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PHILADELPHIA and MELBOURNE, Australia -- (May. 17, 2021) -- A team of scientists from The Wistar Institute in Philadelphia and the Peter MacCallum Cancer Center in Melbourne, Australia, discovered a new checkpoint mechanism that fine-tunes gene transcription. As reported in a study published in Cell, a component of the Integrator protein complex tethers the protein phosphatase 2A (PP2A) to the site of transcription allowing it to stop the activity of the RNA polymerase II enzyme (RNAPII). Disruption of this mechanism leads to unrestricted gene transcription and is implicated in cancer.

The study points to new viable opportunities for therapeutic intervention demonstrating the anti-cancer effect of a new combination treatment in preclinical models of solid and hematopoietic malignancies.

Gene expression is the first step in the process by which the information encoded by a gene is used to make proteins. Controlling the timing and level of gene expression is crucial for cells to perform their specific functions within an organism, adapt to the surrounding conditions and properly respond to external stimuli.

The team, led by Alessandro Gardini, Ph.D., assistant professor in the Gene Expression & Regulation Program at The Wistar Institute, and Ricky Johnstone, Ph.D., professor, executive director of Cancer Research at the Peter MacCallum Cancer Centre, and head of The Sir Peter MacCallum Department of Oncology at the University of Melbourne, discovered a new checkpoint in the regulation of RNAPII, the enzymes that carries out transcription of DNA into RNA for gene expression.

"Cancer is a consequence of altered gene expression, as turning on or off one or more genes at the wrong time or in the wrong cells can dramatically alter their overall behavior and lead to unrestrained growth," said Gardini. "We describe one of the essential ways through which gene transcription is kept in check."

"We think our discovery provides new insight into how gene expression is tightly controlled," said Johnstone. "This represents a completely new potential avenue for cancer treatment and our initial studies in mice suggested this could also improve the effect of another emerging treatment approach -- CDK9 inhibition -- in both blood-based and solid tumours."

Transcription by the RNAPII enzyme takes place in several steps, each tightly controlled through the opposing functions of cyclin-dependent kinases (CDKs), which modify the enzyme by adding phosphate groups to different parts of the protein, and phosphatases that remove those phosphate groups and counteract CDK activity.

The team uncovered the involvement of a phosphatase called Protein Phosphatase 2A (PP2A) in this regulatory balance. Though PP2A performs the majority of phosphatase activities in a cell, this study provides evidence that it also plays a critical role in transcription.

CDK9 is one of the CDKs that activate RNAPII by promoting elongation, the step in which synthesis of a nascent RNA chain continues as RNAPII moves along the DNA template.

The team found that a component of Integrator, a central regulator of transcriptional processes, interacts with the PP2A phosphatase to recruit it to sites of transcription, where it counteracts CDK9 activity, and blocks transcription elongation. PP2A and CDK9 work in tandem to fine-tune the balance between activation and inhibition of transcription.

Then, researchers tested the hypothesis that targeting the PP2A-Integrator-CDK9 axis in cancer by simultaneously blocking CDK9 and activating PP2A could afford therapeutic benefit in mouse models of leukaemia and solid cancers. Combining treatment with inhibitors of CDK9 (CDK9i) and small molecule activators of PP2A (SMAPs) killed acute myeloid leukemia cells, driving prolonged therapeutic effect and significantly longer survival compared to either single agent. Similarly, combination therapy in a solid tumor model demonstrated reduced tumor growth rates and tumor volume, resulting in enhanced overall survival.

Collectively, this study describes a new fundamental mechanism of gene expression regulation and demonstrates that concomitant CDK9 inhibition and PP2A activation results in enhanced anti-cancer effects in preclinical models of both solid and hematopoietic malignancies, opening new avenues for transcription-based anticancer therapy.

Viruses attack the body by sending their genetic code -- DNA and RNA -- into cells and multiplying. A promising class of therapeutics that uses synthetic nucleic acids to target and shut down specific, harmful genes and prevent viruses from spreading is gaining steam.

However, only a handful of siRNA, or other RNA interference-based therapeutics have been approved. One of the main problems is getting the siRNA into the body and guiding it to the target.

Chemical engineering researchers in the Cockrell School of Engineering aim to solve that problem, while improving the targeting effectiveness of siRNA. In a new paper in the Journal of Controlled Release, the researchers created several different types of nanoparticles and analyzed them for the ability to deliver and protect siRNA from the body's immune system.

"The human body is such a diverse place with so many systems to protect us from foreign materials," said Aaliyah Shodeinde, a fourth-year graduate researcher in the McKetta Department of Chemical Engineering working in professor and drug delivery pioneer Nicholas Peppas' lab. "So, whenever you try to introduce a synthetically derived material, it almost immediately activates the immune system's defenses, so you need some kind of protection for the siRNA."

Several different types of nanoparticles created in Peppas' lab proved effective at siRNA delivery. The research team measured how well the particles can take in stimuli from their environment, such as changing levels of pH, and adjust accordingly without breaking down.

The team sought to find the right balance between protection and effectiveness of the siRNAs in silencing harmful genes while also minimizing the toxicity of the particles.

"Researchers need to keep in mind that a perfect system may not be feasible at this time because of the need to find a balance with so many moving parts," Shodeinde said. "What we've been able to achieve successfully is modulating so many different parameters to find that sweet spot."

siRNA is so exciting to researchers because it can be fine-tuned to hinder many different kinds of genes in the body. They then specifically target the mRNA -- short for messenger RNA -- that tell cells what to do. mRNA has become a part of the popular lexicon lately because several of the COVID-19 vaccines use mRNA to tell cells to produce antibodies to fight off the coronavirus spike proteins.

Shodeinde notes that symptoms in many diseases come from the over- or under-production of proteins. siRNA can be configured to find genes enabling this irregular protein production and, more or less, shut them down. This "upstream" solution is something that traditional therapies can't achieve, Shodeinde said.

"siRNAs come in before the protein expression level, so we're hoping that using them to alter the gene expression levels can give us better results," she said.

This work builds on several previous papers that have come out of Peppas' lab focused on developing hydrogels and nanoparticles for drug delivery. Just last week Peppas, Shodeinde and Deidra Ward, a chemical engineering Ph.D. student, published a new paper about this in Advanced Healthcare Materials. In it, the authors discuss their vision for the future of RNA-based therapeutics in the treatment of certain types of cancers.

"The results of this new research from our laboratories are promising and add on to our previous research on siRNA delivery that commenced about 10 years ago and has led to about 15 refereed publications and two issued U.S. patents," said Peppas, the principal investigator of the siRNA paper.

Up next, the researchers want to improve cell targeting. It is key, Shodeinde said, to making sure the siRNAs only interact with target cells and don't shut down anything they're not supposed to.

One of the especially dangerous health risks of being extremely overweight occurs when an obese person begins to accumulate fat in their liver.

This condition--non-alcoholic fatty liver disease (NAFLD)--is the world's most common chronic liver disease and is the primary underlying cause for liver transplants in children and adults. Without such transplants, which are available to only a small percentage of patients, NAFLD over time can be fatal. In fact, (excluding alcohol-related liver damage) more than 30,000 people a year die from NAFLD.

For years, the primary way to treat NAFLD has been through the use of various weight control methods: diet programs, exercise regimens, medications of limited benefit, bariatric surgery, and more. But once people develop progressive NAFLD, simply losing weight is not enough.

Now, after years of studying the numerous mechanisms involved with obesity and NAFLD, a team of 20 scientists at Cincinnati Children's reports taking a significant step forward. Their findings were published online May 17, 2021, in Cell Metabolism.

Introducing ihTh17 cells

The research team reports that excessive fat deposition in the liver due to obesity can alter the microenvironment of the liver in a way that attracts a highly specific population of immune T cells to the liver. These "inflammatory hepatic CXCR3+Th17 cells" or "ihTh17" cells go on to trigger excess inflammation and life-threatening liver damage.

By running a series of experiments using human tissues and cells and multiple lines of genetically modified mice, the team found that obesity itself triggers activity along a molecular "pathway" that starts with excess expression of the CXCL10 and CXCR3 genes. This abnormal activity attracts more and more ihTh17 cells to the liver. The consequence being a scorched earth inflammatory feedback loop that recruits additional immune cells and progressively damages liver function.

After tracing the ihTh17 cell liver recruitment pathway, the team set out to find a way to break the unhealthy cycle of inflammation. They found success with mice bred to lack expression of the gene Pkm2 in their T cells, which appears to be crucial to continued activity along the CXCR3 pathway.

When these modified mice were given obesity-inducing diets, they still got fat. But they suffered notably less liver damage than non-modified mice.

Next, the researchers tested human tissues collected from people with NAFLD. They confirmed that many of the key genes and molecular activities occurring in the mice also could be detected in the human liver cells.

"Our results demonstrate for the first time that ihTh17 cells represent an important component of the complex world of NAFLD pathogenesis," say corresponding author Senad Divanovic, PhD, a member of the Division of Immunobiology at Cincinnati and first author Maria Moreno-Fernandez, PhD, a postdoctoral fellow in the Divanovic laboratory.

Learning more about how to regulate ihTh17 cells' function and their interaction with the liver cells and the immune system could lead to new therapies to reduce the harm caused by NAFLD.

Next steps

But will the treatment approach used in mice also help people? Human gene editing is not likely to be an acceptable option for this condition anytime soon. However, some drugs are known to be capable of blocking Pkm2 activity, Divanovic says.

Those drugs still require more in-depth laboratory evaluation. Ultimately, a promising compound also would need to be tested in multi-year clinical trials. But now, for the first time in years, the team has a promising lead to explore.

"If we can modulate the unwanted inflammatory responses associated with NAFLD in a targeted way we may be able to ameliorate the liver damage and improve the survival and health of people with NAFLD," Divanovic says.

PITTSBURGH, May 17, 2021 - Monoclonal antibodies, a COVID-19 treatment given early after coronavirus infection, cut the risk of hospitalization and death by 60% in those most likely to suffer complications of the disease, according to an analysis of UPMC patients who received the medication compared to similar patients who did not.

UPMC and University of Pittsburgh School of Medicine physician-scientists published the findings today in Open Forum Infectious Diseases, a journal of the Infectious Diseases Society of America. The study involved bamlanivimab, a monoclonal antibody that is now offered only in combination with another monoclonal antibody to further increase its effectiveness--a change mandated by the federal government after the study's completion.

"The fact that we found bamlanivimab to be this effective in keeping our patients with COVID-19 out of the hospital bodes very well for the future use of the currently available monoclonal therapies, something we are studying now," said lead author Ryan Bariola, M.D., associate professor in Pitt's Division of Infectious Diseases and director of the UPMC Community Hospital Antimicrobial Stewardship Efforts (CHASE) Program. "If given early to high-risk patients, this treatment works to prevent COVID-19-related complications. We look forward to research with next-generation monoclonal antibodies and hope to continue to find safe and effective treatments for our patients."

Monoclonal antibodies are a type of medication that seeks out the COVID-19 virus in a person's body and blocks it from infecting their cells and replicating. Currently, the U.S. Food & Drug Administration has granted Emergency Use Authorization to two monoclonal antibody treatments, which are given through a one-time IV infusion. This is the same type of emergency authorization given to the COVID-19 vaccines being administered in the U.S.

Federal and UPMC guidelines require the antibodies be administered within 10 days of COVID-19 symptom onset and diagnosis for patients at high risk of a poor outcome, including patients of advanced age, who are obese or those with conditions such as diabetes or lung disease.

UPMC has given monoclonal antibody infusions to 2,600 qualifying patients. The researchers analyzed data on the first 232 patients treated with bamlanivimab to learn how they've fared since their infusions. They compared antibody-treated patients' data to that of a matched set of patients of similar age and health status who had contracted COVID-19 and were eligible for the treatment but did not receive it.

The strongest effect was seen in older patients. Those age 65 and older who received monoclonal antibodies from UPMC were nearly three times less likely to be hospitalized or die in the following month, compared to their untreated counterparts. The results were less pronounced in younger populations, but overall, more positive results were seen in those who received monoclonal antibody infusions than in those who did not.

UPMC's data also showed a stronger positive effect the earlier patients received the treatment after contracting the virus, and a very low rate of adverse reactions to the infusion, all of which were mild.

"If there's one key take-away that we're seeing in our data, it's this: If you get COVID-19 and are at higher risk for severe illness, ask your doctor about monoclonal antibodies," said Graham Snyder, M.D., M.S., medical director of infection prevention and hospital epidemiology at UPMC and associate professor in Pitt's School of Medicine. "Don't hesitate. Early treatment, while your symptoms are still mild, may be essential."

PULLMAN, Wash. -- Washington State University researchers have developed an innovative way to convert plastics to ingredients for jet fuel and other valuable products, making it easier and more cost effective to reuse plastics.

The researchers in their reaction were able to convert 90% of plastic to jet fuel and other valuable hydrocarbon products within an hour at moderate temperatures and to easily fine-tune the process to create the products that they want. Led by graduate student Chuhua Jia and Hongfei Lin, associate professor in the Gene and Linda Voiland School of Chemical Engineering and Bioengineering, they report on their work in the journal, Chem Catalysis.

"In the recycling industry, the cost of recycling is key," Lin said. "This work is a milestone for us to advance this new technology to commercialization."

In recent decades, the accumulation of waste plastics has caused an environmental crisis, polluting oceans and pristine environments around the world. As they degrade, tiny pieces of microplastics have been found to enter the food chain and become a potential, if unknown, threat to human health.

Plastics recycling, however, has been problematic. The most common mechanical recycling methods melt the plastic and re-mold it, but that lowers its economic value and quality for use in other products. Chemical recycling can produce higher quality products, but it has required high reaction temperatures and a long processing time, making it too expensive and cumbersome for industries to adopt. Because of its limitations, only about 9% of plastic in the U.S. is recycled every year.

In their work, the WSU researchers developed a catalytic process to efficiently convert polyethylene to jet fuel and high-value lubricants. Polyethylene, also known as #1 plastic, is the most commonly used plastic, used in a huge variety of products from plastics bags, plastic milk jugs and shampoo bottles to corrosion-resistant piping, wood-plastic composite lumber and plastic furniture.

For the process, the researchers used a ruthenium on carbon catalyst and a commonly used solvent. They were able to convert about 90% of the plastic to jet fuel components or other hydrocarbon products within an hour at a temperature of 220 degrees Celsius (428 degrees Fahrenheit), which is more efficient and lower than temperatures that would be typically used.

Jia was surprised to see just how well the solvent and catalyst worked.

"Before the experiment, we only speculated but didn't know if it would work," he said. "The result was so good."

Adjusting processing conditions, such as the temperature, time or amount of catalyst used, provided the critically important step of being able to fine-tune the process to create desirable products, Lin said.

"Depending on the market, they can tune to what product they want to generate," he said. "They have flexibility. The application of this efficient process may provide a promising approach for selectively producing high-value products from waste polyethylene."

With support from the Washington Research Foundation, the researchers are working to scale up the process for future commercialization. They also believe their process could work effectively with other types of plastics.

A valve invented by engineer Nikola Tesla a century ago is not only more functional than previously realized, but also has other potential applications today, a team of researchers has found after conducting a series of experiments on replications of the early 20th-century design.

Its findings, reported in the journal Nature Communications, suggest that Tesla's device, which he called a "valvular conduit," could harness the vibrations in engines and other machinery to pump fuel, coolants, lubricants, and other gases and liquids.

Now known as the Tesla Valve, the patented device has inspired strategies for directing streams within flow networks and circuits.

"It's remarkable that this 100-year-old invention is still not completely understood and may be useful in modern technologies in ways not yet considered," explains Leif Ristroph, an associate professor in New York University's Courant Institute of Mathematical Sciences and the paper's senior author. "While Tesla is known as a wizard of electric currents and electrical circuits, his lesser-known work to control flows or fluid currents was truly ahead of its time."

The Tesla Valve--a series of interconnected teardrop-shaped loops--was designed to pass flows of fluid in only one direction and with no moving parts. The device provides a clear path for forward flows, but the route is slower for reverse flows--but this latter drawback in fact points to a potential, unrealized benefit in circumstances when flows need to be controlled rather than unleashed.

To understand the valve's functionality, Ristroph and his co-authors, Quynh Nguyen, an NYU physics graduate student, and Joanna Abouezzi, an NYU undergraduate at the time of the research, conducted a series of experiments in NYU's Applied Mathematics Lab. Here, they replicated the Tesla Valve's design and subjected it to tests that measured its resistance to passing flow in the two directions.

Overall, they found that the device responds a bit like a switch. At low flow rates there is no difference in resistance for forward and reverse flows, but above a certain flow speed the device abruptly "turns on" and significantly checks or resists reverse flows.

"Crucially, this turn-on comes with the generation of turbulent flows in the reverse direction, which 'plug' the pipe with vortices and disrupting currents," explains Ristroph. "Moreover, the turbulence appears at far lower flow rates than have ever previously been observed for pipes of more standard shapes--up to 20 times lower speed than conventional turbulence in a cylindrical pipe or tube. This shows the power it has to control flows, which could be used in many applications."

An image depicting the work is available on Google Drive.

In addition, they found that the valve works even better when the flow is not steady--when it comes in pulses or oscillations, which the device then converts into smooth and directed output flow. This pumping action mimics the AC-DC converters that transform alternating current to direct current.

"We think this is what Tesla had in mind for the device, since he was thinking about analogous operations with electrical currents," observes Ristroph. "He in fact is most famous for inventing the AC motor as well as an AC-DC converter."

Today, given the valve's ability to control flows and to generate turbulence at low speeds, Ristroph sees possibilities for Tesla's early 20th-century invention.

"Tesla's device is an alternative to the conventional check valve, whose moving parts tend to wear out over time," Ristroph explains. "And now we know it is very effective at mixing, and it could be used to harness the vibrations in engines and machinery to pump fuel, coolant, lubricant, or other gases and liquids."

A team of McMaster University researchers who studied heart patients found that stair-climbing routines, whether vigorous or moderate, provide significant cardiovascular and muscular benefits.

The findings, published in closely related studies in the journals Medicine & Science in Sports & Exercise and Frontiers, address the most frequently cited barriers to exercise: time, equipment and access to gym facilities.

"Brief, vigorous stair-climbing and traditional moderate intensity exercise both changed fitness, which is a key predictor of mortality after a cardiac event," says Maureen MacDonald, one of the lead researchers on both studies and a professor in McMaster's Department of Kinesiology.

"We've shown stair-climbing is a safe, efficient and feasible option for cardiac rehabilitation, which is particularly relevant during the pandemic when many people don't have the option to exercise in a gym," she says.

While it is widely known that exercise and lifestyle changes reduce the risk of secondary cardiovascular disease, statistics suggest less than a quarter of all cardiac patients adhere to fitness programs.

Researchers worked closely with the Cardiac Health and Rehabilitation Centre at the Hamilton General Hospital to develop an exercise protocol that did not require specialized equipment or monitoring and could be easily performed outside a laboratory.

Participants with coronary artery disease who had undergone a cardiac procedure were randomly assigned either to traditional moderate-intensity exercise or vigorous stair climbing: three rounds of six flights of 12 stairs, separated by recovery periods of walking, with participants selecting their own stepping pace.

Researchers compared the results and found that individuals who had done traditional exercise and those who had done stair-climbing both increased their cardiorespiratory fitness after four weeks of supervised training and maintained those levels for an additional eight weeks of unsupervised training.

They also reported substantial muscular improvement.

"These patients who had undergone a coronary bypass or stent procedure had muscle that was compromised, compared to age-matched healthy controls," explained Stuart Phillips, a co-author of the studies and a professor in the Department of Kinesiology at McMaster who oversaw the analysis of muscle tissue taken during the study.

Previously, there had been very few studies of the impact of exercise on cardiac patients' muscle specifically. This analysis shows heart patients can still repair and build lost muscle.

"Even in just a short period, whether it was moderate intensity, continuous training or high-intensity stair climbing, there were beneficial adaptations in muscles after a cardiac procedure," Phillips says. "The improvements were clear."

Oncotarget published "The cancer testis antigens CABYR-a/b and CABYR-c are expressed in a subset of colorectal cancers and hold promise as targets for specific immunotherapy" which reported that Calcium-binding tyrosine phosphorylation-regulated protein is expressed in the human germ line but not in adult human tissues, thus, it is considered a cancer testis protein.

The aim of this study is to evaluate the CABYR isoforms: a/b and c mRNA expression in colorectal cancer and to determine if these proteins hold promise as vaccine targets.

CABYR mRNA expression in a set of normal human tissues, including the testis, were determined and compared using semi-quantitative PCR.

Analysis of CABYR protein expressions by immunohistochemistry in tumor and normal colon tissues was also performed.

The percent of patients with a relative expression ratio of malignant to normal tissues over 1 was 70% for CABYR a/b and 72% for CABYR c. The percent with both a M/N ratio over 1 and expression levels over 0.1% of testis was 23.4% for CABYR-a/b and 25.5% for CABYR c. CABYR expression in tumors was further confirmed by immunohistochemistry.

CABYR expression in tumors was further confirmed by immunohistochemistry

Dr. Richard L. Whelan from The Lenox Hill Hospital as well as The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell said, "Colorectal cancer is the third diagnosed cancer type as well as the second most common reason of cancer death in the United States, [1] however, in the last 30 years, there has been a substantial improvement in colorectal cancer associated mortality."

Cancer Testis Antigens, a subcategory of Tumor Associated Antigens, are a group of proteins that hold specific promise because they are expressed in the human germ line, but not in adult human tissues.

As mentioned, because tumors express these proteins while normal adult tissues do not, select CTAs may have value as vaccine targets.

By performing real-time PCR to determine expression levels of CABYR a/b and c in the tissues of lung cancer patients, they were able to find expression in 36% and 42% of lung cancer tissues, respectively.

Additionally, CABYR c is highly expressed in hepatocellular carcinoma tissues and may play an oncogenic role in hepatocarcinogenesis, thus far, the expression of CABYR in colorectal tumors has not been previously studied.

The Whelan Research Team concluded in their Oncotarget Research Output that as regards the shortcomings of this study, the lack of plasma or serum auto-antibody data was already mentioned.

Other shortcomings of the study include the fact that while this study did include tumor samples from CRC stages 2–4 there were only two samples from stage IV patients and none from stage I patients.

Ideally, reasonable numbers of specimens for each cancer stage would be assessed; the need for Stage 4 tumors is especially important to determine if CABYR expression, in general and for the individual isoforms, correlates with disease stage.

Presently, because of the relatively small number of samples studied it is not possible to state whether CABYR expression correlates with tumor stage.

Finally, this report supplies no oncologic outcome data for the patients included in this study.

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DOI - https://doi.org/10.18632/oncotarget.27897

Full text - https://www.oncotarget.com/article/27897/text/

Correspondence to - Richard L. Whelan - Rwhelan1@northwell.edu

Keywords -
cancer testis antigens,
colorectal cancer,
CABYR a/b, c

About Oncotarget

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Journal

Oncotarget

DOI

10.18632/oncotarget.27897

A new study led by KAIST researchers using fruit flies reveals how protein deficiency in the diet triggers cross talk between the gut and brain to induce a desire to eat foods rich in proteins or essential amino acids. This finding reported in the May 5 issue of Nature can lead to a better understanding of malnutrition in humans.

"All organisms require a balanced intake of carbohydrates, proteins, and fats for their well being," explained KAIST neuroscientist and professor Greg Seong-Bae Suh. "Taking in sufficient calories alone won't do the job, as it can still lead to severe forms of malnutrition including kwashiorkor, if the diet does not include enough proteins," he added.

Scientists already knew that inadequate protein intake in organisms causes a preferential choice of foods rich in proteins or essential amino acids but they didn't know precisely how this happens. A group of researchers led by Professor Suh at KAIST and Professor Won-Jae Lee at Seoul National University (SNU) investigated this process in flies by examining the effects of different genes on food preference following protein deprivation.

The group found that protein deprivation triggered the release of a gut hormone called neuropeptide CNMamide (CNMa) from a specific population of enterocytes - the intestine lining cells. Until now, scientists have known that enterocytes release digestive enzymes into the intestine to help digest and absorb nutrients in the gut. "Our study showed that enterocytes have a more complex role than we previously thought," said Professor Suh.

Enterocytes respond to protein deprivation by releasing CNMa that conveys the nutrient status in the gut to the CNMa receptors on nerve cells in the brain. This then triggers a desire to eat foods containing essential amino acids.

Interestingly, the KAIST-SNU team also found that the microbiome - Acetobacter bacteria - present in the gut produces amino acids that can compensate for mild protein deficit in the diet. This basal level of amino acids provided by the microbiome modifies CNMa release and tempers the flies' compensatory desire to ingest more proteins.

The research team was able to further clarify two signalling pathways that respond to protein loss from the diet and ultimately produce the CNMa hormone in these specific enterocytes.

The team said that further studies are still needed to understand how CNMa communicates with its receptors in the brain, and whether this happens by directly activating nerve cells that link the gut to the brain or by indirectly activating the brain through blood circulation. Their research could provide insights into the understanding of similar process in mammals including humans.

"We chose to investigate a simple organism, the fly, which would make it easier for us to identify and characterize key nutrient sensors. Because all organisms have cravings for needed nutrients, the nutrient sensors and their pathways we identified in flies would also be relevant to those in mammals. We believe that this research will greatly advance our understanding of the causes of metabolic disease and eating-related disorders," Professor Suh added.

Scientists at Skoltech Center for Energy Science and Technology have developed an enriched and scalable approach for increasing the capacity of a broad range of metal-ion battery cathode materials. These findings, published in Journal of Materials Chemistry A, can be useful for developing a new generation of advanced rechargeable energy storage devices.

Creation of modern lithium-ion batteries became possible owing to several scientific breakthroughs. One of them, made by a Nobel laureate John B. Goodenough, was the development of cathode materials that contain reversibly extractable lithium ions. Implementation of these materials helped to avoid unsafe anodes, such as lithium metal. However, problems including limited capacity, moderate cycling stability, low charge-discharge rate, issues with environmental friendliness, etc., still had to be solved.

Over the decades, researchers have been putting tremendous effort into developing better battery materials. As a result, various cathode materials with attractive properties have been proposed. However, the batteries that rely on these materials can often reach their full energy density only when they contain unsafe, highly reactive anodes with extractable cations. It is caused by the lack of mobile metal ions in the cathodes. This issue leads to the limited capacity and, in many cases, complicates practical implementation of otherwise appealing materials.

Skoltech PhD student Roman Kapaev under supervision of Prof. Keith Stevenson showed how this problem can be solved for a broad range of materials. It was proposed to treat the cathodes with solutions of reducing agents, which are alkali metal salts derived from aromatic compounds, for example, naphthalene or phenazine.

An important advantage of the approach is its scalability. The process requires no sophisticated conditions and is relatively safe. Additionally, the reducing agents can be recycled after they react with the cathodes because their redox chemistry is reversible. These features make the method promising for large-scale applications.

This approach is suitable for a broad spectrum of organic and inorganic battery materials. Moreover, it turned out to be applicable not only for lithium-ion batteries, but also for sodium- and potassium-ion batteries, which are potentially more sustainable and lower-cost energy storage devices. It was possible to control the content of metal ions in the cathodes by adjusting the amount of the reducing agents or their oxidation potentials.

"The approach can serve as a powerful toolkit, which may be used to improve the performance of various battery materials", -- says Roman Kapaev, -- "It is also a straightforward and inexpensive method with recyclable reagents, so we believe that it is suitable for large scale practical applications".

A weather pattern that pushes snowfall away from parts of Greenland's ice sheet is causing the continent to become darker and warmer, according to Dartmouth research published in Geophysical Research Letters.

The reduction in the amount of fresh, light-colored snow exposes older, darker snow on the surface of the ice sheet. The resulting decrease in reflectivity, known as albedo, causes the ice to absorb more heat, also likely contributing to faster melting.

"As snow ages, even over hours to a few days, you get this reduction in reflectivity, and that's why the fresh snow is so important," said Erich Osterberg, associate professor of earth sciences at Dartmouth and the principal investigator of the study.

According to the research, the decrease in snowfall is the result of "atmospheric blocking" in which persistent high-pressure systems hover over the ice sheet for up to weeks at a time. The systems, which have increased over Greenland since the mid-1990s, push snowstorms to the north, hold warmer air over Western Greenland, and reduce light-blocking cloud cover.

"It's like a triple whammy effect," Osterberg said. "This all contributes to Greenland melting faster and faster."

According to the research, the result isn't only less snowfall, it's a different type of snow on the surface.

As snowflakes melt or evaporate, they become rounded and less reflective than newer, crystal-shaped snow. This causes the snow surface to become darker. According to the research team, a 1% change in reflectivity across Greenland's ice sheet could cause an additional 25 gigatons of ice to be lost over three years.

"Fresh snow looks like what you would draw in a kindergarten class or cut from a piece of paper - it's got all these really sharp points, and that's because it's extremely cold in the atmosphere when the snow falls," said Gabriel Lewis, the first author of the study, who conducted the research as a PhD candidate at Dartmouth. "Once it falls and sits on the surface of the ice sheet in the sun, it changes shape and the snow grains become larger over time."

The team gathered data for the study during a two-summer 2,700-mile snowmobile trek across a region of Greenland's ice sheet known as the western percolation zone.

The researchers found only about 1 part per billion of impurities in the snow. This helped them determine that the changing shape of snowflakes, forced by the persistent high-pressure systems, was the likely cause of the darkening, rather than soot, dust, or microorganisms.

"It's some of the cleanest snow in the world," said Lewis, "In our research area, the impurities do not appear to be enough to account for the change in albedo other research teams have reported."

According to research cited in the study, the Greenland ice sheet has warmed about 2.7 degrees Celsius (4.85 degrees Fahrenheit) since 1982. The continent is experiencing the greatest melt and runoff rates in the last 450 years, at a minimum, and likely the greatest rates in the last 7,000 years.

In our ongoing quest to transform into a more eco-friendly society, hydrogen (H2) is heralded as the clean fuel of tomorrow. Because H2 can be produced from water (H2O) without generating carbon emissions, developing H2-compatible technologies has become a top priority. However, the road ahead is bumpy, and many technical limitations must be ironed out. "Hydrogen is the smallest molecule in nature, and finding feasible ways to store it is a critical issue to realize a hydrogen economy," states Associate Professor Youngjune Park from the Gwangju Institute of Science and Technology (GIST) in Korea. Unlike hydrocarbons, pure H2 must be stored at an extremely high pressure (>100 atmospheres) or low temperature (20 °C). Naturally, this represents a huge economic barrier for H2 storage. But what if we could trap H2 inside ice-like crystals to make storage and transportation less demanding?

These molecular cages exist in nature and are called 'clathrate hydrates.' They are solid water-based compounds with cavities that can accommodate various molecules. Dr. Park's group at GIST has been researching the use of clathrate hydrates as vessels for H2 storage. However, the enclathration of pure H2 is still a slow process that also requires extreme temperature and pressure conditions.

In a recent study published in volume 141 May 2021 print issue of Renewable and Sustainable Energy Reviews, Dr. Park's group explored a feasible solution to this problem. Instead of trying to form clathrate hydrates out of pure H2, previous researchers have suggested mixing it with natural gas, which was experimentally shown to promote enclathration at milder conditions. To improve upon this strategy, the team of GIST scientists set out to find the best hydrogen-natural gas blend (HNGB) for the energy-efficient formation of clathrate hydrates. To this end, they systematically investigated clathrate hydrates produced from HNGBs with different concentrations of methane, ethane, and hydrogen. They carefully analyzed the clathrate formation kinetics and structure and the distribution of trapped molecules.

The team was able to identify the precise gas concentrations at which point methane and ethane, acting as thermodynamic modulators, best enhance the H2 storage capacity of HNGB hydrates. Even at moderate pressure and temperature conditions (2 storage possible for two types of clathrate hydrate cages: two and four H2 molecules in small and large cages, respectively. This feat had not been reported before, and the unprecedented findings of this study could thus help in the design of HNGB hydrate storage media.

Dr. Park observes, "Clathrate hydrates and HNGBs could provide a reasonable mid-term solution for storing what is known as 'blue' hydrogen, which is hydrogen produced using fossil fuel-based technology but with minimal CO2 emissions." Today, blue hydrogen is three times cheaper to produce than eco-friendly 'green' hydrogen. Therefore, the results of this study may help ease the gradual transition away from fossil fuels towards hydrogen, which is our key to a sustainable future.

A randomized double-blind controlled trial of convalescent plasma for adults hospitalized with severe COVID-19 found that mortality at 28 days in the treatment arm was half the rate seen in the control arm (12.6% vs. 24.6%), although treatment was not associated with other improvements in clinical status.

The study was led by investigators from the Center for Infection and Immunity at Columbia University Mailman School of Public Health; Columbia University Irving Medical Center; ICAP at Columbia University; Instituto Nacional de Infectologia and Hospital Federal dos Servidores do Estado in Rio de Janeiro, Brazil; University of Washington; and New York Blood Center. The results are published in the Journal of Clinical Investigation.

According to the investigators, one possible explanation for the discrepancy between lack of clinical improvement and improved survival is that severely ill Covid-19 patients survived but remained hospitalized at their baseline status. The study also reports trends towards improved clinical status among patients who received convalescent plasma less than seven days after symptom onset and those who received convalescent plasma with higher-titers of neutralizing antibody and concomitant corticosteroids.

The investigators conducted this randomized, double-blind, placebo-controlled trial among adults hospitalized with severe and critical COVID-19 at 5 sites, including 73 patients enrolled in New York City and 150 enrolled in Rio de Janeiro. Patients were randomized in a 2:1 ratio to receive a single transfusion of either convalescent plasma or normal control plasma.

The median age of participants was 61 years and two-thirds of them were male. In a subset of nasopharyngeal swab samples from Brazil that underwent viral genomic sequencing, no evidence of neutralization-escape mutants was detected.

"We should not close the door prematurely on research into the therapeutic value of convalescent plasma research for severe COVID-19, particularly in the context of emerging viral variants in low- and middle-income countries," says first and corresponding author Max R. O'Donnell, MD, associate professor of medicine and epidemiology, and member of the Center for Infection and Immunity at Columbia Irving Medical Center. "Locally donated convalescent plasma has the potential to be highly responsive to local viral ecology and sustainable, since many countries already have the infrastructure needed to collect and transfuse donated plasma."

"This is the first clinical trial sponsored by the Global Alliance for Preventing Pandemics. It illustrates the role of international collaborations in responding to emerging infectious diseases," says W. Ian Lipkin, MD, director of the Center for Infection and Immunity and John Snow Professor of Epidemiology at Columbia University Mailman School of Public Health.

PAST RESEARCH ON CONVALESCENT PLASMA

Observational studies have suggested possible clinical efficacy and safety using convalescent plasma, primarily among patients who were not receiving invasive mechanical ventilation and those with shorter durations of illness. Despite these signals, data from randomized controlled trials supporting the use of convalescent plasma in hospitalized COVID-19 patients are limited. Open-label trials, including the large Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial, reported no significant improvements in clinical outcomes among patients hospitalized with severe COVID-19. A double-blind, placebo-controlled trial in Argentina also reported no improvement in clinical outcomes using the therapy with the same type of patients. Another Columbia-led is underway in Brazil to test the effectiveness of convalescent plasma in patients who have less severe disease.

POTENTIAL ADVANTAGES OF CONVALESCENT PLASMA

Convalescent plasma may be donated and transfused locally, therefore its use may be more adaptable to a rapidly changing mix of SARS-CoV-2 variants than other interventions. In contrast, monoclonal antibody therapies may need to be repeatedly engineered and combined to optimize potency among emergent variants. Further, since the collection and distribution of convalescent plasma can be performed using existing blood donation protocols and infrastructure, the therapy may be more scalable for use in low- and middle-income countries.

A long noncoding RNA whose function was previously unknown turns out to play an important role in promoting the body's immune response against cancer and holds promise for enhancing the efficacy of anti-cancer immunotherapy.

That's according to new findings reported in Nature Cell Biology by researchers at the University of Michigan Rogel Cancer Center.

The group dubbed the RNA they identified LIMIT -- for long noncoding RNA inducing major histocompatibility complex class I and immunogenicity of tumor.

"LIMIT is easy to remember, but really it does the opposite. It stimulates immune functions against cancer," says senior study author Weiping Zou, M.D., Ph.D., the Charles B. de Nancrede Professor of Pathology, Immunology, Biology, and Surgery at U-M.

Only a small part of the human genome contains genes that encode proteins. The rest includes more than 30,000 long "noncoding" RNAs, or lncRNAs, most of whose functions remain unknown.

LncRNAs are known to play some important roles in cancer, but very little is known about their roles in the context of the immune system's response to cancer, Zou says.

"LncRNAs have mainly been studied in cancer models that lack a functioning immune system, leaving a big gap in our knowledge," adds study first author Gaopeng Li, Ph.D., a research fellow in Zou's lab. "When it works, immunotherapy can be amazingly successful, but doesn't work in more than half of patients. We wanted to better understand what role lncRNAs play and whether there might be opportunities to target them to improve immunotherapy."

Immunotherapy tends to be most effective in patients with whose tumors are more susceptible to infiltration by the immune system's T cells. By comparing cancers with low levels of T cell infiltration to those with high infiltration, the researchers discovered LIMIT through its association with positive markers of immune response.

After confirming that LIMIT was indeed a long noncoding RNA, the researchers conducted experiments in human tumor cells and mouse cells to better understand its function, explains Zou. And it turns out that LIMIT is regulated by interferon gamma, a cytokine that plays a central role in the body's ability to mount an immune response against an invading threat.

Subsequent experiments in mice showed that LIMIT is a vital component of T cell infiltration into tumors.

"If you get rid of this lncRNA, the mice are much less able to fight off the cancer," Zou says. "The T cells don't go to the tumor and they don't function normally."

Ultimately, the research determined that LIMIT activates a family of genes known as GPBs (for guanylate binding proteins), leading to the activation of other important immune players: heat shock factor-1 (HSF1) and major histocompatibility complex class I (MHC-I).

Using CRISPR techniques to activate LIMIT boosted checkpoint therapy against the tumors in mouse models, while silencing LIMIT made the immunotherapy less effective.

"Very often, there is a loss of MHC-I and interferon gamma signaling in human tumors, which helps the cancer evade the immune system," Zou says. "Our research suggests several new potential therapeutic approaches to overcome this. These include using CRISPR to activate LIMIT and improve MHC-I expression to boost the body's immune response, and also targeting some of the downstream players in this signaling axis, like GBPs."

Southern lesser galagos (Galago moholi), a species of primate that lives in southern Africa, boast big, round eyes and are so small they can fit in your hand.

A new study from an international team of scientists, however, suggests that there may be a downside to their cuteness: The trade in lesser galagos, also known as bushbabies, which some people keep as pets, may have shifted the genetics within their wild populations over the span of decades, according to the research. Those changes could undercut the ability of the critters to adapt as human farms and cities grow throughout the region.

The study was published recently in the journal Primates and was led by researchers from the United States and South Africa, including primatologist Michelle Sauther at the University of Colorado Boulder.

Lesser galagos, she said, are hard to spot: They're nocturnal and live high in the branches of acacia trees. But you may still hear their eerie calls at night in the savannas and forests of South Africa, Botswana, Zimbabwe and other neighboring nations.

"They're called bushbabies because they sound like a baby crying," said Sauther, professor in the Department of Anthropology. "It's kind of spooky."

In their new study, Sauther and her colleagues analyzed the DNA of bushbabies living in the regions around Pretoria and Johannesburg, South Africa, and more remote areas to the north. The team found that populations located far away from each other may share more genes in common than scientists would normally expect--suggesting that something, and probably people, is secretly shuttling the primates around the country.

"You've got populations that are genetically different mixing with each other," said Metlholo Andries Phukuntsi, lead author of the new study and a graduate student at the South African National Biodiversity Institute and the Tshwane University of Technology in Pretoria. "When that happens, you can dilute the local gene pool, and these animals lose their ability to adapt to their habitats."

Bounding bushbabies

Study coauthor Frank Cuozzo said that the findings are significant because scientists today don't know much about these primates, which are cousins to lemurs. But they're worth keeping an eye on, including for their feats of acrobatics.

"From a simple sitting position, they can jump a meter (three feet) into the air, grab a moth and bring it back down," said Cuozzo, a CU Boulder alumnus and primatologist at the Lajuma Research Centre in South Africa.

Those majestic leaps, however, may be growing rarer in parts of South Africa. The country's Limpopo and Gauteng provinces have experienced rapid urbanization in recent decades. In 1980, for example, the Pretoria metropolitan area had an estimated population of about 700,000 people. Today, more than 2.5 million people call the city home.

Sauther suspects that this expansion could be pushing bushbabies out of many areas--and all without anyone knowing.

"What's is worrying is that we talk to farmers, and they're saying, 'We used to see bushbabies back in that orchard, but we don't anymore,'" Sauther said. "That's true even in places like national parks. Some bad things may be happening to them, and it's flying under the radar."

She and her colleagues wanted to find out if southern lesser galagos really are in trouble. To do that, the researchers worked closely with veterinarians to safely collect blood samples from primates living in several different habitats in Limpopo and Gauteng provinces. They then analyzed those samples, plus others kept in biological archives, to take a close look at their mitochondrial DNA--small clusters of genes that mothers pass to their offspring.

Bushbabies on the move

And, as Sauther put it, "something weird is going on."

Phukuntsi explained that, normally, scientists expect that animals that live closer to each other should have more in common genetically than those that live far apart--when wild populations are separated by large distances or barriers like mountains, fewer individuals can travel between them to breed. But what the team discovered in its samples from roughly 40 bushbabies was almost the opposite: Individuals from areas separated by dozens or even more than 200 miles shared a lot of gene mutations. Individuals dwelling within the same populations, in contrast, displayed a surprising amount of genetic divergence.

Something, in other words, seems to be putting the species through the genetic equivalent of a cocktail shaker. And all signs point to the trade in wild animals.

"We think that maybe people are catching them and bringing them to a different area," Phukuntsi said. "But then they become difficult to maintain as pets, so people release them back into the wild."

He added that wild animals have spent thousands of years adapting to the challenges of their particular habitats. If you mix genes up too much, you risk washing away all of those helpful adaptations.

"You can really tell whether a population is healthy or not by looking at its genetic diversity," Phukuntsi said.

For now, the findings suggest that researchers may want to take a closer look at the conservation of these miniature primates. And if you're thinking about keeping a bushbaby in your home: don't, Phukuntsi said. They may be cute, but like all wild primates, they're not well-behaved and don't make good pets.