Culture

Computational tools applied to biology are revolutionizing the study of what happens inside cells during an infection, helping scientists to understand disease mechanisms and contributing to the identification of potential therapeutic targets.

An example is a study published in PLOS Pathogens describing how Brazilian researchers analyzed blood cells from patients infected with chikungunya virus. With the aid of techniques such as complex network analysis, artificial intelligence and machine learning, the group identified gene signatures associated with the disease - sets of genes whose expression is altered by interaction with the virus. They then investigated the role played in cells by the involved genes and determined the importance of these genes to efforts to combat the virus.

Conducted in Brazil, the research was supported by São Paulo Research Foundation - FAPESP. The principal investigator was Helder Nakaya, a professor at the University of São Paulo's School of Pharmaceutical Sciences (FCF-USP). Researchers at the same university's Biomedical Science Institute (ICB-USP) and its Ribeirão Preto Medical School (FMRP-USP), as well as colleagues at Butantan Institute and the Public Health Central Laboratory of Sergipe, among others, also contributed.

"We also identified a set of genes that show during the acute phase whether the patient is likely to develop chronic arthralgia [joint pain and inflammation], a relatively common condition in people infected with chikungunya. However, this finding has yet to be confirmed by future research based on a larger number of samples," Nakaya told.

The article describes the results of analyses using blood samples from 39 subjects born in Sergipe, a state in Northeast Brazil, and infected during the 2016 epidemic. These results were compared with data for a control group comprising 20 uninfected subjects from the same region.

The first step was an analysis of the samples' transcriptomes, comprising all molecules of messenger RNA (which encodes proteins) as well as noncoding RNAs (which do not produce proteins but perform a regulatory role in the genome) expressed in red blood cells, white blood cells and platelets. By quantifying the transcript levels in the samples, the researchers were able to measure the activity levels of 20,000 genes and determine whether their expression increased or decreased during infection; these findings were also compared with results for the control group.

"We focused on protein-coding genes [which express messenger RNA] because their role is easier to interpret. It's relatively easy to know whether they encode cell receptors or transcription factors, for example. In this way, we were able to enhance our understanding of the pathogenesis of chikungunya - how the virus affects cells and which defense systems are activated in response to infection," Nakaya said.

Their analysis revealed the mechanism by which immune cells trigger inflammatory processes to eliminate the virus. The proteins responsible for this immune response are collectively known as the inflammasome, a multiprotein intracellular complex that can be formed by different proteins and result in the production of different proinflammatory molecules. The researchers found that the mediating factor in chikungunya virus infection is the enzyme caspase-1.

The finding was validated in experiments with mice performed in partnership with Dario Zamboni, Full Professor at FMRP-USP. Both Nakaya and Zamboni are affiliated with the Center for Research on Inflammatory Diseases (CRID), one of the Research, Innovation and Dissemination Centers (RIDCs) funded by São Paulo Research Foundation - FAPESP. The CRID is hosted by FMRP-USP.

They found that chikungunya virus infection in mice genetically modified to not express caspase-1 did not lead to the release of a proinflammatory molecule called interleukin-1 beta (IL-1β), whereas it did in wild-type (non-GM) mice.

Similar but diferente

Having identified the gene signatures of chikungunya virus infection, which involve thousands of genes whose expression is altered by the disease, the group compared the results with those obtained using samples from patients infected with dengue virus.

"We noticed that the gene signatures of both diseases were similar to a considerable extent but that some genes were specific to chikungunya. These can be explored further in drug development research," Nakaya said.

In another analysis, the researchers compared the gene expression profile of patients infected with chikungunya virus with the profile of patients suffering from rheumatoid arthritis, an autoimmune disease characterized by chronic joint inflammation.

"In this case, our aim was to discover the difference between arthritis caused by the virus and autoimmune arthritis. We wanted to identify any genes that were specific to the viral infection," Nakaya explained.

Combined analysis of three gene signatures showed that 949 genes were involved in rheumatoid arthritis alone, 632 in dengue alone, and 302 in chikungunya alone. Seven genes were connected with all three conditions: OAS1, C1QB, ANKRD22, IRF7, CXCL10, IFI6, and IFIT3.

The researchers then performed gene coexpression analysis using CEMiTool, a software package developed by Nakaya with FAPESP's support. The aim of this analysis was to understand how the genes interact with each other within the complex network that exists in every cell, forming signaling pathways and metabolic pathways.

"We were able to identify eight main coexpression modules [genes with similar response profiles]. We also identified the network hubs - the genes with the most connections and, hence, the most promising targets to explore for drug development purposes," Nakaya said.

The data used in the study, both the raw data and analysis results, are available in a public repository and can be downloaded by anyone free of charge, he stressed, as can the code for the software package mentioned earlier, so that others can reproduce the results.

"Our research enabled us to produce a list of potential therapeutic targets, and we're now cross-referencing these findings with a database of active compounds. This cross-referencing is being done computationally but on the basis of experimental data compiled from published studies that have pointed to drugs capable of interfering with these genes of interest," Nakaya said.

The group will also continue to analyze the transcripts found in the samples from 39 patients infected with chikungunya virus but are now focusing on noncoding RNAs.

Scientists describe a previously unknown disorder of the immune system: in a distinct subset of immune cells from patients with primary immunodeficiency, cellular respiration is significantly increased. This cellular metabolic overactivity leads to inflammation, as an international research team led by the University of Basel and University Hospital Basel report in the journal Nature Immunology.

The immune system protects us from infections and tumors - a challenging task, not least because harming the body's own healthy tissue must be avoided at the same time. However, rare genetic diseases lead to defects in the immune system known as primary immunodeficiency disorders (PID). One consequence of such disorders is susceptibility to infections, yet certain tumors and non-infectious inflammation (autoimmune diseases) can also occur more frequently.

The researchers tested the hypothesis that the metabolic activity in the immune cells of PID patients can serve as a biomarker. They based this on the fact that cellular metabolism is a key regulator of the functioning of immune cells. In the immune cells of a subset of the examined PID patients, a key metabolic process - cellular respiration - was indeed significantly increased. During cellular respiration, energy is generated in the mitochondria, the "powerhouses of the cell".

Increased cellular respiration

On the basis of this discovery, the researchers were able to decode a new kind of disease mechanism, from the genetic defect via mitochondria and back to signal transduction to the nucleus. The increased cellular respiration was triggered by the hyperactivity of a protein in the respiratory chain. This then signaled the cells to produce inflammatory mediators. With these findings, the researchers were able to successfully administer a targeted treatment approved for another indication.

The study was led by Professor Christoph Hess (Department of Biomedicine (DBM) of the University of Basel and University Hospital Basel, and CITIID, University of Cambridge) and Professor Mike Recher (DBM, University of Basel and University Hospital Basel). "It is an example of how patient-based research can help to decode disease-causing molecular processes," Christoph Hess says. This benefits patients, who may receive more targeted and effective medication with fewer side effects. Further, insights into fundamental biological processes gained from studying rare diseases can also enable new pathophysiological considerations relating to more common diseases.

In marriage, conflict is inevitable. Even the happiest couples argue. And research shows they tend to argue about the same topics as unhappy couples: children, money, in-laws, intimacy.

So, what distinguishes happy couples? According to "What are the Marital Problems of Happy Couples? A Multimethod, Two-Sample Investigation," a study published this August in Family Process, it is the way happy couples argue that may make a difference.

"Happy couples tend to take a solution-oriented approach to conflict, and this is clear even in the topics that they choose to discuss," said lead author Amy Rauer, associate professor of child and family studies and director of the Relationships and Development Lab in the College of Education, Health, and Human Sciences.

Rauer and three colleagues--Allen Sabey of Northwestern University, Christine Proulx of the University of Missouri, and Brenda Volling of the University of Michigan-- observed two samples of heterosexual, mostly white, educated couples who describe themselves as happily married. Fifty-seven of the couples were in their mid- to late 30s and had been married an average of nine years; 64 of the couples were in their early 70s and had been married an average of 42 years.

Couples in both samples similarly ranked their most and least serious issues. Intimacy, leisure, household, communication, and money were the most serious, as well as health for the older couples; couples in both samples ranked jealousy, religion, and family as the least serious.

When researchers observed couples discussing marital problems, all couples focused on issues with clearer solutions, such as the distribution of household labor and how to spend leisure time.

"Rebalancing chores may not be easy, but it lends itself to more concrete solutions than other issues," Rauer said. "One spouse could do more of certain chores to balance the scales."

The couples rarely chose to argue about issues that are more difficult to resolve. And Rauer suggests that this strategic decision may be one of the keys to their marital success.

"Focusing on the perpetual, more-difficult-to-solve problems may undermine partners' confidence in the relationship," Rauer said.

Instead, to the extent it is possible, focusing first on more solvable problems may be an effective way to build up both partners' sense of security in the relationship.

"If couples feel that they can work together to resolve their issues, it may give them the confidence to move on to tackling the more difficult issues," Rauer said.

As to which issues may be more difficult to resolve, couples avoided discussing challenges regarding their spouse's health and physical intimacy. These issues may be more difficult to address without challenging their partner's sense of competence or making the partner feel vulnerable or embarrassed, resulting in more conflict.

"Since these issues tend to be more difficult to resolve, they are more likely to lead to less marital happiness or the dissolution of the relationship, especially if couples have not banked up any previous successes solving other marital issues," Rauer said.

Researchers also found that couples who were married longer reported fewer serious issues and argued less overall. This is consistent with previous research suggesting that older partners' perceptions of spending less time with each other may lead them to prioritize their marriage and decide some issues are not worth the argument.

In other words, couples may want to choose their battles wisely, according to Rauer.

"Being able to successfully differentiate between issues that need to be resolved versus those that can be laid aside for now may be one of the keys to a long-lasting, happy relationship."

RESEARCH TRIANGLE PARK, N.C. -- Round, smooth and iridescent, pearls are among the world's most exquisite jewels; now, these gems are inspiring a U.S. Army research project to improve military armor.

By mimicking the outer coating of pearls (nacre, or as it's more commonly known, mother of pearl), researchers at University at Buffalo, funded by the Army Research Office (ARO), created a lightweight plastic that is 14 times stronger and eight times lighter (less dense) than steel and ideal for absorbing the impact of bullets and other projectiles.

ARO is an element of the U.S. Army Combat Capabilities Development Command's Army Research Laboratory.

The research findings are published in the journal ACS Applied Polymer Materials, and its earlier publication in J. Phys. Chem. Lett. (see related links below)

"The material is stiff, strong and tough," said Dr. Shenqiang Ren, professor in the Department of Mechanical and Aerospace Engineering, a member of University of Buffalo's RENEW Institute, and the paper's lead author. "It could be applicable to vests, helmets and other types of body armor, as well as protective armor for ships, helicopters and other vehicles."

The bulk of the material is a souped-up version of polyethylene (the most common plastic) called ultrahigh molecular weight polyethylene, or UHMWPE, which is used to make products like artificial hips and guitar picks.

When designing the UHMWPE, the researchers studied mother of pearl, which mollusks create by arranging a form of calcium carbonate into a structure that resembles interlocking bricks. Like mother of pearl, the researchers designed the material to have an extremely tough outer shell with a more flexible inner backing that's capable of deforming and absorbing projectiles.

"Professor Ren's work designing UHMWPE to dramatically improve impact strength may lead to new generations of lightweight armor that provide both protection and mobility for Soldiers," said Dr. Evan Runnerstrom, program manager, materials design, ARO. "In contrast to steel or ceramic armor, UHMWPE could also be easier to cast or mold into complex shapes, providing versatile protection for Soldiers, vehicles, and other Army assets."

This is what's known as soft armor, in which soft yet tightly woven materials create what is essentially a very strong net capable of stopping bullets. KEVLAR is a well-known example.

The material the research team developed also has high thermal conductivity. This ability to rapidly dissipate heat further helps it to absorb the energy of bullets and other projectiles.

The team further experimented with the UHMWPE by adding silica nanoparticles, finding that tiny bits of the chemical could enhance the material's properties and potentially create stronger armor.

"This work demonstrates that the right materials design approaches have the potential to make big impacts for Army technologies," Runnerstrom said.

WASHINGTON--Valley fever is endemic to hot and dry regions like the southwestern United States and California's San Joaquin Valley, but a new study predicts climate change will cause the fungal infection's range to more than double in size this century, reaching previously unaffected areas across the western U.S.

In a new study published in AGU's journal GeoHealth, scientists at the University of California, Irvine claim that in a high-warming scenario, the list of affected states will jump from 12 to 17 and the number of individual valley fever cases will grow by 50 percent by the year 2100. The states projected to host newly endemic counties are Montana, Nebraska, North Dakota, South Dakota and Wyoming, and the disease is expected to become more widespread in Colorado, Idaho and Oklahoma, according to the study.

"The range of valley fever is going to increase substantially," said Morgan Gorris, a former UCI PhD student in Earth system science and lead author of the new study. "We made projections out to the end of the 21st century, and our model predicts that valley fever will travel farther north throughout the western United States, especially in the rain shadow of the Rocky Mountains and throughout the Great Plains, and by that time, much of the western U.S. will be considered endemic."

The current valley fever endemicity map used by the national Centers for Disease Control and Prevention is based on a skin-test study conducted on a San Diego naval base in the 1940s. Using this decades-old information as a starting point, Gorris collected health department data on valley fever cases reported by hospitals in many Western states.

Then she and her team studied the climate conditions in places where valley fever is most common. They concluded that counties with more than 10 cases per 100,000 people all had average annual temperatures above 10 degrees Celsius (50 degrees Fahrenheit) and rainfall below 600 millimeters (23.6 inches).

"Morgan made this model based on temperature and rainfall; it provides similar but not exactly the same projections of where the CDC says Valley fever is," said James Randerson, Chancellor's Professor and Ralph J. and Carol M. Cicerone Chair in Earth System Science at UCI and co-author of the new study. "In fact, we think it may guide efforts to build a better contemporary map of where the disease poses a threat to public health."

Gorris said the study is really focused on predicting the expansion of Valley fever. "Both temperature and precipitation are expected to change considerably in the western U.S. in future decades, but it's the increasing temperatures in already dry states that allow the disease to spread," she said.

At present, parts of California and the Southwest are particularly suited for nurturing the fungus, scientifically known as Coccidioides. A smattering of winter rain on dry ground enables fungal growth beneath the surface. When the soil dries, the elongated strands of fungus break apart into spores, some as small as 2 microns in diameter. If they're agitated by earth-moving equipment or the boots of workers, the particles can be lofted into the air and inhaled by people in the area.

Laborers in construction and agriculture, as well as prisoners paving roadways and fighting fires in remote locales, are particularly susceptible to breathing in the airborne spores. It's a burgeoning public health concern because the number of cases in California and other regions has been going up over time.

Once in the lungs, the fungus transforms from strand-like into spherules, tiny balls that grow and spread in pulmonary tissues. About 40 percent of those who inhale the spores become sick. Early symptoms of valley fever are similar to those of the flu: cough, fever, chills and night sweats. For this reason, the disease is often misdiagnosed and can go untreated. In advanced cases, the fungus can be disseminated from the lungs to other parts of the body, potentially causing skin lesions that can result in limb loss.

In extreme cases, the disease can travel to the brain, leading to swelling and death. Roughly 5 percent of people with valley fever will have a severe form of it, and 1 percent will die. Pregnant women, the elderly and individuals with HIV are considered most vulnerable to severe forms of valley fever. Filipinos and those of African descent are also at heightened risk. The disease disproportionately affects people in low-income communities, Randerson said.

"By 2100, for a business-as-usual scenario in which we do not take serious action to limit climate change, we would predict a doubling of the area where this disease is present," he said. "It's a huge expansion and especially worrisome because Valley fever is going to impact previously untouched communities throughout the West."

NEW YORK (September 16, 2019) -- Higher hospital-wide use of four classes of antibiotics thought to increase the risk of the dangerous intestinal illness Clostridioides difficile were associated with increased prevalence of hospital-associated C. difficile, according to a study published today in Infection Control & Hospital Epidemiology, the journal of the Society for Healthcare Epidemiology of America.

For every 100 days of facility-wide antibiotic therapy using one of these four antibiotics considered high risk, researchers found a 12 percent increase in hospital-associated C. difficile infection, though when analyzed separately only cephalosporins were significantly correlated with hospital-associated C. difficile.

C. difficile infections, which can cause life-threatening symptoms ranging from diarrhea to inflammation of the colon, affect nearly a half million patients in the United States each year causing approximately 15,000 deaths per year.

The lack of significant results for C. difficile for some classes of antibiotics may reflect reduced use through stewardship, the authors said.

"This highlights the importance of ongoing monitoring of antibiotic use in hospitals for patient safety as it relates to the effect of antibiotics on C. difficile infections. In the future it will also be important to look at the effect of antibiotic use on both C. difficile infection and antibiotic resistance simultaneously, rather than examining each piece as separate endeavors," said L. Clifford McDonald, MD, medical epidemiologist at the Centers for Disease Control and Prevention (CDC) and an author on the study.

"This is possible in our era of electronic medical records because antibiotic usage data has become more available. A facility can use the National Healthcare Safety Network Antibiotic Use and Resistance Module and interpret results using the standardized antibiotic administration ratio (SAAR) to have a better understanding of how antibiotics are being used and identify areas for improvement."

Recent guidelines identified the four classes of antibiotics examined in this study as high risk, though results of previous research evaluating facility-level use of these antibiotics and rates of C. difficile have been inconsistent. Researchers in this study analyzed microbiological and pharmacy data from 171 hospitals included in the BD Insights Research Database to look at the impact of hospital-wide use of these four classes of antibiotics on hospital-acquired C. difficile.

The four high-risk classes were cephalosporins (used for a wide variety of bacterial infections), fluoroquinolones (used for respiratory and urinary tract infections), carbapenems (broad spectrum antibiotics often reserved for unresponsive infections), and lincosamides (used against staph and strep infections).

Higher C. difficile infection rates were also associated with a larger portion of patients over age 65, higher rates of community-onset C. difficile, longer length of stay, and teaching hospitals.

The vast majority of Americans underestimate the magnitude of economic inequality between Whites and racial minorities, particularly Black and Latinx people, new data indicate.

In a national survey of more than 1,000 adults from racial and socioeconomic backgrounds largely representative of the demographics of the United States, Yale University psychological scientists have found that people overestimate the current state of White-Black wealth equality by 80 percentage points above U.S. government data on actual household wealth.

The results appear in Perspectives on Psychological Science, a journal of the Association for Psychological Science.

The respondents also estimated the wealth gap between White and Latinx families to be greater than the Black-White gap, when the opposite is true, the researchers led by Michael W. Kraus and Jennifer A. Richeson report. Participants' views on the wealth disparity between Asian Americans and Whites were slightly less misguided, but still below the actual figures, they write.

"Americans tend to believe that this is a country that is naturally and automatically ascending toward justice," Kraus says. "This latest work has been about just how deeply these narratives lead us astray from the stark reality of racial economic inequality in our country."

The research expands on a previous examination on the perceptions of racial economic equality held by Black and White Americans that Kraus, Richeson and graduate student Julian Rucker conducted in 2017. On average, the participants in that work overestimated the current state of Black-White economic equality (based on multiple markers of economic well-being) by about 25 percent over federal income statistics.

In the latest work, the team--including postdoctoral scholar Ivuoma Onyeador and graduate student Natalie Daumeyer--surveyed a broadened spectrum of U.S. residents and added questions related to perceptions of Asian American and Latinx family wealth. They also asked participants to estimate Black-White wealth disparities at 12 points in time between 1963 and 2016. Respondents underestimated this wealth disparity at all time points, with participants approximating the gap at about 40 percentage points lower than its actual size in 1963 and 80 points lower in 2016. Overall, more than 97% of participants overestimated Black-White wealth equality.

The researchers also examined perceptions of Black-White wealth equality at multiple levels of family education and income. They predicted that participants would believe that Black families with high income and advanced education were most likely to have the same amount of wealth as their White counterparts. And indeed, they found that participants underestimated the wealth gap between White and Black families at every level of education and income. The results reveal a desire to find some set of perhaps deserving Black families that have achieved economic parity with their White counterparts, which, in turn, maintains the belief that society is indeed fair and just.

The misperceptions of racial economic inequality are caused by many different factors, the Yale researchers say. The inflated estimates of the Latinx-White wealth gap, for instance, could stem from cognitive factors such as the recent national focus on refugees attempting to cross the U.S. southern border and widespread ignorance of Latinx contributions to the country. Similarly, the more accurate perceptions of the Asian-White wealth gap could arise from the fact that Asian Americans have closer wealth parity with Whites than do the other two racial groups, but may also reflect stereotypes about Asian Americans as high-achieving. Kraus, Richeson and undergraduate researcher, Entung Kuo found in a recent study that exposure to narratives that highlight these "model minority" stereotypes of Asian Americans drove people to underestimate wealth differences between Whites and people of Asian heritage in the United States.

In their report, the authors discuss some of the psychological processes and structural forces that may produce these misperceptions about racial progress.

"Americans need to wake up to the notion that race is at the center of economic inequality in the United States," Kraus says. "And if we really value the American Dream, we need to commit to supporting reparative economic action that will make that dream more of a reality for more Americans and certainly for more Americans from racial minority backgrounds."

Richeson says that the scientists have a number of plans for expanding on their research. They intend to examine how people's perceptions of economic equity are influenced by characteristics of people's neighborhoods, including how racially and economically segregated they are and how disseminating information about the racial wealth gap affects support for new policies aimed at correcting race-based economic disparities.

Teen girls--but not boys--who prefer to go to bed later are more likely to gain weight, compared to same-age girls who go to bed earlier, suggests a study funded by the National Institutes of Health. The findings by researchers at Kaiser Permanente in Oakland, California, and other institutions appear in JAMA Pediatrics.

A total of 804 adolescents (418 girls and 386 boys) ages 11 to 16 took part in the study. The children responded to questionnaires on their sleep habits and wore an actigraph--a wrist device that tracks movement. Researchers measured their waist size and calculated their proportion of body fat using a technique called dual-energy x-ray absorptiometry. They also estimated the children's social jet lag--the difference between their weeknight and weekend bedtimes. Those who stayed up far later on weekends than weeknights were considered to have high social jet lag. The authors noted that previous studies had found that adults who preferred to stay up late and had high social jet lag were more likely to gain weight than those who went to be earlier and did not have social jet lag. The researchers undertook the current study to determine if the same associations would be seen in young people.

For girls, staying up later was associated with an average .58 cm increase in waist size and a .16 kg/m2 increase in body fat. Each hour of social jet lag was associated with a 1.19 cm larger waste size and a 0.45 kg/m2 increase in body fat. These associations were reduced--but still remained--after the researchers statistically adjusted for other factors known to influence weight, such as sleep duration, diet, physical activity and television viewing. Although the researchers found slight associations between these measures and waist size and body fat in boys, they were not statistically significant. The researchers concluded that improving sleep schedules may be helpful in preventing obesity in childhood and adolescence, especially in girls.

In a study published in mBio, a journal of the American Society for Microbiology, Jorge Benach and Rafal Tokarz, and their co-authors at Stony Brook University and Columbia University, reported on the prevalence of multiple agents capable of causing human disease that are present in three species of ticks in Long Island.

Tick-borne diseases have become a worldwide threat to public health. In the United States, cases more than doubled, from 22,000 in 2004 to more than 48,000 in 2016, according to the U.S. Centers for Disease Control. Tick-borne diseases range from subclinical to fatal infections with disproportionate incidence in children or the elderly. Moreover, some infections can also be transmitted by blood transfusions and cause severe disease in patients with underlying disorders. While public attention has focused on Lyme disease, in recent years, scientists have uncovered evidence that ticks can carry several different pathogens capable of several different tick-borne diseases, sometimes in a single tick.

In the new study, researchers collected ticks from multiple locations throughout Suffolk county in the central and eastern part of Long Island, where seven diseases caused by microbes transmitted by ticks are present. In total, they examined 1,633 individual ticks for 12 separate microbes. They found that more than half of the Ixodes (deer ticks) were infected with the Lyme disease agent, followed by infections with the agents of Babesiosis and Anaplasmosis. Importantly, nearly one-quarter of these ticks are infected with more than one agent, resulting in the possibility of simultaneous transmission from a single tick bite.

Notably, the lone star tick, a species originating from the southern U.S., has expanded its range, possibly fueled by climate change. This study documents that the invasive lone star tick is abundant in Long Island, and that it is a very aggressive tick that can transmit a bacterium that causes a disease known as Ehrlichiosis. The lone star tick has also been implicated in cases of a novel form of meat allergy, and the immature stages can cause an uncomfortable dermatitis.

"Polymicrobial infections represent an important aspect of tick-borne diseases that can complicate diagnosis and augment disease severity," says corresponding author Jorge Benach, PhD, Distinguished Professor at the Department of Microbiology and Immunology at the Renaissance School of Medicine at Stony Brook University. "Some of the polymicrobial infections can be treated with the same antibiotics, but others require different therapies, thus enlarging the number of drugs to treat these infections."

"In evaluating tick-borne infection, more than one organism needs to be considered," says senior author Rafal Tokarz, PhD, assistant professor of epidemiology in the Center for Infection and Immunity at the Columbia Mailman School of Public Health, and a graduate of the Department of Microbiology and Immunology at Stony Brook University. "This study emphasizes the need to focus on all tick-borne diseases, not just Lyme."

An international team of scientists has announced a breakthrough in its quest to measure the mass of the neutrino, one of the most abundant, yet elusive, elementary particles in our universe.

At the 2019 Topics in Astroparticle and Underground Physics conference in Toyama, Japan, leaders from the KATRIN experiment reported Sept. 13 that the estimated range for the rest mass of the neutrino is no larger than 1 electron volt, or eV. These inaugural results obtained earlier this year by the Karlsruhe Tritium Neutrino experiment -- or KATRIN -- cut the mass range for the neutrino by more than half by lowering the upper limit of the neutrino's mass from 2 eV to 1 eV. The lower limit for the neutrino mass, 0.02 eV, was set by previous experiments by other groups.

"Knowing the mass of the neutrino will allow scientists to answer fundamental questions in cosmology, astrophysics and particle physics, such as how the universe evolved or what physics exists beyond the Standard Model," said Hamish Robertson, a KATRIN scientist and professor emeritus of physics at the University of Washington. "These findings by the KATRIN collaboration reduce the previous mass range for the neutrino by a factor of two, place more stringent criteria on what the neutrino's mass actually is, and provide a path forward to measure its value definitively."

The KATRIN experiment is based at the Karlsruhe Institute of Technology in Germany and involves researchers at 20 research institutions around the globe. In addition to the University of Washington, KATRIN member institutions in the United States are:

The University of North Carolina at Chapel Hill, led by professor of physics and astronomy John Wilkerson, a former UW faculty member

The Massachusetts Institute of Technology, led by professor of physics Joseph Formaggio

The Lawrence Berkeley National Laboratory, led by Nuclear Science Division deputy director Alan Poon

Carnegie Mellon University, led by assistant professor of physics Diana Parno

Case Western Reserve University, led by associate professor of physics Benjamin Monreal

Under Robertson and Wilkerson, the University of Washington became one of KATRIN's founding member institutions in 2001. Wilkerson later moved to the University of North Carolina at Chapel Hill. Formaggio and Parno began their involvement with KATRIN as UW researchers and later moved to their current institutions. In addition to Robertson, other current UW scientists working on the KATRIN experiment are research professor of physics Peter Doe, research associate professor of physics Sanshiro Enomoto and Menglei Sun, a postdoctoral researcher in the UW Center for Experimental Nuclear Physics and Astrophysics.

Neutrinos are abundant. They are one of the most common fundamental particles in our universe, second only to photons. Yet neutrinos are also elusive. They are neutral particles with no charge and they interact with other matter only through the aptly named "weak interaction," which means that opportunities to detect neutrinos and measure their mass are both rare and difficult.

"If you filled the solar system with lead out to fifty times beyond the orbit of Pluto, about half of the neutrinos emitted by the sun would still leave the solar system without interacting with that lead," said Robertson.

Neutrinos are also mysterious particles that have already shaken up physics, cosmology and astrophysics. The Standard Model of particle physics had once predicted that neutrinos should have no mass. But by 2001, scientists had shown with two detectors, Super-Kamiokande and the Sudbury Neutrino Observatory, that they actually do have a nonzero mass -- a breakthrough recognized in 2015 with the Nobel Prize in Physics. Neutrinos have mass, but how much?

"Solving the mass of the neutrino would lead us into a brave new world of creating a new Standard Model," said Doe.

The KATRIN discovery stems from direct, high-precision measurements of how a rare type of electron-neutrino pair share energy. This approach is the same as neutrino mass experiments from the 1990s and early 2000s in Mainz, Germany, and Troitsk, Russia, both of which set the previous upper limit of the mass at 2 eV. The heart of the KATRIN experiment is the source that generates electron-neutrino pairs: gaseous tritium, a highly radioactive isotope of hydrogen. As the tritium nucleus undergoes radioactive decay, it emits a pair of particles: one electron and one neutrino, both sharing 18,560 eV of energy.

KATRIN scientists cannot directly measure the neutrinos, but they can measure electrons, and try to calculate neutrino properties based on electron properties.

Most of the electron-neutrino pairs emitted by the tritium share their energy load equally. But in rare cases, the electron takes nearly all the energy -- leaving only a tiny amount for the neutrino. Those rare pairs are what KATRIN scientists are after because -- thanks to E = mc2 -- scientists know that the miniscule amount of energy left for the neutrino must include its rest mass. If KATRIN can accurately measure the electron's energy, they can calculate the neutrino's energy and therefore its mass.

The tritium source generates about 25 billion electron-neutrino pairs each second, only a fraction of which are pairs where the electron takes nearly all the decay energy. The KATRIN facility in Karlsruhe uses a complex series of magnets to channel the electron away from the tritium source and toward an electrostatic spectrometer, which measures the energy of the electrons with high precision. An electric potential within the spectrometer creates an "energy gradient" that electrons must "climb" in order to pass through the spectrometer for detection. Adjusting the electric potential allows scientists to study the rare, high-energy electrons, which carry information concerning the neutrino mass.

U.S. institutions have made broad contributions to KATRIN, including providing the electron-detector system -- the "eye" of KATRIN -- which looks into the heart of the spectrometer, an instrument built at the UW. The University of North Carolina at Chapel Hill led the development of the detector's data acquisition system, the "brains" of KATRIN. MIT's contribution was the design and development of the simulation software used to model the response of KATRIN. The Lawrence Berkeley National Laboratory contributed to the creation of the physics analysis program and provided access to national computing facilities, and quick analysis was enabled by a suite of applications that originated at the UW. The Case Western Reserve University was responsible for the design of the electron gun, central to calibrating the KATRIN apparatus. Carnegie Mellon University contributed primarily to analysis, with special attention to background and to fitting, and assisted in analysis coordination for the experiment.

With tritium data acquisition now underway, U.S. institutions are focused on analyzing these data to further improve our understanding of neutrino mass. These efforts may also reveal the existence of sterile neutrinos, a possible candidate for the dark matter that, though accounting for 85% of the matter in the universe, remains undetected.

"KATRIN is not only a shining beacon of fundamental research and an outstandingly reliable high-tech instrument, but also a motor of international cooperation, which provides first-class training of young researchers," said KATRIN co-spokespersons Guido Drexlin of the Karlsruhe Institute of Technology and Christian Weinheimer of the University of Münster in a statement.

Now that KATRIN scientists have set a new upper limit for the mass of the neutrino, project scientists are working to narrow the range even further.

"Neutrinos are strange little particles," said Doe. "They're so ubiquitous, and there's so much we can learn once we determine this value."

The U.S. Department of Energy's Office of Nuclear Physics has funded the U.S. participation in the KATRIN experiment since 2007.

Irvine, Calif., Sept. 16, 2019 - Valley fever is endemic to hot and dry regions such as the southwestern United States and California's San Joaquin Valley, but scientists at the University of California, Irvine predict that climate change will cause the fungal infection's range to more than double in size this century, reaching previously unaffected areas across the western U.S.

In a study published online recently in the American Geophysical Union journal GeoHealth, interdisciplinary UCI researchers claim that in a high-warming scenario, the list of affected states will jump from 12 to 17, and the number of individual Valley fever cases will grow by 50 percent by the year 2100. The states projected to host newly endemic counties are Montana, Nebraska, North Dakota, South Dakota and Wyoming, and the disease is expected to become more widespread in Colorado, Idaho and Oklahoma.

"The range of Valley fever is going to increase substantially," said lead author Morgan Gorris, a former UCI Ph.D. student in Earth system science who was awarded her doctorate in August. "We made projections out to the end of the 21st century, and our model predicts that Valley fever will travel farther north throughout the western United States, especially in the rain shadow of the Rocky Mountains and throughout the Great Plains, and by that time, much of the western U.S. will be considered endemic."

The current Valley fever endemicity map used by the national Centers for Disease Control and Prevention is based on a skin-test study conducted on a San Diego naval base in the 1940s. Using this decades-old information as a starting point, Gorris collected health department data on Valley fever cases reported by hospitals in many Western states.

Then she and her team studied the climate conditions in places where Valley fever is most common. They concluded that counties with more than 10 cases per 100,000 people all had average annual temperatures above 10 degrees Celsius (50 degrees Fahrenheit) and rainfall below 600 millimeters (23.6 inches).

"Morgan made this model based on temperature and rainfall; it provides similar but not exactly the same projections of where the CDC says Valley fever is," said co-author James Randerson, Chancellor's Professor and Ralph J. and Carol M. Cicerone Chair in Earth System Science. "In fact, we think it may guide efforts to build a better contemporary map of where the disease poses a threat to public health."

Gorris said the study is really focused on predicting the expansion of Valley fever: "Both temperature and precipitation are expected to change considerably in the western U.S. in future decades, but it's the increasing temperatures in already dry states that allow the disease to spread."

At present, parts of California and the Southwest are particularly suited for nurturing the fungus, scientifically known as Coccidioides. A smattering of winter rain on dry ground enables fungal growth beneath the surface. When the soil dries, the elongated strands of fungus break apart into spores, some as small as 2 microns in diameter. If they're agitated by earth-moving equipment or the boots of workers, the particles can be lofted into the air and inhaled by people in the area.

Laborers in construction and agriculture, as well as prisoners paving roadways and fighting fires in remote locales, are particularly susceptible to breathing in the airborne spores. It's a burgeoning public health concern because the number of cases in California and other regions has been going up over time.

Once in the lungs, the fungus transforms from strand-like into spherules, tiny balls that grow and spread in pulmonary tissues. About 40 percent of those who inhale the spores become sick. Early symptoms of Valley fever are similar to those of the flu: cough, fever, chills and night sweats. For this reason, the disease is often misdiagnosed and can go untreated. In advanced cases, the fungus can be disseminated from the lungs to other parts of the body, potentially causing skin lesions that can result in limb loss.

In extreme cases, the disease can travel to the brain, leading to swelling and death. Roughly 5 percent of people with Valley fever will have a severe form of it, and 1 percent will die. Pregnant women, the elderly and individuals with HIV are considered most vulnerable to severe forms of Valley fever. Filipinos and those of African descent are also at heightened risk. The disease disproportionately affects people in low-income communities, Randerson said.

"By 2100, for a business-as-usual scenario in which we do not take serious action to limit climate change, we would predict a doubling of the area where this disease is present," he said. "It's a huge expansion and especially worrisome because Valley fever is going to impact previously untouched communities throughout the West."

BOSTON - A new study led by researchers at Massachusetts General Hospital for Children (MGHfC) and Harvard Medical School has found that adolescent sleep timing preferences and patterns should be considered risk factors for obesity and cardiometabolic health, and that the effects are greater in girls than in boys.

Poor quality and short duration of sleep are known to increase obesity and cardiometabolic risk among children. What's rarely been studied, however, is how sleep timing and teens' own preferences for when to sleep and engage in other activities can influence their risk of obesity and poor cardiometabolic health.

"Beyond quantity and quality, timing is a vital component of sleep because it determines if an individual's circadian clock - the internal sleep/wake schedule - is synchronized with the rhythms of their daily activities," says Elsie Taveras, MD, MPH, division chief, General Academic Pediatrics, MGHfC, and senior investigator of a new study published in JAMA Pediatrics. "This is particularly important to adolescents whose evening preferences and academic demands often result in irregular sleep schedules that may cause circadian misalignment. Our research found that 'night owls,' teenagers who prefer to go to bed late but have to get up early for school, had higher waist circumference and greater abdominal fat deposition (adiposity) than the 'morning larks,' those who prefer to go to bed early and get up early to begin their day."

The researchers emphasized the need for consistent sleep-wake patterns throughout the week, including on weekends, to reduce the risk of obesity and promote cardiometabolic health.

The research team studied 804 children who were part of Project Viva, a groundbreaking cohort study begun 20 years ago by researchers at the Harvard Pilgrim Health Care Institute that followed Boston-area mothers and children to characterize early-life factors that influence long-term health. Scientists examined chronotypes (evening versus morning preferences) and "social jet lag" (differences in sleep timing between school and free days) in children 12 to 17 years of age. Evening chronotypes and greater social jet lag were associated with higher adiposity.

"Large variability in sleep patterns across the week can disrupt normal physiology, resulting in obesity and cardiometabolic risk," explains lead author Elizabeth Cespedes Feliciano, ScD, ScM, formerly at the Harvard Chan School of Public Health and now research scientist in the Kaiser Permanente Northern California Division of Research.

"Our study supports the importance of biological clocks in influencing obesity risk." Stronger associations with adiposity were observed for girls versus boys. "While the reasons for that difference are not fully understood, they may include biological and sociocultural influences," says Feliciano.

Helping teenagers address the effects of chronotypes and social jet lag calls for family, clinical and community-based initiatives, according to the investigators. "Families should encourage consistency in their children's sleep schedules and their bed and wake times as well as improvements in their sleep hygiene by limiting electronic media and caffeine use in the evening," says Feliciano.

Schools can also play an important role by enacting polices that delay morning start times and by making it easier for students to devote time during the school day to academic or athletic activities that are spilling more and more into the late night, says Taveras. From a clinical standpoint, she adds, physicians should start to include chronotypes and social jet lag in their preventive counseling. "Physicians should be aware of the importance of encouraging adolescents to follow consistent sleep schedules on weekdays and weekends," she says. "Adolescent girls and 'owls' may especially benefit from keeping consistent sleep schedules."

Bottom Line: This study estimates 1 in 16 U.S. women had an unwanted first sexual intercourse experience that was physically forced or coerced. In an analysis of nationally representative survey data for 13,310 women, 6.5% of the respondents reported a forced first sexual intercourse encounter, which is equivalent to more than 3.3 million women between the ages of 18 and 44. The average age for women at the time of the forced encounter was 15 ½ compared with 17 ½ for those reporting a voluntary first sexual intercourse experience. The average age of the assailant at a first forced sexual intercourse was six years older (27 vs. 21) compared with the partner in a voluntary first sexual experience. Women with a forced first sexual intercourse experience were more likely to have an unwanted first pregnancy or abortion, as well as other gynecological and general health problems. Limitations of the study include its observational design so causal inferences are impossible and authors were unable to account for other potential influencing factors.

Authors: Laura Hawks, M.D., of  Cambridge Health Alliance and Harvard Medical School, Boston, and coauthors

(doi:10.1001/jamainternmed.2019.3500)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Scientists from the University of Cambridge have developed a platform that uses nanoparticles known as metal-organic frameworks to deliver a promising anti-cancer agent to cells.

Research led by Dr David Fairen-Jimenez, from the Cambridge Department of Chemical Engineering and Biotechnology, indicates metal-organic frameworks (MOFs) could present a viable platform for delivering a potent anti-cancer agent, known as siRNA, to cells.

Small interfering ribonucleic acid (siRNA), has the potential to inhibit overexpressed cancer-causing genes, and has become an increasing focus for scientists on the hunt for new cancer treatments.

Fairen-Jimenez's group used computational simulations to find a MOF with the perfect pore size to carry an siRNA molecule, and that would breakdown once inside a cell, releasing the siRNA to its target. Their results were published today in Cell Press journal, Chem.

Some cancers can occur when specific genes inside cells cause over-production of particular proteins. One way to tackle this is to block the gene expression pathway, limiting the production of these proteins.

SiRNA molecules can do just that - binding to specific gene messenger molecules and destroying them before they can tell the cell to produce a particular protein. This process is known as 'gene knockdown'. Scientists have begun to focus more on siRNAs as potential cancer therapies in the last decade, as they offer a versatile solution to disease treatment - all you need to know is the sequence of the gene you want to inhibit and you can make the corresponding siRNA that will break it down. Instead of designing, synthesising and testing new drugs - an incredibly costly and lengthy process - you can make a few simple changes to the siRNA molecule and treat an entirely different disease.

One of the problems with using siRNAs to treat disease is that the molecules are very unstable and are often broken down by the cell's natural defence mechanisms before they can reach their targets. SiRNA molecules can be modified to make them more stable, but this compromises their ability to knock down the target genes. It's also difficult to get the molecules into cells - they need to be transported by another vehicle acting as a delivery agent.

The Cambridge researchers have used a special nanoparticle to protect and deliver siRNA to cells, where they show its ability to inhibit a specific target gene.

Fairen-Jimenez leads research into advanced materials, with a particular focus on MOFs: self-assembling 3D compounds made of metallic and organic building blocks connected together.

There are thousands of different types of MOFs that researchers can make - there are currently more than 84,000 MOF structures in the Cambridge Structural Database with 1000 new structures published each month - and their properties can be tuned for specific purposes. By changing different components of the MOF structure, researchers can create MOFs with different pore sizes, stabilities and toxicities, enabling them to design structures that can carry molecules such as siRNAs into cells without harmful side effects.

"With traditional cancer therapy if you're designing new drugs to treat the system, these can have different behaviours, geometries, sizes, and so you'd need a MOF that is optimal for each of these individual drugs," says Fairen-Jimenez. "But for siRNA, once you develop one MOF that is useful, you can in principle use this for a range of different siRNA sequences, treating different diseases."

"People that have done this before have used MOFs that don't have a porosity that's big enough to encapsulate the siRNA, so a lot of it is likely just stuck on the outside," says Michelle Teplensky, former PhD student in Fairen-Jimenez's group, who carried out the research. "We used a MOF that could encapsulate the siRNA and when it's encapsulated you offer more protection. The MOF we chose is made of a zirconium based metal node and we've done a lot of studies that show zirconium is quite inert and it doesn't cause any toxicity issues."

Using a biodegradable MOF for siRNA delivery is important to avoid unwanted build-up of the structures once they've done their job. The MOF that Teplensky and team selected breaks down into harmless components that are easily recycled by the cell without harmful side effects. The large pore size also means the team can load a significant amount of siRNA into a single MOF molecule, keeping the dosage needed to knock down the genes very low.

"One of the benefits of using a MOF with such large pores is that we can get a much more localised, higher dose than other systems would require," says Teplensky. "SiRNA is very powerful, you don't need a huge amount of it to get good functionality. The dose needed is less than 5% of the porosity of the MOF."

A problem with using MOFs or other vehicles to carry small molecules into cells is that they are often stopped by the cells on the way to their target. This process is known as endosomal entrapment and is essentially a defence mechanism against unwanted components entering the cell. Fairen-Jimenez's team added extra components to their MOF to stop them being trapped on their way into the cell, and with this, could ensure the siRNA reached its target.

The team used their system to knock down a gene that produces fluorescent proteins in the cell, so they were able to use microscopy imaging methods to measure how the fluorescence emitted by the proteins compared between cells not treated with the MOF and those that were. The group made use of in-house expertise, collaborating with super-resolution microscopy specialists Professors Clemens Kaminski and Gabi Kaminski-Schierle, who also lead research in the Department of Chemical Engineering and Biotechnology.

Using the MOF platform, the team were consistently able to prevent gene expression by 27%, a level that shows promise for using the technique to knock down cancer genes.

Fairen-Jimenez believes they will be able to increase the efficacy of the system and the next steps will be to apply the platform to genes involved in causing so-called hard-to-treat cancers.

"One of the questions we get asked a lot is 'why do you want to use a metal-organic framework for healthcare?', because there are metals involved that might sound harmful to the body," says Fairen-Jimenez. "But we focus on difficult diseases such as hard-to-treat cancers for which there has been no improvement in treatment in the last 20 years. We need to have something that can offer a solution; just extra years of life will be very welcome."

The versatility of the system will enable the team to use the same adapted MOF to deliver different siRNA sequences and target different genes. Because of its large pore size, the MOF also has the potential to deliver multiple drugs at once, opening up the option of combination therapy.

Every living organism's cell has a complete copy of DNA, life's instruction book, which is condensed tightly in chromosomes. Every time the cell needs to perform a function, it activates genes that open or close different regions in the DNA. Like following an instruction manual with consecutive pages, it's easier to activate two genes that are closer together to complete a function.

Until now, we knew little how the genome of eukaryotic organisms (organisms with complex cells with a nucleus) organized groups of genes in accordance with their function, i.e. whether they were physically near or not. Previous studies have studied the link between gene clusters and the secondary metabolism, which are responsible to create penicillin and other toxins with antibiotic properties.

In a study published today in Nature Microbiology, researchers from the Centre of Genomic Regulation (CRG) in Barcelona, led by ICREA Professor Toni Gabaldón, now at the Institute for Research in Biomedicine (IRB Barcelona) and the Barcelona Supercomputing Center-Centro Nacional de Supercomputación (BSC-CNS), shed light on this sorting process in primary metabolism. They chose to study fungi because they have smaller genomes and are easier to sequence than other eukaryote species like plants or animals.

"If genes for a specific biological process are placed near each other in the chromosome, they can co-regulate each other in a more coordinated and effective manner," says Gabaldón.

The scientists developed an algorithm capable of identifying genes near each other in genomes of different species according to their evolutionary history, i.e. looking for whether they were conserved clusters in different species of fungi, independently of the function they had. They predicted more than 11000 families of grouped genes in the genome. Of the 300 genomes analysed, they found that a third were part of a conserved group.

"Natural selection means some genes are near each other for functional relevance. The way they're organized isn't random chance - they have been selected because it makes regulating genes easier. We've found that it's pretty common, and that it affects an important proportion of the genome," says Gabaldón. "The selective forces favour the conformations of genes that allow a smaller investment in energy and improved regulatory processes," he adds.

Previous studies of gene groups linked to secondary metabolism observed that they had a switch, a type of transcription factor, to turn them on and off. Other observations also found that these gene groups passed from one species to another in block, known as horizontal transfer, though no one knew why.

The CRG scientists have now provided evidence that horizontal transfer may be less common than previously thought, and their most recent findings don't represent what the genome does as a whole. They saw that a cluster made up of the same groups of genes appeared independently twice, in parallel distant lineages.

Surely, the groups of genes carry out a specific function. "When you need something at a precise moment, it's when you most need it to be co-regulated. A general function, which is active most of the time, doesn't need such precise regulation", says Marina Marcet-Houben, first author of the study.

"Now we have a list of functions to explore. Some might have a pharmaceutical or industrial use. The gene candidates we have found affect a lot of different species that until now hadn't been found. Many of them are interesting genes and it's likely they code a function with an applied potential," adds Gabaldón.

The study's findings were based on public databases. For this reason, the CRG has also publicised its results on primary genes. "We want to give this knowledge back to the scientific community thanks to the information and data we've gathered from the public domain".