Culture

Study finds Nunavik Inuit are genetically unique

A new study has found that an Inuit population in Canada's Arctic are genetically distinct from any known group, and certain genetic variants are correlated with brain aneurysm.

Geographically isolated populations often develop unique genetic traits that result from their successful adaptation to specific environments. Unfortunately, these adaptations sometimes predispose them to certain health issues if the environment is changed. The genetic background of these populations are often poorly understood because they live far from scientific research centres.

Canada's Inuit have higher prevalence of cardiovascular disorders, as well as increased incidence of brain aneurysms, than the general population. To learn about the possible genetic origin of these disorders, researchers at The Neuro (Montreal Neurological Institute and Hospital) of McGill University analyzed the genetic characteristics of 170 Inuit volunteers from Nunavik, a region of northern Quebec. This was done with approval from Nunavik Nutrition and Health Committee in Kuujjuaq, Nunavik.

Using exome sequencing and genome-wide genotyping, the researchers found several interesting traits among the Nunavik Inuit. They are a distinct genetic population, whose closest relatives are the Paleo-Eskimos, a people that inhabited the Arctic before the Inuit.

The Nunavik Inuit have distinct genetic signatures in pathways involving lipid metabolism and cell adhesion. These may be adaptations to adjust to the high-fat diet and extreme cold of the Canadian north.

One of these unique genetic variants correlates with a higher risk of brain aneurysm, also known as intracranial aneurysm, a weakening in the wall of a cerebral artery that causes ballooning. In serious cases the arterial wall may rupture, a potentially fatal condition known as a brain hemorrhage.

This study, published in the journal Proceedings of the National Academy of Sciences, is the first genetic study to highlight the genome-wide architecture of Nunavik Inuit with emphasis on natural selection in gene coding regions, from which may arise the genetic risk responsible for their predisposition to diseases such as intracranial aneurysm.

Non-European populations, particularly those isolated populations in remote areas of the world, are underrepresented, or not present at all, in genetics studies. Understanding the genetic makeup of non-European peoples, especially those isolated populations with unique genetic background, such as Nunavik Inuit, will improve our ability to deliver medical therapies tailored for them.

"In the case of the Nunavik Inuit, our results emphasize the need to provide effective neurological services," says Dr. Guy Rouleau, the study's senior author. "Future research will build on the findings to determine if these unique genetic traits increase risk of aneurysm, and if so, what interventions can be designed to reduce this risk. Thank you to the study participants and the Nunavik Nutrition and Health Committee for their collaboration and input."

Credit: 
McGill University

The truth behind racial disparities in fatal police shootings

Reports of racially motivated, fatal shootings by police officers have garnered extensive public attention and sparked activism across the nation. New research from Michigan State University and University of Maryland reveals findings that flip many of these reports on their heads - white police officers are not more likely to shoot minorities citizens than non-white officers.

"Until now, there's never been a systematic, nationwide study to determine the characteristics of police involved in fatal officer-involved shootings," said Joseph Cesario, co-author and professor of psychology at MSU. "There are so many examples of people saying that when black citizens are shot by police, it's white officers shooting them. In fact, our findings show no support for the idea that white officers are biased in shooting black citizens."

The findings - published in Proceedings of the National Academy of Sciences, or PNAS - are based on an independent database Cesario and his team created that catalogued each police shooting from 2015. The team - led also by co-author David Johnson from University of Maryland - contacted every police department that had a fatal police shooting to get the race, sex and years of experience for every officer involved in each incident. The team also leveraged data from police shooting databases by The Washington Post and The Guardian.

"We found that the race of the officer doesn't matter when it comes to predicting whether black or white citizens are shot," Cesario said. "If anything, black officers are more likely to shoot black citizens, but this is because black officers are drawn from the same population that they police. So, the more black citizens in a community, the more black police officers there are."

The data show that it's not racial bias on behalf of white officers relative to black officers when it comes to fatal shootings, and that's good news. The bad news, Cesario said, are that internal policy changes, such as diversifying police forces, may not reduce shootings of minority citizens.

Beyond officer race, the team drew other conclusions about details related to racial disparities in fatal officer shootings.

"Many people ask whether black or white citizens are more likely to be shot and why. We found that crime rates are the driving force behind fatal shootings," Cesario said. "Our data show that the rate of crime by each racial group predicts the likelihood of citizens from that racial group being shot. If you live in a county that has a lot of white people committing crimes, white people are more likely to be shot. If you live in a county that has a lot of black people committing crimes, black people are more likely to be shot. It is the best predictor we have of fatal police shootings."

By connecting the findings of police officer race, victim race and crime rates, the research suggests that the best way to understand police shootings isn't racial bias of the police officer; rather, by the exposure to police officers through crime.

The vast majority - between 90% and 95% - of the civilians shot by officers were actively attacking police or other citizens when they were shot. Ninety percent also were armed with a weapon when they were shot. The horrific cases of accidental shootings, like mistaking a cell phone for a gun, are rare, Cesario said.

"We hear about the really horrendous and tragic cases of police shootings for a reason: they're awful cases, they have major implications for police-community relations and so they should get attention," Cesario said. "But, this ends up skewing perceptions about police shootings and leads people to believe that all fatal shootings are similar to the ones we hear about. That's just not the case."

One thing that was surprising to the researchers, Cesario said, were the number of mental health cases that resulted in fatal officer shootings.

"It was truly striking and we didn't recognize just how many there were," he said. "This shows how underappreciated mental health is in the national discussion of fatal officer shootings."

Nearly 50% of all fatal shootings involving white civilians were because of mental health; it also accounted for nearly 20% of black civilians and 30% of Hispanics. These included two types of mental health cases: the first was "suicide by cop," in which civilians intentionally antagonize the police because they want an officer to kill themselves; the second was a result of mental disorders, such as when a civilian is suffering from schizophrenia and poses a threat to officers.

Although white officers are not more likely than black officers to shoot black citizens when looking at all fatal shootings, the data are too uncertain to draw firm conclusions once different subtypes of shootings, such as shootings of unarmed citizens, are examined. This is because these types of shootings are too rare for strong conclusions to be drawn.

Cesario said that better record keeping - such as the FBI's National Use-of-Force Data Collection, which launched in 2019 - will enable researchers to understand police shootings in finer detail.

Credit: 
Michigan State University

Gut microbes may affect the course of ALS

image: The repertoire of small molecules (metabolites) in blood, many of which originate in the microbiome, showed a different pattern in patients with ALS (top) compared with healthy individuals (bottom).

Image: 
Weizmann Institute of Science

Researchers at the Weizmann Institute of Science have shown in mice that intestinal microbes, collectively termed the gut microbiome, may affect the course of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. As reported today in Nature, progression of an ALS-like disease was slowed after the mice received certain strains of gut microbes or substances known to be secreted by these microbes. Preliminary results suggest that the findings on the regulatory function of the microbiome may be applicable to human patients with ALS.

"Our long-standing scientific and medical goal is to elucidate the impact of the microbiome on human health and disease, with the brain being a fascinating new frontier," says Prof. Eran Elinav of the Immunology Department. His team performed the study together with that of Prof. Eran Segal of the Computer Science and Applied Mathematics Department. Segal elaborates: "Given increasing evidence that microbiome affects brain function and disease, we wanted to study its potential role in ALS." The study was led by postdoctoral fellows Drs. Eran Blacher and Stavros Bashiardes, and by staff scientist Dr. Hagit Shapiro, all in the Elinav lab. They collaborated with Dr. Daphna Rothschild, a postdoctoral fellow in Eran Segal's lab, and Dr. Marc Gotkine, Head of the Motor Neuron Disease Clinic at Hadassah Medical Center, as well as with other scientists from Weizmann and elsewhere.

The scientists started out demonstrating in a series of experiments that the symptoms of an ALS-like disease in transgenic mice worsened after these mice were given broad-spectrum antibiotics to wipe out a substantial portion of their microbiome. In addition, the scientists found that growing these ALS-prone mice in germ-free conditions (in which, by definition, mice carry no microbiome of their own), is exceedingly difficult, as these mice had a hard time surviving in the sterile environment. Together, these results hinted at a potential link between alterations in the microbiome and accelerated disease progression in mice that were genetically susceptible to ALS.

Next, using advanced computational methods, the scientists characterized the composition and function of the microbiome in the ALS-prone mice, comparing them to regular mice. They identified 11 microbial strains that became altered in ALS-prone mice as the disease progressed or even before the mice developed overt ALS symptoms. When the scientists isolated these microbial strains and gave them one by one - in the form of probiotic-like supplements - to ALS-prone mice following antibiotic treatment, some of these strains had a clear negative impact on the ALS-like disease. But one strain, Akkermansia muciniphila, significantly slowed disease progression in the mice and prolonged their survival.

To reveal the mechanism by which Akkermansia may be producing its effect, the scientists examined thousands of small molecules secreted by the gut microbes. They zeroed in on one molecule called nicotinamide (NAM): Its levels in the blood and in the cerebrospinal fluid of ALS-prone mice were reduced following antibiotic treatment and increased after these mice were supplemented with Akkermansia, which was able to secrete this molecule. To confirm that NAM was indeed a microbiome-secreted molecule that could hinder the course of ALS, the scientists continuously infused the ALS-prone mice with NAM. The clinical condition of these mice improved significantly. A detailed study of gene expression in their brains suggested that NAM improved the functioning of their motor neurons.

Credit: 
Weizmann Institute of Science

Archaeological evidence verifies long-doubted medieval accounts of First Crusade

image: This earpiece, perhaps of Egyptian manufacture, is apparent loot from the First Crusade sack of Jerusalem in July, 1099.

Image: 
Virginia Withers

The University of North Carolina at Charlotte-led archaeological dig on Jerusalem's Mount Zion has been going on for over a decade, looking at an area where there were no known ruins of major temples, churches or palaces, but nonetheless sacred land where three millennia of struggle and culture has long lain buried, evidence in layer upon layer of significant historical events.

Virtually every dig season, a significant discovery has been made at the site, adding real detail to the records of this globally-renowned city, giving new insights to what has often been imperfectly preserved in ancient histories. This year's findings are no different, confirming previously unverified details from nearly thousand-year-old historical accounts of the First Crusade - history that had never been confirmed regarding the five-week siege, conquest, sack and massacre of the Fatamid (Muslim)-controlled city in July of 1099.

The dig's archeological team --- co-directed by UNC Charlotte professor of history Shimon Gibson, Rafi Lewis, a faculty member at the University of Haifa and Ashkelon Academic College, and James Tabor, UNC Charlotte professor of religious studies -- has revealed the rumored, but never physically detected, moat-trench the Fatamid defenders dug along the city's southern wall to protect against siege engines - a defense that contemporary accounts claim helped stymie the southern assault.

Through stratigraphic evidence, the archaeologists have been able to confirm the 11th Century date of the 17-meter-wide by 4-meter-deep ditch, which abutted the Fatimid city wall (built in the same place as the current wall near the current Zion Gate), and have also found artifacts from the assault itself, including arrowheads, Crusader bronze cross pendants, and a spectacular piece of Muslim gold jewelry, which is probable booty from the conquest.

In past seasons, the team found remnants of a Fatamid city gate at the site, which, the archaeologists argue, makes the area a likely focal point for the Crusaders' main southern assault on the city wall. Despite reported attempts to fill the trench by the attacking forces, the southern assault was ultimately unsuccessful. The city's defenses were finally breached by a simultaneous operation from the north.

Near the trench, the archaeologists also unearthed an earthquake-damaged Fatamid structure, which was probably already a ruin at the time of the assault. The arrowheads, crosses and jewelry were found on the floor of the structure.

"There was, apparently, an extramural quarter of scattered buildings, outside the city to the south, and we excavated a building that was in a ruinous state, possibly damaged by the earthquake of 1033," Gibson said. "You can imagine the Crusaders coming at and attacking the city from the south and they find the ditch and this ruined building, and they made use of it for cover, and that explains some of the arrowheads because they would have been raining down upon them" Gibson speculated.

"This is enormously important for Crusader scholarship," said Lewis, an expert on medieval warfare, "because not only do we have the remains of the ditch that we only knew about from the sources but we also have the remains of the frontline battle itself."

The archaeology clarifies a historical picture that is mainly only known from contemporary chroniclers who had been considered questionable in their accuracy. By all accounts, the Crusader attack on the city of Jerusalem was a bloody one and took place on two sides of the city. While the principal forces broke into the city from the north, little has been known about the attack from the south.

Peter Tudebode, a contemporary chronicler, recounts that the Provencal forces led by Raymond de Saint Gille on the south side, positioned themselves somewhere on Mount Zion and proceeded to attack the wall. However, there was a ditch in front of the wall and they could not get their wooden siege tower up against the wall, and so Raymond asked his men, under cover of night, to fill in the ditch for payment of gold dinars. Though the siege tower was able to proceed, the southern assault still did not succeed because of the defenders aggressive counter-measures.

Until the current find, however, there was no evidence that a ditch, trench or moat ever existed, calling into question the reality of the accounts of the southern assault.

The Mount Zion dig team's discovery of the trench came through a puzzling observation made in earlier seasons at the site. "Just outside the city wall we noticed that, although the slope of the hill went down [from the wall], we found that the slope of a layer of fill was going in the opposite direction, dipping down [towards the wall]," Gibson noted. "That was our first clue - there was some feature that had been cut into the ground, which had been filled in later."

The fill provided the dating that explained what the structure was: "What was nice was that the ditch itself was sealed with a burnt layer that had coins in it from the time of King Baldwin III," Gibson said.

Baldwin III was an early crusader king who fought a civil war against his mother, in the course of which he burnt much of Jerusalem. Baldwin's fiery attack was known to be in 1153, about half a century after the conquest, thus dating the ditch as a landscape feature in the period before.

"The ditch got filled in and it disappeared - to such an extent that a lot of archaeologists who had been working at different points in time believed that maybe this ditch was a figment of the chroniclers' imaginations," Gibson said. "That's why this discovery is so important - for the first time, we can confirm details that appear in major historical texts."

The artifacts associated with the find provide some intriguing details about the historical moment of the First Crusade. In the ditch's fill the archaeologists found what might be a part of a battle standard made of metal, as well as pieces of Chinese celadon ware pottery, which show active trade with the far east during the Fatamid period.

The jewelry, which includes fine gold workmanship with pearls and colored beads, was found by staff archaeologists John Hutchins and Melanie Samed, and they carefully extracted it from the ruined house, where it had lain for 920 years. Gibson is fairly certain that it is booty from the sack or carried by the soldiers carrying out the attack, rather than a dropped domestic item, noting that looting was a real interest of the crusaders.

"It's large and valuable, not something you would lose, you see, " Gibson said. "This piece of jewelry may have been of Egyptian origin and it seems to have been used as an attachment for the ear, and because of its large size, perhaps also to hold a veil in position around a women's head." The Fatamid dynasty came from Egypt, and the gold work is a familiar Egyptian style of the period, with the use of gold and pearls in jewelry mentioned in documents from the Cairo Genizah.

Details bringing the moment of conquest to life are particularly important because the battle marks a critical moment in Jerusalem's history. The crusaders takeover is one of several catastrophic moments in Jerusalem's dramatic and violent history when the city was essentially wiped out and re-colonized by its conquerors.

"For three days, or perhaps even a week, the crusaders perpetrated every single atrocity under the sun - rape, pillage, murder," Gibson said. "The chroniclers talk about 'rivers of blood' running in the streets of the city, and it may not be an exaggeration. Terrible crimes were committed, and a lot of people died, Christians included. Local Christians were considered just as heretical as the Muslims and the Jews. They turned Jerusalem into a ghost town."

It is expected that further analysis of the artifacts will reveal further insights.

Credit: 
University of North Carolina at Charlotte

Critical heart drug too pricey for some Medicare patients

An effective drug to treat chronic heart failure may cost too much for senior citizens with a standard Medicare Part D drug plan, said a study co-authored by a John A. Burns School of Medicine (JABSOM) researcher at the University of Hawaii at Manoa.

The therapy is a combination of sacubitril/valsartan called Entresto®. Researchers found that, even with insurance, the cost to Medicare patients may be more than $1,600 a year.

"This drug is the standard of care for the people with significant congestive heart failure according to both the American Heart Association and American College of Cardiology guidelines, yet it's priced so high that, even with insurance, patients may not be able to afford it," said senior author Chien-Wen Tseng, HMSA Endowed Chair in Health Services and Quality Research at JABSOM and physician investigator with Honolulu's Pacific Health Research and Education Institute.

The study co-authors worry that, since Entresto® is a pricey, brand-name drug, such high copayments may result in patients not taking it at all. And that comes with a steep price.

"The science shows that this drug can help save lives," said Tseng, pointing to clinical studies showing the therapy has reduced deaths from heart failure by 20 percent. "We need to figure out a way to deal with its $5,000 price tag, and how folks on Medicare can afford to pay $1,600 each year in copayments to benefit from it."

Current laws prohibit the U.S. Department of Health and Human Services from negotiating drug prices with pharmaceutical companies on behalf of Medicare Part D beneficiaries. As a result, said lead researcher Colette DeJong of the University of California at San Francisco, "Paying $1,600 per year for a single drug could be a huge hardship for many older adults who lived on an average income of less than $25,000 in 2017. Changing the laws that prevent Medicare from negotiating drug prices on behalf of seniors and people living with disabilities would be one step toward curbing these skyrocketing out-of-pocket costs."

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University of Hawaii at Manoa

Vampire algae killer's genetic diversity poses threat to biofuels

image: New DNA analysis has found genetic diversity in Vampirovibrio chlorellavorus, complicating efforts to protect algae ponds and the biofuels industry from this destructive pest. The predatory bacterium sucks out the contents of the algae cells, ultimately transforming a productive green algae pond to a vat of rotting sludge.

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Seth Steichen and Judith K. Brown, Plant Sciences, University of Arizona, Tucson, Ariz.

LOS ALAMOS, N.M., July 22, 2019--New DNA analysis has revealed surprising genetic diversity in a bacterium that poses a persistent threat to the algae biofuels industry. With the evocative name Vampirovibrio chlorellavorus, the predatory pest sucks out the contents of the algae cells (thus the vampire reference) and reduces a productive, thriving, green algae pond to a vat of rotting sludge.

"DNA sequences show what are likely different species, suggesting a much larger diversity in this family than we originally assumed," said Blake Hovde, a Los Alamos National Laboratory biologist. "That means the treatment for one algae pest might not work for another, which can be a big problem for large-scale algae cultivation in the future."

The research team sequenced two strains of Vampirovibrio from the same pond. The two samples collected one year apart came from an outdoor algae cultivation system in the Sonoran Desert of Arizona run by University of Arizona collaborators Seth Steichen and Judith Brown. The team sequenced and analyzed the genomes to identify the genes involved in predation, infection and cell death of the valuable Chlorella algae that the bacterium targets.

"Our genomic analyses identified several predicted genes that encode secreted proteins that are potentially involved in pathogenicity, and at least three apparently complete sets of virulence (Vir) genes," Hovde said. Those genes are characteristic of bacteria that carry out cell invasion.

With Chlorella algae valued as a key source of harvestable biomass for biofuels and bioproducts, it is extremely useful to be able to enhance the fundamental understanding of interactions between a unique bacterial pathogen and its green algal host, Hovde noted. The results of this research have direct relevance to the success of large-scale commercial algal production projects underway to advance U.S. energy security (biofuels) and the production of aquaculture feedstocks and algal-based nutraceuticals.

For future work, the team is following up with a project with the Joint Genome Institute to characterize six more pest genomes from the same family to see if the diversity of these organisms continues to expand, or if the researchers can start categorizing these pests into species groups.

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DOE/Los Alamos National Laboratory

Adolescents who skip breakfast may develop obesity

A paper published in Scientific Reports describes how researchers affiliated with the University of São Paulo's Medical School (FM-USP) in Brazil and colleagues at institutions in Europe evaluated behaviors leading to weight gain in adolescents. Childhood obesity can favor the premature emergence of health issues such as type 2 diabetes and cardiovascular disease.

The main finding is that skipping breakfast, a common habit among teenagers, correlates directly with increased waist circumference and body mass index in this age group.The habit can lead to an unbalanced diet and other unhealthy behaviors, potentially making the adolescents vulnerable to weight gain.

"We found that skipping breakfast is associated with adiposity markers in adolescents regardless of where they live and how much sleep they get, or whether they're male or female," said epidemiologist Elsie Costa de Oliveira Forkert, a member of the Youth/Child Cardiovascular Risk and Environmental (YCARE) Research Group in FM-USP's Preventive Medicine Department.

"By skipping breakfast, millions of children and adolescents around the world are probably replacing a more healthy homemade meal including dairy products, whole-grain cereal and fruit with fast food at an venue on the way to school, or at the school itself," Forkert said.

"This typically means consuming industrialized hypercaloric foods of low nutritional value, such as deep-fried snacks, pastries, sodas and other sugary drinks, which are all directly associated with the development of obesity."

The study was part of Forkert's postdoctoral research, supported by São Paulo Research Foundation - FAPESP. Scientists at institutions in Austria, Belgium, Germany, Greece, Italy and Spain collaborated.

Analyzing data from two major surveys conducted in Europe and Brazil, the scientists assessed the association between energy balance-related behaviors in adolescence and markers of total and abdominal adiposity.

The European data came from the "Healthy Lifestyle in Europe by Nutrition in Adolescence" cross-sectional study (HELENA-CSS, 2006-07), which involved 3,528 adolescents in ten major cities. The subjects were between 12.5 years and 17.5 years of age and were stratified by age, gender, region, and socioeconomic status. Males and females accounted for roughly half of the study population each (47.7% and 52.3%, respectively). The principal investigator was Luis Alberto Moreno, a professor at the University of Zaragoza's Health Science School in Spain.

The Brazilian data came from a survey entitled "Brazilian Cardiovascular Adolescent Health" (BRACAH). Using a similar methodology, this survey was conducted in 2007 in Maringá, the third-largest city in Paraná state. It involved 991 adolescents aged 14-18 years of age. Males accounted for 45.5% and females accounted for 54.5% of the study population. The adolescents were assessed for cardiovascular risk factors and health-related behaviors.

The principal investigator for this survey was Augusto Cesar Ferreira de Moraes, a professor in the Epidemiology Department of the University of São Paulo's Public Health School (FSP-USP).

The new study analyzed weight, height and body mass index data as indicators of overall obesity and waist circumference and waist-height ratios as indicators of abdominal obesity.

"Energy balance-related behaviors were measured by means of a questionnaire covering physical activity levels at school or at home, during leisure or while commuting, etc. Approximately 60 or more minutes per day of moderate to vigorous physical activity was considered adequate. Less than that was considered insufficient," Forkert said.

According to Forkert, sedentary behaviors were analyzed in terms of habitual screen time (television, computer, video games), and subjects were asked to specify how many hours they usually slept on weekdays and weekends.

A separate questionnaire was applied to explore attitudes and concerns regarding food choices, preferences, healthy eating habits and lifestyle, and included a specific question about breakfast that asked subjects to agree or disagree (more or less strongly on a scale from 1 to 7) with the statement "I often skip breakfast".

The scientists used the data from these surveys to investigate whether adolescents who skipped breakfast had higher adiposity markers on average than those who did not.

"Among all the energy balance-related behaviors analyzed, the strongest correlation was between skipping breakfast and the augmented average levels of obesity markers," Forkert said.

Sedentary habits and more calories

Data from both the European and Brazilian surveys showed that male adolescents were heavier and taller on average and had larger waist circumferences than females.

"For boys who skipped breakfast, the average waist circumference was 2.61 cm larger in Europe and 2.13 cm larger in Brazil than those of boys who usually ate breakfast," Forkert said.

"On the other hand, when we looked at how sleep time influenced the association between the other behaviors and the obesity markers, we found that the average body mass index for European and Brazilian boys who skipped breakfast was 1.29 kg/m² and 1.69 kg/m² higher, respectively, than those who ate breakfast, even when they got sufficient sleep [eight hours or more per day]".

For European and Brazilian boys, skipping breakfast was the predominant energy balance-related behavior that correlated positively with obesity indicators such as body mass index, waist circumference and waist-height ratio.

"The same was true of European girls. Skipping breakfast correlated positively with total and abdominal obesity even when sleep time was adequate," Forkert said. "For example, the average waist circumference increased by 1.97 cm, and the waist-height ratio was 0.02 higher".

In Brazil, girls were more sedentary than boys. In Europe, sedentary habits prevailed less among girls than among boys, but girls were also less physically active, although they were more active than Brazilian boys. The sedentary behaviors of these girls (more than two hours per day) resulted in an increased waist circumference (1.20 m on average), even when sleep time was adequate.

"However, among Brazilian boys who slept less than eight hours per day, less sleep was protective for total obesity, which fell by 0.93 kg/m² on average," Forkert said.

"The adolescents with more sedentary habits who spent more time watching television, using a computer or playing video games probably had an unbalanced diet and consumed unhealthy food while watching television or playing," she added, although such behaviors were not investigated in the study. "Sedentary behaviors associated with relatively high calorie consumption lead directly to obesity".

Credit: 
Fundação de Amparo à Pesquisa do Estado de São Paulo

Connection to HIV care helps hardly reached US populations suppress the virus

Gay, bisexual and other men who have sex with men and transgender women with HIV, who are not in care, can be engaged in care when reached and connected with HIV treatment services, according to findings from a clinical trial supported by the National Institutes of Health. Nearly half of the study participants achieved and maintained viral suppression by one year, researchers reported today at the 10th IAS Conference on HIV Science (IAS 2019) in Mexico City.

Effective HIV treatment resulting in sustained viral suppression benefits the health of the person with HIV and also prevents sexual transmission of the virus to others. The clinical trial, called HPTN 078, assessed an HIV prevention strategy involving a peer-to-peer recruitment method to identify, recruit and link to HIV care men and transgender women with unsuppressed HIV in the United States. It also evaluated whether a case management intervention could help them achieve and maintain viral suppression.

Ninety-four percent of eligible volunteers with unsuppressed HIV identified through the recruitment process were enrolled in the study and engaged in HIV care, and 91% of these study participants were retained after 12 months. Researchers observed no differences in one-year viral suppression rates between those who received standard HIV care and those who received the case management intervention.

"To end the HIV epidemic in the United States, we must close implementation gaps to ensure that all people with HIV are diagnosed and receive the treatment and care they need to achieve and maintain viral suppression," said Anthony S. Fauci, M.D., director of the NIH National Institute of Allergy and Infectious Diseases (NIAID). "The HPTN 078 findings demonstrate that populations not engaged in care are indeed reachable when a concerted effort is made, underscoring the importance of developing and optimizing strategies to identify people with HIV and connect them to HIV treatment services."

HPTN 078 screened and enrolled volunteers in four U.S. cities with high HIV burdens--Atlanta; Baltimore; Birmingham, Alabama; and Boston. The study was funded by NIAID and the National Institute of Mental Health (NIMH), both part of NIH, and conducted by the NIH-funded HIV Prevention Trials Network (HPTN).

In the United States, the HIV epidemic is concentrated among gay and bisexual men and transgender people, particularly those who are black or Latinx. Of the 144 men and transgender women with unsuppressed HIV enrolled in the study, 84% were black and 7% were Latinx. Two-thirds were unemployed, and 64% reported an annual income less than $20,000. Most (86%) reported having had previous experience with antiretroviral therapy (ART) to treat HIV.

Study participants assigned randomly to the intervention worked with case managers who helped them navigate health care and supportive services and provided tailored support for ART adherence. These study participants also had the option to receive automated motivational messages and reminders to take their medications and to attend appointments by text, email and phone. Participants determined the intensity of the intervention by choosing the frequency and content of interactions with their case manager and automated messaging. Study participants enrolled in the standard care arm were offered existing programs for supportive services, ART initiation, treatment adherence and retention in care at participating HIV clinics in the four cities.

After 12 months, 48% of all study participants had achieved and maintained viral suppression, with no difference between the standard care and case management intervention arms. Notably, it took time for many of the study participants to achieve viral suppression, and the investigators observed progressive increases in rates of viral suppression--28% at 3 months, 36% at 6 months, 39% at 9 months and 48% at 12 months. According to the Centers for Disease Control and Prevention, among all adults and adolescents with HIV in the United States, 53% had achieved viral suppression and 49% were retained in continuous HIV care in 2016. The HPTN 078 findings indicate that a large proportion of the men and transgender women with unsuppressed HIV can be engaged or re-engaged in HIV care.

"HPTN 078 highlights the willingness of people with unsuppressed HIV to engage in treatment when connected with HIV care services," said Dianne Rausch, Ph.D., director of the NIMH Division of AIDS Research. "The lack of difference in viral suppression between the standard care and case management arms underscores the effectiveness of the current standard of HIV care in the United States, but additional interventions appear necessary to further increase the proportion of people who maintain viral suppression."

"We are encouraged to see that nearly half of participants whose HIV was unsuppressed at the beginning of the study had achieved and maintained viral suppression after one year. However, additional issues--such as high levels of poverty, social factors like stigma, and individual-level factors including mental health and substance use--must be addressed to achieve higher rates of viral suppression among disenfranchised men who have sex with men and transgender women in the United States," said Chris Beyrer, M.D., M.P.H., of The Johns Hopkins University. Dr. Beyrer, protocol chair of HPTN 078, presented the findings at IAS 2019. Robert H. Remien, Ph.D., of Columbia University co-chaired the study and was lead author on the conference presentation.

To identify gay, bisexual and other men who have sex with men and transgender women with unsuppressed HIV, HPTN 078 investigators assessed a recruitment strategy in which a small group of individuals recruited their peers. The newly recruited people then referred others, who in turn recruited other people. HPTN investigators also recruited people directly into the study. Overall, the investigators screened 1,305 men and transgender women, among whom they identified 154 with unsuppressed HIV, 144 (94%) of whom enrolled in the study.

Credit: 
NIH/National Institute of Allergy and Infectious Diseases

Astronomers map vast void in our cosmic neighborhood

image: Shaded gray contours outline the extent of the Local Void, while blue dots show major mass constituents (large galaxies, galaxy groups, and clusters). The curved blue lines show the derived motions of these massive objects, after removing the overall expansion of the universe. The most important galaxy congregations are given special symbols, like the red ball identifying the Virgo Cluster. The dominant pattern of motions revealed by the orbits is a flow away from the Local Void.

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UH

An astronomer from the University of Hawaii Institute for Astronomy and an international team published a new study that reveals more of the vast cosmic structure surrounding our Milky Way galaxy.

The universe is a tapestry of galaxy congregations and vast voids. In a new study being reported in The Astrophysical Journal, Brent Tully's team applies the same tools from an earlier study to map the size and shape of an extensive empty region they called the Local Void that borders the Milky Way galaxy. Using the observations of galaxy motions, they infer the distribution of mass responsible for that motion, and construct three-dimensional maps of our local Universe.

Galaxies not only move with the overall expansion of the universe, they also respond to the gravitational tug of their neighbors and regions with a lot of mass. As a consequence, relative to the overall expansion they are moving towards the densest areas and away from regions with little mass - the voids.

Although we live in a cosmic metropolis, back in 1987 Tully and Richard Fisher noted that our Milky Way galaxy is also at the edge of an extensive empty region that they called the Local Void. The existence of the Local Void has been widely accepted, but it remained poorly studied because it lies behind the center of our galaxy and is therefore heavily obscured from our view.

Now, Tully and his team have measured the motions of 18,000 galaxies in the Cosmicflows-3 compendium of galaxy distances, constructing a cosmographic map that highlights the boundary between the collection of matter and the absence of matter that defines the edge of the Local Void. They used the same technique in 2014 to identify the full extent of our home supercluster of over one hundred thousand galaxies, giving it the name Laniakea, meaning "immense heaven" in Hawaiian.

For 30 years, astronomers have been trying to identify why the motions of the Milky Way, our nearest large galaxy neighbor Andromeda, and their smaller neighbors deviate from the overall expansion of the Universe by over 600 km/s (1.3 million mph). The new study shows that roughly half of this motion is generated "locally" from the combination of a pull from the massive nearby Virgo Cluster and our participation in the expansion of the Local Void as it becomes ever emptier.

Credit: 
University of Hawaii at Manoa

First impressions go a long way in the immune system

image: The repertoire of immune cells taken from blood samples after exposure to a bacterium (inside the circle, cell types; outside, subtypes) and their activation levels. Based on an algorithm, the information can be obtained from a normal blood test with no need for expensive genetic single-cell sequencing

Image: 
Weizmann Institute of Science

First impressions are important - they can set the stage for the entire course of a relationship. The same is true for the impressions the cells of our immune system form when they first meet a new bacterium. Using this insight, Weizmann Institute of Science researchers have developed an algorithm that may predict the onset of such diseases as tuberculosis. The findings of this research were recently published in Nature Communications.

Dr. Roi Avraham, whose group in the Institute's Biological Regulation Department conducted the research, explains: "When immune cell and bacterium meet, there can be several outcomes. The immune system can kill the bacteria; the bacteria can overcome the immune defenses; or, in the case of diseases like tuberculosis, the bacterium can lie dormant for years, sometimes causing disease at a later stage and sometimes remaining in hibernation for good. We think that the junction in which one of those paths is chosen takes place early on - some 24-48 hours after infection."

The scientists first tested real meetings between immune cells and bacteria - this time between blood samples (which contain immune cells) and the Salmonella bacterium. Led by Drs. Noa Bossel Ben Moshe and Shelly Hen-Avivi in Avraham's group, the research team used a method that has been developed in recent years, at the Weizmann Institute among other places, to sequence the gene activity in thousands of individual cells. In other words, they could see what each cell looked like as it responded to the Salmonella bacteria and they could map out the activation profiles of each. This, indeed revealed patterns not seen in standard lab tests, and it seemed to confirm their hypothesis - there were indeed, differences that enabled them to trace responses from the initial meetings to the later outcomes.

Such single-cell sequencing is still limited to specialized labs, however. The group asked whether there was a way to connect their results to real-time blood tests in real patients. For this, they turned to their single cell databases on Salmonella infection and immune responses and developed an algorithm - based on a method known as deconvolution - that would then enable them to extract similar information from standard data sets. This algorithm uses information available from the standard blood tests and extrapolates to the properties of the individual blood cells in the experiments. "The algorithm we developed," says Bossel Ben Moshe, "can not only define the ensemble of immune cells that take part in the response, it can reveal their activity levels and thus the potential strength of the immune response."

The first test of the algorithm was in blood samples taken from healthy people in the Netherlands. These samples were infected, in a lab dish, with Salmonella bacteria, and the immune response recorded. Comparisons with existing genomic analysis methods showed that the standard methods did not uncover differences between groups, while the algorithm the group had developed revealed significant ones that were tied to later variations in bacteria-killing abilities.

The group then asked whether the same algorithm could be used to diagnose the onset of tuberculosis, which is caused by a bacterium that often chooses the third way - dormancy -- and thus can hide out in the body for years. Up to a third of the world's population carries the tuberculosis bacterium, though only a small percentage of these actually become ill. Still, some two million die of the disease each year, mostly in underdeveloped areas of China, Russia and Africa. The researchers turned to another database - a British one that followed patients and carriers for a period of two years -- so the group could apply the algorithm to blood test results from both groups, as well as from the subset who went from carrier to disease onset during that period.

The researchers found that the activity levels of immune cells called monocytes could be used to predict the onset or course of the disease. "The algorithm is based on the 'first impressions' of immune cells and Salmonella, which cause a very different type of illness than mycobacterium tuberculosis," says Hen-Avivi. "Still, we were able to predict, early on, which of the carriers would develop the active form of the disease."

Once tuberculosis symptoms appear, patients have to take three different antibiotics over the course of nine months, and antibiotic resistance has become rampant in these bacteria. "If those who are at risk of active disease could be identified when the bacterial load is smaller, their chances of recovery will be better," says Avraham. "And the state medical systems in countries where tuberculosis is endemic might have a better way to keep the suffering and incidence of sickness down while reducing the cost of treatment."

The researchers intend to continue in this line of research - to expand their own database on tuberculosis and other pathogens so to as to refine the algorithm and work on developing the tools that may, in the future, be used to predict who will develop full-blown disease. With the refined algorithm further avenues of research may lead to methods of predicting the course of a number of infectious diseases.

Credit: 
Weizmann Institute of Science

Use of non-hospital-based provider-to-patient telehealth grew nearly 1,400%

NEW YORK, NY--July 23, 2019--From 2014 to 2018, private insurance claim lines for non-hospital-based provider-to-patient telehealth grew 1,393 percent, according to a new white paper on telehealth from FAIR Health, a national, independent nonprofit organization dedicated to bringing transparency to healthcare costs and health insurance information. The study draws on data from FAIR Health's comprehensive repository of over 29 billion private healthcare claim records--the largest in the country.

This was a greater increase than for all other types of telehealth studied and for telehealth overall. The increase was greater in urban than rural areas. Claim lines for non-hospital-based provider-to-patient telehealth increased 1,227 percent in urban areas, 897 percent in rural areas.

The four types of telehealth--the remote provision of clinical services through telecommunications technology--studied in the white paper were:

Provider-to-patient-non-hospital-based telehealth. The provider and the patient communicate via telehealth without relation to a hospital. For example, a patient who is home and has not had a recent hospitalization has a video chat with a provider to show his or her rash.

Provider-to-patient-discharge telehealth. The telehealth visit is a follow-up after the patient is discharged from an inpatient stay in the hospital.

Physician-to-patient-emergency department (ED)/inpatient telehealth. The patient is in the hospital, whether in the ED or as an inpatient, communicating via telehealth with a physician.

Provider-to-provider telehealth. The telehealth exchange involves consultation between healthcare professionals.

The telehealth white paper expands on a previous FAIR Health white paper that reported on telehealth and other alternative venues of care, such as urgent care centers and retail clinics. The new white paper provides additional details, delving into the different types of telehealth, the most common telehealth diagnostic categories and what happens to patients after a telehealth visit.

Among the findings of the new study:

Claim lines related to telehealth overall grew 624 percent from 2014 to 2018.

In 2018, non-hospital-based provider-to-patient telehealth accounted for 84 percent of all telehealth claim lines, compared with 52 percent in 2014.

In the period 2014-2018, the age group most associated with telehealth overall was that of individuals age 31-40, who accounted for 21 percent of the distribution of all telehealth claim lines. But most of the claim lines (82 percent) for discharge-related provider-to-patient telehealth were associated with individuals 51 and older.

Sixty-five percent of all telehealth claim lines in the period 2014-2018 were associated with females. But for telehealth visits associated with a hospital discharge, 53 percent of claim lines were submitted for females.

The top three reasons individuals sought treatment from a provider via non-hospital-based telehealth, from most to least common, were acute upper respiratory infections, mood (affective) disorders, and anxiety and other nonpsychotic mental disorders.

In 2018, the telehealth diagnosis with the highest rate of patients who had an in-person visit within 15 days of a non-hospital-based provider-to-patient telehealth visit for the same or a very similar diagnosis was heart failure.

Dr. Martin A. Makary, Chief of Islet Transplant Surgery and Professor of Surgery at Johns Hopkins, stated: "FAIR Health has released an excellent study of an emerging type of care and its impact on the healthcare landscape. The analysis reveals aspects of telehealth that have not previously been studied in this level of detail."

FAIR Health President Robin Gelburd commented: "As telehealth continues its rapid growth, we are pleased to use our unparalleled data repository to uncover layers that have been difficult to study. We offer the information in this report for the benefit of all healthcare stakeholders with an interest in the emergence and contours of telehealth."

Credit: 
FAIR Health

Learning to look

image: Detection of inoviruses across ecosystems. The map displays the location and type of samples from which new inovirus sequences were identified as part of the global metagenome search. The image is related to a Nature Microbiology paper released July 22, 2019, by a team led by Simon Roux, a research scientist at the US Department of Energy Joint Genome Institute.

Image: 
Simon Roux

To answer the question, "Where's Waldo?" readers need to look for a number of distinguishing features. Several characters may be spotted with a striped scarf, striped hat, round-rimmed glasses, or a cane, but only Waldo will have all of these features.

As described July 22, 2019, in Nature Microbiology, a team led by scientists at the U.S. Department of Energy (DOE) Joint Genome Institute (JGI), a DOE Office of Science User Facility, developed an algorithm that a computer could use to conduct a similar type of search in microbial and metagenomic databases. In this case, the machine "learned" to identify a certain type of bacterial viruses or phages called inoviruses, which are filamentous viruses with small, single-stranded DNA genomes and a unique chronic infection cycle.

"We're not sure why we systematically manage to miss them; maybe it's due to the way we currently isolate and extract viruses," said the study's lead author Simon Roux, a JGI research scientist in the Environmental Genomics group.

Training the Search Tool

Inoviruses are stealth agents that can enter and exit through the cell membrane without lysing the bacterial host. They can also influence their host's growth and pathogenicity, in turn affecting the microbe's own eukaryote host. As their small genomes can be easily manipulated through genetic engineering, inoviruses are used for several biotechnological applications, most notably, phage display. The search tool Roux and his colleagues developed first worked on a reference dataset that included genome sequences known to be affiliated with the Inoviridae. "What we're really doing is looking for a particular gene found in all inoviruses, and then checking the surrounding genes," he said. "If these genes are similar in size and function to those in typical bacterial or archaeal genomes, the sequence is most likely not an inovirus. But if these nearby genes are both short and novel, then that's a very good indicator that it is a genuine inovirus."

After Roux manually curated the results and refined the algorithm, the search tool combed through more than 70,000 microbial and metagenome datasets, ultimately identifying more than 10,000 inovirus-like sequences compared to the 56 previously known inovirus genomes. "These genomes are so special, regular search methods don't work," said Roux. "The machine learning approach allows you to quickly scale up once you've found the right features that you can use to identify the inoviruses."

Overhauling the Perception of Inovirus Diversity

The results revealed inoviruses are in every major microbial habitat--including soil, water, and humans--around the world. By the numbers, the new approach detected inoviruses in 3,609 (6 percent) of the 56,868 microbial genomes and 2,249 of the 6,412 (35 percent) metagenomes mined for this study. "We're simply getting much better at seeing them, which means we can now study their biology much more meaningfully," Roux noted of the result.

"It troubled me for a long time that we had only a handful of representatives of this virus group," said virologist Mart Krupovic of the Institut Pasteur, one of the study co-authors and an expert on inoviruses. "The result of this hidden diversity of inoviruses now overhauls our perception of this virus group - from minor curiosities they become a prominent component of the prokaryotic virome associated with nearly all bacterial phyla across virtually every ecosystem."

By significantly expanding the known diversity of these viruses, genomic analyses led the team to propose that the Inoviridae should be classified as an order of viruses, with six families. Additionally, the team uncovered a range of genetic diversity among inoviruses with more than 3,400 different proteins, many linked to key functions such as virion structure and extrusion, and DNA replication and integration. The researchers also learned how an inovirus' strategy of integrating itself within a host can lead to beneficial or antagonistic interactions with other co-infecting phages and with the host's CRISPR-Cas immunity systems.

Countering Co-Infections, Ensuring Host Survival

Many bacteria have CRISPR-Cas systems that incorporate short sequences from infecting viruses and phages to help the bacterial host resist foreign genetic elements. In some cases, Roux and his colleagues found that the inoviruses were being targeted by their hosts' own CRISPR-Cas systems, termed "self-targeting," and yet still survived. The persistence of these "self-targeting" inoviruses suggested they had found a way to deactivate the CRISPR-Cas systems, and led the researchers to predict the presence of anti-CRISPRs, recently discovered inhibitors of bacterial CRISPR-Cas systems that have no conserved structural motifs or domain architectures.

"Anti-CRISPRs are important from the standpoint of phage-bacterial coevolution and are also useful tools in CRISPR-Cas applications, but we are limited in our predictive methods to discover new anti-CRISPRs," said Adair Borges, a graduate student in bacterial immunologist Joe Bondy-Denomy's lab at the University of California, San Francisco. Both are co-authors on the study. "By finding a new anti-CRISPR locus, in an inovirus for example, we would be able to discover all the new anti-CRISPRs that are associated with that genetic neighborhood. So anti-CRISPR loci are powerful discovery tools, by finding even one new anti-CRISPR locus, you are unlocking many new anti-CRISPRs."

Borges worked with Roux and found that the inoviruses don't need to make their own anti-CRISPRs. Instead, she said, the inoviruses she studied "piggyback" off the anti-CRISPRs made by the co-infecting phages in the same host cell, relying on their shared desire to avoid CRISPR-Cas immunity. In addition, Borges also showed that inoviruses might prevent new phages from infecting a cell in which the inovirus has established itself through a process called superinfection exclusion, which is another way by which they can help their host survive.

"It is an exciting time to be studying filamentous phages!" said Krupovic. "We can now start inquiring into their impact on microbial communities in the environment and also those associated with humans."

Credit: 
DOE/Lawrence Berkeley National Laboratory

Laugh tracks make 'dad jokes' funnier

Many people complain about television shows that use recorded laugh tracks. But researchers reporting in the journal Current Biology on July 22 have found that laugh tracks really do work.

According to the new evidence, the sound of a laugh track makes people rate corny "dad jokes" as being funnier. Laugh tracks work best when the recording features spontaneous laughter as opposed to posed laughter. The findings held up in both neurotypical people and in those diagnosed with autism.

"I'm fascinated that not only does laughter make the joke seem funnier, but that the more spontaneous the laughter, the funnier it makes the joke!" said Sophie Scott (@sophiescott) of the University College London.

Scott's team often conducts studies in which they ask people to rate laughter or other sounds in different ways. In the new study, they wanted an implicit measure of the effect of laughter, by asking study participants to rate how funny they found jokes with and without laughter. Read aloud by a professional comedian, the jokes were intentionally groan-worthy "dad jokes."

First, they established baseline ratings of how funny the jokes were perceived to be on a scale from one to seven. Next, they presented a different group of participants, including 48 neurotypical individuals and 24 individuals with autism, with the same jokes. This time, half of the jokes were paired with short, spontaneous laugh tracks and the other half with short, posed laughs.

The ratings revealed that the addition of laughter increases how funny a joke is perceived to be, irrespective of type of laughter. But the kind of laughter does matter. The addition of spontaneous laughs led to greater increases in the funniness rating than did the addition of posed laughs.

The researchers say it was somewhat unexpected and therefore intriguing to find that the effect of laughter was the same for neurotypical and autistic participants. It suggests that everyone is likely influenced by laughter, whether they realize it or not.

In future studies, the researchers hope to explore the way that laughter influences brain activity in response to jokes. "We want to do a brain-scanning study so we can see how the laughter influences joke perception in the brain, and whether this is the same for everyone," Scott said.

Credit: 
Cell Press

What gives meteorites their shape? New research uncovers a 'Goldilocks' answer

image: Meteoroids coming from outer space are randomly shaped, but many of these, which land on earth as meteorites, are found to be carved into cones. To explore the forces that produce cone-shaped meteorites, researchers replicated meteoroids traveling through outer space: clay objects, attached to a rod, served as 'mock meteorites' that erode while moving through water.

Image: 
NYU's Applied Mathematics Laboratory

Meteoroids coming from outer space are randomly shaped, but many of these, which land on earth as meteorites, are found to be carved into cones. Scientists have now figured out how the physics of flight in the atmosphere leads to this transformation.

The progression, discovered through a series of replication experiments in New York University's Applied Mathematics Lab, involves melting and erosion during flight that ultimately results in an ideal shape as meteoroids hurl through the atmosphere. The findings are reported in the journal Proceedings of the National Academy of Sciences (PNAS).

"Slender or narrow cones flip over and tumble, while broad cones flutter and rock back and forth, but we discovered between these are cones that fly perfectly straight with their point or apex leading," explains Leif Ristroph, an assistant professor in NYU's Courant Institute of Mathematical Sciences, who led the study. "Amazingly, these 'Goldilocks' cones of the 'just right' angles exactly match the shapes of eroded clay resulting from our experiments and of actual conical meteorites."

"By showing how the shape of an object affects its ability to fly straight, our study sheds some light on this long-standing mystery about why so many meteorites that arrive on Earth are cone shaped," he adds.

The forces behind the peculiar shapes of meteorites, which are meteors or "shooting stars" that survive the fiery flight through the atmosphere and land on Earth, have long been a mystery.

"The shapes of meteorites are not as they are in space, since they are actually melted, eroded, and reshaped by atmospheric flight," explains Ristroph. "While most meteorites are randomly shaped 'blobs,' surprisingly many--some say about 25 percent--are 'oriented meteorites,' and complete samples of these look almost like perfect cones."

To explore the forces that produce cone-shaped meteorites, the researchers, who included Jun Zhang, a professor of physics and mathematics at the Courant Institute and NYU Shanghai, replicated meteoroids traveling through outer space: clay objects, attached to a rod, served as "mock meteorites" that erode while moving through water.

The clay objects held in the water current were eventually carved into cones of the same angularity as conical meteorites--not too slender and not too broad.

However, the researchers recognized the limitations of this experimental design: unlike the clay objects, actual flying meteoroids are not held in a fixed position and can freely rotate, tumble, and spin. This distinction raised the following question: what allows meteorites to keep a fixed orientation and successfully reach Earth?

The team, which also included Khunsa Amin and Kevin Hu, both NYU undergraduates, and Jinzi Huang, an NYU doctoral student at the time of the work, then conducted additional experiments in which they examined how different shaped cones fell through water. Here they discovered that narrow cones flip over while broad cones flutter. However, in between these two are "just right" cone shapes that fly straight.

"These experiments tell an origin story for oriented meteorites: the very aerodynamic forces that melt and reshape meteoroids in flight also stabilize its posture so that a cone shape can be carved and ultimately arrive on Earth," observes Ristroph. "This is another interesting message we're learning from meteorites, which are scientifically important as 'alien visitors' to Earth whose composition and structure tell us about the universe."

Credit: 
New York University

Molecular 'clutch' puts infection-fighting cells into gear

image: The composition of LAT clusters changes on its travel towards the center leading to changes in their binding to the actin network: in the distal supramolecular activation cluster (D-SMAC) zone, LAT clusters contain Nck and WASP and bind strongly to actin network leading to their transport together with the actin retrograde flow; at the transition to the peripheral SMAC, characterized by concentric organized acto-myosin arcs, LAT clusters loose Nck and WASP leading to a weaker interaction with actin allowing them to be swept towards the central SMAC by the radially constricting acto-myosin arcs.

Image: 
Dr. Darius Köster, University of Warwick

Two proteins that act as a 'clutch' in cells to put them in gear and drive our immune response have been identified for the first time.

A team of biochemists and cell biologists--gathered from the University of Warwick (UK), the University of Texas Southwestern (UTSW) Medical Center (USA), University of California, San Francisco (UCSF) (USA), and from the National Centre for Biological Sciences (NCBS-TIFR), Bangalore (India) -- working together at the Marine Biological Laboratory, Woods Hole in the United States thanks to funding by the Howard Hughes Medical Institute -- have uncovered a process within cells that shows how they move contents around inside them. It appears that they move in a manner similar to switching gears in a car.

The research, published in the journal eLife, could give insights into the mechanisms that activate immune cells and could eventually drive the development of new treatments.

The research focused on the composition of protein condensates - clusters of different types of proteins bound together that are found inside cells. These condensates have been found to play significant roles in many biological processes, and have also been implicated in diseases, including Huntington's disease, amyotrophic lateral sclerosis, and several types of cancer.

One system that protein condensates play an important role in is the activation of T cells, which are very important for producing antibodies and for communicating to the rest of the body that there is an infection present. T cells are constantly screening for small amounts of antigen presenting cells, which are vital for an effective adaptive immune response, so have to be easily but accurately triggered.

When a T cells binds to an antigen presenting cell, the T cell receptors are activated, and a cascade of processes are triggered. The T cell starts to rearrange its cortex and create a zone around these receptors called the immunological synapse.

A network of filaments within the cell made from actin guides a condensate carrying a protein called LAT from the cell periphery towards the centre of the cortex continuously to keep the T cell activated.

The researchers were able to demonstrate that two adaptor proteins, Nck and N-WASP/WASP, act like a 'clutch' in a car, allowing the condensate to slot into the correct gear position and speed up its progress to the centre of the cell.

The discovery sheds light on the control mechanisms for the activation of our immune response, and potentially could open opportunities to design T cells that are only active for particular problems.

Dr. Darius Köster, an Assistant Professor at the Centre for Mechanochemical Cell Biology - Warwick Medical School, explains: "Proteins condensates have distinct compositions and distinct preferential locations within cells, and they are associated with distinct biological functions, including DNA replication, RNA metabolism, signal transduction, synaptic transmission, and stress response.

"For this research, colleagues rebuilt these condensates in vitro to demonstrate that LAT can be the seed for forming these protein assemblies. We then combined this system with a rebuilt actin cortex system to get a better understanding of what happens to phase-separating protein bunches in the vicinity of an actively moving actin network.

"Depending on which modular molecules are used in the LAT clusters, their interaction with actin changes. It's a bit like a clutch in your car, some molecules interact weakly with the actin, but by adding another molecule they will interact much more strongly.

"Using this reconstituted system allowed us to make much more minute changes to the protein condensate composition that would not be so easy to do in the live cell."

Professor Satyajit Mayor (NCBS-TIFR) commented on the unique way in which scientists from different institutes and continents came together with their respective experience and expertise to collaborate on solving a central question that is emerging in the new area of phase separating membrane-less molecular assemblies.

He comments: "This effort was made possible by a unique collaboration. An idea supported by Howard Hughes Medical Institute (HHMI), produced the 'HHMI/MBL Summer Institute', (organized primarily by the HHMI investigators Mike Rosen (UTSW), Ron Vale (UCSF) and Jim Wilhelm (UC San Diego) to study the mechanisms that control the composition and consequent function of these exciting phases in living cells. While the lead author of this study, Jon, was reconstituting the phase separating T Cell receptor signalling complex (at UTSW) along with Xiaolei Su (at UCSF), Darius brought his in vitro actomyosin membrane cortex (developed at the NCBS) to the heady collaborative atmosphere of the Marine Biological Laboratory in Woods Hole, Massachusetts. The natural consequence was to mix one system with the other. The understanding gained from this active mixture provided crucial insights into the functioning of the molecular clutch that couples the T cell signalling complex with a centripetally moving acting cytoskeleton. This coupling in turn regulates the function of T cell receptors in aiding the immune system to recognize foreign antigens."

Dr. Michael Rosen echoes this sentiment, adding: "The Summer Institute brought together scientists from across the globe to participate in a unique collaborative environment at the MBL. By living and working together for eight weeks over several summers, we were able to make scientific discoveries that would have been impossible for any of our groups individually. The work described in our eLife paper, combining extremely complex biochemistry with cutting-edge imaging and image analysis, exemplifies the spirit and accomplishments of the Summer Institute."

Credit: 
National Centre for Biological Sciences