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Comment by Dr. Krishna Kumari Challa on October 22, 2024 at 9:45am

'Nano-weapon' discovery boosts fight against antibiotic-resistant hospital superbugs

Researchers have discovered how a bacteria found in hospitals uses "nano-weapons" to enable their spread, unlocking new clues in the fight against antibiotic-resistant superbugs.

Published in Nature Communications, the Monash Biomedicine Discovery Institute (BDI)–led study investigated the common hospital bacterium, Acinetobacter baumannii.

A. baumannii is particularly dangerous as it is often resistant to common antibiotics, making infections hard to treat. Due to this, the World Health Organization has listed it as a top-priority critical bacterium, where new treatments are urgently needed.

Bacteria rarely exist alone; like plants and animals, different types compete for space and resources. In many environments, A. baumannii must engage in bacterial 'warfare' to survive in the presence of other species.

To outcompete surrounding bacteria, A. baumannii (and many other bacteria) use a nano-weapon called the Type VI Secretion System (T6SS). This is a tiny needle-like machine that injects toxins directly into nearby bacteria, killing them so that A. baumannii can dominate.

Using advanced microscopy on a highly purified bacterial protein, researchers discovered the molecular structure of a key toxin from a hospital strain of A. baumannii.

They learned how this toxin, called Tse15, is attached to the needle and then delivered into other bacteria to kill them. They showed that the toxin is stored in a protective cage-like structure inside A. baumannii, preventing it from harming the bacterium itself. When ready to attack other bacteria, the toxin must be released from the cage.

This happens through a series of interactions between the toxin, the exterior of the cage, and the T6SS needle. Once the needle injects the toxin into a competitor, the toxin activates and kills the other bacterium, allowing A. baumannii to take over that surface.

The find is a significant step in the fight against antibiotic-resistant superbugs.

Understanding how such toxins are delivered may allow us to engineer new protein toxins for delivery into bacteria. By learning how this system works, scientists can explore new ways to fight against antibiotic resistant bacteria like A. baumannii.

Brooke K. Hayes et al, Structure of a Rhs effector clade domain provides mechanistic insights into type VI secretion system toxin delivery, Nature Communications (2024). DOI: 10.1038/s41467-024-52950-x

Comment by Dr. Krishna Kumari Challa on October 22, 2024 at 9:26am

Evolution in action: How ethnic Tibetan women thrive in thin oxygen at high altitudes

Breathing thin air at extreme altitudes presents a significant challenge—there's simply less oxygen with every lungful. Yet, for more than 10,000 years, Tibetan women living on the high Tibetan Plateau have not only survived but thrived in that environment.

A new study  answers some of those questions. The research, published in the journal Proceedings of the National Academy of Sciences of the United States of America, reveals how the Tibetan women's physiological traits enhance their ability to reproduce in such an oxygen-scarce environment.

The findings not only underscore the remarkable resilience of Tibetan women but also provide valuable insights into the ways humans can adapt in extreme environments. Such research also offers clues about human development, how we might respond to future environmental challenges, and the pathobiology of people with illnesses associated with hypoxia at all altitudes.

Researchers  studied 417 Tibetan women aged 46 to 86 who live between 12,000 and 14,000 feet above sea level in a location in Upper Mustang, Nepal on the southern edge of the Tibetan Plateau.

They collected data on the women's reproductive histories, physiological measurements, DNA samples and social factors. They wanted to understand how oxygen delivery traits in the face of high-altitude hypoxia (low levels of oxygen in the air and the blood) influence the number of live births—a key measure of evolutionary fitness.

They discovered that the women who had the most children had a unique set of blood and heart traits that helped their bodies deliver oxygen. Women reporting the most live births had levels of hemoglobin, the molecule that carries oxygen, near the sample's average, but their oxygen saturation was higher, allowing more efficient oxygen delivery to cells without increasing blood viscosity; the thicker the blood, the more strain on the heart.

This is a case of ongoing natural selection. Tibetan women have evolved in a way that balances the body's oxygen needs without overworking the heart.

One  genetic trait they studied likely originated from the Denisovans who lived in Siberia about 50,000 years ago; their descendants later migrated onto the Tibetan Plateau.

The trait is a variant of the EPAS1 gene that is unique to populations indigenous to the Tibetan Plateau and regulates hemoglobin concentration. Other traits, such as increased blood-flow to the lungs and wider heart ventricles, further enhanced oxygen delivery.

These traits contributed to greater reproductive success, offering insight into how humans adapt to lifelong levels of low oxygen in the air and their bodies.

Beall, Cynthia M., Higher oxygen content and transport characterize high-altitude ethnic Tibetan women with the highest lifetime reproductive success, Proceedings of the National Academy of Sciences (2024). DOI: 10.1073/pnas.2403309121. doi.org/10.1073/pnas.2403309121

Comment by Dr. Krishna Kumari Challa on October 22, 2024 at 9:08am

Chemical trick activates antibiotic directly at the pathogen

Due to increasing resistance, it is becoming more and more frequent that common and well-tolerated antibiotics no longer work against dangerous bacterial pathogens.

Colistin was developed in the 1950s. Due to its highly nephrotoxic effect, it was no longer used in humans for many decades after its development. The lack of effective antibiotics, however, has made its revival necessary: for example, in the treatment of dangerous hospital germs such as carbapenem-resistant enterobacteriaceae or Acinetobacter baumannii. Colistin is also on the list of essential medicines of the World Health Organization (WHO).

Colistin is a last-resort antibiotic that is usually only used for severe infections with resistant bacteria. This is due to its severe kidney-damaging side effects, which occur in about 30% of treated patients.

The last-resort antibiotic colistin is an important helper in this emergency. However, its administration is associated with risks of severe side effects: It has a strong nephrotoxic effect, and long-term consequences cannot be ruled out.

It would be advantageous if colistin could be chemically modified so that it is no longer as damaging to the kidneys while maintaining its high antibiotic efficacy.

A research team has now been able to produce an inactivated, harmless form of colistin that is only activated in the body with the help of chemical switches.

In this so-called click-to-release technique, the chemical switches are specifically bound to the disease-causing bacteria. The administered masked colistin is therefore activated specifically at the site of action. The researchers hope that this could reduce side effects. The study is published in the journal Angewandte Chemie International Edition.

The researchers hope that this approach can help minimize the side effects of antibiotics and other medical agents in the future and make them more tolerable for patients.

Jiraborrirak Charoenpattarapreeda et al, A Targeted Click‐to‐Release Activation of the Last‐Resort Antibiotic Colistin Reduces its Renal Cell Toxicity, Angewandte Chemie International Edition (2024). DOI: 10.1002/anie.202408360

Comment by Dr. Krishna Kumari Challa on October 21, 2024 at 9:35am

How Some Fish Regrow Their Fins

Animals like the African killifish can regrow entire body parts after amputation, but how cells know where and how much to grow after injury remains a mystery. A recent iScience publication from Augusto Ortega Granillo, Alejandro Sànchez Alvarado, and their research team at the Stowers Institute for Medical Research sheds light on the mechanisms of positional memory.

1. Otsuki L, Tanaka EM. Positional memory in vertebrate regeneration: A century’s insights .... Cold Spring Harb Perspect Biol. 2021;14(6):a040899.
2. Ortega Granillo A, et al. Positional information modulates transient regeneration-activated c.... iScience. 2024;27(9):110737.

Comment by Dr. Krishna Kumari Challa on October 19, 2024 at 11:09am

Sound of Earth’s magnetic flip 41 000 years ago

Comment by Dr. Krishna Kumari Challa on October 19, 2024 at 9:08am

Scientists show how sperm and egg come together like a key in a lock

How a sperm and an egg fuse together?

New research by scientists  provides tantalizing clues, showing fertilization works like a lock and key across the animal kingdom, from fish to people. This mechanism is really fundamental across all vertebrates.

 The team found that three proteins on the sperm join to form a sort of key that unlocks the egg, allowing the sperm to attach. Their findings, drawn from studies in zebrafish, mice, and human cells, show how this process has persisted over millions of years of evolution. Results were published this week in the journal Cell.

Scientists had previously known about two proteins, one on the surface of the sperm and another on the egg's membrane. Working with international collaborators, researchers used Google DeepMind's artificial intelligence tool AlphaFold—whose developers were awarded a Nobel Prize earlier this month—to help them identify a new protein that allows the first molecular connection between sperm and egg. They also demonstrated how it functions in living things.

It wasn't previously known how the proteins "worked together as a team in order to allow sperm and egg to recognize each other".

The work provides targets for the development of male contraceptives in particular.

Victoria E. Deneke et al, A conserved fertilization complex bridges sperm and egg in vertebrates, Cell (2024). DOI: 10.1016/j.cell.2024.09.035

Comment by Dr. Krishna Kumari Challa on October 19, 2024 at 8:55am

Researchers were able to create a map showing drug resistance across different cancers, focusing on colon, lung, and Ewing sarcoma. The map uncovers more about the mechanisms of drug resistance, highlights DNA changes that may be potential treatment biomarkers, and identifies promising combinations or second-line therapies.

The team found that cancer mutations fall into four different categories depending on the impact of the DNA change. Drug resistance mutations, otherwise known as canonical drug resistance mutations, are genetic changes in the cancer cell that lead to the drug being less effective. For example, changes that mean the drug can no longer bind to its target in the cancer cell.

Drug addiction mutations lead to some of the cancer cells using the drug to help them grow, instead of destroying them. This research supports the use of drug holidays in the case of drug addiction mutations, which are periods without treatment. This could help destroy the cancer cells with this type of mutation, as the cells are now dependent on treatment.

Driver mutations are gain-of-function genetic changes that allow cancer cells to use a different signaling pathway to grow, avoiding the pathway that the drug may have blocked.

Lastly, drug sensitizing variants are genetic mutations that make the cancer more sensitive to certain treatments and could mean that patients with these genetic changes in their tumor would benefit from particular drugs.

The research focused on colon, lung, and Ewing sarcoma cancer cell lines, as these are all prone to developing resistance and have limited second-line treatments available. The team used 10 cancer drugs that are either currently prescribed or going through clinical trials to help highlight if any of these could be repurposed or used in combination to address resistance, decreasing the time it would take to get any potential treatments to the clinic.

Understanding more about the four different types of DNA changes can help support clinical decisions, explain why treatments are not working, support the idea of drug holidays in certain patients, and help develop new treatments. This knowledge also helps accelerate drug companies' research into next-generation cancer inhibitors that could better prevent drug resistance.

Base editing screens define the genetic landscape of cancer drug resistance mechanisms, Nature Genetics (2024). DOI: 10.1038/s41588-024-01948-8

Part 2

Comment by Dr. Krishna Kumari Challa on October 19, 2024 at 8:54am

How scientists are trying to tackle drug resistance in cancer therapies

One of the major challenges in cancer treatment is drug resistance. Mutations in cancer cells mean that over time they become less responsive to therapies. After cancer has become resistant to the initial treatment, the following therapies are known as second-line therapies and options for these can be limited. Understanding what molecular changes are causing the resistance, and what can be done to tackle this, can help uncover new options and inform clinical pathways for specific mutations.

All cancer mutations that cause drug resistance fall into one of four categories. New research has detailed each type, helping to uncover targets for drug development and identify potential effective second-line therapies.

In a new large-scale study, researchers  used CRISPR gene editing to map the genetic landscape of drug resistance in cancers, focusing on colon, lung, and Ewing sarcoma. The team explains how known mutations impact drug resistance and highlights new DNA changes that could be explored further.

The research,  published in Nature Genetics, investigated the effect of mutations on the sensitivity to 10 cancer drugs, also identifying possible effective second-line treatments based on a person's genetic makeup.

By understanding the mechanisms of how cancers become resistant to treatment, researchers can identify new targets for personalized therapies, help treat patients based on their cancer's genetic makeup, give second-line treatment options to those who currently have none, and help further research to develop next-generation cancer drugs that could avoid drug resistance emerging.

Part 1

Comment by Dr. Krishna Kumari Challa on October 19, 2024 at 8:21am

Climate justice broadly encompasses recognition that (1) climate change impacts are unequally felt across society; (2) the worst affected groups often have the least say in the selection and implementation of societal responses to climate change, and (3) climate change-related policymaking processes often fail to recognize the legitimate interests of politically voiceless communities, consequently contributing to further disenfranchisement of marginalized groups. It is a framework that enables those involved in policymaking to identify and tackle the multiple different ways in which the climate crisis intersects with longstanding patterns of social injustice.

Comment by Dr. Krishna Kumari Challa on October 19, 2024 at 8:15am

Bumblebee queens choose to hibernate in pesticide-contaminated soil, scientists discover

An alarming discovery by researchers raises concerns for bumblebee health, survival and reproduction. U of G environmental sciences researchers have found that bumblebee queens are more likely to hibernate in soil contaminated with pesticides than in clean soil—for reasons they still don't quite understand.

The team conducted field experiments in which newly emerged queens of the common eastern bumblebee (Bombus impatiens) were left to fly freely in outdoor enclosures, mate and then choose a site in which to hibernate for the winter.

The choice was between clean soil or soil contaminated with one of five common pesticides, including insecticides and fungicides, across different concentrations.

The School of Environmental Sciences researchers then carefully searched through the soils for hibernating bumblebee queens. They found queens avoided the pesticide-free soil and, in fact, were about twice as likely to be drawn to the pesticide-contaminated soil.

Most bees in the study survived, but other consequences for the colony are highlighted in the study, published in Science of the Total Environment.

"This raises serious concerns for bumblebee health," say the researchers, "especially as this group of important insect pollinators already face many challenges.

Bumblebee queens typically hibernate underground during winter before emerging in spring to start new colonies. Researchers wanted to investigate how bees respond to contaminants at this key but vulnerable life stage.

Previous studies showed that pesticides on crops can either attract or repel bees, depending on the type, the environmental situation and the concentration used.

One possible explanation is that pesticides altered the soil properties and made it more appealing to the queens.

For example, the fungicides used in the study could have killed soil fungi and nematodes, and queens might avoid soils with fungi because they can be harmful during hibernation.

Another possibility is that the queens could have developed an "acquired taste" for pesticides, as researchers put it, due to prior exposure in their environment.

They might also be looking for something new, as novelty-seeking behavior is common for bees and often leads the colony to discover new resources.

More research is needed to fully understand the mechanisms behind this unexpected queen behaviour. But the findings suggest the need to reconsider how pesticides are used and managed in agricultural settings as exposure to pesticides is contributing to a worldwide decline of insects.

 Sabrina Rondeau et al, Bumblebee (Bombus impatiens) queens prefer pesticide-contaminated soils when selecting underground hibernation sites, Science of The Total Environment (2024). DOI: 10.1016/j.scitotenv.2024.176534

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