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Comment by Dr. Krishna Kumari Challa on November 27, 2024 at 10:48am

Using a mouse model, this study used global metabolic analysis to investigate changes in metabolites during an enteric infection. The mice were infected with one of two pathogens, L. monocytogenes, which replicates in the intestine, liver and gall bladder, or C. rodentium, which replicates in the caecum and colon.

The different infection groups led to both shared and specific changes in bile metabolites. Moreover, hundreds of new metabolites that are in the bile metabolome were described. More specifically, the researchers found that enteric infection dynamically changes the composition of bile in order to provide intestinal defense.
While these findings bridge a large gap in knowledge regarding bile composition, the researchers note that the 812 bile metabolites identified in this study likely only represent a subset of all bile metabolites.

Ting Zhang et al, Enteric bacterial infection stimulates remodelling of bile metabolites to promote intestinal homeostasis, Nature Microbiology (2024). DOI: 10.1038/s41564-024-01862-z

Part 2

Comment by Dr. Krishna Kumari Challa on November 27, 2024 at 10:47am

Intestinal infections can change bile composition, leading to changes in immune function

Intestinal infections can change the composition of liver bile, leading to changes in immune function and gut bacteria, potentially helping fight off harmful bacteria.

Researchers have identified a new axis of host defense by studying what happens during enteric infection—a term that encompasses all types of intestinal infections including so-called "stomach flu."

A new study from infectious disease investigators 

uncovers how bile, a solution produced by the liver and responsible for the absorption of fat, plays a role in the fight against infections.

While the study was conducted in mice, the researchers anticipate that the findings likely apply to humans as well. Results are published in Nature Microbiology.

The changes the researchers  detected in the composition of bile with infection are beneficial for the intestine to clear infection. 

These findings findings reveal the intricate and dynamic nature of bile composition, shedding new light on the liver's critical role in defending the intestine from infection. These insights enhance our understanding of the liver's broader functions in regulating physiological stability and metabolic processes.

Part 1

Comment by Dr. Krishna Kumari Challa on November 27, 2024 at 9:32am

How cancer cells fend off starvation and death from chemotherapy

Laboratory experiments with cancer cells have revealed two ways in which tumors evade drugs designed to starve and kill them.

While chemotherapies successfully treat cancers and extend patients' lives, they are known not to work for everyone for long, as cancer cells rewire the process by which they convert fuel into energy (metabolism) to outmaneuver the drugs' effects. Many of these drugs are so-called antimetabolics, disrupting cell processes needed for tumor growth and survival.

Three such drugs used in the study—raltitrexed, N-(phosphonacetyl)-l-aspartate (PALA), and brequinar—work to prevent cancer cells from making pyrimidines, molecules that are an essential component to genetic letter codes, or nucleotides, that make up RNA and DNA.

Cancer cells must have access to pyrimidine supplies to produce more cancer cells and to produce uridine nucleotides, a primary fuel source for cancer cells as they rapidly reproduce, grow, and die. Disrupting the fast-paced but fragile pyrimidine synthesis pathways, as some chemotherapies are designed to do, can rapidly starve cancer cells and spontaneously lead to them dying (apoptosis).

This new  study shows how cancer cells survive in an environment made hostile by the persistent shortage of the energy from glucose (the chemical term for blood sugar) needed to drive tumor growth.

This better understanding of how cancer cells evade the drugs' attempts to kill them in a low-glucose environment, the researchers say, could lead to the design of better or more effective combination therapies.

Publishing in the journal Nature Metabolism online Nov. 26, study results showed that the low-glucose environment inhabited by cancer cells, or tumor microenvironment, stalls cancer cell consumption of existing uridine nucleotide stores, making the chemotherapies less effective.

Normally, uridine nucleotides would be made and consumed to help make the genetic letter codes and fuel cell metabolism. But when DNA and RNA construction is blocked by these chemotherapies, so too is the consumption of uridine nucleotide pools, the researchers found, as glucose is needed to change one form of uridine, UTP, into another usable form, UDP-glucose.

The irony, researchers say, is that a low-glucose tumor microenvironment is in turn slowing down cellular consumption of uridine nucleotides and presumably slowing down rates of cell death. Researchers say cancer cells need to run out of pyrimidine building blocks, including uridine nucleotides, before the cells will self-destruct.

In other experiments, low-glucose tumor microenvironments were also unable to activate two proteins, BAX and BAK, sitting on the surface of mitochondria, a cell's fuel generator. Activation of these trigger proteins disintegrates the mitochondria, and instantly sets off a series of caspase enzymes that help initiate apoptosis (cell death).

Conclusion of the study:  low glucose slows down the consumption and exhaustion of uridine nucleotides needed to fuel cancer cell growth and hinders resulting apoptosis, or death, in cancer cells.

Glucose limitation protects cancer cells from apoptosis induced by pyrimidine restriction and replication inhibition, Nature Metabolism (2024). DOI: 10.1038/s42255-024-01166-w

Comment by Dr. Krishna Kumari Challa on November 26, 2024 at 7:26am

The study identified a quadratic relationship between rainfall and divorce rates, with the highest rates of divorce occurring in years with either extremely low or high rainfall during the breeding season.

An extreme rainfall event in 1997 was a significant outlier in the data, with exceptionally high rainfall correlating with a sharp increase in divorce rates. When this event was excluded from the analysis, a clearer negative relationship between rainfall and divorce emerged.

Despite rainfall impacting divorce rates, the study found no direct link between reproductive success (i.e., the number of offspring produced) and the likelihood of divorce, suggesting that other, as yet unidentified, factors may be influencing partnership stability.

This study adds to the growing body of evidence showing how environmental factors, particularly those linked to climate change, can directly influence the social dynamics and reproductive strategies of wildlife.

As climate change intensifies, it is critical to understand how fluctuations in environmental conditions, such as rainfall, affect the stability of socially monogamous species.

This research not only enhances our understanding of animal behavior in the face of climate variability but also provides valuable insights that could inform conservation efforts for species vulnerable to the effects of climate change.

 A. A. Bentlage et al, Rainfall is associated with divorce in the socially monogamous Seychelles warbler, Journal of Animal Ecology (2024). DOI: 10.1111/1365-2656.14216

Part 2

Comment by Dr. Krishna Kumari Challa on November 26, 2024 at 7:25am

Did you know that birds are separating and divorcing too?

Bird divorce rates may be linked to fluctuations in rainfall

A 16-year study on a closed population of Seychelles warblers (Acrocephalus sechellensis) on Cousin Island, Seychelles, has uncovered significant findings about how environmental factors—specifically rainfall—affect the stability of pair bonds in birds.

An international team of researchers  found that fluctuations in rainfall prior to and during the breeding season significantly influence the likelihood of "divorce" between mates, highlighting the broader implications of climate cahnge for animal reproduction and conservation. The study is published in the Journal of Animal Ecology.

Divorce, in the context of socially monogamous species, refers to the termination of a pair bond while both individuals are still alive. This mating strategy is often associated with poor reproductive success and has been observed in various bird species. However, the relationship between environmental factors, particularly climate fluctuations, and divorce is the new way of studying the problem.

Social monogamy implies that two birds have formed a pair bond and associate with the same partner, usually over many years and even lifetimes. Pair-bonded birds usually live and raise young together.

Researchers analyzed 16 years of data and found a complex, non-linear relationship between  rainfall patterns and divorce rates, with divorce being more likely during years of both low and high rainfall.

This relationship was notably influenced by an extreme climatic event—the 1997 El Niño-induced rainfall spike.

Part 1

Comment by Dr. Krishna Kumari Challa on November 26, 2024 at 7:16am

Scientists create a 'minimal cell membrane' with just two lipids

Lipids, or fats, are essential to life. They form the membranes around cells, protecting them from the outside. In nature, there is an enormous diversity of lipids, with each organism having its own unique combination. But what are the minimum lipid requirements for a cell to survive?

A research team   showed that cells can function with just two lipids. They created a cell with a minimal, adaptable membrane, offering a unique platform to study how lipid complexity evolved and how it can be engineered for synthetic life. Their findings are published in Nature Communications.

Membranes are like bubbles that encapsulate cells and separate them from their surroundings. Membranes also serve as platforms where molecules interact, coordinating processes essential to life.

"There is an enormous diversity of lipids in nature, and almost every organism has its own set of lipids, known as lipidome. Human cells, for example, employ hundreds of different types of lipids. Yet, these different mixtures of lipids, all provide solutions to the same key evolutionary challenges: creating a stable barrier and organizing biomolecules in space and time.

For their study, the group started with mycoplasma mycoides, a naturally simple pathogenic bacterium. Unlike most cells, mycoplasma cannot make its own lipids and must instead use those provided by its host. By systematically supplementing cells with different lipid combinations, the researchers narrowed down the essential combination needed for survival and division.

They found that the cells can survive on a "diet" of just two lipids: cholesterol and another so-called bilayer-forming lipid, phosphatidylcholine.

These two lipids are not necessarily the only ones that could support life but having both a bilayer-forming lipid, which provides the basic structure for the cell membrane, and a non-bilayer-forming lipid, such as cholesterol, which adds stability, seems to be a fundamental requirement.

The team observed the cells with a minimal lipid diet under an electron microscope and saw dramatic effects on cell shape and size. Some cells grew up to ten times their usual size, while others formed unusual shapes and deformations.

The researchers observed that  about half of the cells with only two lipids appeared completely normal. They were round and divided well. Despite the drastic reduction in lipid complexity, they continued to function surprisingly well.

Reverse engineering the complexity of life

Having identified the minimal lipid diet, the researchers applied it to a "minimal cell" called JVCI-Syn3A, which was engineered at the J. Craig Venter Institute to contain only the genes essential for survival. Now, with both a minimal genome and lipidome, this cell provides a powerful new tool for synthetic biology.

This minimal cell system provides a unique platform to study how lipids support life. Using the principles of bottom-up synthetic biology, researchers can now reintroduce different parts of the lipidome in a directed way and explore the corresponding changes in cell function.

This knowledge could one day help us design synthetic cells with bespoke membranes for special applications in biotechnology and medicine.

Isaac Justice et al, A tuneable minimal cell membrane reveals that two lipid species suffice for life, Nature Communications (2024). DOI: 10.1038/s41467-024-53975-y

Comment by Dr. Krishna Kumari Challa on November 26, 2024 at 6:47am

UTIs are extraordinarily common but kidney infections are not—now we know know why

Infections in the lower urinary tract rarely migrate to the kidneys, but the precise mechanism that the human body employs to keep the twin organs disease-free has remained a medical mystery—until now.

A multidisciplinary team solved the conundrum in an elegant series of experiments. Researchers found that highly specialized biological structures called neutrophil extracellular traps—NETs—are pivotal in protecting the kidneys from infection.

NETs are sticky webs of wispy strands that quite literally serve as traps. They ensnare bacteria that attempt to migrate northward to the kidneys from the lower urinary tract. NETs add to an array of antimicrobial activities mounted by the body to beat back infection.

Writing in Science Translational Medicine, the researchers presented compelling evidence that sticky mesh-like immune NETs serve as a crucial antibacterial defense against infection. The team's study not only revealed the presence of NETs in the urinary tract but also answered a longstanding question in UTI research: What spares the kidneys from pathogens?

"These findings highlight the role of NETosis in preventing ascending infections in the urinary tract.

NETosis refers to the formation of NETs, which prevent any of the various species of bacteria—E. coli, Enterococcal faecalis, Proteus mirabilis, among others—from migrating upward from the bladder to the kidneys. The study focused on E. coli, the most common bacterial cause of UTIs.

The process of NETosis is another wonder of human biology. It reveals how the body, and more specifically, the immune system, creates structures to ensnare pathogens. The key entity in NETosis is the neutrophil, an immune cell, which is signaled to undergo a unique form of cell death. As it succumbs, the neutrophil releases its DNA, histones, and granule proteins, leaving behind a mesh-like structure, a net. E. coli and other bacteria become entrapped just as insects are snared by a spider's web. The process of NETosis isn't rare because NETs are found in the urine of healthy people, the researchers confirmed.

Andrew P. Stewart et al, Neutrophil extracellular traps protect the kidney from ascending infection and are required for a positive leukocyte dipstick test, Science Translational Medicine (2024). DOI: 10.1126/scitranslmed.adh5090

Comment by Dr. Krishna Kumari Challa on November 25, 2024 at 9:17am

How humans evolved to be 'energetically unique'

Humans, it turns out, possess much higher metabolic rates than other mammals, including our close relatives, apes and chimpanzees, finds a Harvard study. Having both high resting and active metabolism, researchers say, enabled our hunter-gatherer ancestors to get all the food they needed while also growing bigger brains, living longer, and increasing their rates of reproduction.

Humans are off-the-charts different from any creature that we know of so far in terms of how we use energy.

The paper, published in Proceedings of the National Academy of Sciences, challenges a previous consensus that human and non-human primates' metabolic rates are either the same or lower than would be expected for their body size.

Using a new comparison method that they say better corrects for body size, environmental temperature, and body fat, the researchers found that humans, unlike most mammals including other primates, have evolved to escape a tradeoff between resting and active metabolic rates.

Animals take in calories through food and, like a bank account, spend them on expenses mostly divided between two broad metabolic categories: resting and physical activity.

In other primates, there is a distinct tradeoff between resting and active metabolic rates, which helps explain why chimpanzees, with their large brains, costly reproductive strategies, and lifespans, and thus high resting metabolisms, are "couch potatoes" who spend much of their day eating.

Generally, the energy animals spend on metabolism ends up as heat, which is hard to dissipate in warm environments. Because of this tradeoff, animals such as chimpanzees who spend a great deal of energy on their resting metabolism and also inhabit warm, tropical environments, have to have low activity levels.

"Humans have increased not only our resting metabolisms beyond what even chimpanzees and monkeys have, but—thanks to our unique ability to dump heat by sweating—we've also been able to increase our physical activity levels without lowering our resting metabolic rates.

The result is that we are an energetically unique species.

The team's analysis shows that monkeys and apes evolved to invest about 30 to 50% more calories in their resting metabolic rates than other mammals of the same size, and that humans have taken this to a further extreme, investing 60% more calories than similar-sized mammals.

Andrew K. Yegian et al, Metabolic scaling, energy allocation tradeoffs, and the evolution of humans' unique metabolism, Proceedings of the National Academy of Sciences (2024). DOI: 10.1073/pnas.2409674121

Comment by Dr. Krishna Kumari Challa on November 25, 2024 at 9:09am

Oldest known alphabet unearthed in ancient Syrian city

What appears to be evidence of the oldest alphabetic writing in human history is etched onto finger-length, clay cylinders excavated from a tomb in Syria by a team of Johns Hopkins University researchers.

The writing, which is dated to around 2400 BCE, precedes other known alphabetic scripts by roughly 500 years, upending what archaeologists know about where alphabets came from, how they are shared across societies, and what that could mean for early urban civilizations.

At Umm-el Marra, the archaeologists uncovered tombs dating back to the Early Bronze Age. One of the best-preserved tombs contained six skeletons, gold and silver jewelry, cookware, a spearhead, and intact pottery vessels. Next to the pottery, the researchers found four lightly baked clay cylinders with what seemed to be alphabetic writing on them.

Maybe they detail the contents of a vessel, or maybe where the vessel came from, or who it belonged to. Without a means to translate the writing, the researchers can only speculate.

Using carbon-14 dating techniques, researchers confirmed the ages of the tombs, the artifacts, and the writing.

The results were presented  at the American Society of Overseas Research's Annual Meeting on Nov 21st.

Comment by Dr. Krishna Kumari Challa on November 25, 2024 at 8:53am

A Rare, Fatal Skin Disease Has Been Cured in Patients For The First Time
A rare and potentially fatal skin infection with nightmarish outcomes may soon have a cure.

The infection starts as a seemingly harmless rash, and before a person knows it, more than 30 percent of the skin on their body begins to blister and peel off in sheets, usually starting with the face and chest before progressing to the mouth, eyes, and genitals.
Infections, organ failure, and pneumonia can soon follow. In a third of all cases, the condition proves fatal. For those who survive, recovery can take months and usually requires similar treatment to burn victims.

The debilitating infection is an immune response to medication, called toxic epidermal necrolysis (TEN), and while it is thankfully very rare, impacting a million or two people worldwide every year, its onset is highly unpredictable.

TEN is linked with more than 200 medications, and it can impact all age groups and ethnicities, although it tends to be more common in females than males and is 100 times more prevalent in those with the human immunodeficiency virus ( HIV).
An international team of researchers now have cured seven patients with TEN or a slightly less severe version of the infection, known as Stevens–Johnson syndrome (SJS). None of the patients reported side effects.
All seven people treated with this therapy in their study experienced rapid improvement and a full recovery, in staggering results that have likely unlocked a cure for the condition.
One of those patients was a 59-year-old man who developed TEN across 35 percent of his body after beginning treatment for lung cancer. The patient had lost so much skin, his predicted mortality risk was nearly 60 percent.

Upon taking a novel immune inhibitor, however, his infection stopped progressing. After 16 days, he was almost fully healed.
The class of drugs, called JAK inhibitors (JAKi), seem to work by suppressing an overactive immune pathway.

Scientists discovered the importance of this signaling pathway using skin samples from patients with TEN, to see which individual cells were driving the deadly disease. Altogether, they identified six proteins involved in the JAK/STAT pathway that are upregulated in those with the skin infection.

The JAK/STAT pathway is the main driver of skin inflammation, damaged skin cells, and epidermal detachment.

Using rodent models of TEN, researchers found that one to three days after taking an oral JAK inhibitor, the skin infections had noticeably improved.
All seven patients responded well to the treatment and were discharged in good health, paving the way for a future clinical trial.

https://www.nature.com/articles/s41586-024-08061-0#Sec9

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