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Comment by Dr. Krishna Kumari Challa on March 27, 2023 at 9:44am

From mutation to arrhythmia: Desmosomal protein breakdown as an underlying mechanism of cardiac disease

Mutations in genes that form the desmosome are the most common cause of the cardiac disease arrhythmogenic cardiomyopathy (ACM), which affects one in 2,000 to 5,000 people worldwide. Researchers  now discovered how a mutation in the desmosomal gene plakophilin-2 leads to ACM. They found that the structural and functional changes in ACM hearts caused by a plakophilin-2 mutation are the result of increased desmosomal protein degradation. The findings of this study, published in Science Translational Medicine on March 22, 2023, further our understanding of ACM and could contribute to the development of new therapies for this disease.

ACM is a progressive and inheritable cardiac disease for which currently no treatments exist to halt its progression. Although patients initially do not experience any symptoms, they are at a higher risk of arrhythmias and resulting sudden cardiac arrest. As the disease progresses, patches of fibrotic and fat tissue form in the heart which can lead to heart failure. At this stage, patients require a heart transplantation as treatment.

More than 50% of all ACM cases are caused by a mutation in one of the desmosomal genes, which together form complex protein structures known as desmosomes. Desmosomes form "bridges" between individual heart muscle cells, allowing the cells to contract in a coordinated manner. Most of the desmosomal mutations that cause ACM occur in a gene called plakophilin-2.

The researchers used the genetic tool  CRISPR/Cas9 to introduce the human plakophilin-2 mutation in mice to mimic ACM. This allowed them to study progression of the disease in more detail. They observed that old ACM mice carrying this mutation had lower levels of desmosomal proteins and heart relaxation issues, similar to ACM patients.

Strikingly, the researchers discovered that the mutation lowered levels of desmosomal proteins even in young, healthy mice of which the heart contracted normally. From this they concluded that a loss of desmosomal proteins could underlie the onset of ACM caused by a plakophilin-2 mutation.

The researchers then moved on to explain the loss of desmosomal proteins. For this they studied both RNA and protein levels in their ACM mice. "The levels of desmosomal proteins were lower in our ACM mice compared to healthy control mice. However, the RNA levels of these genes were unchanged. They discovered that these surprising findings are the result of increased protein degradation in ACM hearts.

When the researchers treated their ACM mice with a drug that prevents protein degradation, the levels of desmosomal proteins were restored. More importantly, the restored levels of desmosomal proteins improved calcium handling of heart muscle cells, which is vital for their normal function.

The results of this study raise new insights into ACM development and indicate that protein degradation could be an interesting target for future therapies.

 Desmosomal protein degradation as an underlying cause of arrhythmogenic cardiomyopathy. Science Translational Medicine, 2023; 15 (688) DOI: 10.1126/scitranslmed.add4248

Comment by Dr. Krishna Kumari Challa on March 25, 2023 at 12:13pm

ARTEMIS: Advanced Robotic Technology for Enhanced Mobility and Improved Stability

Comment by Dr. Krishna Kumari Challa on March 25, 2023 at 12:04pm

Research team finds indirect evidence for existence of dark matter surrounding black holes

Dark matter does not emit or reflect light, nor does it interact with electromagnetic forces, making it exceptionally difficult to detect. Nevertheless, a research team has proven that there is a substantial amount of dark matter surrounding black holes. The study results are published in the journal The Astrophysical Journal Letters.

The team selected two nearby black holes (A0620-00 and XTE J1118+480) as research subjects, with both considered as binary systems. That is, each of the black holes has a companion star orbiting it. Based on the orbits of the companion stars, observations indicate that their rates of orbital decay are approximately one millisecond (1ms) per year, which is about 50 times greater than the theoretical estimation of about 0.02ms annually.

To examine whether dark matter exists around black holes, the team applied the "dark matter dynamical friction model"—a theory widely held in academia—to the two chosen binary systems, through computer simulations. The team found that the fast orbital decay of the companion stars precisely matches the data observed.

Notably, this is indirect evidence that dark matter around black holes can generate significant dynamical friction, slowing down the orbital speed of the companion stars.

Man Ho Chan et al, Indirect Evidence for Dark Matter Density Spikes around Stellar-mass Black Holes, The Astrophysical Journal Letters (2023). DOI: 10.3847/2041-8213/acaafa

The findings, which verified a theoretical hypothesis formulated in the late 20th century, represent a breakthrough in dark matter research. According to the hypothesis, dark matter close enough to black holes would be swallowed, leaving the remnants to be redistributed. The process ends up forming a "density spike" around the black holes.

Comment by Dr. Krishna Kumari Challa on March 25, 2023 at 11:21am

The fast and the fibrous: Developing the muscles you need for speed

Different types of exercise encourage the formation of different types of muscle fibers, or the cells that make up your muscles. Slow twitch muscle fibers support endurance activities like long-distance running, while fast twitch fibers are needed for short, powerful movements such as those involved in heavy weight lifting. Now, researchers in Japan have shed new light on a family of proteins involved in the development of these muscle fiber types.

Comment by Dr. Krishna Kumari Challa on March 25, 2023 at 9:26am

Tiny nanoparticle could have big impact on patients receiving corneal transplants

Corneal transplants can be the last step to returning clear vision to many patients suffering from eye disease. Each year  more than 184,000 corneal transplantation surgeries are performed annually in the world.

However, rejection rates for the corneal grafts can be as high as 10%. This is largely due to poor patient compliance to the medications, which require frequent administrations of topical eyedrops over a long period of time.

This becomes especially acute when patients show signs of early rejection of the transplanted corneas. When this occurs, patients need to apply topical eyedrops hourly to rescue the corneal grafts from failure.

The tedious process of eyedrop dosing causes a tremendous burden for patients. The resulting noncompliance to medical treatment can lead to even higher graft-rejection rates.

Research by a team  may make the corneal grafts more successful by using nano particles to encapsulate the medication. The novel approach could significantly improve patient compliance, according to a paper recently published in Science Advances titled "Six-month effective treatment of corneal graft rejection."

Each nanoparticle encapsulates a drug called dexamethasone sodium phosphate, one of the most commonly used corticosteroids for various ocular diseases treatment such as ocular inflammation, non-infectious uveitis, macular edema and corneal neovascularization. By using the nanoparticles to control the release of the medicine over time, patients would require only one injection right after the corneal transplantation surgery without the frequent eye drops. These studies have shown that using this method the medication maintains its efficacy for six months on a corneal graft rejection model.

In addition, because the medicine is released slowly and directly where it is most needed, the approach requires much lower doses than current standard eyedrop treatment while providing better efficacy and safety profiles.

Tuo Meng et al, Six-month effective treatment of corneal graft rejection, Science Advances (2023). DOI: 10.1126/sciadv.adf4608

Comment by Dr. Krishna Kumari Challa on March 25, 2023 at 7:32am

Comment by Dr. Krishna Kumari Challa on March 25, 2023 at 7:32am

Comment by Dr. Krishna Kumari Challa on March 25, 2023 at 7:31am

Comment by Dr. Krishna Kumari Challa on March 24, 2023 at 1:11pm

'Forever Chemicals' May Reduce Fertility in Women by Up to 40%, Study Finds

Robust chemicals once used in everything from cosmetics to waterproofing to food containers to firefighting foam could have a significant impact on the fertility of women worldwide.

A new study led by researchers from the Icahn School of Medicine at Mount Sinai in the US uncovered evidence in a sample of women in Singapore linking plasma concentrations of perfluoroalkyl substances (PFAS) with an increase in the difficulty of becoming pregnant.

Though the nature of this connection isn't clear, the results add to growing concerns that concentrations of so-called 'forever chemicals' across Earth's surface are silently putting our health at risk and could do for some time to come.

Per- and poly-fluoroalkyl substances such as PFAS are synthetic compounds that have found a wide range of applications in different consumer products since the mid-20th century. Useful as a barrier against water or oily substances, they're commonly encountered as non-stick and stain-resistant coatings.

One of their perks is the strength of the carbon-fluoride bond, which resists degradation. Unfortunately, this also happens to be one of their liabilities, allowing them to persist for years in the environment in ever-increasing concentrations.

Given that these materials are so widespread and encompass a vast catalog of thousands of variants, the chances of potential toxins hiding out in their midst have become too great to ignore.

"PFAS can disrupt our reproductive hormones and have been linked with delayed puberty onset and increased risks for endometriosis and polycystic ovary syndrome in few previous studies," says the new study's senior author.

What this study adds is that PFAS may also decrease fertility in women who are generally healthy and are naturally trying to conceive.

Just why this is the case is still a matter of speculation, though it's a good bet PFAS might interrupt the typical functioning of reproductive hormones in some way.

This study strongly implies that women who are planning pregnancy should be aware of the harmful effects of PFAS and take precautions to avoid exposure to this class of chemicals, especially when they are trying to conceive.

https://www.sciencedirect.com/science/article/abs/pii/S004896972300...

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Comment by Dr. Krishna Kumari Challa on March 24, 2023 at 12:26pm

Novel drug makes mice skinny even on sugary, fatty diet

Researchers have developed a small-molecule drug that prevents weight gain and adverse liver changes in mice fed a high-sugar, high-fat Western diet throughout life.

When  this drug is given to the mice for a short time, they start losing weight. They all become slim.

The research team discovered the drug by first exploring how magnesium impacts metabolism, which is the production and consumption of energy in cells. This energy, called ATP, fuels the body's processes.

Magnesium plays many key roles in good health, including regulating blood sugar and blood pressure and building bones. But the researchers found that too much magnesium slows energy production in mitochondria, which are cells' power plants. It puts the brake on, it just slows down.

Deleting MRS2, a gene that promotes magnesium transport into the mitochondria, resulted in more efficient metabolism of sugar and fat in the power plants. The result: skinny, healthy mice.

Liver and adipose (fat) tissues in the rodents showed no evidence of fatty liver disease, a complication related to poor diet, obesity and type 2 diabetes.

The drug, which the researchers call CPACC, accomplishes the same thing. It restricts the amount of magnesium transfer into the power plants. In experiments, the result was again: skinny, healthy mice. 

Lowering the mitochondrial magnesium mitigated the adverse effects of prolonged dietary stress.

A drug that can reduce the risk of cardiometabolic diseases such as heart attack and stroke, and also reduce the incidence of liver cancer, which can follow fatty liver disease, will make a huge impact. 

Travis R. Madaris, Manigandan Venkatesan, Soumya Maity, Miriam C. Stein, Neelanjan Vishnu, Mridula K. Venkateswaran, James G. Davis, Karthik Ramachandran, Sukanthathulse Uthayabalan, Cristel Allen, Ayodeji Osidele, Kristen Stanley, Nicholas P. Bigham, Terry M. Bakewell, Melanie Narkunan, Amy Le, Varsha Karanam, Kang Li, Aum Mhapankar, Luke Norton, Jean Ross, M. Imran Aslam, W. Brian Reeves, Brij B. Singh, Jeffrey Caplan, Justin J. Wilson, Peter B. Stathopulos, Joseph A. Baur, Muniswamy Madesh. Limiting Mrs2-dependent mitochondrial Mg2+ uptake induces metabolic programming in prolonged dietary stress. Cell Reports, 2023; 42 (3): 112155 DOI: 10.1016/j.celrep.2023.112155

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