Earth

The evolution of testes

The loss of anatomical features is a frequent evolutionary event. For example, humans and other great apes have lost their tail and whales have lost their legs. The most convincing evidence comes from the presence of vestiges in fossils. Unfortunately, the fossil record preserves predominantly vestiges of hard structures such as bones or teeth. Consequently, resolving the evolution of soft-tissue structures such as muscle or brain tissue requires analytical methods. A team of researchers from the Max Planck Institute of Molecular Cell Biology and Genetics, the Max Planck Institute for the Physics of Complex Systems, the Senckenberg Natural History Collections Dresden and the Natural History Museum Frankfurt now provide a new approach to resolve the evolution of soft-tissue structures, focusing on the evolution of testes in mammals.

Resolving the evolution of soft-tissue structures, crucially depends on accurate knowledge of the evolutionary relationships between the considered species. If these relationships are not fully resolved, the evolution of soft-tissue structures remains uncertain. Michael Hiller, who is affiliated with the two Max Planck Institutes and the Center for Systems Biology Dresden, says: "Instead of investigating soft-tissue structures directly, we traced the evolution of genes that are required for their formation."

For their investigation, the researchers used the descent of testes as an example. In almost all adult mammals, testes are located either in a scrotum or in the lower abdomen. But testes initially develop deep inside the abdomen at a position close to the kidneys, as seen in mammalian embryos. The final testicular position is the result of a descent process that occurs during animal development. However, several African species such as elephants, tenrecs, golden moles, elephant shrews, manatees, and rock hyraxes differ from the other mammals by lacking any descent and having testes at their initial abdominal position. It is an open question whether these African species lost the testicular descent process or whether other mammals gained that feature. Thomas Lehmann from the Senckenberg Frankfurt adds: "The evolution of testicular descent is controversial, because it is not fully understood how the African species are related to other mammals."

Non-functional genes

"To resolve this controversy, we analyzed DNA sequence data of 71 mammals and discovered that these African mammals possess non-functional remnants of two genes that are strictly required for testicular descent in other mammals" explains Virag Sharma, the first author of the study. This shows that functional versions of these genes were once present in the ancestors of African mammals that lack testicular descent today. These "molecular vestiges" suggest that the testicular descent process took place in the ancestor and was subsequently lost in African mammals.

"Importantly, this conclusion holds regardless of ongoing controversies about the evolutionary relationships among mammals" explains Heiko Stuckas from the Senckenberg Dresden. "The increasing availability of DNA sequence data of many species provides unprecedented opportunities to hunt for molecular vestiges and thus resolve debates on evolution of other anatomical traits" concludes Michael Hiller, who supervised the study.

Credit: 
Max-Planck-Gesellschaft

NASA finds depression strengthening into Tropical Storm Emilia

image: The GPM core observatory satellite passed over Tropical Depression Six-E on June 28 at 1:30 a.m. EDT (0530 UTC) as it was strengthening into a tropical storm. Powerful storms circling the center of the depression and in a band extending north of center were producing rainfall at a rate greater than 1.4 inches per hour. GPM data was overlaid on NOAA's GOES-West satellite infrared imagery.

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Credits: NASA/JAXA/NRL

The Global Precipitation Measurement mission or GPM core satellite passed over Tropical Depression Six-E in the Eastern Pacific Ocean and found heavy rainfall occurring in two areas. Shortly after GPM passed overhead, the depression strengthened into Tropical Storm Emilia.

Tropical Depression Six-E developed on June 27 at 5 p.m. EDT and strengthened into the fifth tropical storm of the Eastern Pacific Ocean season by 5 a.m. EDT on June 28.

The GPM core observatory satellite passed over Tropical Depression Six-E on June 28 at 1:30 a.m. EDT (0530 UTC) as it was strengthening into a tropical storm. Data collected by the GPM satellite's Microwave Imager (GMI) showed that powerful storms circling the center of the depression. Those storms were producing rainfall at a rate greater than 1.4 inches per hour. A Band of thunderstorms extending north of the center were also producing rainfall at greater than 1.4 inches per hour. GPM is a joint mission between NASA and the Japan Aerospace Exploration Agency, JAXA.

At 11 a.m. EDT (1500 UTC) on Thursday, June 28, 2018 the center of Tropical Storm Emilia was located near latitude 14.4 degrees north and longitude 112.4 degrees west. That's about 610 miles (980 km) south-southwest of the southern tip of Baja California, Mexico. The National Hurricane Center (NHC) said that Emilia was moving toward the west-northwest near 14 mph (22 kph), and this general motion with some decrease in forward speed is expected over the next few days. The estimated minimum central pressure is 1005 millibars.

Maximum sustained winds remain near 40 mph (65 kph) with higher gusts. Some strengthening is forecast during the next 48 hours before weakening begins on Sunday, July 1.

Credit: 
NASA/Goddard Space Flight Center

Video clips, spicy soap operas, games slash STD rates in gay young men

Online program -- Keep It Up! -- weaves HIV prevention into dating, sexual experiences of young gay men, who are at highest risk for disease

Reduced gonorrhea and chlamydia by 40 percent

One in six young men are projected to get HIV in their lifetime

CHICAGO --- A novel online HIV prevention program with spicy soap operas and interactive games -- like a rising thermometer of sexual risk -- reduced sexually transmitted infections in gay young men by 40 percent, reports a Northwestern Medicine study.

"That is a huge effect," said lead author Brian Mustanski, director of The Institute for Sexual and Minority Health and Wellbeing at Northwestern University Feinberg School of Medicine. "We were expecting it be 20 percent."

This is the first online HIV prevention program to show effects on a biological outcome. It is targeted to young men ages 18 to 29 who have sex with men, who have the highest rate of HIV infections in the U.S. The results show the effectiveness of an online program to promote safe sex in this highest risk group.

These young men represent 2 percent of young people in the U.S. but account for almost 70 percent of HIV diagnoses, according to the Centers for Disease Control and Prevention (CDC). Their rate of new HIV diagnoses is 44 times higher than that of other men.

"The numbers are alarming," Mustanski said. "The CDC estimates that without an intervention half of young black gay men and a quarter of Latino gay men will get HIV at some point in their lives."

The study will be published June 28 in the American Journal of Preventive Medicine.

Prior studies using eHealth HIV prevention programs used self-reports to determine their effectiveness. "People can sometimes forget or may not always tell the truth. A biological outcome is often considered more trustworthy," Mustanski said.

Mustanski and colleagues developed the program called Keep it Up! The study included 901 participants primarily from the Atlanta, Chicago and New York City study sites. Participants who used Keep It Up! had a 40 percent lower incidence of sexually transmitted disease -- specifically chlamydia and gonorrhea -- compared with the control group at 12 months.

Instead of the typical HIV prevention approach, which provides facts about how HIV is transmitted and how to use a condom, Keep It Up! focuses on the lives of young gay men and weaves HIV prevention information into their typical experiences.

Each of the program's modules targets a particular setting that is relevant to the men such as dating and starting new relationships. One is about going to a bar and using drugs and alcohol.

In that episode, men learned the benefits of avoiding substance use in sexual situations and how to reduce their risk when they do use substances (e.g., making sure to bring a condom with them, so they don't need to navigate obtaining and deciding to use a condom while intoxicated).

In one of the interactive games, men could look at different sexual behaviors and rate them on a "thermometer of risk." Then the game tells them if they got it right.

"The game let them see 'what are things I can do that are pleasurable but wouldn't put me at risk?'" Mustanski said.

A soap opera tracks a group of young men who make assumptions about their partners. "One guy assumes the guy he is dating is monogamous, but he never talked to the guy about it. In fact, his partner was dating a few people," Mustanski said.

"We know that the majority of HIV transmissions in young gay/bisexual guys occur in a serious relationship, so it is important for them to have explicit discussions about whether their relationship is open or closed and that both partners get tested for HIV and share their status," Mustanski said.

Another man in the video assumes his partner is HIV negative while the partner assumes he is positive. "It shows you can't assume it's your partner's job to disclose their HIV status. It's really important to have everyone take responsibility for those conversations," Mustanski said. The video emphasizes the importance of regular HIV testing and skills negotiating condom use.

Participants said they learned a lot from the games and soap opera.

One commented, "I didn't really think about my own behavior until I watched the soap opera. When I saw those characters, I was judging them, but then I realized I was doing the same (risky) thing."

"It motivated me to get tested," another man wrote about participating in the program. "I had waited two years because I was afraid of the result, so without Keep It Up I would still be in the dark. Also, I liked that the content dealt with real-world situations like meeting at clubs or online."

PrEP was Food and Drug Administration approved as an HIV prevention medication around the start of the trial, so the team moved quickly to add content on PrEP into the booster sessions of the intervention. That content was designed so it could be easily updated as new information emerged about PrEP.

Mustanski emphasized, "The core principals of how we motivated risk reduction are equally applicable to PrEP. eHealth interventions need to be updatable as new developments occur in the HIV prevention landscape."

Study participants had received a HIV-negative test during screening. They had not been in a monogamous relationship for at least six months prior to recruitment and reported at least one or more acts of condom-less anal sex during that period. Participants completed online questionnaires and performed testing for urethral and rectal gonorrhea and chlamydia upon enrollment as well as 12 months post intervention.

Mustanski hopes to get a grant for a trial to implement and disseminate the program in 50 U.S. counties. "It's not enough just to put it on a website. We want to find the most cost-effective way to get this out in the community and how to reach the people with the highest risk," he said.

In 2015, the U.S. National HIV/AIDS strategy called for a 15 percent reduction in HIV incidence among young gay men who have sex with men. Only two of 59 current HIV-related evidence-based interventions target them. HIV prevention programs for gay young men should not be simple modifications of those developed for heterosexual youth, because gay young men have different challenges related to their sexual orientation, such as feeling isolated or not having supportive networks.

Credit: 
Northwestern University

Bioanalysis publishes special focus issue on 'Biomarker Assay Validation'

The Future Science Group (FSG) published journal, Bioanalysis, which is a leading MEDLINE indexed journal for bioanalysts, today announced the release of its Special Focus Issue on 'Biomarker Assay Validation (BAV) '.

This Special Focus Issue hopes to offer readers of the journal an insight into the various issues that exist surrounding the BAV, how these issues have evolved over the years, as well as the recent regulatory activities around these.

This issue was guest edited by Steven Piccoli (Neoteric) and Fabio Garofolo (Angelini Pharma).

Dr. Piccoli stated: "The issues of biomarker assay validation have evolved over the years, reflecting significant changes in thought-provoking chemotypes, steady advances in analytical technologies and a much more granular interrogatory proposed in support of precision medicine."

He continued: "In order to explore these concerns, this themed issue of Bioanalysis has been dedicated to Biomarker Assay Validation and shares with the reader scientific insight, regulatory opinion and pertinent examples of the current processes."

In this issue, parallelism assessments in LBA biomarker assay development and validation, clinical biomarker validation, the evolution of fit-for-purpose biomarker validations as well as many other important topics are discussed by experts and key opinion leaders in the biomarker field.

Another highlight of this issue is the progress update for the C-Path White Paper on the joint FDA &C-Path Initiative collaboration on analytical validation of biomarker assays used in the FDA biomarker qualification process.

Hannah Makin, one of the co-editors for Bioanalysis commented: "We are delighted to publish this Special Focus Issue, which aims to provide a glimpse into the critical questions that are raised by the issues of biomarker assay validation, as well as the recent regulatory activities surrounding these. We hope that this Special Focus Issues highlights the importance of communication between scientists, regulators, and stakeholders in order to tackle difficult medical challenges and ultimately achieve significant healthcare improvements for patients."

Credit: 
Future Science Group

New diagnosis method could help spot head and neck cancers earlier

Oral squamous cell carcinomas (OSCCs) are the most common head and neck cancers, but are often diagnosed late.

Now, researchers in Germany have developed a new cell-based test that could help provide earlier and more reliable diagnosis of OSCCs.

Writing in Science Physical Oncology, the researchers explain how they tested the mechanical properties of OSCC cells, and found they were 'softer' than benign cells.

Lead authors Professor Josef Käs and Professor Torsten W. Remmerbach, from the University of Leipzig, said: "Early diagnosis and treatment of OSCCs is essential to enabling recovery. But in up to 60 per cent of cases the diagnosis is late because the growth has not been recognised, or has been mistaken as harmless."

The research team examined if cells' mechanical properties could be used as a marker for malignancy. As well as being softer than benign cells, the team saw that cancer cells exhibited a faster contraction than their benign counterparts when testing the relaxation behaviour after stress release.

Professor Remmerbach said: "This new way of drawing distinction between malignant and benign cells could enable an early confirmation of cancer diagnoses, by testing cell samples of suspect oral lesions."

The researchers used an optical stretcher to analyse the properties of the cells. Their experiments revealed that cells of primary OSCCs were deformed by 2.9 per cent, rendering them softer than cells of healthy mucosa, which were deformed only by 1.9 per cent.

Co-author Dr Jörg Schnauß said: "What we found also has implications for the way studies in cancer research are carried out. Many studies are performed with cancer cell lines rather than primary cells. When comparing the mechanical properties of both, our results showed that long time culturing leads to softening of cells.

"This softening in the culturing process could potentially affect the significance of test results. Because of that, we suggest that future research uses primary cells to ensure accuracy."

Credit: 
IOP Publishing

Research shows graphene forms electrically charged crinkles

image: Stacks of graphene tend to form saw-tooth crinkles when compressed. Those crinkles have an electrical charge that could be useful in studying DNA or guiding nanoscale self-assembly.

Image: 
Kim Lab / Brown University

PROVIDENCE, RI (Brown University) -- Researchers from Brown University have discovered another peculiar and potentially useful property of graphene, one-atom-thick sheets of carbon, that could be useful in guiding nanoscale self-assembly or in analyzing DNA or other biomolecules.

A study published in Proceedings of the Royal Society A demonstrates mathematically what happens to stacks of graphene sheets under slight lateral compression -- a gentle squeeze from their sides. Rather than forming smooth, gently sloping warps and wrinkles across the surface, the researchers show that layered graphene forms sharp, saw-tooth kinks that turn out to have interesting electrical properties.

"We call these quantum flexoelectric crinkles," said Kyung-Suk Kim, a professor in Brown's School of Engineering and the paper's senior author. "What's interesting about them is that each crinkle produces a remarkably thin line of intense electrical charge across the surface, which we think could be useful in a variety of applications."

The charge, Kim says, is generated by the quantum behavior of electrons surrounding the carbon atoms in the graphene lattice. When the atomic layer is bent, the electron cloud becomes concentrated either above or below the layer plane. That electron concentration causes the bend to localize into a sharp point, and produces a line of electrical charge roughly one nanometer wide and running the length of the crinkle. The charge is negative across the tip of an upraised ridge and positive along the bottom of a valley.

That electrical charge, Kim and his colleagues say, could be quite useful. It could, for example, be used to direct nanoscale self-assembly. The charged crinkles attract particles with an opposite charge, causing them to assemble along crinkle ridges or valleys. In fact, Kim says, particle assembly along crinkles has already been observed in previous experiments, but at the time the observations lacked a clear explanation.

Those previous experiments involved graphene sheets and buckyballs -- soccer-ball-shaped molecules formed by 60 carbon atoms. Researchers dumped buckyballs onto different kinds of graphene sheets and observed how they dispersed. In most cases, the buckyballs spread out randomly on a layer of graphene like marbles dropped on smooth wooden floor. But on one particular type of multilayer graphene known as HOPG, the balls would spontaneously assemble into straight chains stretching across the surface. Kim thinks flexoelectric crinkles can explain that strange behavior.

"We know that HOPG naturally forms crinkles when it's produced," Kim said. "What we think is happening is that the line charge created by the crinkles causes the buckyballs, which have an electric dipole near the line charge, to line up."

Similarly, strange behaviors have been seen in experiments with biomolecules like DNA and RNA on graphene. The molecules sometimes arrange themselves in peculiar patterns rather than flopping out randomly as one might expect. Kim and colleagues think that these effects can be traced to crinkles as well. Most biomolecules have an inherent negative electrical charge, which causes them to line up along positively charged crinkle valleys.

It might be possible to engineer crinkled surfaces to take full advantage of the flexoelectric effect. For example, Kim envisions a crinkled surface that causes DNA molecules to be stretched out in straight lines making them easier to sequence.

"Now that we understand why these molecules line up the way they do, we can think about making graphene surfaces with particular crinkle patterns to manipulate molecules in specific ways," Kim said.

Kim's lab at Brown has been working for years on nanoscale wrinkles, crinkles, creases and folds. They've shown that the formation of these structures can be carefully controlled, bolstering the possibility of crinkled graphene tailored to a variety of applications.

Credit: 
Brown University

Most accurate picture of Zika yet creates potential for therapeutics

image: Researchers at Purdue have achieved a cryo-EM structure of mature Zika virus at 3.1Å resolution. The three envelope glycoproteins are colored yellow, blue and red.

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Purdue University photo/Madhumati Sevvana

Researchers have created the most accurate picture of Zika to date, finding probable drug-binding pockets on the surface of the virus and paving the way for vaccine design.

Purdue researchers were the first to discover the structure of Zika virus in 2016. Using cryo-electron microscopy (cryo-EM), they created an image of the virus at a resolution of 3.8 Ångstrom, a unit used to express the size of atoms and molecules. Now, they've scaled that number down to 3.1, bringing them even closer to seeing atomic details of the virus. The findings were published in the journal Structure (Cell Press).

"This is the most accurate picture we have of the virus so far," said Michael Rossmann, the Hanley Distinguished Professor of Biological Sciences at Purdue. "These results will give us ways to efficiently design antiviral compounds and provide a basis for structure-based vaccine design."

The research team used new virus preparation methods and updated data processing techniques to get this improved resolution. The result of cryo-EM is an electron potential map, which can be interpreted by building an atomic model. The best fit between the model and the map is achieved using statistical adjustments known as "refinement."

"Our team extended and optimized the routine crystallographic refinement methods," Rossmann said.

Zika virus belongs to the family of flaviviruses that are transmitted by mosquitos and ticks. Rossmann's team compared the new Zika structure to other flaviviruses such as Dengue, West Nile and Japanese Encephalitis virus, which are structurally similar but cause different disease symptoms. Zika virus causes babies to be born with abnormally small heads and sometimes smaller brains, a condition known as microcephaly, and may result in Guillain-Barre syndrome in adults. Dengue Fever, on the other hand, causes flu-like symptoms and a skin rash.

"We compared the surface properties of these viruses and observed differences in the landscape of the surface exposed residues," said Madhu Sevvana, a postdoctoral researcher at Purdue and lead author of the paper. "We found certain structural differences on the surface, which could be a starting point for further mutational analyses."

Credit: 
Purdue University

NASA looks at Daniel's concentrated center

image: On June 25 at 5:50 a.m. EDT (0950 UTC), infrared data from the Moderate Resolution Imaging Spectroradiometer or MODIS instrument showed a very small area of strong thunderstorms around tropical storm Daniel's center of circulation. Those thunderstorms had contact temperatures near minus 63 degrees Fahrenheit or minus 53 degrees Celsius (yellow).

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Credits: NASA/NRL

The fourth tropical cyclone of the Eastern Pacific season formed on Saturday, June 23. It strengthened into a tropical storm, and on June 25, 2018, NASA's Aqua satellite passed overhead and analyze the storm in infrared light which provides valuable temperature data.

On June 25 at 5:50 a.m. EDT (0950 UTC), infrared data from the moderate resolution imaging spectroradiometer or MODIS instrument showed a very small area of strong thunderstorms around tropical storm Daniels center of circulation. Those thunderstorms had contact temperatures near minus 63 degrees Fahrenheit or minus 53 degrees Celsius. NASA research has shown that cloud tops that cold can produce heavy rainfall.

There are no coastal watches or warnings in effect. Daniel is far from land at 575 miles west-southwest of the southernmost tip of Baja California, Mexico.

At 11 a.m. (1500 UTC), the National Hurricane Center said the center of Tropical Storm Daniel was located near latitude 19.0 North, longitude 117.8 West. Daniel is moving toward the northwest near 9 mph (15 kph). A turn toward the west-northwest is expected by tonight, followed by a westward motion on Tuesday and Wednesday.

Maximum sustained winds have decreased to near 40 mph (65 km/h) with higher gusts. Additional weakening is forecast, and Daniel is expected to weaken to a depression later today or tonight. The cyclone is then forecast to degenerate to a remnant low pressure area Tuesday or Tuesday night.

Credit: 
NASA/Goddard Space Flight Center

Researchers find prostate cancer drug byproduct can fuel cancer cells

video: New Cleveland Clinic study published in JCI finds that prostate cancer drug byproduct can fuel cancer cells.

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Cleveland Clinic

June 25, 2018, Cleveland: A genetic anomaly in certain men with prostate cancer may impact their response to common drugs used to treat the disease, according to new research at Cleveland Clinic. The findings may provide important information for identifying which patients potentially fare better when treated with an alternate therapy.

In a newly published study in Journal of Clinical Investigation, researchers found that abiraterone, a common prostate cancer drug, yields high-levels of a testosterone-like byproduct in men with advanced disease who have a specific genetic variant.

The study's lead researcher, Nima Sharifi, M.D., Cleveland Clinic Lerner Research Institute Department of Cancer Biology, previously discovered that men with aggressive prostate cancer who have a specific variant in the HSD3B1 gene have poorer outcomes than patients without the variant. HSD3B1 encodes an enzyme that allows cancer cells to use adrenal androgens for fuel. This enzyme is overactive in patients with the variant HSD3B1(1245C).

In the new study, Dr. Sharifi and his team, including first author Mohammad Alyamani, Ph.D., found that men with the genetic anomaly metabolize abiraterone differently than men without the variant.

"We are hopeful these finding will lead to us being able to better tailor prostate cancer treatments based on a patient's specific genetic make-up," said Dr. Sharifi. "More studies are needed, but we have strong evidence that HSD3B1 status affects abiraterone metabolism and probably its effectiveness. If confirmed, we hope to identify an effective alternative drug that might be more effective in men with this genetic anomaly."

Traditional therapy for advanced prostate cancer - called androgen deprivation therapy (ADT) - blocks cells' supply of androgens (male hormones), which they use to grow and spread. While ADT is successful early on, cancer cells grow resistant, allowing the disease to progress to a lethal phase called castration-resistant prostate cancer (CRPC). In CRPC, cancer cells utilize an alternative source of androgens produced in the adrenal glands. Abiraterone blocks these adrenal androgens.

In the study, the researchers examined small molecule byproducts of abiraterone in several groups of men with CRPC and found that patients with the gene variant had high levels of a metabolite called 5α-abiraterone. The metabolite tricks androgen receptors into turning on dangerous pro-cancer pathways. Remarkably, this byproduct of abiraterone - which is designed to block androgens - may behave like an androgen and cause prostate cancer cells to grow. Investigating abiraterone's impact on clinical outcomes in CRPC patients will be an important next step.

"This study adds to our understanding of the deleterious effect of inherited variants of the HSD3B1 gene and holds promise for precision medicine approaches in the management of men with advanced prostate cancer," said Eric Klein, M.D., chair of Cleveland Clinic Glickman Urological and Kidney Institute.

"This study helps to define a novel resistance pathway for abiraterone, a commonly used medication for patients with advanced prostate cancer. Dr. Sharifi's results could enable selection of different systemic therapies for patients who are carriers of certain genetic alterations in the HSD3B1 gene in order to prolong clinical response," said Howard Soule, Ph.D., executive vice president and chief science officer of the Prostate Cancer Foundation. "The Prostate Cancer Foundation is thankful to Dr. Sharifi for his continued investigations to improve therapy for advanced prostate cancer patients, and is proud to have funded this study."

Credit: 
Cleveland Clinic

Inhaled nitric oxide may reduce kidney complications from heart surgery

image: Administration of nitric oxide gas during and for 24 hours following heart surgery decreased the risk of patients developing acute and chronic kidney problems, a randomized, controlled trial conducted in China found.

Image: 
ATS

June 22, 2018-- Administration of nitric oxide gas during and for 24 hours following heart surgery decreased the risk of patients developing acute and chronic kidney problems, a randomized, controlled trial conducted in China found.

The study, "Nitric Oxide Decreases Acute Kidney Injury and Stage 3 Chronic Kidney Disease after Cardiac Surgery," is published online in the American Thoracic Society's American Journal of Respiratory and Critical Care Medicine.

Researchers studied 244 adults in Xi'an, China, who underwent surgery to replace more than one heart valve. Because of the duration of the procedure, the patients required placement on cardiopulmonary bypass (a heart-lung machine) for at least 90 minutes.

"Previous studies showed that prolonged cardiopulmonary bypass causes disruption of circulating red blood cells and the release of hemoglobin, which can cause acute kidney injury, leading to kidney failure and the need for long-term hemodialysis," said lead study author Lorenzo Berra, MD, medical director of respiratory care at Massachusetts General Hospital in Boston and assistant professor at Harvard Medical School. "We tested whether administration of nitric oxide, a gas normally produced by cells in the lining of blood vessels, might render hemoglobin 'inert,' thereby decreasing the risk of both acute and chronic kidney injury."

The authors found that patients who received 80 parts per million of nitric oxide during and for 24 hours after surgery were less likely to develop acute kidney injury, with a decrease from 64 percent in the placebo-treated patients to 50 percent in those who received nitric oxide.

The risk of progressing to more serious kidney disease (Stage 3 Chronic Kidney Disease) was also reduced at 90 days, with a decrease from 33 percent in the placebo-treated patients to 21 percent in those who received nitric oxide. After one year, 31 percent in the placebo group had serious kidney disease compared to 18 percent in the nitric oxide group.

There was also a decrease in the overall mortality rate after one year, from 6 percent in the placebo group to 3 percent in the nitric oxide group. This decrease did not reach statistical significance, possibly because of the relatively small number of patients included in the study, the researchers wrote.

According to the authors, several drugs have been tested and shown to be ineffective at protecting the kidneys after cardiac surgery. This is the first study to show that a pharmacological treatment can reduce acute and chronic kidney injury resulting from cardiac surgery.

Importantly, the authors noted that administration of nitric oxide gas appears to be safe: nitric oxide delivery did not have to be reduced or stopped in any of the patients who received the gas.

The authors caution that study results may not be generalizable to all cardiopulmonary bypass patients. In the Chinese study, all patients underwent the same type of surgery, and most of the patients were young (average age: 48) because their heart valve problems were caused by rheumatic fever. In North America and Europe, degenerative heart disease is a more common cause of valve dysfunction, and these older patients are more likely to have additional medical problems.

The researchers are now conducting a similar trial at the Massachusetts General Hospital to determine whether nitric oxide provides similar benefits as those seen in the Chinese study.

Compared to the younger, relatively healthy patients in the Chinese study, Dr. Berra said, "We believe that the older patients with an increased number of cardiovascular risk factors, including obesity, hypertension and diabetes, may derive even greater benefit from nitric oxide administration during and after heart surgery."

Credit: 
American Thoracic Society

New research on avian response to wildfires

As we enter another wildfire season in California, attention will turn to the inevitable fires and efforts to extinguish them. After these fires burn, land managers are tasked with deciding how, where, and when to act to manage these new conditions. It is vital that land managers use the latest science to understand the effects that fire has on the ecosystem and the wildlife species that inhabit them. New research Point Blue Conservation Science explores these effects, looking at impacts of the severity of fire on birds and how that changes as the time since fire increases. Scientists looked across 10 fires up to 15 years after they burned through forests in the northern Sierra Nevada. Key among the findings is the observation that wildfire had a strong effect on the density of many of the bird species that were studied.

However, the severity of the fires affected different bird species differently. Of the 44 species studied, 18 reached their maximum densities after high-severity fire, 10 in moderate-severity, and 16 in areas affected by low-severity fire.

Over the last century humans have reduced the influence of fire across this ecosystem, but as the climate warms and the amount of fuels in these forests increase, the area burning annually and the severity of fires has been increasing. Understanding how species that rely on these forests respond to such fires can help inform management of fires and post-fire environments.

"One of the most important things we found was how varied the response was between areas that burned at different levels of severity as well the time after the fire it took for different species to reach their peak abundance," said lead author Dr. Paul Taillie who was a field technician on the project with Point Blue and is now a researcher at North Carolina State University. "This reinforces the idea that mixed severity fires are crucial to sustaining a diversity of bird life in Sierra forests and that these burned landscapes are providing important habitat for decades after they burn."

In addition to comparing the effects of different burn severities and the amount of time since fire, researchers also investigated more complex and nuanced responses of birds to fire than has been investigated in fire-prone western forests. Rather than simply increasing or decreasing consistently across the 15-year post-fire period, many species exhibited more complex patterns, for example increasing rapidly but reaching a plateau and then declining again. Other species' responses to burn severity varied across the 15 year post-fire period investigated.

The researchers also compared bird populations in post-fire forests to populations in unburned forests. Of the species studied, 30 percent had higher densities in burned forest, with all but one of those in areas of high severity fires. Just 11 percent reached greater densities in unburned forest.

"Our findings really illustrate how dynamic the avian community is after these fires. Many of the species peaked in density during a narrow window of time after fire in a specific burn severity class. We just don't see this rapid change in the bird community in green forests even after mechanical fuel reductions. It suggests we be cautious in prescribing post-fire management actions that alter the trajectory of these forests," said researcher Ryan Burnett, Sierra Nevada Director at Point Blue. "We hope this research helps land managers make informed decisions about managing these dynamic post-fire bird habitats."

Credit: 
Point Blue Conservation Science

Envisioning a future where all the trees in Europe disappear

Vegetation plays an important role in shaping local climate: just think of the cool shade provided by a forest or the grinding heat of the open desert.

But what happens when widespread changes, caused by or in response to global warming, take place across larger areas? Global climate models allow researchers to play out these kinds of thought experiments. The answers that result can serve as a warning or a guide to help policymakers make future land use decisions.

With this as a backdrop, a team of researchers from the Norwegian University of Science and Technology and Justus-Liebig University Giessen in Germany decided to use a regional climate model to see what would happen if land use in Europe changed radically. They looked what would happen with air temperature, precipitation, and temperature extremes if Europe were completely deforested to either bare land or just ground vegetation. They also considered what might happen if Europe's cropland were converted to either evergreen or deciduous forests.

The researchers knew that climate change impacts tend to be underestimated at a regional level, "because the projected global mean temperature changes are dampened by averaging over the oceans, and are much smaller than the expected regional effects over most land areas," the team wrote in their paper, recently published in Environmental Research Letters. "This applies to both mean and extreme effects, as changes in regional extremes can be greater than those in global mean temperature up to a factor of three."

"We wanted to perform a quantitative analysis of how much land cover changes can affect local climate. Important transitions in the land use management sector are envisioned in near future, and we felt important to benchmark the temperature response to extreme land cover changes"said Francesco Cherubini, a professor in NTNU's Industrial Ecology Programme, and first author of the study. "Decisions regarding land uses are frequently taken at a subnational level by regional authorities, and regional projections of temperature and precipitation effects of land cover changes can help to maximize possible synergies of climate mitigation and adaptation policies, from the local to the global scale."

Future extreme land use changes are not as improbable as you might think. As the global population continues to grow, more land will come under pressure to produce food.

Alternatively, demand for crops for biofuels could also drive what kind of vegetation is cultivated and where.

One future vision of what the world might look like, called Shared Socio-economic Pathways, estimates that global forest areas could change from about - 500 million hectares up to + 1000 million hectares in 2100, with between 200 and 1500 million hectares of land needed to grow bioenergy crops. In fact, the higher end of this range could be realized under the most ambitious climate change mitigation targets.

Changes in land use can have a complicated effect on local and regional temperatures.

When the ground cover is altered, it changes how much water is retained by the soil or lost to evaporation. It can also affect how much sunlight the ground reflects, which scientists call albedo.

The researchers knew that other studies had shown contradictory effects, particularly from deforestation. Some showed that deforestation reduced air temperatures near the ground surface, and increased daily temperature extremes and number of hot days in the summer. Other studies found increases in the occurrence of hot dry summers.

But when the researchers ran their model to see what would happen if land was deforested, they found a slight annual cooling over the region overall, but big differences locally.

Their model showed that when forests were replaced by bare land, the temperatures cooled by just -0.06 ? regionally. The cooling was slightly greater (-0.13? regionally) if the researchers assumed that forests were replaced by herbaceous vegetation. In some locations, cooling can exceed average values of -1 C.

On their own, these regional changes may not seem like much. But when the researchers looked more closely at how these changes were distributed across the region, they found that there was a cooling in the northern and eastern part of the region, and a warming effect in western and central Europe. They also found that deforestation led to increased summer temperature extremes.

"Regional cooling from deforestation might look counter-intuitive, but it is the outcome of the interplay among many different physical processes. For example, trees tend to mask land surface and increase the amount of solar energy that is not reflected back to the space but it is kept in the biosphere to warm the climate," said Bo Huang, a postdoc in the Industrial Ecology Programme who was one of the paper's co-authors. "This particularly applies to areas affected by seasonal snow cover, because open land areas covered by snow are much more reflective than snow-covered forested land."

The researchers found an annual average cooling across the whole of Europe, but with a clear latitudinal trend and seasonal variability. Despite the average cooling effects, they found that deforestation tends to increase local temperatures in summer, and increase the frequency of extreme hot events.

When the researchers ran their model to see what would happen if cropland was replaced by either evergreen or deciduous forests, they found a general warming in large areas of Europe, with a mean regional warming of 0.15 ? when the transition was to evergreen forests and 0.13 ? if the transition was to deciduous forests.

Much as in the deforestation thought experiment, the researchers found that the changes were stronger at a local scale, as much as 0.9 °C in some places. And the magnitude and significance of the warming gradually increased at high latitudes and in the eastern part of the region. Areas in western Europe actually showed a slight cooling.

Cherubini says that understanding how regional vegetation changes play out at more local levels is important as decision makers consider land management policies to mitigate or adapt to climate change.

"It is important to increase our knowledge of land-climate interactions, because many of our chances to achieve low-temperature stabilization targets are heavily dependent on how we manage our land resources," Cherubini said. "We need more research to further validate and improve the resolution of regional climate change projections, since they are instrumental to the design and implement the best land management strategies in light of climate change mitigation or adaptation."

Credit: 
Norwegian University of Science and Technology

Dying cancer cells make remaining glioblastoma cells more aggressive and therapy-resistant

image: Ichiro Nakano

Image: 
UAB

BIRMINGHAM, Ala. - A surprising form of cell-to-cell communication in glioblastoma promotes global changes in recipient cells, including aggressiveness, motility, and resistance to radiation or chemotherapy.

Paradoxically, the sending cells in this signaling are glioblastoma cells that are undergoing programmed cell death, or apoptosis, according to research by a team at institutes in the United States, Russia and South Korea.

The dying cancer cells send their signals by means of extracellular vesicles induced and released during apoptosis. These vesicles -- small, membrane-bound blobs known as exosomes -- carry components that alter RNA splicing in the recipient glioblastoma cells, and this altered splicing promotes therapy resistance and aggressive migration.

This mechanism thus becomes a possible target for new therapies to treat glioblastoma, a primary brain cancer, and the mechanism may apply to other cancer types as well.

"Clinically, our data may provide the rationale to the molecular targeting of RNA splicing events or specific splicing factors for novel cancer therapies," said Ichiro Nakano, M.D., Ph.D., leader of the international study being published in Cancer Cell. "This may lead to decreased acquisition of therapy resistance, as well as reduction in the migration of cancer cells."

Nakano is an academic neurosurgeon at the University of Alabama at Birmingham who conducts both brain tumor translational research and clinical brain tumor surgery. He is professor of neurosurgery in the UAB School of Medicine and a senior scientist for the UAB Comprehensive Cancer Center.

Glioblastoma exhibits invasive behavior, abrupt growth and poor patient survival. As the number of the cancer cells rapidly increases, abundant apoptotic tumor cells are intermingled with neighboring proliferating tumor cells. The apoptotic cells can account for up to 70 percent of the tumor cell population.

The discovery of this unusual cell-to-cell communication began with a simple experiment -- injecting a combination of lethally irradiated human glioblastoma cells, which makes them apoptotic, and "healthy" glioblastoma cells into a mouse xenograft model. This combination led to much more aggressive tumor growth, as seen in brain scans, compared to "healthy" glioblastoma cells or irradiated glioblastoma cells alone. The combination was also more therapy-resistant.

The UAB researchers and colleagues found that, after induction of apoptosis, glioblastoma cells shed significantly higher numbers of exosomes with larger average sizes.

Those apoptotic exosomes, when combined with "healthy" glioblastoma cells, significantly increased tumor growth in the xenograft model and cell motility in bench experiments. Also, while the "healthy" glioblastoma cells alone had a clear border between the tumor and adjacent normal tissue in the xenograft, the glioblastoma cells co-injected with apoptotic exosomes invaded into adjacent brain tissue. Exosomes shed by non-apoptotic cells did not have these effects.

To discover the mechanism underlying these changes, the researchers looked at what was inside the apoptotic exosomes. The vesicles were enriched with spliceosomal proteins and several U snRNAs -- parts of the cellular machinery that remove introns from pre-messenger RNA.

These are normally confined to the nuclei of cells; but the Nakano team found that, as the glioblastoma cells underwent apoptosis, the spliceosomal proteins were transported out of the nucleus to the cell cytoplasm, where they could be packaged into vesicles for release.

Glioblastoma cell subtypes include the proneural subtypes and the mesenchymal subtype. Recent data have shown that, after therapy, glioblastoma cells shift from the less aggressive proneural subtype to the more aggressive and therapy-resistant mesenchymal subtype. The researchers found that apoptotic exosomes induced substantial alternate RNA splicing in recipient cells that resembled the splicing patterns found in the mesenchymal glioblastoma subtype.

Part of this was caused by the splicing factor RBM11, which is encapsulated in the vesicles. The researchers found that exogenous RBM11 caused upregulation of endogenous RBM11 in the recipient cells and activated glycolysis. Overexpression of RBM11 increased the migration of glioblastoma cells.

They also found that RBM11 altered RNA splicing to produce an isoform of the protein cyclinD1 that promotes DNA repair and an isoform of the protein MDM4 that has significantly higher anti-apoptotic activity. These changes can make the cells more therapy-resistant.

Examination of the Cancer Genome Atlas database showed that elevated expression of those two isoforms is associated with poor prognoses for glioblastoma patients.

Finally, the Nakano-led team looked at paired glioblastoma specimens of primary and recurrent tumors from matched patients. In most of the 43 pairs of matched samples, the RBM11 protein levels were substantially higher in the recurrent glioblastoma compared to the original, untreated tumors. In two other patient cohorts, they found that the higher RBM11 levels correlated with poor post-surgical survival for glioma patients.

Credit: 
University of Alabama at Birmingham

The Lancet: Police killings of unarmed black Americans impact mental health of wider black American population

Study highlights population mental health impact of events widely perceived to be a symptom of structural racism.

Police killings of unarmed black Americans have adverse effects on the mental health of black American adults in the general population, according to a new population-based study. With police killings of unarmed black Americans widely perceived to be a symptom of structural racism, the findings highlight the role of structural racism as a driver of population health disparities, and support recent calls to treat police killings as a public health issue.

The study was led by the Perelman School of Medicine at the University of Pennsylvania and Boston University School of Public Health (USA), in collaboration with Harvard University, and is published in The Lancet.

Police kill more than 300 black Americans - at least a quarter of them unarmed - each year in the USA. Black Americans are nearly three times more likely than white Americans to be killed by police and nearly five times more likely to be killed by police while unarmed [1]. Beyond the immediate consequences for victims and their families, the population-level impact has so far been unclear.

The quasi-experimental study combines data from the 2013-2015 US Behavioral Risk Factor Surveillance System (BRFSS), a nationally-representative, telephone-based survey of adults, with data on police killings from the Mapping Police Violence (MPV) database. By using statistical analysis, the authors estimate the "spillover" effect of police killings of unarmed black Americans on the mental health of other black Americans living in the general population.

A total of 103,710 black Americans took part in the BRFSS survey during the three-year study period and rated how many days in the past 30 days they felt their mental health (in terms of stress, depression and problems with emotion) was "not good." Half of the respondents were women, and half had been to university. 38,993 respondents (49% of the weighted sample) resided in a USA state where at least one police killing of an unarmed black American had occurred in the 90 days prior to the survey.

Each additional police killing of an unarmed black American in the 90 days before the survey was associated with an estimated 0.14 additional days of poor mental health among black Americans who lived in the same state. The greatest effects were seen 30-60 days after the police killing.

Black Americans are exposed to an average of four police killings in their state of residence each year. Extrapolating their findings to total population of 33 million black American adults, the authors estimate that police killings of unarmed black Americans could contribute 55 million excess poor mental health days per year among black American adults in the USA. These estimates suggest that the population mental health burden due to police killings is nearly as large as the population mental health burden associated with diabetes among black Americans.

"Our study demonstrates for the first time that police killings of unarmed black Americans can have corrosive effects on mental health in the black American community," says co-lead author Atheendar S. Venkataramani, a health economist and general internist at the University of Pennsylvania. "While the field has known for quite some time that personal experiences of racism can impact health, establishing a link between structural racism - and events that lead to vicarious experiences of racism - and health has proved to be more difficult." [2]

Adverse effects on mental health were limited to black Americans, and exposure to police killings of unarmed black Americans was not associated with any changes in self-reported mental health of white Americans. Exposure to police killings of armed black Americans was also not associated with changes in self-reported mental health among black or white Americans.

"The specificity of our findings is striking," says co-lead author Jacob Bor, a population health scientist at the Boston University School of Public Health. "Any occasion in which police resort to deadly force is a tragedy, but when police use deadly force against an unarmed black American, the tragedy carries with it the weight of historical injustices and current disparities in the use of state violence against black Americans. Many have interpreted these events as a signal that our society does not value black and white lives equally. Our findings show these events also harm the mental health of black Americans." [2]

The authors suggest that the mental health effects of police killings of unarmed black Americans might be conveyed through several different channels, including heightened perceptions of threat and vulnerability, lack of fairness, lower social status, lower beliefs about one's own worth, activation of prior traumas, and identification with the deceased.

The authors note several limitations that should prompt further research in the field. First, the BRFSS public-use dataset was limited to state-level identifiers, and there was no information on the extent to which respondents were directly aware of police killings nor whether respondents were aware of police killings in other states. If police killings affected the mental health of black Americans living in other states, then the study findings would be an underestimate of the true effect. Secondly, the measures used in the BRFSS are self-reported. Thirdly, the study does not focus on other ways in which the criminal justice system disproportionately targets black Americans, and it is likely that other forms of structural racism--such as segregation, mass incarceration, and serial forced displacement--also contribute to poor population mental health. Finally, the study did not include data on other vulnerable populations, such as Hispanics or Native Americans, nor did it consider the impact of police killings on the mental health of police officers themselves.

Senior author Alexander Tsai, a psychiatrist at the Massachusetts General Hospital and Harvard Medical School, says, "Therapists and first responders are all too familiar with the potentially devastating effects of vicarious trauma. By highlighting the effect of police killings on the wider community, our study provides evidence on a national scale that racism can be experienced vicariously. Interventions are needed to reduce the prevalence of these killings and to support the mental health of communities affected when they do occur. For example, in the wake of such killings, affected police departments could deploy greater resources to community problem oriented policing, give community stakeholders subpoena powers in investigating officer-involved shootings, and pursue disciplinary actions against involved officers with greater transparency." [2]

In a linked Comment, Dr Rhea W Boyd, Palo Alto Medical Foundation (USA) writes: "Racism lands, violently, on bodies - not as a function of race but as a function of how humans order society (racial hierarchy), assign power (racial supremacy), and distribute resources (racial inequity). Labelling the attributable mental health outcome a "spillover effect", the authors adjoin the taxonomy of terms such as "weathering" and "toxic stress" to articulate potential pathophysiological mechanisms for the built harm of racism. This intentional naming of racism is crucial to advancing an anti-racist praxis in medicine and public health... Despite (the) limitations, the findings (of the study) are urgent and instructive. (The authors') work to acknowledge and address the clinical impact of police killing black Americans sits within a broader clinical imperative to rigorously define and intervene in the relationship between structural racism and clinical outcomes. This evidence should ignite inquiry into the broader health impacts of police violence and advance the challenge to confront racial health inequities as products of racism."

Credit: 
The Lancet

Rare in-vivo study shows weak brain nodes have strong influence on memory network

Our ability to learn, remember, problem solve, and speak are all cognitive functions related to different parts of our brain. If researchers can identify how those brain parts communicate and exchange information with each other, clinicians and surgeons can better understand how diseases like Alzheimer's and brain cancer affect those cognitive functions.

The majority of existing simulation studies show that the parts of the brain with high connectivity, the so-called "hubs", are most important when it comes to several different cognitive tasks. But the results of a recent and rare in-vivo study just published in Nature Communications demonstrate that the nucleus accumbens (NAc) - a part of the brain with weak connections - plays an unexpectedly influential role in enhancing the memory network.

The study was led by Gino Del Ferraro, Research Associate in the Levich Institute at the City College of New York in collaboration with a team of CCNY researchers and a group of researchers at Instituto de Neurosciencia in Spain, led by Andrea Moreno. Del Ferraro and team provided the theoretical analysis, modeling and predictions, while the Spanish team performed the in-vivo validations of the predictions.

The study's goal was to identify which areas of the brain could be stimulated to enhance memory by identifying which are the influential nodes in the memory brain network within the three different areas for brain integration: hippocampus, prefontal cortex and nucleus accumbens (NAc).

Previous studies of cognitive tasks showed the NAc was downstream of the hippocampus and the prefontal cortex and thus not influential for brain integration. In fact Del Ferraro and team proved that, for memory formation, the NAc is upstream and influential.

The results of the CCNY-led research are worth noting, as is the methodology used to achieve them. Del Ferraro observes: "The effects of removing a node from a network has been studied with simulations, both for human and animal brain networks, but direct in-vivo validations are rare. Thus, up to this point, there was no well-grounded approach to predict which nodes are essential for brain integration."

Del Ferraro and team are currently collaborating with Memorial Sloan Kettering Cancer Center in NYC, trying to apply similar techniques on people who have brain cancer in the language parts of the brain. They are attempting to identify which are the essential nodes for language production so that if patients undergo neural surgery, the surgeon knows which parts of the brain need to be preserved.

Credit: 
City College of New York