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Comment by Dr. Krishna Kumari Challa on March 10, 2023 at 11:49am

Scientists harness power, precision of RNA to make mutations invisible

Scientists have discovered a new way to suppress mutations that lead to a wide range of genetic disorders.

A study recently published in the journal Molecular Cell describes a strategy that co-opts a normal RNA modification process within cells to transform disease genes into normal genes that produce healthy proteins. The findings are significant because they may ultimately help researchers alter the course of devastating disorders such as cystic fibrosis, muscular dystrophy and many forms of cancer.

About 15% of mutations that lead to genetic diseases are called nonsense mutations. Aptly named, nonsense mutations occur when an mRNA molecule contains an early "stop" signal. When the mRNA takes genetic instructions from DNA to create a protein, this early stop sign orders the cell to stop reading the instructions partway through the process. This results in the creation of an incomplete protein that can lead to disease.

A team of researchers  designed an artificial guide RNA—a piece of RNA that can modify other types of RNA—to target mRNA molecules that contain early stop signals (also called premature termination codons). Guide RNAs are a natural mechanism that cells use all the time; This  team altered this already existing process.

Like DNA, RNA is made up of molecular building blocks that are represented by the letters A (adenine), G (guanine), U (uracil), and C (cytosine). Premature termination codons always have the building block U in the first position (for example, UAG, UAA or UGA). The team's artificial guide RNA was designed to modify the U in the first position, changing the molecular makeup of the targeted mRNA so that the stop signal is no longer—or less well—recognized by the cell.

Researchers tested the artificial guide RNA in yeast cells and in human disease cells (derived from cystic fibrosis and neurofibromatosis patients). In both cases, they found the action of the artificial guide RNA rendered the premature termination codon (stop sign) invisible, allowing cells to read the genetic instructions all the way through and create full-length, functional proteins.

They also discovered that the guide RNA suppressed another mechanism in the cell known as nonsense-mediated mRNA decay or NMD. One of the major surveillance systems in the body, NMD targets and eliminates mRNAs with premature termination codons, so no protein is produced. Curbing NMD is another way the artificial guide RNA ensured that a significant amount of mRNA was present in the cell, and that the genetic instructions carried by the targeted mRNAs were read all the way through and translated into complete proteins.

Hironori Adachi et al, Targeted pseudouridylation: An approach for suppressing nonsense mutations in disease genes, Molecular Cell (2023). DOI: 10.1016/j.molcel.2023.01.009

Comment by Dr. Krishna Kumari Challa on March 10, 2023 at 11:41am

Bacterial enzyme traps and breaks down PFAS molecules

Highly nondegradable chemicals such as PFAS and pesticides can have useful properties in some situations, but are extremely difficult for nature to remove afterwards. Now researchers have found that certain bacteria use an enzyme that acts as a molecular nutcracker to crush the harmful substances.

All cells contain a large number of enzymes, each of which functions as a small machine that carries out a specific task. Inside E. coli bacteria, researchers have found an enzyme, C-P lyase, that enables the microbe to degrade highly stable chemicals. By rapidly freezing purified samples of the enzyme, the researchers have succeeded in capturing the molecular nutcracker in two different states that represent an open and closed form, respectively. The results show that the bacterium uses the energy from ATP, the cellular energy source, to both open and close the nutcracker.

Two similar, ATP-consuming modules, which are mostly known from transport proteins, have been put together to be able to open and close the enzyme.

The results, which have recently been published in the journal, Nature Communications, are expected to be useful in developing dedicated strains of bacteria that survive by breaking down the difficult substances and therefore potentially can be of great importance for the future use of pesticides in agriculture.

Søren K. Amstrup et al, Structural remodelling of the carbon–phosphorus lyase machinery by a dual ABC ATPase, Nature Communications (2023). DOI: 10.1038/s41467-023-36604-y

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Comment by Dr. Krishna Kumari Challa on March 10, 2023 at 11:34am

So researchers now turned to the genome editing technology CRISPR to test the roles of a variety of genes in hyperoxia.

Using CRISPR, the researchers removed, one at a time, more than 20,000 different genes from human cells grown in the lab and then compared the growth of each group of cells at 21 percent oxygen and 50 percent oxygen.

This kind of unbiased screen let researchers probe the contributions of thousands of different pathways in hyperoxia rather than just focusing on those we already suspected might be involved.

Four molecular pathways stood out in the screen as being involved in the effects of hyperoxia. They related to diverse cellular functions including the repair of damaged DNA, the production of new DNA building blocks, and the generation of cellular energy.

It took some molecular sleuthing to discover that each pathway had a critical protein that contained iron atoms connected to sulfur atoms—so-called "iron-sulfur clusters"—in its molecular structure.

The researchers went on to show that in as little as 30 percent oxygen, the iron-sulfur clusters in the four proteins become oxidized—they chemically react with oxygen atoms—and that change causes the proteins to degrade. As a result, cells stop functioning correctly and consume even less oxygen, causing a further increase in oxygen levels in the surrounding tissues.

One important thing found in this work is that hyperoxia is not impacting cells and tissues solely through reactive oxygen species, as many had assumed. That means the use of antioxidants—which can combat reactive oxygen species to some degree—is unlikely to be sufficient to prevent oxygen toxicity.

 Alan H. Baik et al, Oxygen toxicity causes cyclic damage by destabilizing specific Fe-S cluster-containing protein complexes, Molecular Cell (2023). DOI: 10.1016/j.molcel.2023.02.013

Part 2

Comment by Dr. Krishna Kumari Challa on March 10, 2023 at 11:30am

Researchers discover how too much oxygen damages cells and tissues

Breathing air that contains higher levels of oxygen than the usual 21 percent found in Earth's atmosphere can cause organ damage, seizures, and even death in people and animals, particularly if it's in excess of the body's oxygen needs. Until now, however, scientists have mostly speculated about the mechanisms behind this phenomenon, known as oxygen toxicity, or hyperoxia.

Now, researchers at Gladstone Institutes have discovered how excess  oxygen changes a handful of proteins in our cells that contain iron and sulfur—a chemical process similar to the rusting of iron. In turn, those "rusty" proteins trigger a cascade of events that damage cells and tissues. The findings, published in the journal Molecular Cell, have implications for conditions such as heart attacks and sleep apnea.

At high levels, oxygen is toxic to every form of life, from bacteria and plants to animals and people. Of course, not enough oxygen is also fatal; there's an intermediate, "Goldilocks" amount under which most life on Earth thrives—not too much and not too little.

While clinicians have long studied the details of how oxygen shortage impacts cells and tissues (for example, in heart attacks and strokes), the effects of excess oxygen have been relatively understudied.

Studies have recently revealed, for instance, that breathing too much supplemental oxygen might be detrimental to heart attack  patients and premature infants. Similarly, in obstructive sleep apnea,  the sudden bursts of oxygen that follow pauses in breathing have been shown to be a key component of how the disorder increases patients' risks of chronic health problems.

Part 1

Comment by Dr. Krishna Kumari Challa on March 10, 2023 at 10:59am

Low-dose radiation linked to increased lifetime risk of heart disease

Exposure to low doses of ionizing radiation is associated with a modestly increased excess risk of heart disease, finds an analysis of the latest evidence published by The BMJ recently.

The researchers say these findings "have implications for patients who undergo radiation exposure as part of their medical care, as well as policy makers involved in managing radiation risks to radiation workers and the public." A linked editorial suggests that these risks "should now be carefully considered in protection against radiation in medicine and elsewhere."

It's well recognized that exposure to high dose radiation can damage the heart, but firm evidence linking low dose radiation to heart disease (e.g., scatter radiation dose from radiotherapy or working in the nuclear industry) is less clear.

To address this knowledge gap, an international team of researchers examined scientific databases for studies evaluating links between a range of cardiovascular diseases and exposure to radiation (mostly radiotherapy and occupational exposures).

They excluded uninformative datasets or those largely duplicating others, leaving 93 studies, published mainly during the past decade, suitable for analysis. These studies covered a broad range of doses, brief and prolonged exposures, and evaluated frequency (incidence) and mortality of various types of vascular diseases.

After taking account of other important factors, such as age at exposure, the researchers found consistent evidence for a dose dependent increase in cardiovascular risks across a broad range of radiation doses.

For example, the relative risk per gray (Gy) increased for all cardiovascular disease and for specific types of cardiovascular disease, and there was a higher relative risk per dose unit at lower dose ranges (less than 0.1 Gy), and also for lower dose rates (multiple exposures over hours to years).

At a population level, excess absolute risks ranged from 2.33% per Gy for a current England and Wales population to 3.66% per Gy for Germany, largely reflecting the underlying rates of cardiovascular disease mortality in these populations.

This equates to a modest but significantly increased excess lifetime risk of 2.3-3.9 cardiovascular deaths per 100 persons exposed to one Gy of radiation, explain the authors.

Ionising radiation and cardiovascular disease: systematic review and meta-analysis, The BMJ (2023). DOI: 10.1136/bmj-2022-072924

Comment by Dr. Krishna Kumari Challa on March 9, 2023 at 1:19pm

Heavy alcohol consumption increases brain inflammation and influences decision making

For people with alcohol use disorder (AUD), there is a constant, vicious cycle between changes to the brain and changes to behavior. AUD can alter signaling pathways in the brain; in turn, those changes can exacerbate drinking.

Now, scientists  have uncovered new details about the immune system's role in this cycle. They reported in the journal Brain, Behavior and Immunity on Feb. 28, 2023, that the immune signaling molecule interleukin 1β (IL-1β) is present at higher levels in the brains of mice with alcohol dependence. In addition, the IL-1β pathway takes on a different role in these animals, causing inflammation in critical areas of the brain known to be involved in decision-making.

These inflammatory changes to the brain could explain some of the risky decision-making and impulsivity we see in people with alcohol use disorder.

In addition, these findings are incredibly exciting because they suggest a potential way to treat alcohol use disorder with existing anti-inflammatory drugs targeting the IL-1β pathway.

AUD is characterized by uncontrolled and compulsive drinking, and it encompasses a range of conditions including alcohol abuse, dependence and binge drinking. Researchers have previously discovered numerous links between the immune system and AUD—many of them centered around IL-1β. People with certain mutations in the gene that codes for the IL-1β molecule, for instance, are more prone to developing AUD. In addition, autopsies of people who had AUD have found higher levels of IL-1β in the brain.

In the new study, researchers compared alcohol-dependent mice with animals drinking moderate or no alcohol at all. They discovered that the alcohol-dependent group had about twice as much IL-1β in the medial prefrontal cortex (mPFC), a part of the brain that plays a role in regulating emotions and behaviors.

The research team then went on to show that IL-1β signaling in the alcohol-dependent group was not only increased, but also fundamentally different. In mice that had not been exposed to alcohol, as well as in mice that had drunk moderate amounts of alcohol, IL-1β activated an anti-inflammatory signaling pathway. In turn, this lowered levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), a signaling molecule known to regulate neural activity in the brain.

However, in alcohol-dependent mice, IL-1β instead activated pro-inflammatory signaling and boosted levels of GABA, likely contributing to some of the changes in brain activity associated with AUD. Notably, these changes in IL-1β signaling in the alcohol-dependent mice persisted even during alcohol withdrawal.

F.P. Varodayan, A.R. Pahng, T.D. Davis, P. Gandhi, M. Bajo, M.Q. Steinman, W.B. Kiosses, Y.A. Blednov, M.D. Burkart, S. Edwards, A.J. Roberts, M. Roberto. Chronic ethanol induces a pro-inflammatory switch in interleukin-1β regulation of GABAergic signaling in the medial prefrontal cortex of male mice. Brain, Behavior, and Immunity, 2023; 110: 125 DOI: 10.1016/j.bbi.2023.02.020

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

A spontaneous gravity prior: newborn chicks prefer stimuli that move against gravity

Comment by Dr. Krishna Kumari Challa on March 9, 2023 at 9:34am

Enzyme that turns air into electricity discovered, providing a new clean source of energy

Scientists have discovered an enzyme that converts air into energy. The finding, published recently in the journal Nature, reveals that this enzyme uses the low amounts of the hydrogen in the atmosphere to create an electrical current. This finding opens the way to create devices that literally make energy from thin air.

The researchers produced and analyzed a hydrogen-consuming enzyme from a common soil bacterium. Recent work by the team has shown that many bacteria use hydrogen from the atmosphere as an energy source in nutrient-poor environments. Bacteria can use the trace hydrogen in the air as a source of energy to help them grow and survive, including in Antarctic soils, volcanic craters, and the deep ocean. But this new discovery made it clear that this enzyme used by the bacteria can produce electricity from air.

The researchers extracted the enzyme responsible for using atmospheric hydrogen from a bacterium called Mycobacterium smegmatis. They showed that this enzyme, called Huc, turns hydrogen gas into an electric current. Huc is extraordinarily efficient. Unlike all other known enzymes and chemical catalysts, it even consumes hydrogen below atmospheric levels—as little as 0.00005% of the air we breathe.

The researchers used several cutting-edge methods to reveal the molecular blueprint of atmospheric hydrogen oxidation. They used advanced microscopy (cryo-EM) to determine its atomic structure and electrical pathways, pushing boundaries to produce the most resolved enzyme structure reported by this method to date. They also used a technique called electrochemistry to demonstrate the purified enzyme creates electricity at minute hydrogen concentrations.

Laboratory work performed by researchers shows that it is possible to store purified Huc for long periods. It is astonishingly stable. It is possible to freeze the enzyme or heat it to 80 degrees celsius, and it retains its power to generate energy. This reflects that this enzyme helps bacteria to survive in the most extreme environments. 

Huc is a "natural battery" that produces a sustained electrical current from air or added hydrogen. While this research is at an early stage, the discovery of Huc has considerable potential to develop small air-powered devices, for example as an alternative to solar-powered devices.

The bacteria that produce enzymes like Huc are common and can be grown in large quantities, meaning we have access to a sustainable source of the enzyme.

 Chris Greening, Structural basis for bacterial energy extraction from atmospheric hydrogen, Nature (2023). DOI: 10.1038/s41586-023-05781-7. www.nature.com/articles/s41586-023-05781-7

Comment by Dr. Krishna Kumari Challa on March 9, 2023 at 7:39am

UN forges historic deal to protect ocean life: what researchers think

High Seas Treaty aims to preserve marine biodiversity while encouraging research-capacity building among nations.

Nations forge a historic High Seas Treaty

After two decades of talks and a marathon 38-hour final session of negotiations, United Nations member countries have agreed on a framework to protect marine biodiversity and provide oversight of international waters. The High Seas Treaty will cover waters outside countries’ national .... The treaty establishes a mechanism to designate marine protected areas and creates several groups — including a scientific and technical body — to oversee regulations covering issues including marine genetic resources. “We’re ecstatic,” says Kristina Gjerde, who researches marine environmental law. “This long-awaited treaty contains many of the vital things we need to safeguard our oceans.”

Comment by Dr. Krishna Kumari Challa on March 8, 2023 at 11:33am

International Women's Day 2023 - "DigitALL: Innovation & Technology for Gender Equality"

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