Comment

Comment by Dr. Krishna Kumari Challa on February 14, 2023 at 10:10am

Study reveals how drug resistant bacteria secrete toxins, suggesting targets to reduce virulence

Antimicrobial resistance represents one of the top 10 global public health threats according to the World Health Organization, and scientists have been scrambling to find new tools to cure the most deadly drug-resistant infections.

New research work  suggests that reducing virulence in drug resistant infections rather than trying to kill bacteria  outright may offer an alternative approach to treatment.

The study revealed how two proteins enable the methicillin-resistant Staphylococcus aureus (MRSA) bacterium to secrete the toxins that make people sick. The research suggests that therapies targeting these two proteins could disable MRSA, making it less deadly and possibly even harmless. Such an approach would also reduce the risk of promoting antibiotic resistance.

The paper, which was published on February 13, 2023, in the Proceedings of the National Academy of Science suggests that similar mechanisms may exist in other bacteria, pointing to the potential for a new approach to treating other bacterial infections.

 Dickey, Seth W. et al, Two transporters cooperate to secrete amphipathic peptides from the cytoplasmic and membranous milieus, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2211689120. doi.org/10.1073/pnas.2211689120

Comment by Dr. Krishna Kumari Challa on February 13, 2023 at 11:39am

The nucleolus within the cell nucleus is also a condensate, which appears as a diffuse dark speck under the microscope. This is where many proteins with positively charged tails like to linger. Many of these provide the machinery required for protein synthesis, making this condensate essential for cellular functions.

The mutant protein HMGB1 with its positively charged molecular tail is attracted to the nucleolus as well, as the team observed from experiments with isolated protein and with cell cultures.

But since the mutated protein region has also gained an oily, sticky part, it tends to clump. The nucleolus loses its fluid-like properties and increasingly solidifies, which Niskanen was able to observe under the microscope. This impaired the vital functions of the cells – with the mutated protein, more cells in a culture died compared to a culture of cells without the mutation.

What scientists discovered in this one disease might apply to many more disorders. It is likely not a rare unicorn that exists only once.

The research team then searched databases of genomic data from thousands of individuals looking for similar incidents. In fact, the scientists were able to identify more than six hundred similar mutations in 66 proteins, in which the reading frame had been shifted by a mutation in the protein tail, making it both more positively charged and more “greasy”. Of the mutations, 101 had previously been linked to several different disorders.

For a cell culture assay, the team selected 13 mutant genes. In 12 out of 13 cases, the mutant proteins had a preference to localize into the nucleolus. About half of the tested proteins impaired the function of the nucleolus, resembling the disease mechanism of BPTA syndrome.

1. Martin A. Mensah, Henri Niskanen, Alexandre P. Magalhaes, Shaon Basu, Martin Kircher, Henrike L. Sczakiel, Alisa M. V. Reiter, Jonas Elsner, Peter Meinecke, Saskia Biskup, Brian H. Y. Chung, Gregor Dombrowsky, Christel Eckmann-Scholz, Marc Phillip Hitz, Alexander Hoischen, Paul-Martin Holterhus, Wiebke Hülsemann, Kimia Kahrizi, Vera M. Kalscheuer, Anita Kan, Mandy Krumbiegel, Ingo Kurth, Jonas Leubner, Ann Carolin Longardt, Jörg D. Moritz, Hossein Najmabadi, Karolina Skipalova, Lot Snijders Blok, Andreas Tzschach, Eberhard Wiedersberg, Martin Zenker, Carla Garcia-Cabau, René Buschow, Xavier Salvatella, Matthew L. Kraushar, Stefan Mundlos, Almuth Caliebe, Malte Spielmann, Denise Horn, Denes Hnisz. Aberrant phase separation and nucleolar dysfunction in rare genetic diseases. Nature, 2023; DOI: 10.1038/s41586-022-05682-1

Part 2

**

Comment by Dr. Krishna Kumari Challa on February 13, 2023 at 11:38am

Protein droplets may cause many types of genetic disease

Most proteins localize to distinct protein-rich droplets in cells, also known as “cellular condensates”. Such proteins contain sequence features that function as address labels, telling the protein which condensate to move into. When the labels get screwed up, proteins may end up in the wrong condensate. According to an international team of researchers from clinical medicine and basic biology, this could be the cause of many unresolved diseases.

Patients with BPTA syndrome have characteristically malformed limbs featuring short fingers and additional toes, missing tibia bones in their legs and reduced brain size. As the researchers found out, BPTAS is caused by a special genetic change that causes an essential protein to migrate to the nucleolus, a large proteinaceous droplet in the cell nucleus. As a result, the function of the nucleolar condensate is inhibited and developmental disease develops.

Affected individuals have complex and striking malformations of the limbs, face, and nervous and bone systems, only partially described by the already-long disease name “brachyphalangy-polydactyly-tibial aplasia/hypoplasia syndrome” (BPTAS).

 To track down the cause,  researchers decoded the genome of five affected individuals and found that the gene for the protein HMGB1 was altered in all patients.

This protein has the task of organizing the genetic material in the cell nucleus and facilitates the interaction of other molecules with the DNA, for example to read genes.

In mice, a complete loss of the gene on both chromosomes is catastrophic and leads to death of the embryo. In some patients with only one copy mutated, however, the cells are using the intact copy on the other chromosome, resulting only in mild neurodevelopmental delay. But the newly discovered cases did not fit this scheme.

A closer look revealed that different mutations of HMGB1 have different consequences. The sequencing data showed that in the affected individuals with the severe malformations, the reading frame for the final third of the HMGB1 gene is shifted.After translation to protein, the corresponding region is now no longer equipped with negative but with positively charged amino acid building blocks. This can happen if a number of genetic letters not divisible by three is missing in the sequence, because exactly three consecutive letters always code for one building block of the protein.

However, the tail part of the protein does not have a defined structure. Instead, this section hangs out of the molecule like a loose rubber band. The purposes of such protein tails (also called “intrinsically disordered regions”) are difficult to study because they often become effective only in conjunction with other molecules. So how might their mutation lead to the observed disease?

To answer this question, the medical researchers approached biochemists  who work with cellular condensates that control important genes. These droplet-like structures behave much like the oil and vinegar droplets in a salad dressing. Composed of a large number of different molecules, they are separated from their surroundings and can undergo dynamic changes.

Researchers think condensates are formed in the cell for practical reasons.

 Molecules for a specific task are grouped together in this way, say to read a gene. For this task alone several hundred proteins need to somehow make their way to the right place.
Intrinsically disordered regions, which tend not to have an obvious biochemical role, are thought to be responsible for forming condensates.

Part1

Comment by Dr. Krishna Kumari Challa on February 13, 2023 at 11:21am

Drugs Hitch a Ride on Algae for Targeted Delivery

A new microrobot uses algae to transport antibiotics into the lungs of mice with pneumonia.

When you swallow a pill, only a fraction of the drug ends up where it’s needed. Active compounds diffuse across the intestinal wall and are diluted in rivers of blood, aimlessly drifting with the currents. For more precise delivery, scientists are recruiting motile, single-celled organisms as vehicles that transport drugs to specific sites in the body.

So far, researchers have harnessed swimming bacteria for targeted drug delivery. In one case, magnetotactic bacteria guided by an external magnetic field carried nanosize liposomes loaded with a chemotherapy drug to mouse tumors. But bacteria are prime targets for the immune system that are often destroyed before they reach their destination.

Now, a team at the University of California, San Diego has built a microscopic robot—or microrobot—using Chlamydomonas reinhardtii, a species of microalgae, which are less likely to elicit an immune response than bacteria.

Researchers attached antibiotic-filled nanoparticles to the microbes’ surfaces using click chemistry, the Nobel Prize-winning
method that uses rapid reactions to connect molecules. Inside the body, modified algae beat their flagella to swim through the blood and dive deep into tissues. Each nanoparticle is wrapped in a neutrophil membrane, which promotes immune evasion and allows the microrobots to latch onto pathogens, depositing the drugs in their vicinity.

The researchers tested the algae in mice with a severe form of pneumonia caused by Pseudomonas aeruginosa bacteria. Known as ventilator-associated pneumonia (VAP), the potentially fatal infection is picked up by human patients during ventilator use in hospitals. Microrobots were delivered directly into mouse lungs through a tube leading into the windpipe. After one week, infections disappeared in all treated mice. Their untreated littermates died within three days.

The researchers then compared the microrobots to intravenous injection, the current standard treatment for VAP. Treatment with microalgae worked despite a dose of antibiotics 3,000 times smaller than was needed intravenously, which could reduce side effects.

Taking advantage of the algae’s natural fluorescence, the researchers dissected and imaged the mouse lungs. Light radiated from the whole organ for over 24 hours and from homogenized lung tissue for three days, indicating that the robots had dispersed throughout the tissue and dodged immune attack long enough for successful drug delivery.

https://www.nature.com/articles/s41563-022-01360-9.epdf?sharing_tok...

Comment by Dr. Krishna Kumari Challa on February 13, 2023 at 10:54am

Scientists discover receptor that blocks COVID-19 infection

scientists have discovered a protein in the lung that blocks SARS-CoV-2 infection and forms a natural protective barrier in the human body.

This protein, the leucine-rich repeat-containing protein 15 (LRRC15), is an inbuilt receptor that binds the SARS-CoV-2 virus without passing on the infection.

The research opens up an entirely new area of immunology research around LRRC15 and offers a promising pathway to develop new drugs to prevent viral infection from coronaviruses like COVID-19 or deal with fibrosis in the lungs.
 This new receptor acts by binding to the virus and sequestering it which reduces infection.

The COVID-19 virus infects humans by using a spike protein to attach to a specific receptor in our cells. It primarily uses a protein called the angiotensin-converting enzyme 2 (ACE2) receptor to enter human cells. Lung cells have high levels of ACE2 receptors, which is why the COVID-19 virus often causes severe problems in this organ of infected people.

Like ACE2, LRRC15 is a receptor for coronavirus, meaning the virus can bind to it. But unlike ACE2, LRRC15 does not support infection. It can, however, stick to the virus and immobilize it. In the process, it prevents other vulnerable cells from becoming infected.

Scientists think it acts a bit like Velcro, molecular Velcro, in that it sticks to the spike of the virus and then pulls it away from the target cell types.

LRRC15 is present in many locations such as lungs, skin, tongue, fibroblasts, placenta and lymph nodes. But the researchers found human lungs light up with LRRC15 after infection.

Scientists  can now use this new receptor to design broad acting drugs that can block viral infection or even suppress lung fibrosis. 
The study has been published in the journal PLOS Biology. 

https://journals.plos.org/plosbiology/article?id=10.1371/journal.pb...

Comment by Dr. Krishna Kumari Challa on February 11, 2023 at 11:28am

Tracing the origin of life—a new abiotic pathway for the formation of peptide chains from amino acids

A team of scientists has discovered a new abiotic pathway for the formation of peptide chains from amino acids—a key chemical step in the origin of life. The current study provides strong evidence that this crucial step for the emergence of life can indeed occur even in the very inhospitable conditions of space.

The origin of life is one of the great questions of mankind. One of the prerequisites for the emergence of life is the abiotic—not by living beings caused chemical—production and polymerization of amino acids, the building blocks of life.

Two scenarios are being discussed for the emergence of life on Earth: On the one hand, the first-time creation of such amino acid chains on Earth, and on the other hand, the influx from space. For the latter, such amino acid chains would have to be generated in the very unfavorable and inhospitable conditions in space.

A team of researchers now made a significant discovery in the field of abiotic peptide chain formation from amino acids for the smallest occurring amino acid, glycine, a molecule that has been observed several times extraterrestrially in recent years.

A study published in the Journal of Physical Chemistry A, which also made the cover of the journal, shows that small clusters of glycine molecules exhibit polymerization upon energy input. A reaction occurs within a cluster consisting of two glycine molecules. The two amino acids become a dipeptide and a water molecule. The reaction of a dipeptide to a tripeptide within a cluster was also demonstrated by the researchers.

This new  study sheds light on the less likely unimolecular scenario for the formation of such amino acid chains in the extreme conditions of space. Researchers  were able to show that peptide chain growth occurs through unimolecular reactions in excited cluster ions, without the need for contact with an additional partner such as dust or ice.

The recent paper provides evidence that the first step toward the origin of life can occur in the highly unlikely conditions of space.

Denis Comte et al, Glycine Peptide Chain Formation in the Gas Phase via Unimolecular Reactions, The Journal of Physical Chemistry A (2023). DOI: 10.1021/acs.jpca.2c08248

Comment by Dr. Krishna Kumari Challa on February 11, 2023 at 11:19am

Scientists develop test that can identify respiratory viruses within five minutes

Scientists have developed a world-first diagnostic test, powered by artificial intelligence, that can identify known respiratory viruses within five minutes from just one nasal or throat swab. The new diagnostic test could replace current methods that are limited to testing for only one infection—such as a lateral flow test for COVID-19—or otherwise are either lab-based and time-consuming or fast and less accurate.

The new virus detection and identification methodology is described in a paper published in ACS Nano. The paper demonstrates how machine learning can significantly improve the efficiency, accuracy and time taken to not only identify different types of viruses, but also differentiate between strains.

The ground-breaking testing technology combines molecular labeling, computer vision and machine learning to create a universal diagnostic imaging platform that looks directly at a patient sample and can identify which pathogen is present in a matter of seconds—much like facial recognition software, but for germs.

Preliminary research demonstrated that this test could identify the COVID-19 virus in patient samples and further work determined that the test could be used to diagnose multiple respiratory infections.

In the study, the researchers began by labeling viruses with single-stranded DNA in over 200 clinical samples from John Radcliffe Hospital. Images of labeled samples were captured using a commercial fluorescence microscope and processed by custom machine-learning software that is trained to recognize specific viruses by analyzing their fluorescence labels, which show up differently for every virus because their surface size, shape and chemistry vary.

The results show the technology is able to rapidly identify different types and strains of respiratory viruses, including flu and COVID-19, within five minutes and with >97% accuracy.

 Nicolas Shiaelis et al, Virus Detection and Identification in Minutes Using Single-Particle Imaging and Deep Learning, ACS Nano (2022). DOI: 10.1021/acsnano.2c10159

Comment by Dr. Krishna Kumari Challa on February 11, 2023 at 9:55am

Cockatoos know to bring along multiple tools when they fish for cashews

Comment by Dr. Krishna Kumari Challa on February 10, 2023 at 10:21am

New land creation on waterfronts is increasing

Humans are artificially expanding cities' coastlines by extending industrial ports and creating luxury residential waterfronts. Developers have added over 2,350 square kilometers of land (900 square miles, or about 40 Manhattans) to coastlines in major cities since 2000, according to a new study.

The study reports the first global assessment of coastal land reclamation, which is the process of building new land or filling in coastal water bodies, including wetlands, to expand a coastline. The researchers used satellite imagery to analyze land changes in 135 cities with populations of at least 1 million, 106 of which have done some coastline expansion.

The study was published in the journal Earth's Future.

It's quite important to capture this. There are more and more people, and our footprint is going up. Inevitably, there are ecologic consequences.

The researchers found that  industrialization and a need for urban space have driven much coastal land reclamation, while a smaller proportion of expansion projects are for "prestige," such as the palm tree-shaped islands of Dubai.

About 70% of coastal land expansion has been carried out in low-lying regions that are likely to be exposed to extreme sea level rise by the end of the century. Both environmental impacts and projected coastal inundation suggest these developed coastlines are not sustainable, but cities will likely continue to build them, the researchers say.

Ecological impacts: 

New land is typically created by piling sediments in the ocean, building cement sea walls and structures to contain sediments or cement, or by filling in wetlands and other shallow water bodies near the coast. These methods require vast volumes of sediment and disturb ecosystems irreversibly, as other research has established.

The ecological impacts of reclamation are immense. Reclamation is a massive civil engineering project that fundamentally alters the characteristics of the space that it targets. Coastal wetlands are particularly hard-hit. In the Yellow Sea, for example, more than half of tidal flats were lost mainly due to reclamation.

The creation of land will make sense where it's needed, but you have to do it in a responsible way … and think about whether it is really needed. Those are value judgments.

Other environmental impacts include adding sources of point-source pollution, changing the patterns of sediment movement and altering the biosphere, all of which can impact ocean-based economies such as fishing and tourism. And unequal access to newly created shoreline can exacerbate class divides.

Reclamation also impacts distant ecosystems where fill materials such as sand and gravel are quarried. With a global shortage of sand,  construction companies are quarrying sand and clay from the seabed, which destroys benthic ecosystems.

Dhritiraj Sengupta et al, Mapping 21st Century Global Coastal Land Reclamation, Earth's Future (2023). DOI: 10.1029/2022EF002927

Comment by Dr. Krishna Kumari Challa on February 10, 2023 at 9:39am

Calorie restriction slows pace of aging in healthy adults

In a first of its kind randomized controlled trial an international team of researchers shows that caloric restriction can slow the pace of aging in healthy adults. The CALERIE intervention slowed pace of aging measured from participants' blood DNA methylation using the algorithm DunedinPACE (Pace of Aging, Computed from the Epigenome). The intervention effect on DunedinPACE represented a 2-3 percent slowing in the pace of aging, which in other studies translates to a 10-15 percent reduction in mortality risk, an effect similar to a smoking cessation intervention. The results are published online in the journal Nature Aging.

The CALERIE Phase-2 randomized controlled trial is the first ever investigation of the effects of long-term calorie restriction in healthy, non-obese humans. The trial randomized 220 healthy men and women at three sites in the U. S. to a 25 percent calorie-restriction or normal diet for two years. CALERIE is an acronym for 'Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy'.

To measure biological aging in CALERIE Trial participants, the researchers analyzed blood samples collected from trial participants at pre-intervention baseline and after 12- and 24-months of follow-up. Humans live a long time, so it isn't practical to follow them until we see differences in aging-related disease or survival. Instead, we rely on biomarkers developed to measure the pace and progress of biological aging over the duration of the study. The team analyzed methylation marks on DNA extracted from white blood cells. DNA methylation marks are chemical tags on the DNA sequence that regulate the expression of genes and are known to change with aging.

In the primary analysis teh researchers focused on three measurements of the DNA methylation data, sometimes known as "epigenetic clocks". The first two, the PhenoAge and GrimAge clocks, estimate biological age, or the chronological age at which a person's biology would appear "normal". These measures can be thought of as "odometers" that provide a static measure of how much aging a person has experienced. The third measure studied by the researchers was DunedinPACE, which estimates the pace of aging, or the rate of biological deterioration over time. DunedinPACE can be thought of as a "speedometer".

The study found evidence that calorie restriction slowed the pace of aging in humans. But calorie restriction is probably not for everyone. These findings are important because they provide evidence from a randomised trial that slowing human aging may be possible. They also give us a sense of the kinds of effects researchers might look for in trials of interventions that could appeal to more people, like intermittent fasting or time-restricted eating.

A follow-up of trial participants is now ongoing to determine if the intervention had long-term effects on healthy aging.

Daniel Belsky, Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial, Nature Aging (2023). DOI: 10.1038/s43587-022-00357-y. www.nature.com/articles/s43587-022-00357-y

• ‹ Previous
• 1
• …
• 197
• 198
• 199
• 200
• 201
• …
• 856
• Next ›
• Page