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Comment by Dr. Krishna Kumari Challa on December 13, 2022 at 11:05am

Experimental cancer therapy shows success in more than 70% of patients in global clinical trials

A new therapy that makes the immune system kill bone marrow cancer cells was successful in as many as 73% of patients in two clinical trials, according to researchers . 

The therapy, known as a bispecific antibody, binds to both T cells and multiple myeloma cells and directs the T cells—white blood cells that can be enlisted to fight off diseases—to kill multiple myeloma cells. The researchers described this strategy as "bringing your army right to the enemy." The success of the off-the-shelf immunotherapy, called talquetamab, was even seen in patients whose cancer was resistant to all approved multiple myeloma therapies. It uses a different target than other approved therapies: a receptor expressed on the surface of cancer cells known as GPRC5D. Talquetamab was tested in phase 1 and phase 2 trials. The phase 1 trial, which was reported in the New England Journal of Medicine, established two recommended doses that were tested in the Phase 2 trial. The results of the Phase 2 trial were reported at the American Society of Hematology annual meeting on Saturday, December 10. The study participants had all been previously treated with at least three different therapies without achieving lasting remission, suggesting talquetamab could offer new hope for patients with hard-to-treat multiple myeloma. This means that almost three-quarters of these patients are looking at a new lease on life.

The efficacy and safety findings in the phase 1 study were validated in the phase 2 trial presented at ASH. The overall response rate in these two groups was about 73%.

Ajai Chari et al, New England Journal of Medicine (2022).

Conference: www.hematology.org/meetings/annual-meeting

Comment by Dr. Krishna Kumari Challa on December 12, 2022 at 12:14pm

Antibodies to common antibiotic possible new risk factor for type 1 diabetes

Antibodies produced against the commonly used antibiotic, gentamicin, appear to increase the risk of type 1 diabetes in children already genetically at risk, scientists say.

When  scientists compared the blood of nearly 300 individuals with type 1 diabetes to healthy controls, they found that a higher level of antibodies against gentamicin was associated with increased risk of progression to type 1 diabetes. G418 and sisomicin, analogs of gentamicin, also showed a similar association.

Their study analyzed samples from the Diabetes Autoimmunity Study in the Young (DAISY) and Phenome and Genome of Diabetic Autoantibody (PAGODA). The databases studied did not state whether study participants had been given gentamicin. However, anywhere between 5-10% of newborns receive the broad-spectrum antibiotic to treat potentially lethal sepsis.

They report in the journal Nature Communications that a similar percentage, 5.3% of the participants, had high levels of these antibodies and a high percentage of this group later developed type 1 diabetes.

To compound the scenario, it's known that premature babies are considered at higher risk for both sepsis and type 1 diabetes. The current standard of care for newborns with sepsis is giving gentamicin, per World Health Organization guidelines.

These infections are common, and the babies need the antibiotic because their own immune systems are not well developed at that juncture, and the drug may be a lifesaving therapy.

It's not uncommon for antibiotics to prompt production of antibodies because the body views them as foreign. In this study, scientists looked at antibodies to glycans, which are found on the surface our cells as well as the cells of microorganisms like bacteria and are known to be a ready target for this immune response.

Gentamicin and other similar antibiotics are a class of compounds called aminoglycosides, which are commonly used to treat serious infections, and are also broadly classified as glycans because of their sugar content.

When the  scientists did "profiling" of all the antibodies, they clustered the glycans two ways. The first was by glycans with similar function and secondly, by antibody levels in patients. They also found an association between the multitasking FUT2 gene and the antibodies against both gentamicin and the islet cells of the pancreas. The  data reveals that they are compounding the risks.

Paul M. H. Tran, Fran Dong, Eileen Kim, Katherine P. Richardson, Lynn K. H. Tran, Kathleen Waugh, Diane Hopkins, Richard D. Cummings, Peng George Wang, Marian J. Rewers, Jin-Xiong She, Sharad Purohit. Use of a glycomics array to establish the anti-carbohydrate antibody repertoire in type 1 diabetes. Nature Communications, 2022; 13 (1) DOI: 10.1038/s41467-022-34341-2

Comment by Dr. Krishna Kumari Challa on December 12, 2022 at 10:57am

Researchers reveal how trauma changes the brain

Exposure to trauma can be life-changing—and researchers are learning more about how traumatic events may physically change our brains. But these changes are not happening because of physical injury; rather, the brain appears to rewire itself after these experiences.

Understanding the mechanisms involved in these changes and how the brain learns about an environment and predicts threats and safety is a focus of neuro-scientists. 

Scientists  are learning more about how people exposed to trauma learn to distinguish between what is safe and what is not. Their brain is giving them insight into what might be going awry in specific mechanisms that are impacted by trauma exposure, especially when emotion is involved.

Their research, recently published in Communications Biology, identified changes in the salience network—a mechanism in the brain used for learning and survival—in people exposed to trauma (with and without psychopathologies, including PTSD, depression, and anxiety).

Using fMRI, the researchers recorded activity in the brains of participants as they looked at different-sized circles—only one size was associated with a small shock (or threat). Along with the changes in the salience network, researchers found another difference—this one within the trauma-exposed resilient group. They found the brains of people exposed to trauma without psychopathologies were compensating for changes in their brain processes by engaging the executive control network—one of the dominant networks of the brain.

The possibility of threat can change how someone exposed to trauma reacts. Researchers found this to be the case in people with post-traumatic stress disorder (PTSD). Patients with PTSD can complete the same task as someone without exposure to trauma when no emotion is involved. However, when emotion invoked by a threat was added to a similar task, those with PTSD had more difficulty distinguishing between the differences.

 researchers observed that people with PTSD had less signaling between the hippocampus (an area of the brain responsible for emotion and memory) and the salience network (a mechanism used for learning and survival).

They also detected less signaling between the amygdala (another area linked to emotion) and the default mode network (an area of the brain that activates when someone is not focused on the outside world). These findings reflect the inability of a person with PTSD to effectively distinguish differences between the circles.

Xi Zhu et al, Sequential fear generalization and network connectivity in trauma exposed humans with and without psychopathology, Communications Biology (2022). DOI: 10.1038/s42003-022-04228-5

Comment by Dr. Krishna Kumari Challa on December 11, 2022 at 6:52am

The toughest material on Earth

Scientists have measured the highest toughness ever recorded, of any material, while investigating a metallic alloy made of chromium, cobalt, and nickel (CrCoNi). Not only is the metal extremely ductile—which, in materials science, means highly malleable—and impressively strong (meaning it resists permanent deformation), its strength and ductility improve as it gets colder. This runs counter to most other materials in existence.

Dong Liu et al, Exceptional fracture toughness of CrCoNi-based medium- and high-entropy alloys at 20 kelvin, Science (2022). DOI: 10.1126/science.abp8070

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Did physicists make a wormhole in the lab? Not quite, but a new exp...

Scientists made headlines last week for supposedly generating a wormhole. The research, reported in Nature, involves the use of a quantum computer to simulate a wormhole in a simplified model of physics.

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Forget net-zero: Aim for net-negative to halt global warming, argue...

In the fight against climate change, the lever every policymaker has been focusing on has been the reduction in (net) emissions. Curbing the rate at which greenhouse gases are pumped into the atmosphere clearly remains a priority. Yet every serious scientific analysis—in particular the latest IPCC report—agrees that a substantial amount of CO2 must be removed from the atmosphere via negative-emission technologies if we want to have a reasonable chance of limiting the temperature increase by the end of the century to 1.5 to 2C above pre-industrial levels.

Comment by Dr. Krishna Kumari Challa on December 11, 2022 at 6:49am

Another defining property is the level of gene expression in stem cells, which must have hundreds of genes expressed. To determine if 3a/3b fit this property, they took the progeny with 3a/3b glowing in red and all other cells glowing in green and used a sorting machine that separated the red and green cells. they then applied single-cell sequencing technology to ask, which genes are being expressed in the red cells and in the green cells. That data confirmed that at the molecular level only the progeny of the 3a/3b cells matched stem cells and not the progeny of any other cell.

That was definitive confirmation of the fact that we found the cellular source of the stem cell population in our system. But, importantly, knowing the cellular source of stem cells now gives them a way to capture the cells as they mature and define what genes are involved in making them.

They generated a huge dataset of embryonic development at the single-cell level detailing which genes were being expressed in all of the cells in embryos from the beginning to the end of development. They allowed the converted 3a/3b cells to develop a little bit further, but not all the way to hatchling stage. They then captured these cells using the sorting technology. By doing this they could clearly define which genes were specifically being expressed in the lineage of cells that make the stem cells.

This study reveals a set of genes that could be very important controllers for the formation of stem cells. Homologues of these genes have important roles in human stem cells and this is relevant across species.

The researchers plan to continue digging deeper into the mechanism of how these genes are working in the stem cells of Hofstenia miamia, which will help to tell how nature evolved a way to make and maintain pluripotent stem cells. Knowing the molecular regulators of aPSCs will allow researchers to compare these mechanisms across species, revealing how pluripotent stem cells have evolved across animals.

Mansi Srivastava, Embryonic origins of adult pluripotent stem cells, Cell (2022). DOI: 10.1016/j.cell.2022.11.008. www.cell.com/cell/fulltext/S0092-8674(22)01420-9

Part 3

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Comment by Dr. Krishna Kumari Challa on December 11, 2022 at 6:46am

The researchers knew that worm hatchlings contain aPSCs, so reasoned they must be made during embryogenesis. Ricci used transgenesis to create a line that caused embryo cells to glow in fluorescent green due to the introduction of the protein Kaede into the cell. Kaede is photo-convertible, which means shining a laser beam with a very specific wavelength on the green will convert it to a red color. You can then zap the cells with a laser to turn individual green cells of the embryo into a red color.

Using transgenic animals with photo-conversion is a very new twist the researchers devised in the lab to figure out the fates of embryonic cells.

 They followed the embryo's development as it split from single cell to multiple cells. Early division of these cells is marked by stereotyped cleavage, which means embryo to embryo cells divide in the exact same pattern such that cells can be named and studied consistently. This raised the possibility that perhaps every single cell has a unique purpose. For instance, at the eight-cell stage it's possible the top, left corner cell makes a certain tissue, while the bottom, right cell makes another tissue.

To determine the function of each cell, they systematically performed photo-conversion for each of the cells of the early embryo, creating a full fate map at the eight-cell stage. They then tracked the cells as the worm grew into an adult that still carried the red labeling. The repetitious process of following each individual cell again and again across many embryos made it possible for them to trace where each cell was working.

At the sixteen-cell stage embryo they found a very specific pair of cells that gave rise to cells that looked to be the neoblasts.

To be certain, the researchers put this particular set of cells, called 3a/3b in H. miamia, on trial. In order to be the neoblasts the cells must satisfy all of the known properties of stem cells. Are the progeny of those cells making new tissue during regeneration? The researchers found that yes, the progeny of only those cells made new tissue during regeneration.

Part 2

Comment by Dr. Krishna Kumari Challa on December 11, 2022 at 6:43am

Researchers discover embryonic origins of adult pluripotent stem cells

Stem cells are a biological wonder. They can repair, restore, replace, and regenerate cells. In most animals and humans these cells are limited to regenerating only the cell type they are assigned to. So, hair stem cells will only make hair. Intestine stem cells will only make intestines. But, many distantly-related invertebrates have stem cell populations that are pluripotent in adult animals, which means they can regenerate virtually any missing cell type, a process called whole-body regeneration.

Even though these adult pluripotent stem cells (aPSCs) are found in many different types of animals (such as sponges, hydras, planarian flatworms, acoel worms, and some sea squirts) the mechanism of how they are made is not known in any species.

In a new study in Cell researchers  have identified the cellular mechanism and molecular trajectory for the formation of aPSCs in the acoel worm, Hofstenia miamia.

H. miamia, also known as the three-banded panther worm, is a species that can fully regenerate using aPSCs called "neoblasts." Chop H. miamia into pieces and each piece will grow a new body including everything from a mouth to the brain.

 Researchers developed a protocol for transgenesis in H. miamia. Transgenesis is a process that introduces something into the genome of an organism that is not normally part of that genome. This method allowed the researchers to pursue this question of how these stem cells are made.

One common characteristic among animals that can regenerate is the presence of pluripotent stem cells in the adult body. These cells are responsible for re-making missing body parts when the animal is injured. By understanding how animals like H. miamia make these stem cells, they felt they could better understand what gives certain animals regenerative abilities.

There are some unifying features of these stem cell populations in adult animals such as the expression of a gene called Piwi.

Part 1

Comment by Dr. Krishna Kumari Challa on December 11, 2022 at 6:33am

Do You Flush With The Lid Up? You Won't After Watching This

New research shows the impact of flushing the toilet in a whole new light. Using bright green lasers and camera equipment, a team of  engineers ran an experiment to reveal how tiny water droplets, invisible to the naked eye, are rapidly ejected into the air when a lid-less, public restroom toilet is flushed. These aerosolized particles are known to transport pathogens and could pose an exposure risk to public bathroom patrons. This visualization method, however, provides experts in plumbing and public health with a consistent way to test improved plumbing design and disinfection and ventilation strategies, in order to reduce exposure risk to pathogens in public restrooms.

Comment by Dr. Krishna Kumari Challa on December 10, 2022 at 10:17am

A surprising discovery: The female locust has superhero-like abilities

A new Tel Aviv University study has discovered that the female locust has superpowers. The findings of the study reveal that the female locust's central nervous system has elastic properties, allowing her to stretch up to two or three times her original length when laying her eggs in the ground, without causing any irreparable damage.

We are not aware of a similar ability in almost any living creature. Nerves in the human nervous system, for example, can stretch only up to 30% without tearing or being permanently damaged. In the future, these findings may contribute to new developments in the field of regenerative medicine, as a basis for nerve restoration and the development of synthetic tissues.

When the female locust is ready to lay her eggs, she digs a hole in the ground that will offer them protection and optimal conditions for hatching. For this purpose, she is equipped with a unique digging apparatus, consisting of two pairs of digging valves which are located at the tip of the abdomen, on either side of the ovipositor (a tube-like organ used for laying eggs).

"As she digs, the female extends her body, until sensors located along its length signal that she has reached a suitable point for depositing her eggs. Thus, an adult female, whose body length is about four to five centimeters, may, for the purpose of laying her eggs, stretch her body to a length of 10–15 centimeters, then quickly return to her normal length, and then extend again for the next egg-laying.

The superpower of the locust is almost something out of science fiction. There are only two other known examples in nature of a similar phenomenon: the tongue of the sperm whale, and a certain type of sea snail whose nervous systems are able to extend significantly due to an accordion-like mechanism they have. Scientists sought to identify the biomechanical mechanism that gives the female locust its wonderful ability.

In the study, the researchers removed the central nervous systems from female locusts and placed them in a liquid simulating their natural environment, under physiological conditions similar to those inside the body. Using highly sensitive measuring instruments, they measured the forces needed to extend the nervous system.

Contrary to previous hypotheses and examples we are familiar with, they did not find any accordion-like mechanism. They discovered that the nervous system of the female locust has elastic properties, which enable it to elongate and then return by itself to its original state, ready for reuse, without any damage caused to the tissue. This finding is almost incomprehensible from a biomechanical and morphological point of view.

The researchers hope that in the future their findings will help to develop synthetic tissues with a high level of flexibility, and to restore nerves in regenerative medicine therapies.

https://www.sciencedirect.com/science/article/pii/S258900422201567X

Comment by Dr. Krishna Kumari Challa on December 10, 2022 at 10:10am

Scientists shed new light on genetic changes that turn 'on' cancer genes

Cancer, caused by abnormal overgrowth of cells, is the second-leading cause of death in the world. Researchers  have zeroed in on specific mechanisms that activate oncogenes, which are altered genes that can cause normal cells to become cancer cells.

Cancer can be caused by genetic mutations, yet the impact of specific types such as structural variants that break and rejoin DNA, can vary widely. The findings, published in Nature on December 7, 2022, show that the activity of those mutations depends on the distance between a particular gene and the sequences that regulate the gene, as well as on the level of activity of the regulatory sequences involved.

This work advances the ability to predict and interpret which genetic mutations found in cancer genomes are causing the disease.

Most genetic mutations have no impact on a cancer and the molecular incidents that lead to oncogene activation are relatively rare.

Using CRISPR-Cas9 gene editing, the researchers introduced genetic mutations by cutting DNA in certain locations of the genome. They found that some of the variants they created had major impacts on the expression of nearby genes, and could ultimately cause cancer, but that most had essentially no impact. Some genes appeared to go haywire when they were brought into environments with novel regulatory sequences, and others were not affected at all. The type of sequence that was introduced appeared to have a huge impact on whether or not the cell became cancerous.

Their next move is to test whether there are other factors in the genome that contribute to the activation of oncogene.

Zhichao Xu, Dong-Sung Lee, Sahaana Chandran, Victoria T. Le, Rosalind Bump, Jean Yasis, Sofia Dallarda, Samantha Marcotte, Benjamin Clock, Nicholas Haghani, Chae Yun Cho, Kadir C. Akdemir, Selene Tyndale, P. Andrew Futreal, Graham McVicker, Geoffrey M. Wahl, Jesse R. Dixon. Structural variants drive context-dependent oncogene activation in cancer. Nature, 2022; DOI: 10.1038/s41586-022-05504-4

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