Earth

Air quality in the US may be linked with increased mortality and reduced life expectancy according to research from Imperial College London and the Center for Air, Climate and Energy Solutions at Carnegie Mellon University.

The study, published in the journal PLOS Medicine, analysed concentrations of fine particles in the air, called PM2.5, across all counties in the contiguous USA (excluding Alaska and Hawaii) between 1999 and 2015.

These particles are mainly emitted from automobiles, power plants and industry, and known to be hazardous to health. The tiny particles, around 30 times smaller than the width of a human hair, can be inhaled deep into the lungs, and have been associated with increased risk of a range of conditions including heart attack and various forms of lung disease.

The amount of this fine particle pollution in the US has declined since 1999. The current US annual PM2.5 standard is set at 12 microgram per cubic meter of air (ug/m3). The highest concentration of PM2.5 during the study period was 22.1ug/m3, in 1999, Fresno County, California.

In 2015 the highest concentration was in Tulare County, California (13.2ug/m3), with the lowest amount recorded in Apache County, Arizona (2.8ug/m3).

However, the new research shows that at levels between 2.8ug/m3 and 13.2ug/m3 , which is mostly below the current standard, air pollution was associated with an estimated 15,612 deaths in females, and 14,757 deaths in men. The deaths were from cardiorespiratory conditions, which refers to heart and lung disorders (such as heart attack and various lung diseases including asthma).

These deaths would lower national life expectancy by 0.15 years for women, and 0.13 years for men. The life expectancy loss due to PM2.5 was largest around Los Angeles and in some southern states, such as Arkansas, Oklahoma and Alabama.

At any PM2.5 concentration, life expectancy loss was, on average, larger in counties with lower income than in wealthier counties.

Professor Majid Ezzati, lead author of the research from Imperial's School of Public Health said: "We've known for some time that these particles can be deadly. This study suggests even at seemingly low concentrations - mostly below current limits - they still cause tens of thousands of deaths. Lowering the PM2.5 standard below the current level is likely to improve the health of the US nation, and reduce health inequality."

He added: "US PM2.5 concentrations are generally lower than those in many Europe cities -- which suggests there may also be substantial number of deaths in Europe associated with air pollution."

In the study, the research team - all part of the Center for Air, Climate and Energy Solutions - assessed data from over 750 air quality monitoring stations from across the US, and combined this with other sources of air pollution data, such as satellite images.

The team then combined this with death counts from the National Center for Health Statistics. There were a total of 41.9 million deaths between 1999 to 2015 in the USA, with 18.4 million of these deaths from cardiorespiratory diseases, for which there is strong evidence of an association with air pollution.

Using a series of statistical models (the computer code for which is publicly available), the team combined all this data and estimated the increase in death rate per 1ug/m3 of PM2.5, and hence the additional deaths above the lowest recorded PM2.5 concentration of 2.8ug/m3.

The team factored in various factors that could affect the results, such as age, education, poverty and smoking rates. They could only indirectly account for other factors such as healthcare access and diet, that affect deaths in different counties.

Researchers at the Center for Theoretical Physics of Complex Systems (PCS), within the Institute for Basic Science (IBS, South Korea), and colleagues have reported a novel phenomenon, called Valley Acoustoelectric Effect, which takes place in 2D materials, similar to graphene. This research is published in Physical Review Letters and brings new insights to the study of valleytronics.

In acoustoelectronics, surface acoustic waves (SAWs) are employed to generate electric currents. In this study, the team of theoretical physicists modelled the propagation of SAWs in emerging 2D materials, such as single-layer molybdenum disulfide (MoS2). SAWs drag MoS2 electrons (and holes), creating an electric current with conventional and unconventional components. The latter consists of two contributions: a warping-based current and a Hall current. The first is direction-dependent, is related to the so-called valleys - electrons' local energy minima - and resembles one of the mechanisms that explains photovoltaic effects of 2D materials exposed to light. The second is due to a specific effect (Berry phase) that affects the velocity of these electrons travelling as a group and resulting in intriguing phenomena, such as anomalous and quantum Hall effects.

The team analyzed the properties of the acoustoelectric current, suggesting a way to run and measure the conventional, warping, and Hall currents independently. This allows the simultaneous use of both optical and acoustic techniques to control the propagation of charge carriers in novel 2D materials, creating new logical devices.

The researchers are interested in controlling the physical properties of these ultra-thin systems, in particular those electrons that are free to move in two dimensions, but tightly confined in the third. By curbing the parameters of the electrons, in particular their momentum, spin, and valley, it will be possible to explore technologies beyond silicon electronics. For example, MoS2 has two district valleys, which could be potentially used in the future for bit storage and processing, making it an ideal material to delve into valleytronics.

"Our theory opens a way to manipulate valley transport by acoustic methods, expanding the applicability of valleytronic effects on acoustoelectronic devices," explains Ivan Savenko, leader of the Light-Matter Interaction in Nanostructures Team at PCS.

Living cells contain tens of thousands of genes that serve as instruction guides for making the proteins cells need to survive. These genes function in highly cooperative and interdependent ways, and scientists have long known that a change in the expression of one gene can affect how other genes function. These interdependencies can impact a cell's ability to survive.

In a new study, scientists at the University of Maryland and the National Cancer Institute identified 12 distinct types of gene-pair interactions in which varying levels of expression in the two genes correlated with cancer patient survival. The results, which were published in the journal Cell Reports on July 23, 2019, suggest that genes involved in such paired interactions could provide new targets for cancer therapy.

"Relying on specific cancer vulnerabilities, such as a particular mutated gene's functional relationship with other genes, is potentially an effective approach to treating cancer," said the study's senior author Sridhar Hannenhalli, a professor in the Department of Cell Biology and Molecular Genetics at UMD.

This approach is already being explored in one type of gene-pair relationship called synthetic lethality, in which inactivation of both genes is lethal to a cell, but inactivation of one gene by itself is not. In cancer cells where mutations inactivate one gene, drugs inhibiting the partner gene would be lethal to cancer cells but have minimal or no effect on healthy tissue in which the first gene is expressed normally.

This new work revealed a broad spectrum of important gene-pair relationships in addition to synthetic lethality. Many of these new relationships were more abundant in the researchers' data than synthetic lethality, which means they may offer many more potential targets for cancer therapy.

"Our work expands the potential scope of strategies, thus far restricted to synthetic lethality, by generalizing the concept of exploiting genetic interactions to include many other yet unexplored types of gene-pair relationships," said Hannenhalli, who has a joint appointment in the University of Maryland Institute for Advanced Computer Studies (UMIACS). "We believe this lays the foundation for using a computational method for identifying and studying additional types of genetic interactions in the future."

The paper presents a new, data-driven method for identifying gene interactions that could impact cancer patient outcomes, which Hannenhalli developed in collaboration with former UMD graduate student Assaf Magen (Ph.D. '19, computer science), the first author of the study, and Eytan Ruppin, currently at the National Cancer Institute and the former director of the Center for Bioinformatics and Computational Biology at UMD.

Using data from 5,288 tumors representing 18 different cancer types, the team defined six interactions in which each gene in a pair could be expressed at a low, medium or high level. They then considered that each of those combinations could be associated with a "positive" or "negative" outcome for patient survival. That brought the total number of potential gene-pair relationship types to 12.

Using a novel computational strategy, the researchers assessed all possible combinations of genes in their dataset. Out of 163 million potential gene pairs, the researchers identified nearly 72,000 gene-pair interactions associated with a positive or negative patient survival. Of the genes involved in these interactions, a significant proportion are known to be involved in cell division and proliferation, which have clear links to cancer.

According to Hannenhalli, identifying gene-pair relationships can help scientists understand why mutations in certain genes lead to cancer in one tissue but not another, because their interacting partners might be expressed differently in different types of tissue. Similarly, gene-pair relationships could explain why certain drugs are effective for one patient but not another. The relationships also might help researchers identify subtypes of certain cancers, such as breast cancer, which may help with prognosis and therapy.

Using their findings on gene-pair interactions, the researchers were able to better predict patient outcomes in their data on tumor gene expression, compared with conventional methods that use expression of individual genes alone.

Hannenhalli stressed that there is still much work to be done to identify which gene pairs actually have a direct impact on cancer patient survival. The next step, he said, is to collaborate with cancer biologists or clinicians to begin experimenting with therapies targeted at some of the gene pairs identified in this study.

Illumination consumes more than 20 percent of electricity. Thus, finding an efficient, stable, single-phase warm white-light material is very important. Lead hybrid perovskites have drawn interest for excellent photoelectric performance and simple synthesis. Lead perovskites with white-light emission have been studied, but the photoluminescence quantum efficiencies (PLQEs) are low. However, the large-scale application of lead perovskites is hindered by toxicity and instability. Therefore, the substitution of Pb with less toxic or non-toxic elements and the replacement of organic cations with relatively stable inorganic cations are conceived.

Very recently, Keli Han's group in State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Science reports a series of bulk lead-free double perovskites: Cs2AgBi1-xInxCl6 (0 The Cs2AgBi0.125In0.875Cl6 nanocrystals and microcrystals are synthesized. They reveal that the PLQE decreases with the size decreasing, due to the enhancement of PL quenching effect caused by the increase of permanent defects. Furthermore, the Cs2AgBi0.125In0.875Cl6 bulk crystal possesses excellent stability. Therefore, it's promising as a new highly efficient warm white-light emitting material in applications of LEDs.

A gamelike intervention developed by school psychology researchers in UT's College of Education, Health, and Human Sciences may help reduce hallway disruptions among elementary school children.

The intervention rewards classes of students for quickly transitioning from one room or activity to another. When implemented with three classes of students from grades one through six at a summer school program, disruptions during class transitions were reduced by up to 74 percent.

"Hallways are daunting spaces for teachers," said Christopher Skinner, professor of school psychology and co-author of the study, which was published in the Journal of Positive Behavior Interventions. "Being quick in transitions helps significantly reduce inappropriate behavior."

In the study, which was led by Associate Professor Merilee McCurdy, students were timed for one class transition a day (for example, from the gym to an academic classroom). A goal time was selected before the class and explained to the children. If the class met the goal time, a letter was rewarded at the end of the transition and placed on a Velcro board in the classroom. By the end of the week, classes had the chance to earn five letters.

"The letters were P-A-R-T-Y, in that order," Skinner said. "After successfully meeting the transition time for a fifth day, classes were rewarded with a 20-minute party with snacks and games."

If there were any disruptions by students--either stepping out of line, yelling, hitting, or running in the hallway--during a transition, classes were penalized by having five seconds added to their overall time.

"One student who misbehaves could risk the reward for the rest of the group," Skinner said.

On top of a notable reduction in disruptive behavior, class transitions were also much quicker. Relative to baseline transition times taken before the game was introduced, each class showed a decrease ranging from 91 to 172 seconds.

Similar games have been introduced by Skinner and colleagues in elementary school settings to boost math scores and help children who display emotional and behavioral disorders to improve social skills.

The reward in such interventions must meet at least two criteria to reap the desired result for teachers.

"It must be a bonus rather than an expected part of the class day," Skinner said. "And it must not involve a punishment. If the reward is a game of dodgeball, there are going to be children who don't want to play."

In other words, if the students dislike the reward, they may not try as hard in the class activity.

Other than class parties, Skinner's reward suggestions include additional recess or computer time or listening to music.

Since each classroom is unique, there's another way for teachers to identify the best rewards for their students.

"A suggestion box, or a simple class poll, can go a long way," Skinner said.

After a cancer patient receiving an immunotherapy developed encephalitis and died 18 months into treatment, researchers at Vanderbilt-Ingram Cancer Center (VICC) investigated why the complication occurred, performing a molecular analysis of the disease's pathology and mining data to determine the incidence of similar occurrences.

The molecular analysis revealed the presence of T cells known to react to Epstein-Barr virus in the affected tissue of the Vanderbilt patient. In addition, the investigators noted one very highly prevalent but uncharacterized T cell population that appeared similar to Epstein-Barr virus-specific T cells. They also conducted a data review, which identified 22 cases of meningoencephalitis among 2,501 patients treated with immune checkpoint inhibitors at four large academic medical centers, but it is not known whether the commonly occurring virus was a factor with those cases.

The results, published July 22 in Nature Medicine, are the latest findings by VICC researchers chronicling rare but serious toxicities that may occur with immune checkpoint inhibitors, the most widely prescribed class of immunotherapies. The researchers have previously identified myocarditis, pneumonitis, hepatitis, colitis and vasculitis as possible complications. Checkpoint inhibitors unleash the immune system to attack cancer, but they may also spur an attack on organs, resulting in inflammation that can, in most cases, be effectively treated with steroids.

"By no means are these sorts of reports meant to scare the public," said the study's senior author, Justin Balko, PharmD, PhD, assistant professor of Medicine. "These are incredibly rare, but they are significant enough because these drugs are being used much more frequently in an increasing number of cancer types. The more patients we use them in, the more that fraction as an absolute number of patients affected becomes larger."

Researchers are trying to understand what triggers these adverse reactions to immune checkpoint inhibitors and are looking for biomarkers that may indicate which patients are most susceptible.

"It remains a total mystery at this point," said Douglas Johnson, MD, MSCI, assistant professor of Medicine, the lead author of the study.

The molecular analysis of tissue from the Vanderbilt patient identified Epstein-Barr-virus-specific T cell receptors and Epstein-Barr-positive lymphocytes. It is believed to be the first published report of a molecular analysis of a neurotoxicity due to checkpoint inhibitors, the first evidence linking a viral infection to an adverse event from the class of drugs and the first detailed identification and phenotyping of culprit immune cell populations.

"While this encephalitis case seemed to be associated with some sort of viral process, it is still very unclear how often this happens," Johnson said. "I think there is more research that needs to be done to tease out the role of viral infection as it relates to immune therapy side effects."

The molecular analysis revealed something unexpected with the patient's immune response: a higher frequency of CD4 positive T cells with a 'killer' profile, which are usually thought to play more of a helper role in immune responses, occurred than CD8 positive T cells, which are typically the 'killer' cells.

"The field is starting to recognize more that these CD4 positive T cells can really play a major role, not just in toxicity, but also in anti-tumor responses," Balko said.

Johnson agreed that role of the CD4 positive T cells with immune-related adverse events merits further study.

"We tend to think of the CD8 positive T cells as being more important for an immune therapy side effect," Johnson said. "Showing a CD4 positive link is interesting and important."

A research team lead by MIMS/SciLifeLab research group leader Jonas Barandun, Umeå University, Sweden, uses cryo-electron microscopy to provide near atomic details of the smallest known eukaryotic cytoplasmic protein synthesis machine, the microsporidian ribosome.

150 years ago, the European silk industry was threatened by an unknown epidemic killing the silkworms. At that time, Louis Pasteur was able to identify the source of infection and made important suggestions for treatment. The silk production in Europe survived. Today, a microsporidian parasite is known as the cause of this epidemic and silk worm diseases still cause more than 100 million USD losses to the Chinese silk industry every year.

Microsporidiosis is not restricted to silk worms. The diverse phylum of the microsporidia contains thousands of different species with parasites for essentially every animal. At least 14 of them can infect humans. Particularly challenged by microsporidia are not only aquacultures, sericultures and honey bee populations in which infections can wipe out entire hives, but also immunocompromised patients. Microsporidia are a risk for the environment, agriculture and human health and the US National Institutes of Health (NIH) recently added the parasitic fungi to the list of emerging pathogens of high priority. Even if microsporidia infections are among the most common parasitic diseases in all animals, relatively little is known about their fascinating molecular life which is shaped by an accelerated evolutionary rate and extreme genome compaction.

Together with researchers from The Rockefeller University and Connecticut Agricultural Experiment Station, Jonas Barandun, new group leader at The Laboratory for Molecular Infection Medicine Sweden (MIMS), publishes the cryo-electron microscopy structure of the microsporidian ribosome which visualizes the effect of extreme genome compaction on an essential molecular machine (Nature Microbiology, 22 July 2019).

The smallest eukaryotic genome

Microsporidian parasites can survive as spores in soil, water and air where they arrest in a dormant state. Once ingested by a host, they use a unique, ultra-fast infection mechanism to inject the entire content of the spore into the host cell. Once inside of a cell, microsporidia steal small molecules, such as ATP, from their host organism. This parasitic nature allowed them to lose many important genes to produce these small molecules. This compaction resulted in the smallest genome ever described in eukaryotes - even smaller than some bacterial genomes - containing approximately 2000 highly compacted genes.

"Microsporidia are the minimalists among the parasitic eukaryotes, reducing their genome to a minimum which is needed for survival and replication. This makes them ideal model organisms to study minimally required components of a molecular process" commented Jonas Barandun.

Unexpected findings with the help of cryo-electron microscopy

The first challenging step was to obtain sufficient cellular amounts to extract ribosomes. To overcome this challenge, Jonas Barandun teamed up with a microsporidia specialist, Charles Vossbrinck, from the Connecticut Agricultural Experiment Station, who grew the microsporidium Vairimorpha necatrix in larvae of the corn earworm Helicoverpa zea, a pest that can cause big damage to cotton and corn crops. After extraction of spores from the host organism, ribosomes were isolated from them and cryo-EM and mass-spectrometry studies were performed in the laboratory of Sebastian Klinge, a ribosome specialist at Rockefeller University in New York, USA, together with Mirjam Hunziker. This allowed the team to provide a near-atomic model of the smallest known eukaryotic cytoplasmic ribosome.

In the studied organism, Vairimorpha nectatrix, the ribosomal RNA is approximately 30% shorter than the rRNA in yeast and even 15% shorter than the bacterial rRNA in E. coli.

"While it was known that the microsporidian rRNA is significantly smaller than the related yeast rRNA, it was unclear if this compacted rRNA still was able to bind all the eukaryotic ribosomal proteins. Surprisingly, despite the loss of some of their RNA binding sites, almost all ribosomal proteins were still present in the structure, some of them exclusively bound by other ribosomal proteins and not in contact with RNA anymore" explains Jonas.

Compared to the closest related ribosome structure from fungi, microsporidian ribosomes have lost only two ribosomal proteins. In one region of the ribosome, where several RNA elements have been removed, a previously unknown microsporidia specific protein compensates for the extensive loss of RNA and serves as a placeholder.

During their evolution to organisms with highly compacted genomes, microsporidia have removed essentially all eukaryotic expansion segments - insertions present in the eukaryotic ribosomal RNA. The findings represent a reversion of the evolutionary expansion found in eukaryotic ribosomes. In eukaryotic ribosomes, expansion segments interact extensively with ribosomal proteins and a loss of these elements could also coincide with loss of the proteins that are bound to them.

"The most surprising finding was that the characterized ribosome appeared to be functionally inactivated by two microsporidian dormancy factors (MDF1, MDF2) and we can now assign a potential role to these two proteins of unknown function", says Jonas.

Ribosomes were isolated from microsporidian spores, the extracellular dormant spore stage of the organism. As the parasite depends heavily on the resources of its host, an efficient shutdown mechanism for cellular processes could be advantageous to preserve energy during the spore stage. One of these two identified factors exists in all eukaryotic organisms, even in humans, but its role remained elusive. Future work will be required to confirm a similar role of this protein in other eukaryotic organisms.

Our eyes -- the windows to the soul -- need constant care, and as we age, they sometimes also need significant repair.

The panes of these windows -- the corneas -- are transparent tissues that have been the focus of some of the oldest and most common transplantation surgeries. Now thanks to researchers in Kyoto, some such transplants may become even safer.

The team, led by Kyoto University physicists and Kyoto Prefectural University of Medicine (KPUM) ophthalmologists, has developed a 'quantitative biomarker' that makes it possible to assess the quality of corneal cells -- and even predict their long-term efficacy -- through simple observation. A report on their findings appeared recently in Nature Biomedical Engineering.

"Cornea transplantations become necessary when 'corneal endothelial cells' decrease in number, resulting in haziness," explains project leader Motomu Tanaka.

Endothelia don't multiply well in the human body, which is why there has been a need to rely on the transplantation of donor corneas for treatment. Fortunately, in 2009 a team of ophthalmologists at KPUM succeeded in developing a method to culture the cells in a dish.

"These new cells could then be then transplanted into the eyes of patients and restore their corneas to health," says KPUM's Morio Ueno.

This method has shown significant promise in clinical trials, but two major obstacles to wider application remain: quality control of cells before injection and confirmation of long-term functionality.

Typically, cell quality is assessed through protein expression patterns via 'flow cytometry'. However, a single test requires almost 100,000 cells and relies heavily on the observations and experience of senior professionals.

"Cells in a tissue are constantly interacting with each other to maintain a steady state, called homeostasis," explains first author Akihisa Yamamoto, adding that the concept of 'colloid physics' -- a method for measuring interactions of micro- and nanoparticles -- was employed to assess the cornea cells.

"Calculating the interactions between all cells in the cornea allowed us to find the 'spring constant', correlating with collective cell order."

Assessment is relatively simple. Researchers only need to extract the 'rims' of the cells, either from a microscopic image of the cells in a culture dish or from ophthalmological inspection images of the patients' eyes. Both the quality of the cells and their long-term efficacy can be determined with just one equation.

The procedure has potential applications in preemptive medicine, enabling clinicians and doctors to intervene before more severe symptoms appear.

"Our results are thanks to the united effort of physicists and doctors engaged in regenerative medicine," concludes Tanaka. "We foresee that our 'quantitative biomarker', and the concept behind it, will be applied to other epithelial cell cultures and tissues in the future."

DURHAM, N.C. - Engaging disenfranchised men who have sex with men (MSM) living with HIV in the U.S. is possible, but the best way to help them achieve and maintain viral suppression is not yet known, according to findings from HPTN 078 being reported today at the 10th IAS Conference on HIV Science (IAS 2019) in Mexico City. Although almost all participants were retained in the study, only half were virally suppressed at the end of one year.

HPTN 078 was designed to compare the effectiveness of a combined HIV prevention strategy, including a peer-to-peer referral method to recruit MSM living with unsuppressed HIV and an intervention to help them achieve and maintain viral suppression, to the standard of care. Specifically, researchers used direct deep-chain, respondent-driven sampling (DC-RDS), augmented with direct recruitment, to identify gay, bisexual and other MSM with unsuppressed HIV.

In the U.S., the HIV epidemic is concentrated among gay and bisexual men and transgender people, particularly those who are black or Latinx. HPTN 078 enrolled study volunteers in four U.S. cities with high HIV burdens--Atlanta; Baltimore; Birmingham, Alabama and Boston. Overall, 1,305 individuals (95 percent identified as male, 69 percent as black and 12 percent as Latinx) were screened, among whom 902 (69 percent) were living with HIV and 154 (12 percent) were virally unsuppressed. Of those with unsuppressed HIV, 144 (94 percent) were enrolled in the study and assigned to either the intervention or the standard of care. In the study cohort, 97 percent identified as male and 2 percent as transgender female; 84 percent were black, and 7 percent were Latinx. Two-thirds were unemployed, and 64 percent reported an annual income of less than $20,000. Most (86 percent) reported having previous experience with antiretroviral therapy (ART) to treat HIV.

Study participants randomly assigned to the case management intervention worked with a case manager who helped them navigate health system, made referrals to supportive services and provided tailored support for ART adherence. These study participants were also offered automated motivational messages and reminders to take their medications and attend appointments by text, email or phone. Participants were able to choose the frequency and content of interactions with the case manager and automated messaging. Study participants enrolled in the standard of care arm were offered existing programs for supportive services, ART initiation, adherence and retention in care at participating HIV clinics in the study communities.

After one year, 91 percent of the participants remained in follow-up in the study with 48 percent achieving viral suppression. However, there were no difference in viral suppression noted between participants who received the case management intervention and those who received the standard of care. Researchers noted a steady increase in overall viral suppression over time - 28 percent at 3 months, 36 percent at 6 months, 39 percent at 9 months - suggesting that the study participants had to overcome personal, practical and structural barriers before achieving success.

"The findings from HPTN 078 are encouraging. We were able to engage a population into care that historically has been hard to reach," said Dr. Wafaa El-Sadr, HPTN co-principal investigator, and professor of epidemiology and medicine at Columbia University in New York. "We are compelled by the value of ART for individual and societal benefits to continue to seek comprehensive strategies that will succeed in reaching and engaging all persons living with HIV with effective treatment interventions."

"HPTN 078 has shown us that we can reach and engage MSM living with HIV in the U.S., and it was encouraging that most were virally suppressed. But those living with unsuppressed HIV are in real need of re-engagement, facing multiple social and structural challenges including poverty, high rates of unemployment and self-reported stigma." said Dr. Chris Beyrer, HPTN 078 protocol chair.

"These findings remove the idea that we cannot reach people who are currently not engaged into care," said Dr. Robert H. Remien, HPTN 078 protocol co-chair. "We were able to enroll 94 percent of eligible study participants. The data shows that the longer people were in the study, the more likely they were to be virally suppressed."

"The HPTN is committed to helping address the epidemic in the communities with the highest burden of HIV," said Dr. Myron Cohen, HPTN co-principal investigator and director of the Institute for Global Health at the University of North Carolina in Chapel Hill. "What we've learned in HPTN 078 will guide the development of new research to reduce HIV among MSM in the U.S., in keeping with the government's initiative to end HIV in America."

A new study using a special type of electron microscope using samples cooled to extremely cold temperatures provides critical information for drug developers seeking to reduce nausea and vomiting side effects of cancer treatments. Published in Nature Communications, the study offers a glimpse into how widely-used anti-nausea drugs attach to their target protein in the gastrointestinal tract. High-resolution images obtained by this method provide key details about how the drugs attach into a binding pocket on the protein--and offer clues into how their design might be improved.

The study focused on a specific class of drugs used to manage nausea, vomiting, and irritable bowel syndrome, called setrons. Setrons are generally well-tolerated, but some cancer patients do not respond to them, explained study lead Sudha Chakrapani, PhD, associate professor of physiology and biophysics at Case Western Reserve University School of Medicine.

"Cancer patients who have vomiting later in their treatment plans--delayed emesis--don't tend to respond to setrons," Chakrapani said. "There is a constant need for better drugs." Drug improvement has been stalled by a lack of models showing exactly how drugs like setrons attach to their target protein in the body--the serotonin (3) receptor. Without a precise model, drug developers have been unable to understand exactly which elements of setron-receptor interactions are most important, and how to enhance them.

The new study provides the highest-resolution images to date of a setron settling inside the binding pocket of a serotonin (3) receptor. Researchers tracked the receptor-drug interactions, to less than a billionth of a meter--using a cryo-electron microscope. Cryo-electron microscopy (cryo-EM) has only recently become available for small protein targets and was the focus of the 2017 Nobel prize in chemistry.

Cryo-EM images revealed setrons use the same attachment site as the receptor's natural binding partner in the body, serotonin, but take a slightly different "pose" that changes the receptor shape slightly. The differences helped the researchers build a more precise model of how setrons work on a molecular level.

Said Sandip Basak, co-first author on the paper, "In the past, we didn't have the confidence to model the drug in its binding pocket. Now we can precisely do that. We can also watch the drug move in the pocket using molecular dynamics simulations."

Chakrapani collaborated with colleagues at Mt. Sinai to identify the most stable interactions between setrons and serotonin receptors. The team watched as setrons twisted and turned in the pocket, revealing key portions of the drug and the receptor that are required for a tight connection. They then mutated the key portions, which eliminated setrons' affinity for the serotonin receptors. Together, the experiments helped reveal which portions of setrons and serotonin receptors are most important, and might be most promising to enhance therapeutically.

"Identifying the binding pocket and the interactions that are most important, and the orientation of the drug in the binding pocket, lays the foundation for designing drugs that are going to be more efficient," said Yvonne Gicheru, who is a co-first author on the paper.

The high-resolution images were collected on a Titan Krios cryo-electron microscope in collaboration with colleagues at Stanford University. The installation of the first Titan Krios microscope at the cryo-EM Core here at Case Western Reserve has just been completed and is now one of two operational microscopes in Northeast Ohio.

The efficient extraction of oil and gas from within the Earth's crust requires accurate images of subsurface rock structures. Some materials are hard to capture, so KAUST researchers have developed a computational method for modeling large accumulations of subsurface salt, a challenging material to derive accurately from seismic imaging data.

Seismic imaging involves sending soundwaves into the ground, where they will be reflected at boundaries between rock structures. Scientists analyze the reflected soundwaves to determine subsurface rock types and formations, and to pinpoint fossil fuel reservoirs.

However, in some regions, such as the Gulf of Mexico, the subsurface is peppered with salt bodies, which are huge accumulations of salt formed millions of years ago deep inside the Earth. Salt is a low-density, buoyant substance, meaning that salt bodies gradually rise through the Earth's crust over time. This causes stress-related complexities between the salt and the surrounding rock layers. Furthermore, the salt's crystal structure means that soundwaves are reflected at random, and there are no useable low frequencies retained in the seismic data.

"Data from salt zones are presently analyzed by highly trained experts rather than modeled by a computer," explains Mahesh Kalita, a KAUST Ph.D. student in Tariq Alkhalifah's group. "This is a time-consuming and expensive process that carries the risk of human error. We've developed a robust computational method for interpreting seismic data from salt bodies quickly and more accurately."

Existing models use a technique called full waveform inversion (FWI) to minimize the disparity between observed and modeled data. However, the lack of low frequencies in soundwave data from salt bodies means that a traditional FWI fails. Kalita and the team developed a two-part optimization process to refine FWI for salt body imaging.

"For the topmost layer of salt, we get a good enough signal to determine where the salt body begins, but then the soundwave energy rapidly disperses," says Kalita. "Our technique takes the initial data from this top layer and 'smears' it across the most likely area that the salt body encompasses. We call this technique 'flooding'."

The resulting model is then tested alongside observed data to check that the surrounding rock structures match up and to ensure the model has not been "over-flooded." Initial trials using a 1990s dataset from the Gulf of Mexico showed promise, with the new technique generating an accurate representation of local salt bodies.

"We will next trial our automated technique on recent, high-quality datasets that incorporate more three-dimensional details," says Kalita.

(BOSTON) -- A study co-authored by Boston University School of Public Health (BUSPH) researchers and published in the American Journal of Industrial Medicine finds that an injury serious enough to lead to at least a week off of work almost triples the combined risk of suicide and overdose death among women, and increases the risk by 50 percent among men.

"These findings suggest that work-related injuries contribute to the rapid increase in deaths from both opioids and suicides," says study senior author Dr. Leslie Boden, professor of environmental health at BUSPH. "Improved pain treatment, better treatment of substance use disorders, and treatment of post-injury depression may substantially improve quality of life and reduce mortality from workplace injuries."

To estimate the association between workplace injury and death, Boden and his colleagues looked at 100,806 workers in New Mexico, 36,034 of whom had lost-time injuries from 1994 through 2000. The researchers used workers' compensation data for that period, Social Security Administration earnings and mortality data through 2013, and National Death Index cause of death data through 2017. They found that men who had had a lost-time injury were 72 percent more likely to die from suicide and 29 percent more likely to die from drug-related causes. These men also had increased rates of death from cardiovascular diseases. Women with lost-time injuries were 92 percent more likely to die from suicide and 193 percent more likely to die from drug-related causes.

Previous research by the authors showed that women and men who had had to take at least a week off after a workplace injury were more than 20 percent more likely to die from any cause. They write that this new study highlights the roles of suicide and opioids as major causes of those deaths.

Advocates of healthy eating often extol the benefits of adding antioxidants to one's diet. These compounds are thought to suppress "free radical" molecules in the body that can age cells as a response to stress.

These destructive free radicals - known as reactive oxygen species - also exist in marine ecosystems and are thought to degrade the cells of phytoplankton and other organisms. A new paper, however, suggests that these molecules actually play a beneficial role, upending some conventional wisdom.

Julia Diaz, a newly hired marine biogeochemist at Scripps Institution of Oceanography at the University of California San Diego, and colleagues report that the reactive oxygen species produced by one type of phytoplankton, the diatom Thalassiosira oceanica, protects cells from overproduction of a compound that is used to power photosynthesis. In essence, that reactive oxygen species acts to protect cells' batteries from the effects of overcharging.

The study, "NADPH-dependent extracellular superoxide production is vital to photophysiology in the marine diatom Thalassiosira oceanica," appears July 22 in the journal Proceedings of the National Academy of Sciences.

"Our findings point to a new role for reactive oxygen species in the photosynthetic health of this diatom. The next challenge is to determine whether this process also exists in other phytoplankton species," said Diaz.

The findings could have implications for marine organisms and their chemical environment. The type of reactive oxygen species studied by Diaz is known as superoxide, which is a charged oxygen atom. Superoxide has been identified as a probable culprit in die-offs of fish and marine animals when toxic algae blooms spread in the ocean, suggesting a need for scientists to better understand how and why it is produced in certain circumstances. The varying positive and negative roles of superoxide could be a critical factor in how marine ecosystems respond to climate change. It is possible, Diaz said, that superoxide production could mitigate stress, which is a form of ocean resilience to changing climate that has not been understood previously.

Superoxide is present throughout ocean ecosystems but how it is used by diatoms like T. oceanica had been a mystery. They need sunlight and carbon to conduct photosynthesis and have a variety of ways to perform the task to adapt to either low or intense-light conditions. A compound they make called NADPH is the power source that lets them take up and "fix" carbon into carbohydrates. Very bright light can cause diatoms to overproduce NADPH.

After studying superoxide production in diatoms at various light levels, Diaz and colleagues concluded that, akin to a surge protector, making superoxide protects cells at times when too much NADPH is produced and restores balance to keep photosynthesis at peak efficiency.

Diaz, who joined the Scripps faculty as an assistant professor this month, performed this research as a postdoctoral scholar at Woods Hole Oceanographic Institution in Woods Hole, Mass., and as an assistant professor at the University of Georgia Skidaway Institute of Oceanography. Sydney Plummer, who also contributed to the study, will continue this research as Diaz's student in the Scripps PhD program beginning this fall.

Pneumonia resulting from exposure to Legionella - although uncommon and affecting only 1 in 100,000 in Europe - has a higher than 10% fatality rate. The pathogenic bacterium Legionella pneumophila has more than 300 toxins that it uses to infect humans. Once the aerosols containing the bacteria are inhaled, Legionella enters the lungs where it starts infecting human cells, causing pneumonia.

Legionella toxins especially target the innate immune pathways facilitating the survival of the bacteria inside human cells and allowing the replication of the bacteria. Due to the large number of toxins it is difficult to see the effects of deleting one or multiple of these toxins on the Legionella infection capacities. This is further complicated by the fact that several toxins with similar functions exist inside the bacteria. This makes Legionella hard to target with specific drugs.

Focus on the SidJ toxin

Researchers from EMBL Grenoble and the Goethe University in Frankfurt have now studied the toxin SidJ in detail. It is an important toxic protein of Legionella that gets injected into the human cytoplasm and enables the successful infection and replication of the bacteria. In contrast to the other toxins in Legionella, the deletion of SidJ alone leads to a considerable growth defect of the bacteria in human cells. This makes SidJ one of the most important toxins of Legionella and an attractive target to curb Legionella infection.

While SidJ has been studied in the field for already more than a decade, the precise function of it remained unknown until today. "SidJ has no sequence similarity to any of the proteins with a known function. We had to resort to standard biochemical methods and mass spectrometry to determine its function", explains Bhogaraju. "While working out its mechanism proved to be challenging, it was also very exciting!"

In particular, the missing detailed molecular study of the toxin hindered the development of drugs that can target SidJ. The work by multidisciplinary scientists of Bhogaraju and Dikic groups now describes the molecular function of this protein in detail, elucidates its importance for Legionella infection and provides the identity of the human proteins that are targeted by SidJ.

Toxin at work

The group showed that SidJ possesses protein glutamylation activity: it attaches the amino acid glutamate to a target protein as post-translational modification. "This kind of activity is a first for bacterial proteins", says Ivan Dikic, Director of the Institute of Biochemistry II at Goethe University. SidJ glutamylates many human proteins that are involved in tackling microbial infections and innate immunity. In order to do this, SidJ interacts with the human protein Calmodulin - a highly conserved multifunctional intermediate calcium-binding messenger protein. "Legionella has cleverly evolved to use Calmodulin to trigger SidJ's activity and as a result prevents SidJ's activation before the infection in the human body takes place", says Dikic.

The cryogenic electron microscopy structure of SidJ interacting with human Calmodulin also revealed that the toxin has a kinase domain fold. "This is a both interesting and important find, as the kinase fold is druggable" says Michael Adams, a PhD student in Bhogaraju group.

Start of a long way to therapeutic usage

The outcome of the study is going to prime many studies in the future, further dissecting the mechanism of SidJ mediated glutamylation. Importantly, since the researchers found that SidJ has a kinase fold, this discovery will initiate the search for a drug molecule with potential therapeutic effects.

"While our work doesn't have a direct pharmaceutical application, our results on the structural and functional characteristics of one of the most important toxins of Legionella, will lead to future studies aiming to target this protein for therapeutic uses", says Sagar Bhogaraju.

When a fruit fly decides it wants to walk in a particular direction, it sticks to its plan with impressive resolve. Now, Rockefeller scientists have begun to understand how insect brains make and meet navigational goals.

In monitoring itinerant flies, the researchers showed that the animals compare their current heading direction to a goal direction, calculate the difference, and use this information to inform their next step. These findings, described in Nature Neuroscience, shed light on how brains use internal goals to direct moment-to-moment actions at a cellular level.

One direction

Animals ranging from insects to mammals have specific neurons that keep track of which way they're facing. Referred to as head-direction or heading cells, these neurons play a vital role in an animal's survival (it's difficult to search for resources like food or shelter if you can't keep track of which way you're currently heading).

Still, scientists remained unsure of how heading cells guide moment-to-moment behavior--how, for example, the neurons might prompt an animal to turn left or right, speed up or slow down. To investigate these questions, Jonathan Green, Vikram Vijayan and Peter Mussells Pires--researchers in the lab of Gaby Maimon--analyzed ambling fruit flies.

"These flies will walk in the same direction for meters at a time," says Maimon. "But we wanted to prove that they're not just walking straight by chance--we believed that they have an internal goal direction, along which they intend to walk."

In a series of experiments, the researchers tethered individual flies to a plate with a tiny fly-sized hole, which kept them in place. The flies then walked on an air-cushioned ball, which rotates as the animal scampers along its surface. Surrounding the ball was a cylindrical LED array, with one vertical line illuminated. This bright bar served as a visual landmark that, to the flies, might register as the sun, the moon, or some other distant reference point by which keep track of their heading.

As the researchers had anticipated, the flies excelled at walking in a straight line with reference to the bright stimulus. For example, if an animal began its journey with the illuminated bar 45 degrees to its right, then it often maintained this orientation for tens of minutes and sometimes over an hour (a long pilgrimage for flies). More impressively, when the researchers manipulated the LED display such that bar jumped to the right or left, the animals turned their bodies until the bar was back at their preferred angle.

This experiment confirms that flies don't walk straight by chance, but rather have an internally-generated goal orientation that informs their every step. Supporting this model, the researchers found that the further the LED bar shifted, the harder the animals turned their bodies.

Moreover, following a bar jump, the animals slowed down--suggesting that they move at full speed only when they know they're walking along their goal direction.

Navigating the brain

Next, the researchers monitored and manipulated the brain activity of flies as they pursued navigational goals. Specifically, they tinkered with the flies' heading cells, also called E-PGs, which are thought to act like a biological compass: As a fly turns, different E-PGs become active, creating an internal representation of the animal's orientation.

By stimulating E-PGs, Maimon's team was able to rotate the fly compass, leading the animals to believe that they were they were straying from their intended trajectory. Following this intervention, the researchers found, flies would slow their pace and turn at an angle commensurate with the degree to which their compass had been rotated.

This outcome suggests that flies aim to keep their neural compass needle at some internally-generated goal angle--and that they modify their behavior to ensure that the needle stays in that sweet spot. In other words, flies seem to use their internal compass-like neurons much like a hiker uses a traditional compass on a long hike.

The researchers conclude that while E-PGs track a fly's current heading, a different group of neurons or a set of neuronal connections, not yet discovered, must store the animal's goal direction. The fly brain then calculates the difference between its current direction and its goal to determine which way to turn, and how hard.

"We've known that flies have a compass-like system in their brain since 2015, but this work is the first to describe how the animals use this system to guide navigational behavior," says Maimon. "Because mammalian brains have heading cells with similar properties, our work may ultimately help us better understand how humans navigate--a process that's impaired in psychiatric disorders, like Alzheimer's disease."