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Comment by Dr. Krishna Kumari Challa on April 17, 2023 at 11:46am

To understand the mechanism, one must know how cyclic peptides are structured: they consist of a central ring structure to which side chains are attached. The molecules are flexible and can dynamically change their structure to adapt to their environment.

 simulations reveal in detail how a cyclic peptide penetrates the membrane: First, the molecule anchor itself to the membrane’s surface, before penetrating it perpendicular to the membrane. It then changes its three-​dimensional shape while passing through, rotating once about its longitudinal axis before reaching the other side of the membrane, where it exits again.

These changes in shape have to do with the different environments the molecule experiences as it moves through the membrane: The body consists largely of water. Both inside and outside of cells, biochemical molecules are mostly present in aqueous solution. Cell membranes, on the other hand, are made up of fatty acids, so water-​repellent conditions prevail within them. To enable it to cross the membrane, the cyclic peptide changes its three-​dimensional shape to briefly become as hydrophobic as possible.

For the present study, the researchers investigated eight different cyclic peptides. These are model peptides with no medicinal effect – scientists at pharmaceutical giant Novartis developed them for basic research.

The new findings can now be used in discovering cyclic peptides as new drug candidates. However, the researchers point out a certain trade-​off: there are side chains that provide ideal conditions for cyclic peptides to anchor to the membrane surface, but that make it difficult for the peptides to cross the membrane. This new knowledge helps researchers to give advance thought to which side chains they want to use and where on the molecule they are most helpful. All of this could speed up drug discovery and development by ensuring right from the outset that researchers are investigating potential active ingredients that can eventually be taken as a tablet.

https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c01837

Linker SM, Schellhaas C, Kamenik AS, Veldhuizen MM, Waibl F, Roth HJ, Fouché M, Rodde S, Riniker S: Lessons for Oral Bioavailability: How Conformationally Flexible Cyclic Peptides Enter and Cross Lipid Membranes, Journal of Medicinal Chemistry 2023, 66: 2773, doi: external page10.1021/acs.jmedchem.2c01837call_made

Part 2

Comment by Dr. Krishna Kumari Challa on April 17, 2023 at 11:42am

How drugs get into the blood

Computer simulations have helped researchers understand in detail how pharmaceutically active substances cross cell membranes. These findings can now be used to discover new drug candidates more efficiently.

There is a need for new drugs. For example, many of the antibiotics that we have been using for a long time are becoming less effective. Chemists and pharmaceutical scientists are frantically searching for new active substances, especially those that can penetrate cell membranes, as these are the only ones that patients can take orally in the form of a tablet or syrup. Only these active ingredients pass through the intestinal wall in the small intestine and enter the bloodstream to reach the affected area in the body. For active ingredients that cannot penetrate the cell membrane, physicians have no choice but to inject them directly into the bloodstream.

That is why researchers are trying to understand which molecules can penetrate cell membranes and how exactly they do this. For one important and promising class of substances – cyclic peptides – chemists  have now decoded additional details of the relevant mechanism. 

Only modelling allows researchers such detailed, high-​resolution insights.

Cyclic peptides are ring-​shaped molecules that are much larger than the small molecules that make up the majority of today’s drugs. In some areas of application, however, chemists and pharmaceutical scientists are coming up against their limits with small molecules, which is why they are turning to larger molecules like the cyclic peptides. This substance class includes many pharmaceutically active natural substances, such as cyclosporine, an immunosuppressant that for decades has been used after organ transplants, and many antibiotics.

Using computer modelling and a lot of supercomputer power, researchers were able to elucidate how cyclic peptides similar to cyclosporine cross a membrane.

Part 1 

Comment by Dr. Krishna Kumari Challa on April 17, 2023 at 8:56am

Link between a vitamin deficiency and  'double-jointedness' and hypermobile Ehlers-Danlos  syndrome

Researchers have discovered a possible genetic cause for hypermobility (commonly known as double-jointedness) and a range of associated connective tissue disorders such as hypermobile Ehlers-Danlos syndrome, according to preliminary findings published in the journal Heliyon.

You may know someone with overly flexible joints, a friend or family member who can easily slide into a split or bend limbs to impossible angles. But hypermobility is a more serious condition than being "double-jointed."

For those with hypermobile Ehlers-Danlos syndrome (EDS), the same conditions that create fragile connective tissue can cause a range of symptoms that, on the surface, can seem unrelated: physical conditions such as joint pain, chronic fatigue, thin tooth enamel, dizziness, digestive trouble and migraines; and psychiatric disorders, such as anxiety and depression. Women with hypermobile EDS may also be at increased risk for endometriosis or uterine fibroids.

Researchers have long struggled to find the cause of hypermobility and hypermobile EDS. Of the 13 subtypes of EDS, hypermobile EDS comprises more than 90% of the cases. But until this study, hypermobile EDS was the only subtype without a known genetic correlate. As a result, symptoms have often been treated individually rather than as the result of a single cause.

Researchers now have linked hypermobility to a deficiency of folate—the natural form of vitamin B9—caused by a variation of the MTHFR gene.

Those with this genetic variant can't metabolize folate, which causes unmetabolized folate to accumulate in the bloodstream. The folate deficiency may prevent key proteins from binding collagen to the extracellular matrix. This results in more elastic connective tissue, hypermobility, and a potential cascade of associated conditions.

The discovery could help doctors more accurately diagnose hypermobility and hypermobile EDS by looking for elevated folate levels in blood tests as well as the MTHFR genetic variant.

Jacques Courseault et al, Folate-dependent hypermobility syndrome: A proposed mechanism and diagnosis, Heliyon (2023). DOI: 10.1016/j.heliyon.2023.e15387

Comment by Dr. Krishna Kumari Challa on April 16, 2023 at 1:30pm

What Is an Annular Eclipse?

Comment by Dr. Krishna Kumari Challa on April 16, 2023 at 1:25pm

How a virus causes chromosomal breakage, leading to cancer

The Epstein-Barr virus (EBV) is easily spread through bodily fluids, primarily saliva, such as kissing, shared drinks or using the same eating utensils. Not surprisingly then, EBV is also among the most ubiquitous of viruses: More than 90% of the world’s population has been infected, usually during childhood.

EBV causes infectious mononucleosis and similar ailments, though often there are no symptoms. Most infections are mild and pass, but the virus persists in the body, becoming latent or inactive, sometimes reactivating. Long-term latent infections are associated with several chronic inflammatory conditions and multiple cancers.

In a new paper, published April 12, 2023 in the journal Nature, researchers describe for the first time how the virus exploits genomic weaknesses to cause cancer while reducing the body’s ability to suppress it.

These findings show “how a virus can induce cleavage of human chromosome 11, initiating a cascade of genomic instability that can potentially activate a leukemia-causing oncogene and inactivate a major tumor suppressor”.

It’s the first demonstration of how cleavage of a ‘fragile DNA’ site can be selectively induced.

Throughout every person’s genome or full set of genes are fragile sites, specific chromosomal regions more likely to produce mutations, breaks or gaps when replicating. Some are rare, some are common; all are associated with disorders and disease, sometimes heritable conditions, sometimes not, such as many cancers.

In the new study, the researchers focused on EBNA1, a viral protein that persists in cells infected with EBV. EBNA1 was previously known to bind at a specific genomic sequence in the EBV genome at the origin of replication. The researchers found that EBNA1 also binds a cluster of EBV-like sequences at a fragile site on human chromosome 11 where increasing abundance of the protein triggers chromosomal breakage.

Other prior research has shown that EBNA1 inhibits p53, a gene that plays a key role in controlling cell division and cell death. It also suppresses tumor formation when normal. Mutations of p53, on the other hand, are linked to cancer cell growth.

When the scientists examined whole-genome sequencing data for 2,439 cancers across 38 tumor types from the Pan-Cancer Analysis of Whole Genomes project, they found that cancer tumors with detectable EBV revealed higher levels of chromosome 11 abnormalities, including 100% of the head and neck cancer cases.

This discovery suggests that susceptibility to EBNA1-induced fragmentation of chromosome 11 depends on the control of EBNA1 levels produced in latent infection, as well as the genetic variability in the number of EBV-like sequences present on chromosome 11 in each individual. Going forward, this knowledge paves the way for screening risk factors for the development of EBV-associated diseases. Moreover, blocking EBNA1 from binding at this cluster of sequences on chromosome 11 can be exploited to prevent the development of EBV-associated diseases.

https://www.nature.com/articles/s41586-023-05923-x

Comment by Dr. Krishna Kumari Challa on April 16, 2023 at 1:16pm

Sex of blood donor has no effect on recipient survival, finds clinical trial

A large clinical trial of more than 8,700 patients published in the New England Journal of Medicine concluded that the sex of a donor has no effect on the survival of recipients of red blood cell transfusions.

The possible impact of the sex of a blood donor on recipient survival has been an unanswered question in transfusion medicine since 2015, when the American National Heart, Lung and Blood Institute identified it as a research priority. Some evidence suggested that sex-related differences such as hormone levels in male and female blood might affect recipient survival, but the results of observational studies have been conflicting.

"To answer this question definitively, researchers needed a large, randomized clinical trial, but those studies are incredibly expensive. By embedding this trial in real-world practice and using practical methods, they answered this question for a fraction of what a trial would normally cost.

And most importantly, the study found no statistically significant differences in overall survival between recipients of male donor blood and recipients of female donor blood.

 The effect of donor sex on recipient mortality in transfusion, New England Journal of Medicine (2023). DOI: 10.1056/NEJMoa2211523

Comment by Dr. Krishna Kumari Challa on April 15, 2023 at 9:51am

Researchers use skin-colonizing bacteria to create a topical cancer therapy in mice

While studying a type of bacteria that lives on the healthy skin of every human being, researchers  may have stumbled on a powerful new way to fight cancer.

After genetically engineering the bacteria, called Staphylococcus epidermidis, to produce a tumor antigen (a protein unique to the tumor that's capable of stimulating the immune system), they applied the live bacteria onto the fur of mice with cancer. The resulting immune response was strong enough to kill even an aggressive type of metastatic skin cancer, without causing inflammation.

Millions of bacteria, fungi and viruses live on the surface of healthy skin. These friendly colonists play a crucial role in maintaining the skin barrier and preventing infection, but there are many unknowns about how the skin microbiota interacts with the host immune system. For instance, unique among colonizing bacteria, staph epidermidis triggers the production of potent immune cells called CD8 T cells—the "killer" cells responsible for battling severe infections or cancer.

The researchers showed that by inserting a tumor antigen into staph epidermidis, they could trick the mouse's immune system into producing CD8 T cells targeting the chosen antigen. These cells traveled throughout the mice and rapidly proliferated when they encountered a matching tumor, drastically slowing tumour growth or extinguishing the tumours altogether.

Even when melanoma had metastasized to the lungs, treatment with the bacteria drastically shrank the size of tumors or eliminated them, significantly improving survival times for the mice. 

When the researchers combined the new treatment with a second type of immunotherapy designed to bolster T cell activity, called "checkpoint blockade," the benefit was even more pronounced: 15 out of 16 established tumors disappeared. When the mice were re-injected with more cancer cells 30 days later, tumors still didn't grow.

"This appears to be evidence of a memory immune response, similar to what happens after a vaccine."

The researchers now think that the host organism produces these T cells to essentially vaccinate itself against the colonists, protecting against inevitable cuts and scrapes that could allow bacteria to breach the skin barrier.

In these experiments, they have basically tricked the host into thinking that the tumour is bacterially infected and then the host is going after that tumour aggressively.

The researchers have discovered that the host is vaccinating itself, day in and day out, against organisms that live at barrier surfaces. If they can direct even a bit of this immune attention toward specific cancers—or potentially infectious diseases—they will have a very effective, low-cost therapy that can simply be applied to the skin.

Will this therapy work in human beings? This has to be tested now.

 Y. Erin Chen et al, Engineered skin bacteria induce antitumor T cell responses against melanoma, Science (2023). DOI: 10.1126/science.abp9563

Comment by Dr. Krishna Kumari Challa on April 14, 2023 at 1:28pm

Bladder ‘Memory’ Influences Urinary Tract Infection Recurrence in Mice

Urinary tract infections leave permanent epigenetic marks in the mouse bladder epithelium, reprogramming its response to subsequent infections, a study finds.

One of the main challenges for treating urinary tract infections is their high recurrence, especially in women. The underlying mechanisms of this high recurrence rate are not well understood, but having suffered from a previous UTI is a significant risk factor. A study in mice published April 10 in Nature Microbiology proposes that this may be partially explained because an initial urinary infection with Escherichia coli—the culprit of most UTI cases—modifies the host’s epithelial epigenome in such a way that it alters the morphology of the bladder in the long term, influencing the response to future infections by the same bacteria.

When people think about how our body fights pathogens, they focus on the immune system. However, this work shows “clear evidence that changes that occur to epithelial cells . . . have long-term consequences for how we react to infections". 

Some of the researchers behind the new study had already reported in 2016 that mice infected with an initial E. coli UTI resulted in either spontaneous resolution or a chronic cystitis, respectively reducing or increasing susceptibility to future infections. The researchers found then that, in each scenario, the E. coli UTI had differentially modified the bladder epithelium in terms of architecture, morphology, and molecular signatures. 

Translating these findings to humans—for instance, to treat recurrent UTIs—is still a distant goal, all sources agree. A lot of other technologies would need to be in place and we need a “better understanding of how you can manipulate the epigenome in a very directed way” in order to develop such therapies.

https://www.nature.com/articles/s41564-023-01346-6

Comment by Dr. Krishna Kumari Challa on April 14, 2023 at 12:36pm

A more than 10% decrease in waist circumference was associated with a 2.14-fold higher risk of all-cause mortality for men and a 34% higher risk of all-cause mortality for women.

There was no significant association between weight gain and increases in waist circumference and all-cause mortality.

The researchers state it is likely that weight loss is an early indicator of the presence of various life-shortening diseases. While weight loss may precede a cancer diagnosis, the study revealed that weight loss also precedes increased mortality from all causes, including deaths from cardiovascular disease, trauma, dementia, Parkinson's disease, and other less common causes.

The weight loss was primarily associated with reduced appetite, leading to reduced food intake. The paper describes appetite as a complex process governed by both the central nervous system and various circulating hormones, any of which might be disrupted ahead of more pronounced disease presentation.

The researchers conclude that physicians and their patients should be aware of the significant association between mortality and elder weight loss.

 Sultana Monira Hussain et al, Associations of Change in Body Size With All-Cause and Cause-Specific Mortality Among Healthy Older Adults, JAMA Network Open (2023). DOI: 10.1001/jamanetworkopen.2023.7482

Part 2

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Comment by Dr. Krishna Kumari Challa on April 14, 2023 at 12:35pm

Significant association found between all-cause mortality and weight loss in the elderly

An international team of researchers  has examined the associations of changes in body weight and waist circumference with all-cause and cause-specific mortality. In the paper, "Associations of Change in Body Size With All-Cause and Cause-Specific Mortality Among Healthy Older Adults," published in JAMA Network Open, the team highlights the startling connection between weight loss and increased risk of death.

The researchers used data from a past study looking at aspirin use in 16,703 Australian participants aged 70 and above. They focused on weight recordings, waist circumference measurements and mortality information over time. The cohort consisted of 7,510 men and 9,193 women. All the individuals were without evident cardiovascular disease, dementia, physical disability, or life-limiting chronic illnesses.

Both body weight and waist circumference changes were categorized as change within 5% (stable), decrease by 5% to 10%, decrease by more than 10%, increase by 5% to 10%, and increase by more than 10%.

Using men with stable weight as a control, men with a 5% to 10% weight loss had a 33% higher risk of all-cause mortality, and those with more than a 10% decrease in body weight had a 289% higher risk.

Compared to women with stable weight, women with a 5% to 10% weight loss had a 26% higher risk of all-cause mortality, and those with more than a 10% decrease in body weight had a 114% higher risk.

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