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Comment by Dr. Krishna Kumari Challa on January 4, 2024 at 11:16am

Pathogenic bacteria use molecular 'shuttle services' to fill their injection apparatus with the right product

Disease-causing bacteria of the genus Salmonella or Yersinia can use tiny injection apparatuses to inject harmful proteins into host cells, much to the discomfort of the infected person. However, it is not only with a view to controlling disease that researchers are investigating the injection mechanism of these so-called type III secretion systems also known as "injectisomes."

If the structure and function of the injectisome were fully understood, researchers could hijack it to deliver specific drugs into cells, such as cancer cells. In fact, the structure of the injectisome has already been elucidated. However, it remained unclear how the bacteria load their syringes so that the right proteins are injected at the right time.

In a study published in Nature Microbiology, a team of scientists  has now been able to answer this question: mobile components of the injectisome comb through the bacterial cell in search of the proteins to be injected, so-called effectors. When they encounter an effector, they transport it like a shuttle bus to the gate of the injection needle.

How proteins of the sorting platform in the cytosol bind to effectors and deliver the cargo to the export gate of the membrane-bound injectisome is comparable to the processes at a freight terminal.

Scientists think that this shuttle mechanism helps to make the injection efficient and specific at the same time—after all, the bacteria have to inject the right proteins quickly to avoid being recognized and eliminated by the immune system. 

 Cytosolic sorting platform complexes shuttle type III secretion system effectors to the injectisome in Yersinia enterocolitica., Nature Microbiology (2024). DOI: 10.1038/s41564-023-01545-1

Comment by Dr. Krishna Kumari Challa on January 4, 2024 at 10:55am

What makes urine yellow? Scientists discover the enzyme responsible

Researchers at the University of Maryland and National Institutes of Health have identified the microbial enzyme responsible for giving urine its yellow hue, according to a new study published in the journal Nature Microbiology.

The discovery of this enzyme, called bilirubin reductase, paves the way for further research into the gut microbiome's role in ailments like jaundice and inflammatory bowel disease.

This enzyme discovery finally unravels the mystery behind urine's yellow colour. It's remarkable that an everyday biological phenomenon went unexplained for so long.

When red blood cells degrade after their six-month lifespan, a bright orange pigment called bilirubin is produced as a byproduct. Bilirubin is typically secreted into the gut, where it is destined for excretion but can also be partially reabsorbed. Excess reabsorption can lead to a buildup of bilirubin in the blood and can cause jaundice—a condition that leads to the yellowing of the skin and eyes. Once in the gut, the resident flora can convert bilirubin into other molecules.

Gut microbes encode the enzyme bilirubin reductase that converts bilirubin into a colourless byproduct called urobilinogen. Urobilinogen then spontaneously degrades into a molecule called urobilin, which is responsible for the yellow color we are all familiar with.

Urobilin has long been linked to urine's yellow hue, but the research team's discovery of the enzyme responsible answers a question that has eluded scientists for over a century.

Aside from solving a scientific mystery, these findings could have important health implications. The research team found that bilirubin reductase is present in almost all healthy adults but is often missing from newborns and individuals with inflammatory bowel disease. They hypothesize that the absence of bilirubin reductase may contribute to infant jaundice and the formation of pigmented gallstones.

Now that we've identified this enzyme, we can start investigating how the bacteria in our gut impact circulating bilirubin levels and related health conditions like jaundice. This discovery lays the foundation for understanding the gut-liver axis.

In addition to jaundice and inflammatory bowel disease, the gut microbiome has been linked to various diseases and conditions, from allergies to arthritis to psoriasis. This latest discovery brings researchers closer to achieving a holistic understanding of the gut microbiome's role in human health.

BilR is a gut microbial enzyme that reduces bilirubin to urobilinogen, Nature Microbiology (2024). DOI: 10.1038/s41564-023-01549-x

Comment by Dr. Krishna Kumari Challa on January 4, 2024 at 10:37am

Mouse study shows gut biome plays a role in social anxiety disorder

A large team of medical, psychological and social researchers has found that certain microbes in the gut biome may play a role in social anxiety disorder. In their study reported in the Proceedings of the National Academy of Sciences the group conducted experiments with fecal transplants in mice and tested them for anxiety.

Social anxiety disorder (SAD) is a condition in which a person experiences higher than normal levels of anxiety when exposed to people in a social setting, particularly people they don't know. Such settings can include parties, participating in classroom discussions or even standing in line at the grocery store.

Prior research has suggested that conditions in the gut microbiome can have an impact on emotions, which led the team on this new effort to wonder if certain microbes in the gut microbiome might play a role in SAD. To find out, they designed and carried out an experiment with lab mice.

The researchers gave the mice drugs to kill their gut microbiomes and then gave some of them fecal transplants from people with SAD. Others were given fecal transplants from people who did not have the disorder to serve as a control. After administering the transplants, the researchers exposed the test mice to a variety of social environments, which included interacting with groups of mice they knew and groups that they did not know. They found that the test mice given the SAD fecal transplants displayed symptoms of SAD, while those given the control did not. They also noted that they saw no differences in anxiety between the groups when the mice were interacting with mice they already knew.

The research team also found what they describe as substantial differences in the mix of microbes in the microbiomes of the two groups—most specifically, they found lower numbers of three types of bacteria in the mice who had been given SAD fecal transplants. They also found different levels of brain chemicals (such as oxytocin) in the two groups, and differences that appeared to promote inflammation in the SAD group.

Nathaniel L. Ritz et al, Social anxiety disorder-associated gut microbiota increases social fear, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2308706120

Comment by Dr. Krishna Kumari Challa on January 4, 2024 at 10:23am

Going dry could reduce risk of some types of cancers

A large international team of doctors and medical researchers has found evidence that suggests people who stop consuming alcoholic beverages can reduce their risk of developing some types of cancers. In their study, reported in the New England Journal of Medicine, the group analyzed the results of multiple prior research efforts to learn more about the impact of alcohol cessation.

Prior research has suggested that regularly consuming alcoholic beverages can raise the risk of developing some types of cancer, such as oral, esophageal and laryngeal cancer and also, in some cases, colon and breast cancer. And last year, the WHO went so far as to claim that no level of alcohol consumption is safe.

The research team wondered if cancer risks associated with regularly drinking alcohol would be reduced if a person stopped. To find out, they analyzed data from more than 90 studies involving alcohol-related cancers, including cessation. They found sufficient evidence that cutting back or ceasing alcohol consumption does reduce the risk of some types of cancers, most particularly those involving the mouth and esophagus. There was less evidence of reduction in the risk of breast, laryngeal or colorectal cancers.

The researchers note that it is not the alcohol in the drinks that causes cancer, but acetaldehyde, which is considered to be a toxin. It is generated by enzymes in the liver during the metabolism of alcohol. Notably, it is the same substance that can give a person a hangover. Reducing alcohol consumption, they noted, reduces the amount of acetaldehyde produced by the body, which in turn reduces the likelihood of developing some types of cancer.

The research team was not able to determine the degree of reduced risk associated with cessation of alcohol, or how long after cessation a person experiences such benefits. They do note, however, that stopping drinking for just one month, only to resume again the next, is not likely to have much effect on cancer risk. Thus, drinkers choosing to go dry in January must maintain their new habit going forward if they wish to reap such rewards.

Susan M. Gapstur et al, The IARC Perspective on Alcohol Reduction or Cessation and Cancer Risk, New England Journal of Medicine (2023). DOI: 10.1056/NEJMsr2306723

Comment by Dr. Krishna Kumari Challa on January 3, 2024 at 8:41am

Matabele ants recognize infected wounds and treat them with antibiotics

The African Matabele ants are often injured in fights with termites. Their conspecifics recognize when the wounds become infected and initiate antibiotic treatment.

The Matabele ants (Megaponera analis), which are widespread south of the Sahara, have a narrow diet: They only eat termites. Their hunting expeditions are dangerous because termite soldiers defend their conspecifics—and use their powerful mandibles to do so. It is therefore common for the ants to be injured while hunting.

If the wounds become infected, there is a significant survival risk. However, Matabele ants have developed a sophisticated health care system: They can distinguish between non-infected and infected wounds and treat the latter efficiently with antibiotics they produce themselves. This is reported by a research team  in the journal Nature Communications.

Researchers have shown that the hydrocarbon profile of the ant cuticle changes as a result of a wound infection.

 It is precisely this change that the ants are able to recognize and thus diagnose the infection status of injured nestmates.

For treatment, they then apply antimicrobial compounds and proteins to the infected wounds. They take these antibiotics from the metapleural gland, which is located on the side of their thorax. Its secretion contains 112 components, half of which have an antimicrobial or wound-healing effect. And the therapy is highly effective: The mortality rate of infected individuals is reduced by 90%, as the research group discovered.

Erik. T. Frank et al, Targeted treatment of injured nestmates with antimicrobial compounds in an ant society, Nature Communications (2023). DOI: 10.1038/s41467-023-43885-w

Comment by Dr. Krishna Kumari Challa on January 3, 2024 at 8:36am

Through rational and machine learning-guided optimization over several rounds of experiments, the team was able to improve the acetyl-CoA yield by a factor of 100. In order to test its in vivo feasibility, incorporation into the living cell should be carried out step by step.

To this end, the researchers divided the THETA cycle into three modules, each of which was successfully implemented into the bacterium E. coli. The functionality of these modules was verified through growth-coupled selection and/or isotopic labeling.

What is special about this cycle is that it contains several intermediates that serve as central metabolites in the bacterium's metabolism. This overlap offers the opportunity to develop a modular approach for its implementation.
Bringing parts of the THETA cycle into living cells is an important proof-of-principle for synthetic biology.

Shanshan Luo et al, Construction and modular implementation of the THETA cycle for synthetic CO₂ fixation, Nature Catalysis (2023). DOI: 10.1038/s41929-023-01079-z

Part 2

Comment by Dr. Krishna Kumari Challa on January 3, 2024 at 8:33am

 Synthetic carbon dioxide fixation in living cells

Synthetic biology offers the opportunity to build biochemical pathways for the capture and conversion of carbon dioxide (CO₂). Researchers have developed a synthetic biochemical cycle that directly converts CO₂ into the central building block Acetyl-CoA.

The researchers were able to implement each of the three cycle modules in the bacterium E.coli, which represents a major step towards realizing synthetic CO2 fixing pathways within the context of living cells.
Developing new ways to capture and convert CO2 is key to tackling the climate emergency. Synthetic biology opens avenues for designing new-to-nature CO2-fixation pathways that capture CO2 more efficiently than those developed by nature.

However, realizing those new-to-nature pathways in different in vitro and in vivo systems is still a fundamental challenge. Researchers have now designed and constructed a new synthetic CO2-fixation pathway, the so-called THETA cycle.

It contains several central metabolites as intermediates and has the central building block, acetyl-CoA, as its output. This characteristic makes it possible to be divided into modules and integrated into the central metabolism of E. coli.

The entire THETA cycle involved 17 biocatalysts and was designed around the two fastest CO2-fixing enzymes known to date: crotonyl-CoA carboxylase/reductase and phosphoenolpyruvate carboxylase.

The researchers found these powerful biocatalysts in bacteria. Although each of the carboxylases can capture CO2 more than ten times faster than RubisCO, the CO2-fixing enzyme in chloroplasts, evolution itself has not brought these capable enzymes together in natural photosynthesis.

The THETA cycle converts two CO2 molecules into one acetyl-CoA in one cycle. Acetyl-CoA is a central metabolite in almost all cellular metabolism and serves as the building block for a wide array of vital biomolecules, including biofuels, biomaterials, and pharmaceuticals, making it a compound of great interest in biotechnological applications. Upon constructing the cycle in test tubes, the researchers could confirm its functionality.
Part 1

Comment by Dr. Krishna Kumari Challa on January 3, 2024 at 8:26am

The results showed that when light hits the retina, visual areas of the brain respond by increasing their activity to represent the pattern of light. Memory areas of the brain also respond to visual stimulation, but, unlike visual areas, their neural activity decreases when processing the same visual pattern.

The researchers report that the study has three unusual findings. The first is their discovery that a visual coding principle is preserved in memory systems.

The second is that this visual code is upside-down in memory systems. When you see something in your visual field, neurons in the visual cortex are driving while those in the memory system are quieted.

Third, this relationship flips during memory recall. If you close your eyes and remember that visual stimuli in the same space, you'll flip the relationship: your memory system will be driving, suppressing the neurons in perceptual regions.

These results provide a clear example of how shared visual information is used by memory systems to bring recalled memories in and out of focus.

Adam Steel et al, A retinotopic code structures the interaction between perception and memory systems, Nature Neuroscience (2024). DOI: 10.1038/s41593-023-01512-3

Part 2

Comment by Dr. Krishna Kumari Challa on January 3, 2024 at 8:24am

Researchers identify new coding mechanism that transfers information from perception to memory

Our memories are rich in detail: we can vividly recall the color of our home, the layout of our kitchen, or the front of our favorite café. How the brain encodes this information has long puzzled neuroscientists.

In a new study, researchers identified a neural coding mechanism that allows the transfer of information back and forth between perceptual regions to memory areas of the brain. The results are published in Nature Neuroscience.

The researchers found that memory-related brain areas encode the world like a 'photographic negative' in space. And that 'negative' is part of the mechanics that move information in and out of memory, and between perceptual and memory systems.

In a series of experiments, participants were tested on perception and memory while their brain activity was recorded using a functional magnetic resonance imaging (fMRI) scanner. The team identified an opposing push-pull like coding mechanism, which governs the interaction between perceptual and memory areas in the brain.

Part 1

Comment by Dr. Krishna Kumari Challa on January 3, 2024 at 7:26am

Closing in on the ultimate quest to regenerate insulin in pancreatic stem cells

Researchers are zeroing in on the ultimate quest to regenerate insulin in pancreatic stem cells and replace the need for regular insulin injections.

researchers have demonstrated in an article published in Signal Transduction and Targeted Therapy that newly made insulin cells can respond to glucose and produce insulin following stimulation with two approved drugs in as little as 48 hours.

Further, they confirmed this pathway of awakening the insulin-producing cells is viable in age groups from 7 to 61, providing much-needed insights into the mechanisms underlying the regeneration of beta cells.

Using pancreatic cells derived from a child and adult type 1 diabetic donors, and from a non-diabetic person, a research  team demonstrated how insulin-producing cells that are destroyed in people with type 1 diabetes can be regenerated into glucose sensing and functionally secreting insulin cells. In this latest study by the Human Epigenetics team, they show small molecule inhibitors that are currently used for rare cancers and approved  can rapidly return insulin production in pancreatic cells destroyed by diabetes. While current pharmaceutical options for diabetes treatment help control blood glucose levels they do not prevent, stop or reverse the destruction of insulin-secreting cells.

The novel therapeutic approach holds the potential to become the first disease modifying treatment for type 1 diabetes by facilitating glucose responsive insulin production by harnessing the patient's remaining pancreatic cells, thereby enabling people living with diabetes to potentially achieve independence from round-the-clock insulin injections.

This disease-modifying treatment also represents a promising solution for the significant number of people living with insulin dependent diabetes, who account for 30% of those with type 2 diabetes.

 Keith Al-Hasani et al, EZH2 inhibitors promote β-like cell regeneration in young and adult type 1 diabetes donors, Signal Transduction and Targeted Therapy (2024). DOI: 10.1038/s41392-023-01707-x

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