it does require that our findings are reasonably robust to the relevant data or methods we employ."

"Designing sound replication studies requires a host of data science skills, from statistical designs to causal inference to signal-noise separation, that are simultaneously tailored by and aimed at substantive understanding," Meng continues.

Guest edited by Victoria Stodden (University of Illinois, Urbana-Champaign), the special theme collection presents research and commentary from an interdisciplinary group of scholars and professionals. Articles include:

Interview with Reproducibility and Replicability in Science Committee Chair Harvey V. Fineberg, President of the Gordon and Betty Moore Foundation and HDSR guest editor, Victoria Stodden, committee member by HDSR Editor-in-Chief Xiao-Li Meng

"Self-Correction by Design" by Marcia McNutt, President of NAS

"Leveraging the National Academies 'Reproducibility and Replication in Science' Report to Advance Reproducibility in Publishing" by Manish Parasha, Assistant Director for Strategic Computing at the White House Office of Science and Technology Policy, and Director of the Office of Advanced Cyberinfrastructure at the National Science Foundation

"Toward Reproducible and Extensible Research: from Values to Action" by Aleksandrina Goeva (Broad Institute), Sara Stoudt (Smith College), Ana Trisovic (Harvard University)

"Reproducibility and Replicability in Economics" by Lars Vilhuber (Cornell University)

"Reproducibility and Replicability in Science, A Metrology Perspective" by Anne L. Plant (National Institute of Standards and Technology) and Robert J. Hanisch (National Institute of Standards and Technology)

"Perspectives on Data Reproducibility and Replicability in Paleoclimate and Climate Science" by Rosemary T. Bush (Northwestern University), Andrea Dutton (University of Wisconsin, Madison), Michael N. Evans (University of Maryland, College Park), Rich Loft (National Center for Atmospheric Research), and Gavin A. Schmidt (National Aeronautics and Space Administration)

"Science Communication in the Context of Reproducibility and Replicability: How Non-Scientists Navigate Scientific Uncertainty" by Emily Howell (University of Wisconsin-Madison)

"Learning Lessons on Reproducibility and Replicability in Large Scale Genome-Wide Association Studies" by Xihong Lin (Harvard University)

"Selective Inference: The Silent Killer of Replicability" by Yoav Benjamini (Tel Aviv University)

"Trust but Verify: How to Leverage Policies, Workflows, and Infrastructure to Ensure Computational Reproducibility in Publication" by Craig Willis (University of Illinois at Urbana-Champaign) and Victoria Stodden

"Reproducibility and Replication of Experimental Particle Physics Results" by Thomas R. Junk (Fermi National Accelerator Laboratory) and Louis Lyons (University of Oxford, Emeritus)

The editors hope to take advantage of the collaborative features available on the open-source publishing platform, PubPub, where HDSR is hosted. Readers around the world can freely read, annotate, and comment on the essays--continuing this important conversation.

People in industrialized regions like the United States of America or Europe are generally urged to eat less meat and animal-source foods as part of a healthier and lower-emissions diet. But such recommendations are not universal solutions in low- or middle-income countries, where livestock are critical to incomes and diets, argue scientists in recently published research in Environmental Research Letters.

"Conclusions drawn in widely publicized reports argue that a main solution to the climate and human health crisis globally is to eat no or little meat but they are biased towards industrialized, Western systems," said Birthe Paul, the lead author and environmental scientist at the Alliance of Bioversity International and the International Center for Tropical Agriculture (CIAT).

For example, of all scientific literature on livestock published since 1945, only 13% covers Africa. Yet Africa is home to 20%, 27% and 32% of global cattle, sheep and goat populations. Eight of the world's top ten institutes publishing livestock research are in the United States, France, the United Kingdom and the Netherlands. Only two, including the International Livestock Research Institute (ILRI), are headquartered in Africa, where the livestock sector is the backbone of the economy and where little data is available.

Authors further argue that a singular focus on negative livestock-related environmental impacts ignores the critical but more positive role livestock play in ecosystem services, income and asset provision or insurance in low- and middle-income countries. It also overlooks more systemic questions about how animals are raised.

"Mixed systems in low- and middle-income countries, where animal production is fully linked with crop production, can actually be more environmentally sustainable," said An Notenbaert, from the Alliance of Bioversity International and CIAT. "In sub-Saharan Africa, manure is a nutrient resource which maintains soil health and crop productivity; while in Europe, huge amounts of manure made available through industrialized livestock production are overfertilizing agricultural land and causing environmental problems."

Across Africa's savanna, pastoralists pen their herds at night, a practice shown to increase nutrient diversity and biodiversity hotspots, enriching the landscape. Feed production may also be more local, whereas, in industrialized systems, it is mostly imported. In Brazil, soybean - a major driver of deforestation in the Amazon - is made into concentrate and exported to feed animals in places like Vietnam as well as Europe.

"Meat production itself is not the problem. Like any food, when it is mass-produced, intensified and commercialized, the impact on our environment is multiplied," said Polly Ericksen, Program Leader of Sustainable Livestock Systems at the International Livestock Research Institute. "Eliminating meat from our diet is not going to solve that problem. While advocating a lower-meat diet makes sense in industrialized systems, the solution is not a blanket climate solution, and does not apply everywhere."

According to the Food and Agriculture Organization, meat consumption in sub-Saharan Africa will be as low as an average of 12.9 kilograms per person by 2028, due to low incomes and climate-induced heat-stress in animals among other factors, with human health implications like malnutrition and stunting. By comparison, meat consumption in the United States is expected to rise above 100 kilograms per person - the highest in the world.

Authors acknowledge that livestock systems are known to be a major source of atmospheric greenhouse gases. But more data is needed for low- and middle-income countries to develop national mitigation strategies. They also urge a need to look beyond making animals more productive and toward resource-efficient and environmental systems that actively reduce emissions from agriculture.

The authors point to a range of higher-impact environmental solutions. Among them, improved animal feed so animals emit less greenhouse gases like methane per kilogram of milk or meat. Better managed grazing land, and mixing crop and livestock where manure is plowed back into the soil, can benefit both farmers and the environment.

"Better decisions about how to reduce global greenhouse gas emissions from livestock and agriculture in low- and middle-income countries can only be driven by better data," said Klaus Butterbach-Bahl, at the Institute of Meteorology and Climate Research, Atmospheric Environmental Research (IMK-IFU) Karlsruhe Institute of Technology (KIT) and ILRI.

"For that, we need more - and not less - locally-adapted and multi-disciplinary research together with local people in low- and middle-income countries, on sustainable livestock development, with all the supporting financial incentives, policies and capacity in place to intensify livestock production in a more sustainable way, on a bigger scale."