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A decline in metabolism and endurance of skeletal muscle is commonly observed in obese patients, but the underlying mechanism is not well-understood. A research team led by Dr Chi Bun CHAN, Assistant Professor from School of Biological Sciences, Faculty of Science, the University of Hong Kong (HKU), uncovers a new mechanism to explain how obesity jeopardizes the functions of skeletal muscle and provides a potential treatment against the disease. The research findings have recently been published in world-leading scientific journal Autophagy.
Obesity is a metabolic disorder with increasing prevalence in modern society. Since 1970s, the global number of obese people has trebled and reached 650 million (~ 13% of the total global population) in 2016. It is widely known that obesity provokes detrimental outcomes in multiple human organs and causes numerous chronic disorders such as diabetes, hypertension, fatty liver diseases, and atherosclerosis. Fat metabolism in the skeletal muscle of obese patients is slower than that of healthy people, which scientists believe is a consequence of abnormal functions in mitochondria (the powerhouses of a cell that convert nutrients into biological energy). However, how obesity impairs the activity of mitochondria is a long unresolved question.
To study the functional impacts of obesity on the skeletal muscle, Dr Chan’s team developed a special obesified mouse model by removing the gene of brain-derived neurotrophic factor (BDNF) exclusively in their skeletal muscle. BDNF is originally identified as an important growth factor for maintaining the survival and activities of neurons. Recent studies have proposed that BDNF is also a muscle-secreted protein (i.e., myokine), but its physiological significance is unknown.
For the first time, Dr Chan’s team found that obesity reduced the amount of BDNF in the skeletal muscle of mice. They also observed that the mice without BDNF in their muscle, called ‘MBKO’ (Muscle-specific BDNF Knockout), gained more body weight and developed severer insulin resistance when the animals were fed with a high-fat diet. In addition, the research team found that MBKO mice have less energy expenditure than their control cohort.
Using a number of biochemical, histological, metabolomic, and molecular analyses, the research team further demonstrated that the mitochondria in the muscle of MBKO mice were unable to recycle, leading to the accumulation of damaged mitochondria in the tissues. Consequently, the lipid metabolism in the muscle of MBKO mice was retarded, causing more lipid accumulation to interfere with insulin sensitivity.
“Clearly, muscle-derived BDNF is a weight-control protein by increasing the energy expenditure and maintaining insulin sensitivity,” said Dr Chan.
“BDNF has long been considered a brain-localized peptide, and its importance in peripheral tissues has been underestimated. Our study provides a new insight to this area, and hopefully we can unlock more functions of this myokine using our MBKO mice,” Dr Chan further added.
In addition to the animal studies, Dr Chan’s team also utilized cultured cell models to pinpoint the molecular mechanism for the defective mitochondrial turnover in BDNF-deficient muscle cells. They found that muscle-secreted BDNF used AMPK-activated protein kinase, the well-known energy sensor in cells, to trigger the Parkin/PINK1 pathway for inducing mitophagy (a highly regulated mechanism to recycle the materials in cells in response to various challenges) in skeletal muscle.
To extend these findings to therapeutic application, the research team further tested if restoring the BDNF signaling in muscle would rescue the obesity-induced mitochondrial damage. They fed the obese mice with 7,8-dihydroxyflavone, a natural bioavailable BDNF mimetic in plants (found in the leaves of Godmania aesculifolia, a plant species in South America) currently used in the clinical trials of Alzheimer’s disease, and found that obesity-induced mitochondrial dysfunction was alleviated.
Together with their previous findings that 7,8-DHF is an effective agent in reducing body weight and improving the insulin sensitivity in obese mice (Chem Biol 2015 22: 355-369; Metabolism 2018 87: 113-122), Dr Chan’s work provides a new explanation on the pernicious nature of obesity and suggests that BDNF-signaling enhancer such as 7,8-DHF is a potential drug for obesity treatment in human beings.
This work was supported by the Hong Kong Research Grant Council, the Health and Medical Research Fund, and HKU Seed Fund for Basic Research.

Recent Cornell research compared the genetic expression profiles of a nonlethal canine tumor and the rare, devastating human oral tumor it resembles, laying the groundwork for potential translational medicine down the road.
While canine acanthomatous ameloblastoma (CAA) is common and nonlethal, it has a strong resemblance to an oral tumor in humans known as ameloblastoma (AM).
As a boarded veterinary dentist and oral surgeon, Dr. Santiago Peralta, associate professor at the College of Veterinary Medicine (CVM) and first author of the recent study in Scientific Reports, sees CAA in his clinic all the time.
“This research was a good example of a full cycle of translational research,” Peralta said. “We took something we were dealing with in the clinical setting, studied it in the bench setting and are now hoping to use it to help veterinary patients and, potentially, humans.”
The resemblance between CAA and AM had long been noted by scientists and clinicians, but no one had confirmed any molecular similarities. A previous study on AM tumors revealed the underlying mutations, piquing the interest of Peralta and his CVM colleagues. “We wondered if we should look at these mutations and see if they precipitate the canine tumor,” Peralta said.
They did just that, publishing a study in Veterinary and Comparative Oncology in 2019, that revealed that both AM and CAA shared mutations in a well-known signaling pathway, known as the RAS-RAF-MAPK pathway.
In their most recent study, Peralta and his colleagues analyzed a large genomic dataset generated by the Cornell Transcriptional Regulation and Expression Facility (TREx) to better understand the biological consequences of these mutations. While doing so, they compared the CAA tumors with another common canine tumor (oral squamous cell carcinoma) and healthy gum tissue. These samples were stored and made available through the Cornell Veterinary Biobank and gene expression was profiled with RNA sequencing by Dr. Jen Grenier and her team at TREx.
The team also used genomic data from human tissues to run comparisons, thanks to their collaboration with a human oral cancer expert at the University of Turku in Finland. Through analyzing these different tissues, Peralta and his team were able to see that the mutations they had identified in their earlier study were largely responsible for the tumors they were seeing.
They also found that CAA and AM are very similar at a molecular level, reinforcing the notion that dogs represent a potentially useful natural model of the human tumor. “All the dysregulated molecules and pathways in CAA tumor tissues were consistent with the mutations we’d found and remarkably similar to those observed in AM,” he said.
Now that they’ve connected the dots between the underlying mutations and dysregulated molecular pathways driving tumor formation, Peralta and his colleagues have been working to establish in vitro and in vivo models of different canine oral tumors that can be used to test potential drugs. Any drugs that might prove effective in treating oral tumors in dogs could also be promising candidates for human patients with analogue disease.
“If dogs truly represent a useful clinical model of the disease, they also represent an immense opportunity,” Peralta said. Because the CAA tumors are much more common in dogs than AM are in humans, scientists can rapidly enroll many more dogs in clinical trials and get more translatable data from those trials.
Furthermore, dogs, which live in same type of environments as humans, are more accurate models of disease than other animal models. “My goal as a veterinarian is to bring solutions back to the clinic. We’re not there yet, but we’ve made a major step toward that,” Peralta said.
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Materials provided by Cornell University. Original written by Lauren Cahoon Roberts. Note: Content may be edited for style and length.

Chronic infectious diseases have a devastating effect on global health. When someone is suffering from a chronic viral infection such as HIV or hepatitis C, their B cells get altered resulting in low-quality antibodies that are not strong enough to help the body clear the infection.
A recent study in mice conducted by the Monash Biomedicine Discovery Institute (BDI), has uncovered that during chronic viral infection, a protein called BMI-1 gets turned on too early in B cells and messes up the delicate balance of gene expression, resulting in antibodies that are unsuccessful in their endeavour to clear the virus from the body.
However, when this protein is targeted, the nature of the B cell can be changed to produce a higher quality antibody that accelerates clearance of a virus and may provide a new therapeutic pathway to help improve and regulate the body’s antibody response to achieve better outcomes.
The findings have now been published in Nature Immunology.
B cells, a type of white blood cell, respond to infection and can eventually turn into plasma cells. It is the plasma cells that make and secrete antibodies. During an infection, some of the B cells that become activated can quickly become plasma cells and start to produce antibodies in the first few days of the body’s immune response. While these antibodies are helpful, they are typically lower in quality and do not clear the infection. However, they do give the immune system some time to allow other B cells to undergo a “training period” to become high-quality memory B cells and plasma cells for immunity.
The memory B cells will act as sentinels for a long time, on guard for the next time the body gets infected with the same pathogen. If reinfected, they can quickly turn into plasma cells and make high-quality antibodies without having to undergo the training again, which helps your body clear the infection quicker and are the reason why vaccines work.
When a patient can’t clear the infection, the immune response reacts by altering the balance in favour of producing antibodies faster, without the adequate training it needs to neutralise the virus and form protective memory B cells and plasma cells.
Lead researcher Associate Professor Kim Good-Jacobson said being able to modulate abnormal antibody responses to accelerate viral clearance and reduce disease in chronic infection has significant benefits to patients and the burden of disease.
“We haven’t been able to produce effective vaccines for several chronic viral infections that can cause long-term health problems for millions of people. We wanted to figure out how antibody responses get disrupted, so we could start to identify targets to regulate the antibody response for better outcomes,” said Associate Professor Good-Jacobson.
“Memory immune cells and high-quality antibodies are powerhouses underpinning immune protection provided by successful vaccines, so working on ways to deliver drugs directly to B cells to improve the antibody response without affecting how well other immune cells work is crucial.”
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Materials provided by Monash University. Note: Content may be edited for style and length.

A simple change in the way donor cells are processed can maximize a single cell’s production of extracellular vesicles, which are small nanoparticles naturally secreted by cells, according to new research from researchers at the University of Illinois Chicago.
The finding offers new avenues for research around cellular therapies, which use transplanted cells — like stem cells or immune cells, either from the patient or a donor — to help the body heal or work better, and patients and their doctors want the most bang for their buck in terms of potency. For injuries in the lungs, like those caused by acute respiratory distress syndrome, treatments that use extracellular vesicles have shown promise, but remain expensive and limited by the number of donated cells needed to reach a therapeutic level.
The researchers, led by Jae-Won Shin, have been studying how extracellular vesicles work. Through experiments, they found that altering the material in which the donor cells are processed can have a strong impact on the potency of extracellular vesicles.
“We were very surprised that a simple environmental change could have such a significant impact,” said Shin, UIC assistant professor in the department of pharmacology and regenerative medicine and the department of biomedical engineering. “This tells us that cells interact differently in different tissues, and this impacts how they secrete extracellular vesicles and influence other cells around them.”
The key, they found, was using a soft hydrogel material that more closely resembles the natural environment of tissues to prepare the particles. When they compared the particles cultured from cells in traditional materials with those cultured in a softer material, they saw that the extracellular vesicles were secreted in a greater quantity in the softer substrate.
“In the stiff substrates, cytoskeletal structures in cells are dense and less flexible. This makes it difficult for extracellular vesicles to exit the cells. But in the soft substrate, these structures are less dense, more bendable and more spread out, making the environment more conducive to the secretion of the particles by cells,” said first author Stephen Lenzini, a UIC alumnus who worked on the study in Shin’s lab as a graduate student.
Shin said, “That’s why fewer donor cells are needed to produce the same number of particles.”
They also compared the therapeutic potential of the particles produced in the different materials. They observed that the same dose of extracellular vesicles produced from the softer substrate was much more effective at facilitating repair processes than the extracellular vesicles produced from a traditional harder substrate.
“Understanding this opens the door for many new avenues of investigation for lab and clinical trials of treatments that use donor extracellular vesicles to repair damaged tissues, like which occurs in the lungs of some COVID-19 patients who face complications like ARDS,” he said.
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Materials provided by University of Illinois at Chicago. Note: Content may be edited for style and length.

Micro-sized cameras have great potential to spot problems in the human body and enable sensing for super-small robots, but past approaches captured fuzzy, distorted images with limited fields of view.
Now, researchers at Princeton University and the University of Washington have overcome these obstacles with an ultracompact camera the size of a coarse grain of salt. The new system can produce crisp, full-color images on par with a conventional compound camera lens 500,000 times larger in volume, the researchers reported in a paper published Nov. 29 in Nature Communications.
Enabled by a joint design of the camera’s hardware and computational processing, the system could enable minimally invasive endoscopy with medical robots to diagnose and treat diseases, and improve imaging for other robots with size and weight constraints. Arrays of thousands of such cameras could be used for full-scene sensing, turning surfaces into cameras.
While a traditional camera uses a series of curved glass or plastic lenses to bend light rays into focus, the new optical system relies on a technology called a metasurface, which can be produced much like a computer chip. Just half a millimeter wide, the metasurface is studded with 1.6 million cylindrical posts, each roughly the size of the human immunodeficiency virus (HIV).
Each post has a unique geometry, and functions like an optical antenna. Varying the design of each post is necessary to correctly shape the entire optical wavefront. With the help of machine learning-based algorithms, the posts’ interactions with light combine to produce the highest-quality images and widest field of view for a full-color metasurface camera developed to date.
A key innovation in the camera’s creation was the integrated design of the optical surface and the signal processing algorithms that produce the image. This boosted the camera’s performance in natural light conditions, in contrast to previous metasurface cameras that required the pure laser light of a laboratory or other ideal conditions to produce high-quality images, said Felix Heide, the study’s senior author and an assistant professor of computer science at Princeton.

SharecloseShare pageCopy linkAbout sharingThis video can not be playedTo play this video you need to enable JavaScript in your browser.Covid booster jabs should be offered to all over-18s to help stop a potential wave driven by the new variant Omicron, UK government advisers say.The Joint Committee on Vaccination and Immunisation also said the minimum gap between the second dose and booster should be reduced to three months. They also recommended children aged 12 to 15 should be invited for a second dose three months after their first.Eleven cases of the Omicron variant have now been detected in the UK. England’s deputy chief medical officer Professor Jonathan Van-Tam told a Downing Street briefing that Omicron was the “new kid on the block” and it has “always been the case that, at some point, we are going to get a variant that gives us heightened concern”.LIVE UPDATES: Booster jabs acceleratedWhen can I get my booster and how do I book it?How worrying is the new Covid variant?Covid variants: Do we need new vaccines yet?Prof Wei Shen Lim, chair of the JCVI, said he was not predicting the new variant would take hold in the UK but the experts wanted to be in the best possible position if there was an increase in infection.He said: “With any vaccine during a pandemic, we get the greatest benefit for individuals and society if the vaccine is deployed before the wave starts. We want to provide boosters early enough… before any possible wave.”In its advice, the JCVI also recommended severely immunosuppressed people should be offered a fourth dose of the vaccine as a booster. They are currently receiving three jabs.The experts added that the booster rollout should take account of vulnerability. Boosters should be offered in order of descending age groups, with priority given those in a Covid at-risk group, they said. The JCVI’s advice has been given to ministers in all parts of the UK. It only gives recommendations and the final decision on measures to combat Covid lies with the politicians. It also said it would continue to review data on the potential benefits and risks of offering the Covid vaccine to children aged 5 to 11.Early evidence suggests the new Omicron variant – initially reported to the World Health Organization from South Africa on Wednesday – has a higher re-infection risk.The UK Health Security Agency said the latest two cases to be detected in the UK have links to travel in southern Africa. They were found in the Camden and Wandsworth areas of London. The aim of this announcement is to get ahead of a potential wave driven by the new variant Omicron.If that happens – and it is an “if” at this stage because so much is unknown about the new variant – giving more people a booster jab will certainly help.While Omicron may make the vaccines less effective, the booster dose has been shown to significantly increase the immune response, which will help counter any advantages this variant may have.But that will only happen if the vaccine is in people’s arms. The NHS is doing around 2.5 million boosters a week on average at the moment. At that rate it will take three months to vaccinate all those eligible.Increasing that will not be easy. Around 50 mass vaccination centres have closed since the spring. Many GPs have also stepped back to concentrate on flu jabs and their day-to-day work.It means the solution is likely to lie in extending the opening hours of current vaccination clinics late into the evenings and bringing in extra staff and volunteers to help.The government has unveiled new rules on face masks and isolation for England to contain the spread of the new variant that are due to come in to force at 04:00 GMT on Tuesday.Health Secretary Sajid Javid told MPs they would be given a chance to debate and vote on those measures.He said: “If it emerges that this variant is no more dangerous than the Delta variant, then we won’t keep measures in place for a day longer than necessary. “Our experience of fighting this virus has shown us it’s best to act decisively and swiftly when we see a potential threat. Which is why we’re building our defences and putting these measures in place without delay.”Mr Javid told MPs he had accepted the JCVI’s advice “in full”. Scotland has also announced it would follow the recommendations, while Wales and Northern Ireland are expected to accept them.The average number of daily confirmed Covid cases in the UK began rising again in early November. A further 42,583 confirmed cases were announced on Monday.THE SLEEPING FORECAST: Get cosy with our winter playlistWHAT IS RACHEL RILEY’S EMBARRASSING HABIT?: Joe Lycett finds out in ‘It’s Not What You Know’

The health secretary says told MPs that vaccinations have been moving at a “blistering pace” with 17 million booster doses given.Sajid Javid said the UK was entering winter in a “strong position” with falling numbers of hospital admissions and deaths.But he said the Omicron variant “spreads very rapidly” and he expected figures to rise beyond the 11 confirmed cases in Britain so far.BBC live page coverage of Covid updates

Engineers often use nature to inspire new materials and designs. A discovery by a multi-institutional team of researchers and engineers about how tendon and bone attach in the shoulder joint has uncovered previously unsuspected engineering strategies for attaching dissimilar materials. The discovery also sheds new light on how the rotator cuff functions and on why rotator cuff repairs fail so frequently.
Guy Genin, the Harold and Kathleen Faught Professor of Mechanical Engineering in the McKelvey School of Engineering at Washington University in St. Louis, and Stavros Thomopoulos, the Robert E. Carroll and Jane Chace Carroll Professor of Orthopaedic Surgery at Columbia University, led a team that discovered a previously unknown fibrous architecture between the rotator cuff tendons and their bony attachments in the shoulder. Results of the work were published in Science Advances Nov. 26.
Rotator cuff tears — among the most common tendon injuries in adults — occur when tendons pull away from or break near the bone. Thirty percent of adults over age 60 have a tear, and more than 60% of adults over age 80 have a tear. Surgery to repair the tears has a high failure rate, ranging anywhere from 30% to 90% depending on age and other factors. Genin, Thomopoulos and their teams have been studying the mechanobiology of these tissues for several years.
To take a closer look at the enthesis, or the transitional material where each of the four rotator cuff tendons attaches to the bone, the team applied a novel micro computed tomography (microCT) technique. The images revealed a hidden site in the supraspinatus tendon enthesis of mouse shoulders where tendon fibers directly inserted into bone over about 30% of the well-known attachment footprint. Through biomechanical analysis, coupled with numerical simulations, they found that the toughness of the healthy rotator cuff arises from the composition, structure and position of the enthesis as the architecture of the fibrous soft tissues interacts with that of the bone. It was the first time researchers have been able to see both the soft and hard tissues in the rotator cuff simultaneously.
“When [lead author] Mikhail Golman first showed us these images, we realized that much of the old picture of how tendon and bone interact had to be redrawn,” Genin said. “The fiber system there seems like fibers in a rope, and we can understand much about where the toughness comes from by understanding how these fibers break sequentially when they are next to the bone. It’s a new way of thinking about how to attach different materials.”
After the team found the hidden site, there were further discoveries as they progressed.
“Every experiment we did revealed fascinating new features of the attachment system,” Thomopoulos said. “We quickly realized that fundamental aspects of this problem needed to be rethought from scratch. Our goal was to understand where the healthy rotator cuff gets its toughness and strength and under what conditions it ruptures. We found that the toughness of the rotator cuff varies as a function of shoulder position, helping to explain differences in the injury patterns seen in patients.”
The team found that the toughness of the rotator cuff comes from having the fibers help to build the bridge between tissue and bone. Toughness refers to how much energy is required to break a structure, while strength refers to how hard one has to pull to break it, Genin said.
“We found that there’s actually a tradeoff between strength and toughness with these fiber systems,” Genin said. “If you reduce the overall strength by allowing some of the fibers to break, you can actually make the structure tougher because the amount of energy absorbed increases.”
Genin said their results showed that replicating the fiber structure is essential for successful and pain-free healing after rotator cuff repair.
“This research gave us a whole new look at this frequently-injured region and presented a new thinking of how to attach these two different materials,” Genin said. “This is not just important for surgeries, but for all kinds of engineering failures that occur when you connect a material to something with a different architecture. By merging the architectural paradigms across the materials and enabling the distributed failure of the elements that come together, you can dramatically increase toughness.”
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Materials provided by Washington University in St. Louis. Original written by Beth Miller. Note: Content may be edited for style and length.

Prevailing theories posit plaques in the brain cause Alzheimer’s disease. New UC Riverside research points to cells’ slowing ability to clean themselves as the likely cause of unhealthy brain buildup.
Along with signs of dementia, doctors make a definitive Alzheimer’s diagnosis if they find a combination of two things in the brain: amyloid plaques and neurofibrillary tangles. The plaques are a buildup of amyloid peptides, and the tangles are mostly made of a protein called tau.
“Roughly 20% of people have the plaques, but no signs of dementia,” said UCR Chemistry Professor Ryan Julian. “This makes it seem as though the plaques themselves are not the cause.”
For this reason, Julian and his colleagues investigated understudied aspects of tau protein. They wanted to understand whether a close examination of tau could reveal more about the mechanism behind the plaques and tangles.
A key but difficult-to-detect difference in the form of tau allowed the scientists to distinguish between people who expressed no outward signs of dementia from those who did. These results have now been published in the Journal of Proteome Research.
Julian’s lab focuses on the different forms that a single molecule can take, called isomers.

How do pollutants and other chemicals that we are exposed to affect our health? Researchers from Linköping University in Sweden have applied a method to identify the proteins in the body affected by chemicals. The method can be used to discover at an early stage whether a substance has biological effects in an organism.
They are in the water we drink, the food we eat and the environment around us — pollutants. More than 100,000 chemicals are used in manufacturing, agriculture, industry and consumer articles. Each day of our lives we are in contact with chemicals that can be absorbed into our bodies. Some of them can have negative effects on our health. Furthermore, some substances become more harmful when combined with others than individually, a phenomenon known as the “cocktail effect.”
One of the challenges in toxicology in recent decades has been to predict the effects of exposure to mixtures of many different chemicals.
“Levels of pollutants are continuously increasing, and it is extremely difficult to test the effects of all chemicals. It is particularly difficult to test mixtures of substances. I believe that our approach can lead to more efficient use of time and money than traditional methods, which test the effects on one biological mechanism at a time,” says Veronica Lizano-Fallas, PhD student in the Department of Biomedical and Clinical Sciences (BKV) at Linköping University.
The researchers emphasise that the method, which they describe in an article in the Journal of Proteomics, can be used to detect, at an early stage, undesired biological effects of substances. These effects can then be studied in more detail using other methods.
“Chemicals interact with proteins in a fairly promiscuous manner, and we often find that several proteins are influenced by the substances we test. We see that the functions of proteins are affected by their interactions with chemicals, which is consistent with the effects of pollutants and harmful substances in the cell,” says Susana Cristobal, professor in BKV, who has led the study.
The new approach applied by the LiU researchers is based on a technique developed to study pharmaceuticals, proteome integral solubility alteration, abbreviated as “PISA.” The researchers have examined how the method can be used to identify the proteins from an organism that interact with pollutants and other chemicals. Aiming to obtain proteins from all types of cells in an organism, its proteome, the researchers extracted proteins from zebrafish embryos. They mixed the proteome with one or several substances.
The researchers have applied the method on four scenarios: an individual pollutant, a mixture of chemicals, a new bioactive substance, and undesired effects of a new drug. They tested, for example, the effects of a well-studied environmental toxin, TCDD, and identified several proteins affected by TCDD that were not known from previous studies. The results suggest that studying the complete proteome of an organism with this method will allow scientists to find more possible molecular interactions between chemicals and proteins.
The research has received financial support from, among other sources, the ERA-NET Marine Biotechnology project CYANOBESITY, which is co-financed by Formas, and the GOLIATH research project, which is financed by the EU’s Horizon 2020 programme.
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Materials provided by Linköping University. Original written by Karin Söderlund Leifler. Note: Content may be edited for style and length.