Enlisting the newly discovered L-IST RNA in the fight against type 2 diabetes

Across the world, type 2 diabetes is on the rise. A research group has discovered a new gene that may hold the key to preventing and treating lifestyle related diseases such as type 2 diabetes.
The results of their research were published in the journal Nucleic Acids Research on June 18, 2021.
Selenoprotein P (SeP) is an essential plasma protein containing the micronutrient selenium. However, too much SeP spells trouble.
Excess SeP increases insulin resistance, thus weakening the effect of insulin, and worsening the metabolism of glucose.
“Excess SeP is the enemy when it comes to type 2 diabetes,” stressed professor Yoshiro Saito from the Graduate School of Pharmaceutical Sciences at Tohoku University and co-author of the study. “Regulating healthy SeP levels is vital for maintaining our health.”
Saito, along with assistant professor Yuichiro Mita from the Graduate School of Life and Medical Sciences at Doshisha University discovered gene “CCDC152.” The gene, which has a similar structure to that of SeP, acts as an RNA that lowers the SeP protein.
Because of this, CCDC152 was named Long Non-coding RNA-Inhibitor of Selenoprotein P Translation (L-IST).
Their study also revealed that epigallocatechin gallate (EGCG), a plant based antioxidant commonly found in green tea, can increase L-IST.
Looking ahead, the researchers believe EGCG supplements can help diabetic patients with high SeP levels. “Overall, our findings have opened up new avenues to explore in the prevention and treatment of lifestyle-related diseases,” added Saito.
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Materials provided by Tohoku University. Note: Content may be edited for style and length.

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Potato and rice protein shakes may be a viable vegan alternative to whey protein shakes, research suggests

A study from the Centre for Nutraceuticals at the University of Westminster found that plant-based protein shakes may be potential viable alternatives to milk-based whey protein shakes, particularly in people with need of careful monitoring of glucose levels.
The study, published in the journal Nutrients, is the first to show potato and rice proteins can be just as effective at managing your appetite and can help better manage blood glucose levels and reduce spikes in insulin compared to whey protein.
During the study the blood metabolic response of participants was measured after drinking potato, rice and whey protein shakes. Appetite was also monitored in the following three hours to understand how these drinks may affect the participants’ hunger and their desire to eat.
The research observed that vegan protein shakes led to a lower rise in blood insulin compared to whey, while potato protein prevented any rise in insulin. This may explain the better blood glucose control following consumption of the plant-based protein and poses the question of whether vegan protein shakes are more suitable for individuals who need to need control their blood glucose levels such as diabetic and obese individuals.
Interestingly, release of the key appetite regulating hormone GLP-1 was greater after drinking the whey protein shake. However, the greater GLP-1 response did not translate to an increased feeling of fullness as there were no differences observed in appetite perception between the three different protein shakes.
Consumer trends in protein intake are on the rise with milk protein derivatives such as whey extensively used in consumer products such as protein shakes, fortified food and beverage products.
There are alternative protein products available for vegetarians and vegans such as soy, rice, wheat and pea proteins but there is a relative lack of evidence on their health benefits in comparison to milk proteins. Potato protein is a novel plant-based protein product that is obtained from the waste material from potato starch production and is a sustainable economic protein source. This study provides the first evidence to suggest that it may be an alternative to whey protein sources.
Professor M Gulrez Zariwala, corresponding author and Director of the Centre for Nutraceuticals at the University of Westminster, said: “Global concerns on sustainability have led to consumer shifts towards ethical eating and a change in dietary habits with increased adoption of vegetarian and vegan diets.
“However, research in this area is still lacking and it would be interesting to clarify whether proteins from plant sources can provide identical metabolic health benefits as those with traditional sources such as milk.
“Our results shed new light in this area and improves our understanding of how plant source proteins can be a more sustainable yet nutritionally beneficial food source. We plan to conduct follow-up studies further research this exciting area.”
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Materials provided by University of Westminster. Note: Content may be edited for style and length.

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Immunologists discover new trick used by MRSA superbug — may aid vaccine development

New research has uncovered a novel trick employed by the bacterium Staphylococcus aureus to thwart the immune response, raising hopes that a vaccine that prevents deadly MRSA infections is a little closer on the horizon.
Immunologists from Trinity College Dublin, working with scientists at GSK — one of the world’s largest vaccine manufacturers — discovered the new trick of the troublesome Staphylococcus aureus, which is the causative agent of the infamous “superbug” MRSA.
They found that the bacterium interferes with the host immune response by causing toxic effects on white blood cells, which prevents them from engaging in their infection-fighting jobs.
Importantly, the study also showed in a pre-clinical model system that the toxicity could be lessened following vaccination with a mutated version of a protein specifically engineered to throw a spanner in the MRSA works. Ultimately, this suggests a vaccine could one day do the same thing in people.
The research was recently published in journal, mBio.
MRSA — a global killer
An estimated 700,000 deaths occur annually due to infections against which antibiotics are no longer effective. If this is allowed to continue, modern medicine as we know it will cease to exist; a common childhood infection or routine surgical procedure could become fatal, with the threat of AMR infection likened to that of climate change in some circles.

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Predicting tooth loss

Tooth loss is often accepted as a natural part of aging, but what if there was a way to better identify those most susceptible without the need for a dental exam?
New research led by investigators at Harvard School of Dental Medicine suggests that machine learning tools can help identify those at greatest risk for tooth loss and refer them for further dental assessment in an effort to ensure early interventions to avert or delay the condition.
The study, published June 18 in PLOS ONE, compared five algorithms using a different combination of variables to screen for risk. The results showed those that factored medical characteristics and socioeconomic variables, such as race, education, arthritis, and diabetes, outperformed algorithms that relied on dental clinical indicators alone.
“Our analysis showed that while all machine-learning models can be useful predictors of risk, those that incorporate socioeconomic variables can be especially powerful screening tools to identify those at heightened risk for tooth loss,” said study lead investigator Hawazin Elani, assistant professor of oral health policy and epidemiology at HSDM.
The approach could be used to screen people globally and in a variety of health care settings even by non-dental professionals, she added.
Tooth loss can be physically and psychologically debilitating. It can affect quality of life, well-being, nutrition, and social interactions. The process can be delayed, even prevented, if the earliest signs of dental disease are identified, and the condition treated promptly. Yet, many people with dental disease may not see a dentist until the process has advanced far beyond the point of saving a tooth. This is precisely where screening tools could help identify those at highest risk and refer them for further assessment, the team said.

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A detailed atlas of the developing brain

Researchers at Harvard University and the Broad Institute of MIT and Harvard have created a first detailed atlas of a critical region of the developing mouse brain, applying multiple advanced genomic technologies to the part of the cerebral cortex that is responsible for processing sensation from the body. By measuring how gene activity and regulation change over time, researchers now have a better understanding of how the cerebral cortex is built, as well as a brand new set of tools to explore how the cortex is affected in neurodevelopmental disease. The study is published in the journal Nature.
“We have had a long-standing interest in understanding the development of the mammalian cerebral cortex, as it is the seat of higher-order cognition and the part of the brain that has expanded and diversified the most during human evolution,” said Paola Arlotta, the co-senior author of the study and the Golub Family Professor of Stem Cell and Regenerative Biology at Harvard University. “In this study, we looked at the cortex with a very fine lens, practically profiling all of its cells, one by one, every day of development. We catalogued changes in gene expression and regulation at an unprecedented level of temporal resolution to build a first single-cell-resolution molecular map of this amazing tissue. The map allowed us to extract first mechanistic principles governing how the cortex is built, and begin to decode how genetic abnormalities affect such highy controlled process in the embryo.”
“In the developing brain, we have to consider three things: the types of cells that are present, where those cells are located, and at what stage they are in development. In addition, by identifying the drivers that direct this process in normal development, we can better understand what may go wrong in disease,” said co-senior author Aviv Regev, who was a core institute member at the Broad Institute when the study began and is currently Head of Genentech Research and Early Development.
The researchers focused on the somatosensory cortex, which may serve as a model for other regions of the cerebral cortex because it contains cells representing all of its major classes. For every day of cortex development, the researchers analyzed the brain using multiple technologies at the single-cell level. They used RNA-seq to measure which genes are expressed, as well as spatial transcriptomics to measure where genes are expressed in the tissue. They also used ATAC-seq to measure which parts of the genome were accessible for regulation.
“These technologies allowed us to look at different modes of gene expression and how genes are regulating each other. By combining these three modalities, we have a stronger sense of which are the important genes for directing neuronal development, for example” said Daniela Di Bella, a postdoctoral fellow in the Arlotta lab and co-first author of the study.
For instance, it has been unclear exactly when the cortex’s diversity of different neuron populations is established. “We found that the different flavors of neurons are decided during the neuron maturation process, rather than pre-established in their stem cells,” Di Bella said.
The researchers also used their data to predict the underlying mechanism of how genetic mutation leads to defects in cortical development, finding which specific developmental steps are failing and which cells are being affected.
“We have created a uniquely comprehensive molecular atlas of the developing somatosensory cortex, and we are continuing to mine the data for more insights,” said co-first author Ehsan Habibi. “Our goal is for our data to serve as a resource for the wider neuroscience community and inform how the field looks at brain development, both during normal and disease processes.”
“These combined, extensive measurements provided us with a first dynamic view of the symphony of molecular events that unfold as this critical region of the brain is built in the embryo,” said Arlotta, who is also an institute member in the Stanley Center for Psychiatric Research at the Broad Institute. “Researchers have been studying the process of development of the cerebral cortex for over a century, but the mechanistic events that govern how cells are made and how they interact to ultimately form functional circuit have remained elusive. As a field, we have historically looked at this complex developing tissue one cell type at a time, and investigated small numbers of genes for their roles in putting together pieces of this amazing puzzle. But the brain does not develop one cell type at the time — it is truly a symphony in the sense that hundreds of cell types undergo development together, using ever-changing lanscapes of genes to form the adult tissue. Now imagine having for the first time the full ‘recipe’ of genes that any given cell class uses as its development unfolds. Imagine also gaining detailed knowledge of the ‘codes of genes’ that turn on or off as distinct lineages of cells separate from each other and get built. This type of overarching mechanistic knowledge offers an opportunity to study cortical development in a brand new way, looking at all cells and all genes. We never had information this complete before and I must admit that I stared at the data in awe, thinking about the type of discovery that it enables.”
“Ten years ago, this study would not have been possible because the technologies either did not exist or were not mature enough yet,” Regev said. “But with advances in single-cell and spatial transcriptomics, and new machine learning algorithms for large data analysis, we were able to map where cells develop, put those maps together, and watch development unfold like a movie over time. We could not only reconstruct the movie, but could also link that picture to a greater biological understanding of brain development. We hope this approach could one day help us better understand and treat diseases of the brain.”
Arlotta added: “It is a pretty interesting movie — one that I have looked forward to filming for most of my scientific career.”
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Materials provided by Harvard University. Original written by Jessica Lau. Note: Content may be edited for style and length.

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No lab required: New technology can diagnose infections in minutes

The idea of visiting the doctor’s office with symptoms of an illness and leaving with a scientifically confirmed diagnosis is much closer to reality because of new technology developed by researchers at McMaster University.
Engineering, biochemistry and medical researchers from across campus have combined their skills to create a hand-held rapid test for bacterial infections that can produce accurate, reliable results in less than an hour, eliminating the need to send samples to a lab.
Their proof-of-concept research, published today in the journal Nature Chemistry, specifically describes the test’s effectiveness in diagnosing urinary tract infections from real clinical samples. The researchers are adapting the test to detect other forms of bacteria and for the rapid diagnosis of viruses, including COVID-19. They also plan to test its viability for detecting markers of cancer.
“It’s going to mean that patients can get better treatment, faster results and avoid serious complications. It can also avoid the unnecessary use of antibiotics, which is something that can buy us time in the battle against antimicrobial resistance,” says Leyla Soleymani, the paper’s co-corresponding author and an associate professor of engineering physics.
“This will give doctors the science to support what they already suspect based on their skills and experience,” says co-corresponding author Yingfu Li, a professor of biochemistry and biomedical sciences.
The new DNA-based technology uses a handheld device similar to a blood-glucose monitor. A microchip analyzes a droplet of bodily fluid such as blood, urine or saliva, using molecules that can detect the specific protein signature of an infection. The device, about the size of a USB stick, plugs into a smartphone, which displays the result.

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Starting the day off with chocolate could have unexpected benefits

Eating milk chocolate every day may sound like a recipe for weight gain, but a new study of postmenopausal women has found that eating a concentrated amount of chocolate during a narrow window of time in the morning may help the body burn fat and decrease blood sugar levels.
To find out about the effects of eating milk chocolate at different times of day, researchers from the Brigham collaborated with investigators at the University of Murcia in Spain. Together, they conducted a randomized, controlled, cross-over trial of 19 postmenopausal women who consumed either 100g of chocolate in the morning (within one hour after waking time) or at night (within one hour before bedtime). They compared weight gain and many other measures to no chocolate intake.
Researchers report that among the women studied: Morning or nighttime chocolate intake did not lead to weight gain; Eating chocolate in the morning or in the evening can influence hunger and appetite, microbiota composition, sleep and more; A high intake of chocolate during the morning hours could help to burn fat and reduce blood glucose levels. Evening/night chocolate altered next-morning resting and exercise metabolism.Frank A. J. L. Scheer, PhD, MSc, Neuroscientist and Marta Garaulet, PhD, Visiting Scientist, both of the Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women’s Hospital. Drs. Scheer and Garaulet are co-corresponding authors of a new paper published in The FASEB Journal.
“Our findings highlight that not only ‘what’ but also ‘when’ we eat can impact physiological mechanisms involved in the regulation of body weight,” said Scheer.
“Our volunteers did not gain weight despite increasing caloric intake. Our results show that chocolate reduced ad libitum energy intake, consistent with the observed reduction in hunger, appetite and the desire for sweets shown in previous studies,” said Garaulet.
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Timely treatment with COVID-19 monoclonal antibodies can reduce hospitalizations, pandemic's stress on health care systems

A newly published study by the University of South Florida Health (USF Health) and Tampa General Hospital (TGH) shows that monoclonal antibodies (MABs) work well in reducing COVID-19 related emergency department visits and hospitalizations when given early to high-risk patients. If used under FDA guidelines, the researchers suggest, this treatment can ease the pandemic’s continuing burden on patients and on limited health care resources.
The collaborative study was published June 4 in Open Forum Infectious Diseases.
Investigational monoclonal antibody therapies, administered intravenously, are specifically designed to block infection by SARS-CoV-2, the virus that causes COVID-19. The FDA has granted emergency use authorization (EUA) of MABs in outpatients with mild-to-moderate COVID-19 at increased risk of developing severe disease. Such high-risk patients are prone to hospitalizations, mechanical ventilation and other complications, including death from coronavirus.
“While the emphasis now is rightfully on getting more vaccines in arms, thousands of people in the U.S. are still infected with COVID-19 every day and a significant number suffer serious complications,” said the study’s senior author Asa Oxner, MD, associate professor and vice chair of the Department of Internal Medicine, USF Health Morsani College of Medicine.
“Unfortunately, only a fraction of those outpatients eligible for monoclonal antibodies receive them,” Dr. Oxner said. “We hope results like ours reinforce to the public and health care providers the importance of targeting timely monoclonal antibody treatment to this high-risk patient population to help minimize stress on health care systems during the COVID-19 pandemic.”
Limited clinical trials previously indicated that MABs work best when given soon after diagnosis. But this USF Health-TGH collaborative study was one of the first to evaluate the practical effectiveness of MABs when administered exclusively to patients deemed at high risk for progression to severe COVID-19. The FDA defines medical conditions and factors that place adults and children age 12 or older at higher risk for COVID-19, including older age (65 plus), obesity, diabetes, immunosuppressive disorders or treatment, chronic lung disease and cardiovascular disease, to name a few.
The academic medical center’s retrospective study, conducted Nov 18, 2020, to Jan. 5, 2021, included high-risk outpatients with a confirmed COVID-19 diagnosis, all experiencing mild-to-moderate symptoms for 10 days or less. A group of 200 patients received one of two MAB therapies (a single infusion) — either casirivimab/imdevimab, a combination drug made by Regeneron, or the medication bamlanivimab made by Eli Lilly. This treatment group was compared against a control group of 200 randomly selected outpatients who declined or were not referred for MABs during the same period.
Among the findings: Overall, patients treated with the MABs were significantly less likely to be hospitalized or visit the emergency department (13.5%) than the control patients (40.5%). These results remained significant when comparing the individual monoclonal antibody therapies against the control group. No deaths were reported in the MABs-treated group, compared to 3.5% in the control group. Patients treated with MABs within six days of symptom onset were significantly less likely to be hospitalized or visit the emergency department (7.7%) than those treated after six days (28.1%). The study data indicated MABs are best given within seven days of initial symptoms to reduce the odds of hospitalization within 29 days of infusion.”Reflecting on our findings, it would be prudent to consider decreasing the FDA eligibility window for MABs to within seven days of symptom onset,” the study authors write. “These medications are a relatively scarce resource, and it would be practical to administer them to patients who are likely to see the most benefit.”
COVID-19 has strained financial and personnel resources across all health systems, with the Florida Hospital Association estimating total losses of $7.4 billion from the beginning of the pandemic through August 2020. The study authors conclude that maximizing the use of monoclonal antibody therapies under EUA guidance has the potential to “keep high-risk COVID-19 patients out of the hospital and reduce the negative impact on the health care system.”
The study co-lead authors were Nicholas Piccicacco, PharmD, and Kristen Zeitler, PharmD, of the TGH Department of Pharmacy.

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Cardiac atrophy findings may set course for preventing harm from long space flights

In many situations, heart muscle cells do not respond to external stresses in the same ways that skeletal muscle cells do. But under some conditions, heart and skeletal muscles can both waste away at fatally rapid rates, according to a new study led by experts at Cincinnati Children’s.
The new findings, based on studies of mouse models, represent an important milestone in a long effort to prevent or even reverse cardiac atrophy, which can lead to fatal heart failure when the body loses large amounts of weight or experiences extended periods of weightlessness in space. Detailed findings were published online June 24, 2021, in Nature Communications.
“NASA is very interested in cardiac atrophy,” says Jeffery Molkentin, PhD, Co-Director of the Heart Institute at Cincinnati Children’s. “It might be the single biggest issue for long-period space flights and astronaut health, especially when re-entering a higher-gravity situation, whether that’s arriving at Mars or returning to Earth.”
Astronauts and cosmonauts have been exercising in orbit to minimize loss of muscle mass ever since doctors observed years ago that returning spacefarers have often been barely able to walk upon returning to Earth. Along the way, clinicians also have observed increased risk of heart trouble during the recovery period.
The new findings from Molkentin and colleagues help explain why the heart also is affected by muscle-wasting conditions, which in turn suggests potential new ways to prevent or treat the problem.
A three-pronged attack on heart cells
The research team studied mouse models in several ways to trace the withering of heart cells to a three-step molecular process.

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New protein engineering method could accelerate the discovery of COVID-19 therapeutics

Discovering and engineering nanobodies with properties suitable for treating human diseases ranging from cancer to COVID-19 is a time-consuming, laborious process.
To that end, University of Michigan researchers found a simple method for identifying nanobodies with drug-like properties suitable for preventing SARS-CoV-2 infections. They demonstrated the approach by generating nanobodies that neutralized the SARS-CoV-2 virus more potently than an antibody isolated from an infected patient and a nanobody isolated from an immunized animal.
Nanobodies are small antibody fragments which bind strongly to their target molecules and block their functions. Currently, antibody and nanobody discovery involves selecting initial lead antibody candidates, followed by time- and labor-intensive modifications to make them suitable for therapeutic applications, said Jennifer Zupancic, doctoral candidate in chemical engineering and co-first author, with Alec Desai, doctoral candidate in chemical engineering. The study is in Cell Chemical Biology.
“A key advantage to this method, both in terms of addressing pandemics and nanobody development more generally, is the ability to select nanobodies that bind strongly more rapidly than with current methods,” said Zupancic.
“This unexpected discovery appears to be a key step toward addressing a long-standing challenge in the field, namely the rapid and simple generation of high-affinity agents (agents that bind strongly) such as nanobodies, without the need for extensive screening and optimization,” said Peter Tessier, the Albert M. Mattocks Professor in Pharmaceutical Sciences and Chemical Engineering, and senior author. He’s also a member of the U-M Biointerfaces Institute,
Nanobodies and antibodies bind to their targets via multiple flexible binding loops called the complementarity-determining regions. Researchers discovered that one or more of the individual binding loops from different lead nanobodies could be combined into single nanobody mutants with improved properties, Zupancic said. That process is called complementarity-determining region swapping.
“This process of CDR swapping resulted in substantial changes to the nanobodies we initially started out to modify,” she said. “It was surprising to us that such large changes not only did not hinder the nanobodies’ ability to bind and neutralize the SARS-CoV-2 virus, but actually greatly improved it.”
Researchers discovered the method accidentally, but found and reported that the technique is simple to perform in a systematic manner.
Generally, approved antibody drugs must demonstrate drug-like properties, including high stability, specificity and solubility, and must also bind strongly to their target. Often, there are tradeoffs between these properties, which frustrate therapeutic antibody development.
“However, we observe that our nanobodies have drug-like properties and also bind to and neutralize the SARS-CoV-2 virus strongly,” she said.
The new method likely can be used to develop nanobodies against other viruses and disease targets. That work is ongoing in the lab now, Zupancic said.
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