Culture

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.

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".

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.

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.

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.

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."

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."

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.

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."

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."

A new mathematical model describes how highly concentrated antibody solutions separate into different phases, similar to an oil and water mixture. This separation can reduce the stability and shelf-life of some drugs that use monoclonal antibodies, including some used to treat autoimmune diseases and cancer. A team of scientists from Penn State and MedImmune, LLC (now AstraZeneca) investigated the thermodynamics and kinetics, the relationships between temperature, energy, and the rates of chemical reactions, of the phenomenon using an innovative method that allows for the rapid study of multiple samples at once. A paper describing their model appears July 22, 2019, in the journal Proceedings of the National Academy of Sciences.

Many drugs today are stored as solids and dissolved in IV bags for delivery to patients, but the pharmaceutical industry has been moving toward drugs that can be stored as liquids and given via a shot. Some of these drug solutions, like those used to treat autoimmune diseases and some cancers, contain high concentrations of monoclonal antibodies--proteins that attach to foreign substances in the body, like bacteria and viruses, flagging them for destruction by the patient's immune system.

"Highly concentrated protein solutions can separate into different phases, like a vinaigrette salad dressing separating into layers over time," said Bradley Rogers, graduate student in chemistry at Penn State and first author of the paper. "Phase separation is one of the pathways that makes these drugs unstable and unsuitable for use. The classical method to understand this process involves manipulating the temperature of one sample over time. We used a temperature gradient microfluidics platform to quickly look at many temperatures simultaneously."

An antibody-rich solution begins as a clear liquid at room temperature, but as the solution cools, cloudy droplets begin to form. Over time, the droplets settle to the bottom, with dilute liquid remaining on top, making the sample appear clear. The team used an innovative device that creates a range of temperatures across a temperature gradient and used a technique called dark-field imaging to measure how quickly this process occurs. Then the team calculated a variety of parameters to better understand the thermodynamics and kinetics of the system, including the temperatures at which phase transitions occur and the amount of energy it takes to go from one phase to the next--activation energies.

"We observed that the rate that a solution separates into two phases has a strange dependence on temperature," said Rogers. "This relationship is much more complicated for concentrated antibody solutions than it is for other systems. We spent a long time trying to make sense of the data, but we eventually developed a model that explains what we are seeing."

The model describes how antibody molecules stick together as the temperature decreases, forming droplets that grow as additional molecules join. This reversible process happens more and more quickly with decreasing temperature, because the solution gets increasingly saturated with free antibody molecules. Then, as the solution continues to cool, droplets stick to other droplets and settle to the bottom. At even colder temperatures, the solution forms a gel and cannot complete the separation, even over the course of a month.

"In a single experiment, we can visualize the homogenous clear solution, the cloudy solution as droplets begin to form, the phase-separated liquid, and the gel," said Paul Cremer, J. Lloyd Huck Chair in Natural Sciences at Penn State and senior author of the paper. "Previous research described these different states, and our model describes the mathematics and temperature-dependent kinetics behind what we believe is happening."

Next, the research team plans to investigate if their model can explain phase separation in other systems. They also plan to test whether parameters gathered from this type of experiment can predict stability and shelf-life of therapeutics.

"If these parameters can help us predict stability and shelf life, we may be able to select better drug candidates," said Rogers. "We may also be able to determine the ideal solution properties for a promising drug candidate to keep it stable."

In addition to Rogers and Cremer, the research team includes Kelvin Rembert, Matthew Poyton, Halil Okur, Amanda Kale, and Tinglu Yang at Penn State and Jifeng Zhang from AstraZeneca. The work was supported by MedImmune LLC (now AstraZeneca). Additional support was provided by the National Science Foundation.

INDIANAPOLIS - Pain is the most common physical symptom for which adults seek medical attention in the United States, while anxiety and depression are the most common mental health symptoms for which adults visit a doctor. Drugs, especially opioids, may not be the only or best therapy.

Highlighting another potential treatment option, a new study led by Regenstrief Institute research scientist Kurt Kroenke, M.D., a pioneer in the treatment of patient symptoms, has found that both online symptom self-management and online symptom self-management plus clinician telecare can be effective for individuals with all three symptoms, which frequently co-occur in this difficult to treat patient population.

"Pain, anxiety and depression can produce a vicious cycle in which the presence of one symptom, if untreated, may negatively affect the response to treatment of the other two symptoms," said Dr. Kroenke. "So treating not just pain but pain and mood symptoms simultaneously is quite important as is doing it how, when and where the patient is most receptive."

In a new paper published in the Journal of General Internal Medicine, Dr. Kroenke and colleagues report that online symptom self-management works to decrease pain, anxiety and depression symptoms. They also found that online symptom self-management works even better when coupled with clinician telecare. In previous studies, Dr. Kroenke and colleagues have found a benefit to adding telecare to usual care in the doctor's office. The researchers have now shown that the intermediate (and less costly) mechanism of online pain and mood self-management is effective and, for some, even more effective when coupled with live phone follow-up with a nurse.

"The magnitude of effect on pain, anxiety and depression we report is comparable to the effect of online and telecare interventions for chronic disorders like hypertension, diabetes and heart disease," said Dr. Kroenke. "The moderate improvement in symptoms we saw at a group level indicates that some individuals had great symptom improvement while others had little improvement. Our results strongly suggest that web-based self-management might be enough for some patients while others may require a combination of online self-management and phone consultations with a nurse manager in order to experience symptom reduction."

To test whether pain, anxiety and depression symptoms could be simultaneously addressed by patients in their homes or other location of their choice, Dr. Kroenke and colleagues conducted the CAMMPS (short for Comprehensive vs. Assisted Management of Mood and Pain Symptoms) trial. This randomized comparative effectiveness study builds upon Dr. Kroenke's previous work including the design of widely used depression and anxiety screening tools and the conduct of several studies demonstrating the effectiveness of telecare.

A total of 294 individuals with arm, leg, back, neck or widespread pain which persisted (for 10 or more years in more than half of CAMMPS participants) despite medication, who also had at least moderately severe depression and anxiety, were divided into two groups.

One group received a web-based self-management program comprised of nine modules (coping with pain; pain medications; communicating with providers; depression; anxiety; sleep; anger management; cognitive strategies; and problem-solving). The other group was given this program plus telecare by a nurse who made scheduled telephone calls as well as contacts prompted by patient responses to the online self-management program or e-mail requests.

A supplementary paper, published in the journal Telemedicine and Telecare, reports that CAMMPS participants in both arms of the study found it helpful and were satisfied -- with higher satisfaction in the group that received both online self-management and telecare. While those in the online self-management group indicated they wanted more human contact, participants in the group that received telecare from a nurse were divided - some wanted more contact, others desired less contact. This led the paper's authors, including first author Regenstrief Institute affiliated scientist Michael A. Bushey, M.D., of the IU School of Medicine and senior author Dr. Kroenke, to conclude that customizable solutions would best suit a range of patients.

"Automated Self-Management (ASM) vs. ASM-Enhanced Collaborative Care for Chronic Pain and Mood Symptoms: The CAMMPS Randomized Clinical Trial"
Journal of General Internal Medicine
Authors in addition to Dr. Kroenke are Fitsum Baye, M.S., and Spencer G. Lourens, PhD, of IU School of Medicine; Erica Evans; Sharon Weitlauf, R.N., Stephanie McCalley and Brian Porter, B.S., of VA Health Services Research and Development Center for Health Information and Communication, Roudebush VA Medical Center; and Regenstrief Institute and VA investigators Marianne S. Matthias, PhD, and Matthew J. Bair, M.D. Dr. Matthias is also on the faculty of the School of Liberal Arts at IUPUI and Dr. Bair is on the faculty of IU School of Medicine.

"Telecare management of pain and mood symptoms: Adherence, utility, and patient satisfaction"
Telemedicine and Telecare
Authors, in addition to Dr. Bushey and Dr. Kroenke, are Julia Weiner, a former Regenstrief Institute summer scholar, Brian Porter, Erica Evans and Sharon Weitlauf of the VA Medical Center; and Fitsum Baye and Spencer Lourens of the IU Richard M. Fairbanks School of Public Health at IUPUI.

The CAMMPS trial was supported by a Department of Veterans Affairs Health Services Research and Development Merit Review award to Dr. Kroenke (IIR 12-095).

COLUMBUS, Ohio - You may think you know what you like - how to spend your time or what profession to pursue. But a new study suggests that your pre-existing self-beliefs, as well as cultural stereotypes, may interfere with your memories and keep you from remembering what truly interests you.

However, researchers at The Ohio State University found that one particular mental technique could help us overcome the barriers that block us from finding our passions.

For example, a young girl could truly enjoy participating in a science project at a summer camp while it is happening. But when she thinks about the experience later, she may remember that she has heard that "science is not for girls" - and that stereotype may cloud her memory.

Instead of remembering the good time she had at the camp, she thinks she must not have enjoyed it. And the potential spark for science is extinguished.

"When we are developing our interests and looking back on our memories, I don't think we realize how biased we can be by our pre-existing beliefs," said study lead author Zachary Niese, who did the research as a doctoral student in psychology at Ohio State.

"People think they know themselves and know if they liked something or not, but often they can be misled by their own thoughts."

In a series of four studies described in a paper published online recently in the Journal of Experimental Psychology: General, Niese and his colleagues found consistent evidence that people can "forget" how much they enjoyed a particular activity because of what they believed going in.

But they also found a powerful tool to counteract that bias: visualizing the activities they do from a first-person perspective.

For example, the girl in the scenario above can later visualize herself being at the camp and picture exactly what she did in the science project, putting her back in touch with the joy that it brought her.

"We can use imagery as a tool to tap into our memories and more accurately identify what our actual experiences are instead of relying on our old beliefs," said study co-author Lisa Libby, associate professor of psychology at Ohio State.

"People sometimes have experiences that are inconsistent with what they think about themselves. We may think we don't like math, so if we enjoy a math class, that doesn't fit in with our view of ourselves, so we dismiss that positive experience. That's what using first-person visual imagery helps overcome."

Imagery perspective has this effect because it changes the frame of mind people use to process events. The first person perspective puts people in a frame of mind in which they pay attention to how the past event itself made them feel, Niese said.

In contrast, the third-person perspective puts people into a more abstract frame of mind in which they tend to rely more on their pre-existing beliefs. Further, imagery perspective is so tightly bound to people's frame of mind that it is even possible to change how people process events by merely showing them photographs taken from one visual perspective or the other, he said.

One of their experiments demonstrated exactly how this works. In this study, 253 undergraduate women began by taking a survey in which they reported their level of interest in science.

Several days later, they played a computer simulation game with the goal of creating a balanced ecosystem by manipulating the amount of grass and number of sheep and wolves to sustain the system. Some of the women played an interesting version of the game that gave them complete control. Others participated in a deliberately boring version that allowed them to simply run through predetermined settings rather than make any choices.

The researchers then had participants complete a task designed to influence their frame of mind in the moment. They showed all the women a series of images and told them to pay attention to each one and try to form an impression of it in their mind.

The images each showed an everyday action (such as wiping up a spill) that differed only in whether the photo was taken from the first-person or third-person perspective. (In other words, whether the person was watching herself clean the spill, or watching it from the perspective of another person.)

Each participant saw all photos in either the first-person or third-person perspective.

After viewing the photos, participants read instructions referring to the ecosystem simulation as a science task and then answered questions about how interesting they thought the task was.

The results showed the power of first-person imagery in influencing how the participants thought about the simulation.

Remember that all the women had reported how interested they were in science several days earlier. For women who viewed the third-person photos, it didn't matter if they played the boring or interesting version of the game. Their reported interest in the activity was very similar to how much interest they reported in science earlier.

If they believed they were interested in science going into the game, they reported that the game was interesting; if they believed they weren't interested in science going in, they reported that the game as not so interesting.

In other words, their pre-existing beliefs completely blinded them to how interesting the game actually was, Niese said.

But not so for the women who viewed the first-person perspective photos. They showed no bias from their pre-existing beliefs. Instead, they accurately reported more interest in the game if they played the interesting version than if they played the boring version.

This meant that women who engaged in an interesting science task were able to accurately recall how interesting it was even when they thought they were the kind of person who wasn't interested in science.

In other words, first-person imagery helped women get in touch with how interesting a science activity actually was rather than be biased by their pre-existing beliefs, Niese said.

The benefits of first-person imagery didn't stop there.

At the end of the study, the researchers offered participants three future "opportunities to do more things like the science task you completed today."

Results showed that the women who played the interesting version of the simulation and who viewed the first-person photos were more likely than others to show greater interest in future science activities.

Many studies show that people's memories are biased by their pre-existing beliefs and cultural stereotypes, Niese said. This research suggests there is a way to overcome those biases, by using first-person imagery to change people's frame of mind while recalling their experiences.

"Part of what is so interesting and surprising about our study is that a simple manipulation - just the way people think about a past event - is changing their conclusions about what they're doing and whether they're interested or not," he said.

"It's something people could do on their own if they wanted to and gain these benefits in situations where cultural stereotypes or pre-existing beliefs might be likely to bias their judgment or cloud their memories."

PITTSBURGH, July 22, 2019 - In the time it takes you to read this sentence, every cell in your body suffers some form of DNA damage. Without vigilant repair, cancer would run rampant, and now scientists at the University of Pittsburgh have gotten a glimpse of how one protein in particular keeps DNA damage in check.

According to a study published today in Nature Structural and Molecular Biology, a protein called UV-DDB--which stands for ultraviolet-damaged DNA-binding--is useful beyond safeguarding against the sun. This new evidence points to UV-DDB being a scout for general DNA damage and an overseer of the molecular repair crew that fixes it.

"If you're going to fix a pothole, you have to find it first. That's what UV-DDB does. It identifies DNA damage so that another crew can come in and patch and seal it," said study senior author Bennett Van Houten, Ph.D., professor of pharmacology and chemical biology at the Pitt School of Medicine and UPMC Hillman Cancer Center.

Surveying 3 billion base pairs, packed into a nucleus just a few microns wide, is a tall order, Van Houten said. Not only is it a lot of material to search through, but it's wound up so tightly that many molecules can't access it.

Keeping with the pothole analogy, one possible search strategy is to walk along the road, waiting to step in a hole. Another option is to fly around in a helicopter, but since molecules can't "see," this approach would require frequently landing to look for rough patches. To get around these shortcomings, UV-DDB combines both search strategies.

"UV-DDB is like a helicopter that can land and then roll for a couple blocks," Van Houten said. "It also has the ability to find damage buried in chromosomes and help DNA repair molecules go places they otherwise couldn't, the way a helicopter can navigate really hilly areas."

When UV-DDB finds damage, it acts like a foreman to help the DNA repair crew get in, fix the faulty bases and detach quickly.

For the first time, Van Houten's team witnessed this molecular tango along a "tightrope" of DNA slung between two silica beads, using real-time, single-molecule imaging.

"The amazing thing is finding those single molecules in 3D space," said study coauthor Simon Watkins, Ph.D., director of Pitt's Center for Biological Imaging. "[Van Houten]'s team has developed an assay that allows them to track the repair enzymes in 3D on the DNA ropes as they repair damage."

To show that UV-DDB performs the same functions in living cells, Van Houten recruited the help of Marcel Bruchez, Ph.D., of Carnegie Mellon University, and Patricia Opresko, Ph.D., of Pitt. Together they inflicted oxidative damage to the chromosomes' protective endcaps--called telomeres. As in the DNA tightrope experiment, UV-DDB rushed to the scene, and when it wasn't available, cells were more sensitive to oxidative stress.

These results help to explain why children born without functional UV-DDB--a rare disease known as xeroderma pigmentosum--are virtually guaranteed to develop skin cancer from sun exposure, Van Houten said. On the other end of the spectrum, cancer patients with higher levels of UV-DDB respond better to therapy.

"It's clear this protein is involved in a very fundamental problem," Van Houten said. "We could not have evolved out of the slime if we didn't have good DNA repair."

Sepsis is a life-threatening condition that occurs when the body's immune response to infection spirals out of control. Bacteria in the bloodstream trigger immune cells to release powerful molecules called cytokines to quickly activate the body's defenses. Sometimes the response goes overboard, creating a so-called "cytokine storm" that leaves people feverish or chilled, disoriented and in pain. In severe cases, it can lead to multi-organ failure and death.

Now, researchers at Washington University School of Medicine in St. Louis have found a set of genes that help cells survive exposure to cytokines. The genes are involved in disposing of cellular waste, a process known as autophagy. Mice that lack key autophagy genes are more likely to die from sepsis, the study shows. The findings raise the possibility that enhancing autophagy could potentially lead to treatments for the deadly condition.

"When we recognize signs of sepsis in patients, we prescribe antibiotics and fluids, but we lack therapies to protect patients from the direct effects of the cytokine storm," said first author Anthony Orvedahl, MD, PhD, an instructor in pediatric infectious diseases. "Our research indicates that if we could modulate autophagy levels in cells, we might be able to promote cell survival and resistance to the cytokine storm, which may ultimately help people survive sepsis."

The study is published online the week of July 22 in Proceedings of the National Academy of Sciences.

Sepsis is a medical emergency and even with prompt medical care, about 15 percent of people do not survive, while many survivors experience longstanding complications. Orvedahl - along with colleagues including senior author Herbert "Skip" Virgin, IV, MD, PhD, now at Vir Biotechnology, and co-author Gary A. Silverman, MD, PhD, the Harriet B. Spoehrer Professor and head of the Department of Pediatrics - set out to find what protects cells from dying during a cytokine storm.

The researchers looked at the effects of interferon gamma, a cytokine that activates immune cells' ability to kill bacteria but can also trigger cell death. By systematically inactivating one gene at a time from immune cells in a dish before treating them with interferon gamma, the researchers discovered that cells need a full complement of autophagy genes to survive exposure to the potent cytokine. Further experiments revealed that a second cytokine, called tumor necrosis factor, was also critical for the accelerated cell death in this system.

"Autophagy is like cleaning the house, getting rid of all the junk inside the cell," Orvedahl said. "If unwanted things start to accumulate via a defect in this recycling system, it's like a tinderbox waiting for a spark. We don't yet know the exact material involved, but we think something builds up and makes cells more vulnerable to dying when they encounter these inflammatory cytokines."

The importance of autophagy on cell survival suggests that the process may also be crucial for the survival of animals - and people - in the midst of a cytokine storm. To find out, the researchers studied four strains of genetically modified mice that lacked one of four autophagy genes in their immune cells, as well as mice with intact autophagy genes. They injected mice with tumor necrosis factor, which is thought to drive the cytokine storm in people. The mice whose autophagy systems were crippled by the absence of important autophagy genes got sick faster and were more likely to die.

Chemical compounds that enhance or block autophagy are already being studied by researchers focused on cancer, cardiovascular disease and other conditions. Therapies that suppress autophagy may increase the risk of sepsis, Orvedahl said. Further, he cautioned that more research is needed before doctors can evaluate whether boosting autophagy is a viable strategy for treating sepsis.

"We can't say for sure that autophagy activation would be protective," Orvedahl said. "We just showed that if mice lack autophagy, they are sicker and more likely to die. But we think that a better understanding of these processes could lead to attractive targets for developing more effective ways to treat sepsis."