Culture

DALLAS, July 23, 2020 -- Genetic testing and counseling for inherited cardiovascular diseases may help patients and their families make well-informed decisions about managing their heart health, according to "Genetic Testing for Inherited Cardiovascular Diseases," a new scientific statement from the American Heart Association, published today in the Association's journal Circulation: Genomic and Precision Medicine.

The statement summarizes what we know - and do not know - about the genes or combination of genes that may influence inherited heart diseases and also provides suggestions for best practices for genetic testing.

"Although genetic testing has seen explosive growth in the past few years, both in the clinical setting and with direct-to-consumer testing, genetic testing for heart disease should be reserved for specific patients," said Kiran Musunuru, M.D., Ph.D., M.P.H., M.L., FAHA, chair of the writing group for the scientific statement and professor of cardiovascular medicine and genetics at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.

According to the statement, cardiovascular conditions that may have an inherited genetic component include:

cardiomyopathies, heart muscle diseases that can lead to heart failure;

thoracic aortic aneurysms and dissections, syndromes that cause the body's major artery to balloon and rupture;

arrhythmic disorders that predispose people to potentially fatal abnormal heart rhythms; and

familial hypercholesterolemia, or highly LDL elevated cholesterol levels that greatly increase the risk of heart attack.

Before considering genetic testing, a health care provider should work with the patient to document their family medical history, ideally, going back three generations, to determine if there is a pattern of certain types of heart disease. Genetic testing should typically be reserved for patients with a confirmed or suspected diagnosis of an inherited cardiovascular disease or for individuals at high risk due to a previously identified disease-causing variant (a gene abnormality that is different from most humans, often responsible for the clinical disease in question) in their family.

Genetic counseling is essential before genetic testing to educate patients on the process and potential results, as well as the potential risks and uncertainties related to testing. Counseling is also critical after genetic testing, so the counselor can explain the results and potential consequences for the patient's health and the health of family members including children.

Since immediate family members - first-degree relatives such as fathers, mothers, siblings or children - might share genetic variants predisposing them to an inherited cardiovascular disease, they are considered to be at higher risk for the same conditions. Once a genetic variant is identified within a family, all first-degree relatives should consider undergoing genetic testing and counseling for that specific mutation whenever possible.

Genetic counselors can also advise and support patients on the best ways to communicate the news of any genetic variants they may discover through genetic testing to other family members. Although privacy laws restrict the ability of health care professionals to disseminate information directly to potentially affected relatives, they can provide written letters that explain the genetic findings, which the patients can give to their family members.

"With most genetic cardiovascular diseases, inheriting a mutation (or variant) from a parent substantially increases the risk of getting the disease but does not guarantee the disease," said Musunuru. "In some cases, it might be possible to act early and prevent the disease. In other cases, having the mutation for a genetically caused cardiovascular condition might lead to different and possibly more aggressive treatment."

Advances in human genetics are improving the understanding of a variety of inherited cardiovascular diseases. However, there are still limitations. Genetic testing might not reveal a cause or confirm a diagnosis of the patient's disease.

In many cases, genetic testing can reveal a mutation that is called "uninterpretable" or a "variant of uncertain significance." A variant of uncertain significance, or VUS, is not considered either definitively pathogenic (disease causing) or benign, meaning that it's unclear if the patient is at increased risk for disease. Since it is unclear whether the VUS increases the risk of disease or not, it can be challenging for doctors to counsel patients on appropriate treatment.

It is also possible that a patient may be diagnosed with an inherited cardiovascular disease, yet genetic testing doesn't reveal any genetic mutations. This makes it difficult to explain why the patient has the disease and whether any of their family members are also at risk.

"Another issue is that we have not yet clarified the full spectrum of genes that are responsible for various inherited cardiovascular diseases - we are still very much in discovery mode, with ongoing research efforts," added Musunuru. "Genetic testing methods are evolving, and reliable classification of variants identified in genetic testing will remain a preeminent challenge for the practice of clinical genetics."

Excessively wet field conditions at harvest throughout the North Central and upper Midwest regions resulted in many fields with deep wheel-traffic compaction as evident by deep ruts from combines and grain wagons. Although this is a common occurrence during years with excessive moisture at harvest, the subsequent economic costs are rarely, if ever, projected for large regions.

In an article recently published in Agricultural & Environmental Letters, researchers review the scientific literature on the persistence and quantity of yield reductions due to deep wheel-traffic compaction and then project the state-level economic costs to farmers that may be expect for the upcoming 2020 and 2021 crops in North Dakota and Minnesota.

The researchers estimate a median of 21% yield reduction to the upcoming 2020 and 2021 corn and soybean crops on lands impacted by deep wheel-traffic compaction during the 2019 harvest. Based on these reductions, they project a minimum economic cost of $587 million USD to farmers for every 10% of lands that were compacted during harvest. Moreover, the actual land area may extend up to 30%, resulting in a range of $0-to-$1.76 billion USD of actual costs to North Dakota and Minnesota farmers.

The findings have implications for government policies incentivizing conservation practices, such as diversified crop rotations and inter-seeding cover crops, to either reduce the occurrence of field traffic on wet soils or promote drier soils at harvest.

The immune systems of mammals - including humans - might struggle to detect and respond to germs from other planets, new research suggests.

Microorganisms (such as bacteria and viruses) could exist beyond Earth, and there are plans to search for signs of them on Mars and some of Saturn and Jupiter's moons.

Such organisms might be based on different amino acids (key building blocks of all life) than lifeforms on Earth.

Scientists from the universities of Aberdeen and Exeter tested how mammal immune cells responded to peptides (combinations of amino acids) containing two amino acids that are rare on Earth but are commonly found on meteorites.

The immune response to these "alien" peptides was "less efficient" than the reaction to those common on Earth.

The study - conducted in mice, whose immune cells function in a similar way to those of humans - suggests extra-terrestrial microorganisms could pose a threat to space missions, and on Earth if they were brought back.

"The world is now only too aware of the immune challenge posed by the emergence of brand new pathogens," said Professor Neil Gow, Deputy Vice-Chancellor (Research and Impact) at the University of Exeter.

"As a thought experiment, we wondered what would happen if we were to be exposed to a microorganism that had been retrieved from another planet or moon where life had evolved.

"Some very unusual organic building blocks exist outside of the planet Earth, and these could be used to make up the cells of such alien microbes.

"Would our immune system be able to detect proteins made from these non-terrestrial building blocks if such organisms were discovered and were brought back to Earth and then accidently escaped?

"Our paper addresses this hypothetical event."

The study was led by scientists at the MRC Centre for Medical Mycology, which moved from Aberdeen to Exeter last year.

Researchers examined the reaction of T cells, which are key to immune responses, to peptides containing amino acids commonly found on meteorites: isovaline and α-aminoisobutyric acid.

The response was less efficient, with activation levels of 15% and 61% - compared to 82% and 91% when exposed to peptides made entirely of amino acids that are common on Earth.

"Life on Earth relies on essential 22 amino acids," said lead author Dr Katja Schaefer, of the University of Exeter.

"We hypothesised that lifeforms that evolved in an environment of different amino acids might contain them in their structure.

"We chemically synthetised 'exo-peptides' containing amino acids that are rare on Earth, and tested whether a mammal immune system could detect them.

"Our investigation showed that these exo-peptides were still processed, and T cells were still activated, but these responses were less efficient than for 'ordinary' Earth peptides.

"We therefore speculate that contact with extra-terrestrial microorganisms might pose an immunological risk for space missions aiming to retrieve organisms from exoplanets and moons."

The discovery of liquid water at several locations in the solar system raises the possibility that microbial life may have evolved outside Earth, and could therefore be accidently introduced into the Earth's ecosystem.

Diets high in protein, particularly plant protein, are associated with a lower risk of death from any cause, finds an analysis of the latest evidence published by The BMJ today.

The researchers say these findings "support current dietary recommendations to increase consumption of plant proteins in the general population."

Diets high in protein, particularly protein from plants such as legumes (peas, beans and lentils), whole grains and nuts, have been linked to lower risks of developing diabetes, heart disease and stroke, while regular consumption of red meat and high intake of animal proteins have been linked to several health problems.

But data on the association between different types of proteins and death are conflicting.

So researchers based in Iran and the USA set out to measure the potential dose-response relation between intake of total, animal, and plant protein and the risk of death from all causes, cardiovascular disease, and cancer.

They reviewed the results of 32 studies that reported risk estimates for all cause, cardiovascular, and cancer mortality in adults aged 19 or older.

All studies were thoroughly assessed for bias (problems in study design that can influence results).

Mathematical models were then used to compare the effects of the highest versus lowest categories of protein intake, and analyses were done to evaluate the dose-response relations between protein intake and mortality.

During a follow-up period of up to 32 years, 113,039 deaths (16,429 from cardiovascular disease and 22,303 from cancer) occurred among 715,128 participants.

The results show that high intake of total protein was associated with a lower risk of all cause mortality compared with low intake.

Intake of plant protein was associated with an 8% lower risk of all cause mortality and a 12% lower risk of cardiovascular disease mortality. Intake of animal protein was not significantly associated with risk of cardiovascular disease and cancer mortality.

A dose-response analysis of data from 31 studies also showed that an additional 3% of energy from plant proteins a day was associated with a 5% lower risk of death from all causes.

Possible reasons for the beneficial effects of plant proteins include their association with favourable changes in blood pressure, cholesterol and blood sugar levels, which might help to lower the risk of conditions such as heart disease and type 2 diabetes, say the researchers.

They point to some limitations, such as differences in the way studies assessed diet and the possibility that some effects may have been due to unmeasured (confounding) factors. What's more, as most of the included studies were from Western nations, the findings may not be applicable to other countries.

However, strengths include the large number of participants and deaths, providing a detailed insight into the association between intake of dietary protein and risk of mortality based on the current evidence, they write.

"These findings have important public health implications as intake of plant protein can be increased relatively easily by replacing animal protein and could have a large effect on longevity," say the researchers.

While further studies are required, these findings "strongly support the existing dietary recommendations to increase consumption of plant proteins in the general population," they conclude.

Restricting the sale of handguns to those aged 21 or older is associated with a reduction in suicide rates among adolescents in the United States, finds a study published by The BMJ today.

The researchers estimate that hundreds of suicides could be prevented every year in the US if the 33 states where 18 year olds can still buy handguns raised the age limit to 21 years.

Suicide rates have been increasing in the US, particularly among adolescents, with firearms accounting for more than half of these deaths.

A previous study based on suicide data from 1976 to 2001 found that policies restricting the sale of handguns to those aged 21 or older were associated with reductions in firearm related suicides but not overall suicides among adolescents aged 18 to 20 years.

To fill this evidence gap, a team of US researchers led by Julia Raifman at Boston University School of Public Health, used more recent data to re-investigate the relation between the minimum age of handgun purchase in US states and suicide among adolescents.

Their findings are based on suicide data for over 500 million person years from adolescents aged 13 to 20 years in all 46 US states that did not change their policies on age for handgun sales between 2001 and 2017 (a "person year" is the number of years of follow up multiplied by the number of people in the study).

The researchers found state policies that limited the sale of handguns to those aged 18 or older were associated with an increased suicide rate (average 344 extra deaths) among adolescents aged 18 to 20 years between 2001 and 2017, based on an analysis of suicide rates by age.

The researchers also found state policies that limited the sale of handguns to those aged 21 or older were associated with an 18% reduction in the suicide rate among adolescents.

This is equivalent to almost two fewer suicides per 100,000 adolescents aged 18 to 20 years, based on analysis of how suicide rates changed before and after states changed the minimum age of handgun purchase.

Further analysis indicated increases in suicide rates in states that lowered the age of handgun sales (Missouri and South Carolina), but no effect was found in states that increased the age of handgun sales (West Virginia and Wyoming) during the study period.

It is possible that the high levels of firearm ownership in Wyoming and West Virginia (66% and 59% of households in 2004, relative to 38% in the 46 comparison states) meant that the change in age of handgun purchases had little effect on access to firearms by adolescents in these states, note the researchers.

This is an observational study, so can't establish cause, and the researchers point to some limitations, such as underreporting of suicides and the possibility that adolescents might cross state lines to buy firearms where age limits are lower.

However, key strengths include use of data on the full population of adolescents in all US states and the complementary, rigorous analytical approaches.

As such, they say "changing the age of handgun sales policies from 18 to 21 years across the country or in the 33 states without such policies might reduce deaths from suicide among adolescents."

Such a change is in keeping with public sentiment, they add, noting that in 2018, 67% of American adults reported support for more policies regulating firearms.

But in a linked editorial, researchers argue that age limits on purchasing won't protect the many young people already living with firearms.

Professor Ann John and colleagues point out that most firearms used by people who die from suicide have been in their homes for years - and that in the US, one in three homes with children contain firearms and in half of these homes, the firearms are not locked up.

They acknowledge that legislation that increases the age at which handguns can be acquired "will likely prevent at least some suicides in young people."

However, they say without accompanying efforts to substantially reduce young people's access to household firearms (both long guns and handguns), "sales laws alone might make us feel better but are unlikely to save many lives."

Newly released data on treatment outcomes of people with cancer diagnosed with COVID-19 reveal a racial disparity in access to Remdesivir, an antiviral drug that has been shown to shorten hospital stays, and increased mortality associated with dexamethasone, a steroid that has had the opposite effect in the general patient population.

The data on 2,186 adults in the United States by the COVID-19 and Cancer Consortium (CCC19) published July 22 in Cancer Discovery is the largest cancer-specific observational study to date of treatments purported to improve COVID-19 outcomes. The data were published shortly after a keynote address by Solange Peters, MD, PhD, president of the European Society for Medical Oncology and one of the study's lead authors, at the American Association for Cancer Research Virtual Meeting: COVID-19 and Cancer.

In this updated report from CCC19, the consortium's researchers confirm and expand upon earlier observations that there was broad use of unproven COVID-19 therapies, almost all of which were outside of clinical trials.

The steroid dexamethasone lowered the death rate among critically ill patients, according to data from the RECOVERY trial in the United Kingdom, but the CCC19 data indicate an association with increased mortality among cancer patients. In the CCC19 analysis, patients receiving high-dose corticosteroids with any other potential COVID-19 treatment were more than twice as likely to die, as compared to patients treated with other medications or patients not requiring any treatment. There were very small numbers of patients treated just with steroids, making analysis of steroids in isolation difficult.

"There is so much enthusiasm about dexamethasone, but our findings in a relatively small subgroup suggest that steroids could be associated with increased mortality in the cancer population," said Jeremy Warner, MD, MS, associate professor Medicine and Biomedical Informatics at Vanderbilt University, the study's corresponding author. "This does have some rational explanation, since cancer is already an immunocompromised state and steroids could potentially make things worse. The RECOVERY trial is the first to show a survival benefit for any treatment of COVID-19, but that study just published in The New England Journal of Medicine does not provide details for the subgroup of patients with cancer."

Remdesivir, which was primarily available as a clinical trial option, was associated with a lower mortality rate when compared to patients receiving any other potential COVID-19 treatment. Black patients were half as likely to receive Remdesivir as white patients.

"Our study reinforces the finding that most COVID-19 treatment occurs outside the context of a formal clinical trial," Warner said. "The exception to this was the drug Remdesivir, which was given mostly through the clinical trial setting. It appears that Black patients were underrepresented in the clinical trials of Remdesivir, likely due to reasons other than purely clinical factors. The unfortunate conclusion is that racial disparities in access to clinical trials continue to exist, and one of our recommendations is that the necessary steps to address such disparities need to be accelerated, especially given that Black patients and other people of color appear to be taking the brunt of the COVID-19 pandemic."

This is the second study and release of data by CCC19. While the mortality rate among cancer patients affected by COVID-19 was 13% in the prior study of 928 patients, the rate was 16% in the newly published study, which involved 2,186 patients.

Patients on the West Coast were more likely to have received Remdesivir and less likely to have been treated with hydroxychloroquine, which a number of studies have shown to be an ineffective treatment that is associated with higher mortality. One reason could be that the number of cases increased on the West Coast after more information was known about the benefits and risks of the two treatments, Warner said.

"We can be much more definitive in stating the risk and ineffectiveness of hydroxychloroquine with this enhanced analysis," said co-senior author, Gary Lyman, MD, MPH, professor of Public Health Sciences and Clinical Research at Fred Hutchinson Cancer Research Center in Seattle. "This higher mortality association is despite what appears to be rational decision making, such as less utilization of this drug in patients with cardiovascular comorbidities."

CAMBRIDGE, MA -- Many people with autism experience sensory hypersensitivity, attention deficits, and sleep disruption. One brain region that has been implicated in these symptoms is the thalamic reticular nucleus (TRN), which is believed to act as a gatekeeper for sensory information flowing to the cortex.

A team of researchers from MIT and the Broad Institute of MIT and Harvard has now mapped the TRN in unprecedented detail, revealing that the region contains two distinct subnetworks of neurons with different functions. The findings could offer researchers more specific targets for designing drugs that could alleviate some of the sensory, sleep, and attention symptoms of autism, says Guoping Feng, one of the leaders of the research team.

"The idea is that you could very specifically target one group of neurons, without affecting the whole brain and other cognitive functions," says Feng, the James W. and Patricia Poitras Professor of Neuroscience at MIT and a member of MIT's McGovern Institute for Brain Research.

Feng; Zhanyan Fu, associate director of neurobiology at the Broad Institute's Stanley Center for Psychiatric Research; and Joshua Levin, a senior group leader at the Broad Institute, are the senior authors of the study, which appears today in Nature. The paper's lead authors are former MIT postdoc Yinqing Li, former Broad Institute postdoc Violeta Lopez-Huerta, and Broad Institute research scientist Xian Adiconis.

Distinct populations

When sensory input from the eyes, ears, or other sensory organs arrives in our brains, it goes first to the thalamus, which then relays it to the cortex for higher-level processing. Impairments of these thalamo-cortical circuits can lead to attention deficits, hypersensitivity to noise and other stimuli, and sleep problems.

One of the major pathways that controls information flow between the thalamus and the cortex is the TRN, which is responsible for blocking out distracting sensory input. In 2016, Feng and MIT Assistant Professor Michael Halassa, who is also an author of the new Nature paper, discovered that loss of a gene called Ptchd1 significantly affects TRN function. In boys, loss of this gene, which is carried on the X chromosome, can lead to attention deficits, hyperactivity, aggression, intellectual disability, and autism spectrum disorders.

In that study, the researchers found that when the Ptchd1 gene was knocked out in mice, the animals showed many of the same behavioral defects seen in human patients. When it was knocked out only in the TRN, the mice showed only hyperactivity, attention deficits, and sleep disruption, suggesting that the TRN is responsible for those symptoms.

In the new study, the researchers wanted to try to learn more about the specific types of neurons found in the TRN, in hopes of finding new ways to treat hyperactivity and attention deficits. Currently, those symptoms are most often treated with stimulant drugs such as Ritalin, which have widespread effects throughout the brain.

"Our goal was to find some specific ways to modulate the function of thalamo-cortical output and relate it to neurodevelopmental disorders," Feng says. "We decided to try using single-cell technology to dissect out what cell types are there, and what genes are expressed. Are there specific genes that are druggable as a target?"

To explore that possibility, the researchers sequenced the messenger RNA molecules found in neurons of the TRN, which reveals genes that are being expressed in those cells. This allowed them to identify hundreds of genes that could be used to differentiate the cells into two subpopulations, based on how strongly they express those particular genes.

They found that one of these cell populations is located in the core of the TRN, while the other forms a very thin layer surrounding the core. These two populations also form connections to different parts of the thalamus, the researchers found. Based on those connections, the researchers hypothesize that cells in the core are involved in relaying sensory information to the brain's cortex, while cells in the outer layer appear to help coordinate information that comes in through different senses, such as vision and hearing.

"Druggable targets"

The researchers now plan to study the varying roles that these two populations of neurons may have in a variety of neurological symptoms, including attention deficits, hypersensitivity, and sleep disruption. Using genetic and optogenetic techniques, they hope to determine the effects of activating or inhibiting different TRN cell types, or genes expressed in those cells.

"That can help us in the future really develop specific druggable targets that can potentially modulate different functions," Feng says. "Thalamo-cortical circuits control many different things, such as sensory perception, sleep, attention, and cognition, and it may be that these can be targeted more specifically."

This approach could also be useful for treating attention or hypersensitivity disorders even when they aren't caused by defects in TRN function, the researchers say.

"TRN is a target where if you enhance its function, you might be able to correct problems caused by impairments of the thalamo-cortical circuits," Feng says. "Of course we are far away from the development of any kind of treatment, but the potential is that we can use single-cell technology to not only understand how the brain organizes itself, but also how brain functions can be segregated, allowing you to identify much more specific targets that modulate specific functions."

Below is an update of COVID-19 articles published in the American Journal of Tropical Medicine and Hygiene (AJTMH). We've highlighted below those that we think may of interest for your reporting.

The Origin of COVID-19 - and Why It Matters: Embargoed until July 22, 2020 at 5:00 PM ET. Email press contact for a copy of the study.

This new perspective offers credible, scientific authority to the narrative and ongoing exploration of how COVID-19 began. The exploration of the origins argues that available data establishes that our current pandemic virus emerged directly or indirectly from bats prevalent in Asia.

The authors point out that scientists have warned since at least 2007 about the emergence and re-emergence of SARS-like viruses, yet few preventive actions have been taken. They call for "vigorous scientific, public health, and societal actions, including significantly increased funding for basic and applied research addressing disease emergence, to prevent this tragic history from repeating itself."

Keep Politics out of Funding Decisions for Medical Research and Public Health: Embargoed until July 22, 2020 at 5:00 PM ET. Email press contact for a copy of the editorial.

Members of American Society of Tropical Medicine and Hygiene's Executive Committee wrote an editorial on the value of science and the ways that the current administration is undermining efforts to protect and improve human health. Recent decisions by the White House are detrimental to human health, especially during the pandemic. The authors urge the President to reinstate essential funding to research coronaviruses and to continue the United States' relationship with the World Health Organization.

STONY BROOK, NY, July 21, 2020 - The genetic material that codes for bat adaptations and superpowers - such as the ability to fly, to use sound to move effortlessly in complete darkness, to tolerate and survive potentially deadly viruses, and to resist aging and cancer - has been revealed and published in Nature. Liliana M. Dávalos, a Stony Brook University evolutionary biologist and co-author, worked as part of the executive committee of the global consortium of scientists, Bat1K, to sequence the genome of six widely divergent living bat species.

Although other bat genomes have been published before, the Bat1K genomes are 10 times more complete than any bat genome published to date.

One aspect of the paper findings shows evolution through gene expansion and loss in a family of genes, APOBEC3, which is known to play an important role in immunity to viruses in other mammals. The details in the paper that explain this evolution set the groundwork for investigating how these genetic changes, found in bats but not in other mammals, could help prevent the worst outcomes of viral diseases in other mammals, including humans.

"More and more, we find gene duplications and losses as important processes in the evolution of new features and functions across the Tree of Life. But, determining when genes have duplicated is difficult if the genome is incomplete, and it is even harder to figure out if genes have been lost. At extremely high quality, the new bat genomes leave no doubts about changes in important gene families that could not be discovered otherwise with lower-quality genomes," said Dávalos, a Professor in Department of Ecology and Evolution in the College of Arts and Sciences at Stony Brook University.

To generate the bat genomes, the team used the newest technologies of the DRESDEN-concept Genome Center, a shared technology resource in Dresden, Germany to sequence the bat's DNA, and generated new methods to assemble these pieces into the correct order and to identify the genes present. While previous efforts had identified genes with the potential to influence the unique biology of bats, uncovering how gene duplications contributed to this unique biology was complicated by incomplete genomes.

The team compared these bat genomes against 42 other mammals to address the unresolved question of where bats are located within the mammalian tree of life. Using novel phylogenetic methods and comprehensive molecular data sets, the team found the strongest support for bats being most closely related to a group called Fereuungulata that consists of carnivorans (which includes dogs, cats and seals, among other species), pangolins, whales and ungulates (hooved mammals).

To uncover genomic changes that contribute to the unique adaptations found in bats, the team systematically searched for gene differences between bats and other mammals, identifying regions of the genome that have evolved differently in bats and the loss and gain of genes that may drive bats' unique traits.

"It is thanks to a series of sophisticated statistical analyses that we have started to uncover the genetics behind bats' 'superpowers,' including their strong apparent abilities to tolerate and overcome RNA viruses," said Dávalos.

The researchers found evidence the exquisite genomes revealed "fossilized viruses," evidence of surviving past viral infections, and showed that bat genomes contained a higher diversity of these viral remnants than other species providing a genomic record of ancient historical interaction with viral infections. The genomes also revealed the signatures of many other genetic elements besides ancient viral insertions, including 'jumping genes' or transposable elements.

There's no doubt that you can lose fat by eating less or moving more--yet after decades of research, the biology underlying this equation remains mysterious. What really ignites the breakdown of stored fat molecules are nerves embedded in the fat tissue, and a new study now reveals that these fat-burning neurons have previously unrecognized powers. If they receive the right signal, they have an astonishing capacity to grow.

That signal is the hormone leptin, which is released by the fat cells themselves. In experiments with mice described on July 22 in the journal Nature, the researchers found that the normally bushy network of neural fibers within fat tissue shrinks in the absence of leptin and grows back when the hormone is given as a drug. These changes were shown to influence the animals' ability to burn the energy stored in fat.

"While the architecture of the nervous system can change significantly as a young animal develops, we did not expect to find this profound level of neural plasticity in an adult," says . Jeffrey M. Friedman, a molecular geneticist at The Rockefeller University.

If confirmed in humans, the findings could advance research on obesity and related diseases, and potentially open the door to developing new treatments that target neurons in fat.

Homing in on neurons in fat

The team began by looking at what happens to mice who do not produce leptin on their own, and how they respond when treated with it.

Discovered in Friedman's lab in 1994, the hormone relays signals between fat deposits and the brain, allowing the nervous system to curb appetite and boost energy expenditure to regulate body weight. When mice are genetically engineered to stop producing leptin, they grow three times heavier than normal mice. They eat more, move less, and cannot survive in what should be tolerable cold because their body can't properly utilize fat to generate heat.

Give these mice a dose of leptin, however, and they quickly begin to eat less and move more. But when the researchers treated them longer, for two weeks, more profound changes occurred: the animals started to break down white fat, which stores unused calories, at normal levels, and regained the ability to use another form of fat tissue, brown fat, to generate heat.

It was this slower change that interested the research team, including the first authors of the Nature paper, Putianqi Wang, a graduate student in the lab, and Ken H. Loh, a postdoctoral fellow. They suspected that changes in neurons outside the brain--those that extend into fat--might explain why this part of the response to leptin took some time.

To the brain and back

Using an imaging technique developed by the lab of Rockefeller's Paul Cohen to visualize nerves inside fat, the researchers traced leptin's effects on the fat-embedded neurons up to the brain's hypothalamus region. From here, they found, leptin's growth-promoting message travels via the spinal cord back to the neurons in fat. "This work provides the first example of how leptin can regulate the presence of neurons in fat, both white and brown," adds Cohen.

Through this pathway, fat appears to be telling the brain how much innervation it needs to function properly. "Fat is indirectly controlling its own innervation and thus function," Friedman says. "It is an exquisite feedback loop."

Future research will analyze the role of this pathway in human obesity and possibly provide a novel approach for therapy. Most obese people produce high levels of leptin, and show a diminished response to hormone injections, suggesting that their brain is resistant to the hormone. Thus, bypassing leptin resistance could have a therapeutic benefit for these patients. "In the new study we see that similar to animals lacking leptin, obese, leptin-resistant animals also show reduced fat innervation," Friedman says. "So we speculate that directly activating the nerves that innervate fat and restoring a normal ability to use stored fat could provide a possible new avenue for treating obesity.

A cave in a remote part of Mexico was visited by humans around 30,000 years ago - 15,000 years earlier than people were previously thought to have reached the Americas.

Painstaking excavations of Chiquihuite Cave, located in a mountainous area in northern Mexico controlled by drugs cartels, uncovered nearly 2000 stone tools from a small section of the high-altitude cave.

Archaeological analysis of the tools and DNA analysis of the sediment in the cave uncovered a new story of the colonisation of the Americas which now traces evidence of the first Americans back to 25,000-30,000 years ago.

The results, which have been published in Nature today (July 22 2020), challenge the commonly held theory that the Clovis people were the first human inhabitants of the Americas 15,000 years ago.

DNA scientist Professor Eske Willerslev, of St John's College, University of Cambridge, and director of The Lundbeck Foundation GeoGenetics Centre, University of Copenhagen, led the study with archaeologist Dr Ciprian Ardelean, of the University of Zacatecas in Mexico.

Professor Willerslev said: "For decades people have passionately debated when the first humans entered the Americas. Chiquihuite Cave will create a lot more debate as it is the first site that dates the arrival of people to the continent to around 30,000 years ago - 15,000 years earlier than previously thought. These early visitors didn't occupy the cave continuously, we think people spent part of the year there using it as a winter or summer shelter, or as a base to hunt during migration. This could be the Americas oldest ever hotel."

The 10-year long research project raises more questions about the early humans who lived in the Americas than it solves.

Dr Ardelean said: "We don't know who they were, where they came from or where they went. They are a complete enigma. We falsely assume that the indigenous populations in the Americas today are direct descendants from the earliest Americans, but now we do not think that is the case.

"By the time the famous Clovis population entered America, the very early Americans had disappeared thousands of years before. There could have been many failed colonisations that were lost in time and did not leave genetic traces in the population today."

Chiquihuite Cave is a high-altitude site, 2750 metres above sea level. Nearly 2000 stone tools and small tool fragments, known as flakes, were discovered. DNA analysis of the plant and animal remains from the sediment packed around the tools in the cave dates the tools and the human occupation of the site to 25,000-30,000 years ago. Human DNA was not found which adds weight to the theory that the early people didn't stay for long in the cave.

Dr Mikkel Winther Pedersen, a geneticist from the University of Copenhagen and one of the first authors of the paper, said: "We identified DNA from a wide range of animals including black bears, rodents, bats, voles and even kangaroo rats. We think these early people would probably have come back for a few months a year to exploit reoccurring natural resources available to them and then move on. Probably when herds of large mammals would have been in the area and who had little experience with humans so they would have been easy prey. The location of Chiquihuite Cave definitely rewrites what has conventionally been taught in history and archaeology and shows that we need to rethink where we look for sites of the earliest people in Americas."

The Chiquihuite Cave site is very difficult to reach and would have been a good vantage point for the early people to defend themselves from as they could look out for miles over the valley without being seen. It is in an area of Mexico that is now controlled by drugs cartels. The academics were escorted by armed police to the base of the mountain before they made their way up to the cave on foot.

Dr Pedersen said: "It was an unforgettable experience. It is a very unsafe place to travel so we were accompanied by Mexican police officers in armoured cars to the foot of the mountain. We left before sunrise to climb up to the cave so that we weren't spotted."

The visiting DNA scientists slept in the cave during their research visit and over the past 10 years Dr Ardelean has spent a number of months living in the cave to carry out the painstaking excavations.

Dr Ardelean added: "The peopling of the Americas is the last holy grail in modern archaeology. Unconventional sites need to be taken seriously and we need to go out and intentionally look for them. This site doesn't solve anything, it just shows that these early sites exist. We are dealing with a handful of humans from thousands of years ago so we cannot expect the signals to be very clear. We have literally dug deeper than anyone has done in the past."

The earliest human DNA from the Americas currently remains at 12,400 years ago, Dr Ardelean explained: "We have shown the previously long held date of human presence is not the oldest date for populating the Americas, it is the explosion date of populating the Americas."

Professor Willerslev concluded: "I will never forget being part of this research, it was an unbelievable experience. The implications of these findings are as important, if not more important, than the finding itself. This is only the start of the next chapter in the hotly debated early peopling of the Americas."

A backstabbing crime boss and thousands of people looking for free tutorials on hacking and identity theft were two of the more interesting findings of a study examining user activity on two online "carding forums," illegal sites that specialize in stolen credit card information.

As instances of online identity theft continue to rise over the course of the coronavirus pandemic, the research helps shed light on the shady world of cybercriminals and how it operates.

"The cybercrime marketplace, like most e-commerce, has continued to expand and carding forums are the most widespread formats in the West for exchanging illicit goods," said Alex Kigerl, a Washington State University criminologist and lead author of the study published in the June edition of Social Science Computer Review.

For the study, Kigerl used hacked and leaked data from the two online marketplaces where credit card information is bought and sold to reveal the activity patterns and messages of some 10,714 of the sites' users.

His analysis of data from the two carding forums revealed the vast majority of users weren't there to buy or sell anything but rather wanted free samples of credentialed goods, malware source codes, and tutorials on hacking and identify theft.

Actual buyers and sellers of stolen information comprised only a fraction of the total user base of the two websites, Fraud and Elitecarders.

These users were primarily buying and selling stolen identity information that enables them to make unauthorized online purchases, set up a bank account in another person's name or even create a clone of a victim's credit card that can be used in physical retail shops.

Kigerl also discovered that the administrator of the two carding forums, the person who is typically in charge of vouching for reputable sellers and banning users who defraud other users, was perhaps the biggest thief of all.

The administrator would offer up fake credit card information and then ban users who purchased it to keep them from reporting the fraud to the public forums.

"This was very unusual behavior because it is generally in the interest of an administrator to promote good interactions so that he or she can make money from offering things like escrow services," Kigerl said. "It just goes to show there really is no honor among thieves."

A growing online black market

Cybercrime, like most e-commerce, has continued to expand throughout the course of the coronavirus pandemic. In June, the FBI reported an almost 75% spike in daily cybercrimes since the start of stay at home restrictions.

Kigerl said the illicit online marketplaces where most of this criminal activity takes place generally fall into one of four categories - internet relay chat, carding shops, darknet marketplaces and carding forums.

By far the most popular, carding forums are easier to access than other cybercrime marketplaces because they are hosted on the regular internet rather than the dark web, which requires a special internet protocol to access.

They consist of multiple boards pertaining to specialized topics such as credit card sellers, malware distribution, and free tutorials.  Users must register a profile with the website to be able to comment.

Profiles can then be used to track trustworthiness ratings, and each board has one or more moderators who can act as a sort of law enforcement agent, banning disruptive members and setting guidelines.

Carding forums also typically have a short shelf life, only lasting for a few months before being taken down by law enforcement.

"It is kind of like whack-a-mole," Kigerl said.  "One of these websites will go down, and the community will just create a new site and start the process over again. Unfortunately, due to issues of jurisdiction and technologically sophisticated ways to hide one's identity online, few of these criminals get apprehended."

Kigerl said that developing a better understanding of how users operate on carding forums and other cybercrime marketplaces could ultimately help to both apprehend criminals and keep regular internet users safe.

"The more time we spend online, the more we risk exposing our personal information to cybercriminals," Kigerl said. "Other than the usual, such as keeping your computer updated, installing AV software and using a spam filter, I recommend using a service like virustotal.com when you encounter a suspicious file or URL. It scans the file or link with dozens of separate antivirus programs and automatically shares any issues with the security community."

A research group has developed a new, lightweight and motor-less device that can be easily attached to an ankle support device - otherwise known as an ankle foot orthosis (AFO). The new device will aid stroke patients in their rehabilitation, improving their walking and preventing falls.

Stroke patients often suffer from motor paralysis as a result of damage to the brain, significantly affecting their walking. Gaits disorder, as it is otherwise known, results in restrictive disabilities and increased health care costs.

Rehabilitation is key to stroke recovery. Yet around 40% of stroke patients struggle to function properly due to problems with their walking abilities.

One part of the problem is due to insufficient knee bending, or knee flexion, during walking. This leads to lower toe clearance - the distance between the toe and the ground when the foot swings forward - and causes patients to fall. To overcome this, patients frequently hip hike on the affected side, a process by which the patient elevates one side of their hip to move their foot. This makes patients walking movement awkward and decreases their motivation in rehabilitation.

Comprised of Professor Shin-Ichi Izumi and Associate Professor Dai Owaki from Tohoku University's Graduate Schools of Medicine and Graduate School of Engineering along with Mr. Takeo Nozaki and Dr. Ken-ichiro Fukushi from NEC Corporation, the research group created a device which gives the ankle greater push-off power using a spring-cam mechanism. The elliptical shaped cam rotates in conjunction with the AFO, pushing against the spring. The resultant reactive force from the spring generates significant ankle push-off power.

The research group conducted clinical experiments on 11 stroke patients with paralysis on one side of the body, demonstrating that the device generated greater ankle power. This in turn aided knee flexion whilst the affected foot was in the swing phase of walking - i.e. when the foot is raised in the air.

"Our device will pave the way for positive impacts on the rehabilitation of stroke patients," said Associate Professor Owaki. He adds, "It will prevent falls and make patients feel more confident in their walking abilities."

Scientists have shed light on how immune cells navigate to the lymph nodes, where they help to fight off harmful bacteria and viruses.

The study, led by scientists at the University of York, reveals how B-cells - crucial agents of the immune response - are faced with a perilous path, swimming through a dense network of other cells, blood and lymphatic vessels, to reach the follicles of the lymph nodes.

The research team discovered that structures inside lymph nodes leave a trail of chemical signals that guide B-cells through these complex tissues - like miniature lighthouses guiding a safe shipping passage.

Once they have reached the lymph nodes (glands which function as filters trapping viruses and bacteria before they can infect other parts of the body) B-cells confront invading pathogens and take molecules from their surfaces known as antigens. They process and present these to T cells, which then manufacture antibodies allowing them to identify and destroy the invaders.

The research is an important step forward in understanding how our immune system works and also why it fails, the authors of the study say.

Co-lead author of the study, Professor Mark Leake, from the Physics of Life group in the Department of Physics at the University of York, said: "Our study suggests that B-cells sniff out a chemical trail which allows them to swim over relatively long distances in a highly complex microenvironment to reach their key destination.

"Relying on a single chemical transmitter to act as a beacon across the whole of the lymph node wouldn't do the trick, since the signal becomes too dilute and swamped by noise. Instead, these multiple signals are like having a trail of breadcrumbs that the cells can follow."

The study may solve the mystery of how cells which are a hundred times smaller than a millimetre are able to travel over distances of around a metre to get to where they are needed in the body.

An international team of researchers from multiple disciplines including immunology, biophysics, cell biology, mathematics and computer science contributed to the research.

The team used fluorescent tags on signalling molecules to track their location in the lymph nodes of mice and human biopsy samples. They employed maths modelling and computer simulations involving machine learning to map out the cell architecture of the follicles of lymph node tissues.

Professor Leake added: "The only way we could gain this incredible new insight is by forming a large research team with a broad range of expertise crossing between multiple traditional science disciplines.

"Research into understanding the workings of the immune system at the scale of single molecules may help us to understand why things go wrong in the case of some diseases of the immune system. It may help pave the way to new drugs that help to improve the immune system's ability to combat emerging threats from harmful viruses and bacteria that the human population have not previously encountered."

Employees of the Department of Physical Chemistry of Kazan Federal University have found out that the mechanisms of polymerization of aryl cyanates in the solid state and in the melt differ in the number of broken multiple bonds of the monomer at the stage that determines the rate of the process.

Solid phase polymerization is widely used to create polymers with controlled structure, molecular weight, and other parameters. In the industry, a number of polycarbonates, polyamides and polyesters for various purposes are obtained by this method. Aryl cyanates are used to create polymer composite materials used, in particular, in the aerospace industry.

As senior researcher Andrey Galukhin explained, for solid-phase polymerization, it is necessary for the reaction to start at a temperature below the melting point. However, for some monomers this condition is not met, so this type of polymerization is not available for them. These include aryl cyanates, which have high thermal, chemical and radiation resistance. It is thanks to these properties that they have found application in the aerospace industry, where they are used as parts of composite materials. The high stability of aryl cyanates is due to the presence of 1,3,5-triazine aromatic fragments as cross-linking sites of polymer chains.

Kazanian scientists were the first to study the solid phase polymerization of aryl cyanate. They assumed that the solid state polymerization of this substance would be very different from the same process in the melt. The authors synthesized a unique monomer with a high melting point (403°C). Since the polymerization temperature of this substance is below its melting point, this made the solid phase reaction possible. A detailed study with differential scanning calorimetry made it possible to obtain important information about the kinetics of this process. It was possible to find out that the mechanisms of solid-phase polymerization and polymerization in a monomer melt differ in the number of broken multiple bonds of the monomer at the stage that determines the rate of the process. Also, it turned out that the rate of solid-phase polymerization does not depend on the degree of monomer conversion, that is, the kinetics is described by a zero-order reaction. The reason for this behavior lies in the topochemical nature of the process taking place in flat monomer crystals.

"Aryl cyanates play a very important role in the aeronautical and aerospace industries, where they are used as binders in composite materials to create various dimensionally stable structures. Expanding our knowledge of the relationship between the reactivity of these monomers and their structure will open up new possibilities for the targeted design of materials with desired properties," concluded Galukhin.