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Comment by Dr. Krishna Kumari Challa on January 25, 2023 at 8:29am

How cancer cells die: Scientists explore new pathways of pyroptosis, killer kin of apoptosis

You can't understand the life cycle of a cell without learning how they die. That is why the concept of apoptosis—programmed cell death—is taught in schools.

What's usually not taught is another way that cells die, a process called pyroptosis, an inflammatory and necrotic form of cell death that primarily involves cancer cells. During chemotherapy, apoptosis can morph into pyroptosis. For patients receiving chemo, apoptosis not only turns into pyroptosis, the process can help activate the immune system. Both the initiation of pyroptosis and activation of the immune system are mediated through specific protein pathways.

To date, most studies have connected chemotherapy-induced pyroptosis to a mediator protein called gasdermin E, which is typically thought of as the sole executioner in this process. Yet, an intriguing round of research has taken a deep dive into the process of pyroptosis, uncovering new molecular pathways that trigger this form of programmed cell death.

New discoveries have emerged from a novel series of investigations that challenge prevailing scientific wisdom about the way cells die under the influence of chemotherapy. The research sheds new light on pyroptosis in chemo-based cancer treatment by expanding the possible number of protein pathways involved in this form of cell death, and hinting that still other pathways may be found in the future.

In response to chemotherapy, the induction of apoptotic cell death can be converted to a form of lytic cell death called pyroptosis.

The term "lytic cell death," or "cell lysis," refers to the breakdown of a cell caused by irrevocable damage to its outermost membrane. A cell can't survive when its contents are spilling out through holes, and that's what pyroptosis is all about. It's bruising and violent—and aimed at cell death. During pyroptosis, a cascade of molecular reactions punch large pores in cell membranes, irrevocably destabilizing, and ultimately, destroying the cells.

For chemo to have an impact, it must trigger biological pathways that lead to cell death. The scientists' elegant recent research, which includes analyses of blood and bone marrow biopsies from patients with acute myeloid leukemia, open a new window of understanding into the multiple pathways that pyroptosis can be triggered under the influence of chemo.

Pyroptosis is a mechanism of programmed, necrotic cell death mediated by the gasdermins, a family of pore-forming proteins. The new research, published in the journal Science Signaling, highlights several pore-forming pathways that can lead to cell death under the influence of widely used chemotherapeutic agents.

Part 1

Comment by Dr. Krishna Kumari Challa on January 24, 2023 at 11:19am

Researchers use bacterial communication as a target for new drugs

The pathogen Pseudomonas aeruginosa is the cause of a large number of serious infections and places a particular burden on immunocompromised patients. The increasing spread of antimicrobial resistance makes it even more difficult to combat the dreaded hospital pathogen.

A research team  has now discovered a new class of active compounds that disrupt the bacterium's chemical communication pathways. This not only reduces the pathogen's disease-causing properties, but also simultaneously enhances the effectiveness of antibiotics. 

Although bacteria are among the simplest life forms on our planet, in the course of evolution they have developed ways to communicate efficiently with one another. Unlike humans, their communication is not mediated with words but with chemical signals. This interaction also plays a fundamental role in infection processes of pathogenic bacteria in humans. For example, bacteria communicate to their swarm when it is time to produce substances that counteract the human immune system. Interfering with these communication pathways is a promising starting point for the development of new therapies.

The researchers  did not focus now on the communication messengers themselves, but on their receptors—i.e., the parts of the bacterium that are responsible for signal processing. In this specific case, the researchers targeted the receptor PqsR.

When this receptor is activated, inflammation-promoting substances and biofilms are formed, in which P. aeruginosa is largely protected from antibiotics. The drug class now described was chemically designed and optimized by the researchers so that it can attack its target PqsR as efficiently as possible. This was based on structural data obtained by X-ray crystallography. 

In further laboratory experiments, the scientists were able to show that the optimized substances reliably prevent the formation of the pro-inflammatory molecule pyocyanin in a large number of clinical isolates of P. aeruginosa. Furthermore, they were able to show that the new active ingredient is capable of impairing biofilm formation and can even further enhance the effect of the antibiotic tobramycin. Finally, the researchers were able to transfer the promising properties of their active substance to a mouse model. Here, the combined administration of tobramycin and the new PqsR inhibitor was able to combat the P. aeruginosa infection significantly better than either substance alone.

The authors see great potential in the new compound class for future application in humans. 

Mostafa M. Hamed et al, Towards Translation of PqsR Inverse Agonists: From In Vitro Efficacy Optimization to In Vivo Proof‐of‐Principle, Advanced Science (2023). DOI: 10.1002/advs.202204443

Comment by Dr. Krishna Kumari Challa on January 24, 2023 at 11:12am

A sugar cane pathogen is gearing up a new era of antibiotic discovery

A potent plant toxin with a unique way of killing harmful bacteria has emerged as one of the strongest new antibiotic candidates in decades.

The antibiotic, called albicidin, is produced by the bacterial plant pathogen Xanthomonas albilineans, which causes the devastating leaf scald disease in sugar cane. Albicidin is thought to be used by the pathogen to attack the plant, enabling its spread. It has been known for some time that albicidin is highly effective at killing bacteria including E. coli and S. aureus. These superbugs, notorious for their growing resistance to existing antibiotics, have prompted a vital need for effective new drugs.

Despite its antibiotic potential and low toxicity in pre-clinical experiments, pharmaceutical development of albicidin has been hampered because scientists did not know precisely how it interacted with its target, the bacterial enzyme DNA gyrase (gyrase). This enzyme binds to DNA and, through a series of elegant movements, twists it up, a process known as supercoiling which is vital for cells to function properly.

Now researchers  have exploited advances in cryo-electron microscopy to obtain a first snapshot of albicidin bound to gyrase. It showed that albicidin forms an L-shape, enabling it to interact with both the gyrase and the DNA in a unique way.

In order for gyrase to do its job, it must momentarily cut the DNA double helix. This is dangerous, as broken DNA is lethal to the cell. Normally, gyrase quickly joints the two pieces of DNA back together again as it works, but albicidin prevents it from happening, resulting in broken DNA and bacterial death. The effect of albicidin is akin to a spanner thrown between two gears.

The way albicidin interacts with gyrase is sufficiently different from existing antibiotics that the molecule and its derivatives are likely to be effective against many of the current antibiotic resistant bacteria.

 By the nature of the interaction, albicidin targets a really essential part of the enzyme and it's hard for bacteria to evolve resistance to that. Trials have already started to use this knowledge to produce new era antibiotics.

Jonathan Heddle, Molecular mechanism of topoisomerase poisoning by the peptide antibiotic albicidin, Nature Catalysis (2023). DOI: 10.1038/s41929-022-00904-1. www.nature.com/articles/s41929-022-00904-1

Comment by Dr. Krishna Kumari Challa on January 24, 2023 at 10:52am

Novel method helps recover obscured images

A novel method that produces a clear image by using a simple cost-effective random scattering medium in real time could help overcome problems of obscured images.

When light passes through a light-scattering material, it is diffused rather than absorbed, which means a clear image of the source object is lost. Scattering media include clouds, which poses problems for Earth-based astronomy, and body tissue, which affects medical imaging.

Previous methods for reconstructing scattered light have required some initial knowledge of the object and the ability to control the wavefront of light illuminating it. This has involved complicated optical elements and high vulnerability to motion and mechanical instability. Computational algorithms are then able to post-process the detected light to generate an image.

To get more efficient ways of reconstruction, speckle-correlation imaging was proposed. This extracts information about the source from fluctuations in the intensity, or speckles, in the transmitted light.

However, many of the technologies based on speckle-correlation need time-consuming and intricately calibrated computational reconstruction. Also, still missing is some information such as the image orientation and location.

Now researchers have developed a way to directly obtain a clear image from a single shot of the speckle image.

They passed light from a small standardized test object through a thin diffusing material. By moving a camera in a direction away from the diffuser, they were able to build a three-dimensional image, taking slices through the speckles.

By looking at enlarged sections of these images, the researchers, to their surprise, could directly see reproductions of the test object; they could see through the random diffuser with the naked eye and real-time video imaging. It required no complex equipment for the active control of light nor prior knowledge of the source or diffusion medium. They could also find the lost orientation information and location of the test object.

Jietao Liu et al, Directly and instantly seeing through random diffusers by self-imaging in scattering speckles, PhotoniX (2023). DOI: 10.1186/s43074-022-00080-2

Comment by Dr. Krishna Kumari Challa on January 24, 2023 at 10:38am

Study reveals new genetic disorder that causes susceptibility to opportunistic infections

Researchers have discovered a new genetic disorder that causes immunodeficiency and profound susceptibility to opportunistic infections including a life-threatening fungal pneumonia.

The discovery, reported Jan. 20 in the journal Science Immunology, will help identify people who carry this in-born error of immunity (IEI).

IEIs, also known as primary immunodeficiencies, are genetic defects characterized by increased susceptibility to infectious diseases, autoimmunity, anti-inflammatory disorders, allergy, and in some cases, cancer.

To date, 485 different IEIs have been identified. It is now thought that they occur in one of every 1,000 to 5,000 births, making them as prevalent as other genetic disorders, including cystic fibrosis and Duchene's muscular dystrophy.

Despite recent medical advances, about half of patients with IEIs still lack a genetic diagnosis that could help them avoid debilitating illness and death. This new work helps with that. 

The error in this case is a mutation in the gene for the protein IRF4, a transcription factor that is pivotal for the development and function of B and T white blood cells, as well as other immune cells.

The researchers sequenced the protein-encoding regions of a boy's - who was suffering from severe and recurrent fungal, viral, mycobacterial, and other infections -  genome  and discovered a de novo IRF4 mutation, which originated in the patient and was not inherited from his parents.

In the current study, the researchers identified seven patients from six unrelated families across four continents with profound combination immunodeficiency who experienced recurrent and serious infections, including pneumonia caused by the fungus Pneumocystis jirovecii. Each patient had the same mutation in the DNA-binding domain of IRF4.

Extensive phenotyping of patients' blood cells revealed immune cell abnormalities associated with the disease, including impaired maturation of antibody-producing B cells, and reduced T-cell production of infection-fighting cytokines.

Two knock-in mouse models, in which the mutation was inserted into the mouse genome, exhibited a severe defect in antibody production consistent with the combined immune deficiency observed in the patients.

The researchers also discovered the mutation had a "multimorphic" effect detrimental to the activation and differentiation of immune cells.

While the mutant IRF4 binds to DNA with a higher affinity than the native form of the protein (in a hypermorphic way), its transcriptional activity in common, canonical genes is reduced (hypomorphic), and it binds to other DNA sites (in a neomorphic way), altering the protein's normal gene expression profile.

This multimorphic activity is a new mechanism for human disease. "We anticipate that variants with multimorphic activity may be more widespread in health and disease," the researchers concluded.

A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency, Science Immunology (2023). DOI: 10.1126/sciimmunol.ade7953

Comment by Dr. Krishna Kumari Challa on January 24, 2023 at 9:58am

Head injury is associated with doubled mortality rate long-term

Adults who suffered any head injury during a 30-year study period had two times the rate of mortality than those who did not have any head injury, and mortality rates among those with moderate or severe head injuries were nearly three times higher, according to new research.

Head injury can be attributed to a number of causes, from motor vehicle crashes, unintentional falls, or sports injuries. What's more, head injury has been linked with a number of long-term health conditions, including disability, late-onset epilepsy, dementia, and stroke.

Studies have previously shown increased short-term mortality associated with head injuries primarily among hospitalized patients. This longitudinal study evaluated 30 years of data from over 13,000 community-dwelling participants (those not hospitalized or living in nursing home facilities) to determine if head injury has an impact on mortality rates in adults over the long term. Investigators found that 18.4 percent of the participants reported one or more head injuries during the study period, and of those who suffered a head injury, 12.4 percent were recorded as moderate or severe. The median period of time between a head injury and death was 4.7 years.

Death from all causes was recorded in 64.6 percent of those individuals who suffered a head injury, and in 54.6 percent of those without any head injury. Accounting for participant characteristics, investigators found that the mortality rate from all-causes among participants with a head injury was 2.21 times the mortality rate among those with no head injury. Further, the mortality rate among those with more severe head injuries was 2.87 times the mortality rate among those with no head injury.

Investigators also evaluated the data for specific causes of death among all participants. Overall, the most common causes of death were cancers, cardiovascular disease, and neurologic disorders (which include dementia, epilepsy, and stroke). Among individuals with head injuries, deaths caused by neurologic disorders and unintentional injury or trauma (like falls) occurred more frequently.

When investigators evaluated specific neurologic causes of death among participants with head injury, they found that nearly two-thirds of neurologic causes of death were attributed to neurodegenerative diseases, like Alzheimer's and Parkinson's disease. These diseases composed a greater proportion of overall deaths among individuals with head injury (14.2 percent) versus those without (6.6 percent).

This highlights the importance of safety measures, like wearing helmets and seatbelts, to prevent head injuries.

 Holly Elser et al, Head Injury and Long-term Mortality Risk in Community-Dwelling Adults, JAMA Neurology (2023). DOI: 10.1001/jamaneurol.2022.5024

Comment by Dr. Krishna Kumari Challa on January 24, 2023 at 9:16am

Milky Way found to be too big for its 'cosmological wall'

Is the Milky Way special, or, at least, is it in a special place in the universe? An international team of astronomers has found that the answer to that question is yes, in a way not previously appreciated. A new study shows that the Milky Way is too big for its "cosmological wall," something yet to be seen in other galaxies.

A cosmological wall is a flattened arrangement of galaxies found surrounding other galaxies, characterized by particularly empty regions called "voids" on either side of it. These voids seem to squash the galaxies together into a pancake-like shape to make the flattened arrangement. This wall environment, in this case called the Local Sheet, influences how the Milky Way and nearby galaxies rotate around their axes, in a more organized way than if we were in a random place in the universe, without a wall.

Typically, galaxies tend to be significantly smaller than this so-called wall. The Milky Way is found to be surprisingly massive in comparison to its cosmological wall, a rare cosmic occurrence.

The new findings are based on a state-of-the-art computer simulation, part of the IllustrisTNG project. The team simulated a volume of the universe nearly a billion light-years across that contains millions of galaxies. Only a handful—about a millionth of all the galaxies in the simulation—were as "special" as the Milky Way, i.e., both embedded in a cosmological wall like the Local Sheet, and as massive as our home galaxy.

M A Aragon-Calvo et al, The unusual Milky Way-local sheet system: implications for spin strength and alignment, Monthly Notices of the Royal Astronomical Society: Letters (2022). DOI: 10.1093/mnrasl/slac161

Comment by Dr. Krishna Kumari Challa on January 22, 2023 at 8:57am

Microalgae abundance and proportions affect nutrient exchange in a coral symbiotic relationship

Comment by Dr. Krishna Kumari Challa on January 22, 2023 at 8:54am

Harnessing the healing power within our cells

Researchers have identified a pathway in cells that could be used to reprogram the body’s immune system to fight back against both chronic inflammatory and infectious diseases. Molecular bio-scientists have discovered that a molecule derived from glucose in immune cells can both stop bacteria growing and dampen inflammatory responses.

The effects of this molecule called ribulose-5-phosphate on bacteria are striking – it can cooperate with other immune factors to stop disease-causing strains of the E. coli bacteria from growing.  It also reprograms the immune system to switch off destructive inflammation, which contributes to both life-threatening infectious diseases such as sepsis as well as chronic inflammatory diseases like respiratory diseases, chronic liver disease, inflammatory bowel disease, rheumatoid arthritis, heart disease, stroke, diabetes and dementia.

The research was carried out on a strain of E. coli bacteria that causes approximately 80 per cent of urinary tract infections and is a common cause of sepsis. Pre-clinical trials were used to confirm the role of this pathway in controlling bacterial infections.

 Human cells were also used to demonstrate that ribulose-5-phosphate reduces the production of molecules that drive chronic inflammatory diseases.

Host-directed therapies which train our immune systems to fight infections, will become increasingly important as more types of bacteria become resistant to known antibiotics.

A bonus is that this strategy also switches off destructive inflammation, which gives it the potential to combat chronic disease.

By boosting the immune pathway that generates ribulose-5-phosphate, scientists may be able to give the body the power to fight back against inflammatory and infectious diseases – not one, but two of the major global challenges for human health.

Many current anti-inflammatory therapies target proteins on the outside of cells but because this pathway occurs inside cells, the researchers devised a new approach to target the pathway using mRNA technology.

Kaustav Das Gupta et al, HDAC7 is an immunometabolic switch triaging danger signals for engagement of antimicrobial versus inflammatory responses in macrophages, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2212813120

Comment by Deepak Menon on January 22, 2023 at 7:10am

Very very interesting research on the DNA trap. Will these trap specific viruses and how will they recognise them?

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