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Comment by Dr. Krishna Kumari Challa on March 9, 2024 at 10:40am

Ebola-fighting potential of engineered bacteria

The  Ebola virus has proven an especially lethal contagion, killing roughly 50% of the people who contract it. The 2019 FDA approval of a vaccine, combined with the subsequent development of two antibody-based drugs, marked unprecedented progress against one species of the virus. Yet the continuing threat posed by several other types of Ebola has left researchers in pursuit of additional treatments—particularly in developing regions of Africa, where limited infrastructure can impede the storage and deployment of vaccines.

One approach to combating viral threats has come in the form of a microbial counterpart: bacteria. In researching inhibitors of HIV, for instance, some researchers identified the promise of lectins, or bacteria-generated proteins that can selectively bind to the surfaces of viral particles, thereby neutralizing them.

Scientists took a special interest in scytovirin, a type of lectin produced by cyanobacteria, likely the Earth's first oxygen-producing organisms. Because scytovirin had shown some early success in inhibiting Ebola, they went about engineering two strains of lactic acid bacteria, which can safely colonize the human body, to display scytovirin on their own surfaces. The study is published in the journal Frontiers in Microbiology.

After constructing research-safe shells of Ebola particles, the virologists introduced them to the two bacterial strains. Their experiments revealed that one of the engineered strains, Lactococcus lactis, could neutralize roughly 54% of the Ebola particles—more than twice the rate of scytovirin-free L. lactis.

The research team  is now testing the bacteria-delivered antiviral in mice, where the virologists are determining whether the engineered L. lactis can neutralize Ebola the way it did in cell cultures. Passing that test could eventually lead to human trials.

If it does continue to perform, L. lactis—which is already used to make cheese and buttermilk—could become a relatively simple, inexpensive, long-term way to protect vulnerable populations against the devastating virus, the team said.

Joshua Wiggins et al, Lactic acid bacterial surface display of scytovirin inhibitors for anti-ebolavirus infection, Frontiers in Microbiology (2023). DOI: 10.3389/fmicb.2023.1269869

Comment by Dr. Krishna Kumari Challa on March 9, 2024 at 10:26am

Egg-laying caecilian amphibians produce milk for their young, find scientists

Parental care for offspring occurs in many animals and is an essential part of the reproduction, propagation and development of an organism. An international research team has revealed for the first time how egg-laying female caecilian amphibians successfully raise their offspring in the nest.

Caecilian amphibians are one of the least known vertebrate groups. The researchers were able to observe that the females of egg-laying amphibians, such as the species Siphonops annulatus, provide their young a similarly high-fat milk in the nest as, for example, egg-laying mammals. This discovery demonstrates the complexity of the evolution of reproductive strategies in vertebrates and expands our knowledge of brood care and communication in amphibians.

The research is published in the journal Science.

In most vertebrates, the yolk is usually the only form of nutrition females provide to the growing embryo. The research team observed that the young of the Brazilian caecilian Siphonops annulatus consumed milk for over two months, which appears to be secreted in response to tactile and acoustic stimulation from the mother's cloaca. The milk consists mainly of fats and carbohydrates and is produced in the glands of the female's oviduct.

Scientists have now discovered a vertebrate system in amphibians that has developed similarly comprehensive brood care mechanisms as known for mammals. This includes the production of fat-rich mother's milk and the release of milk to the young in the nest, known as lactation. This tells us a lot about the evolution and reproductive strategies of this still little-known vertebrate order.

Caecilian amphibians are legless, snake-like amphibians that are widespread in the tropical regions of the world. All caecilian amphibians provide brood care. The female of the Brazilian amphibian Siphonops annulatus lays eggs and raises its hatchlings in the nest with fat-rich "milk" as well as its skin. Parental brood care is therefore similar to that of egg-laying mammals such as echidnas and platypuses.

Pedro L. Mailho-Fontana et al, Milk provisioning in oviparous caecilian amphibians, Science (2024). DOI: 10.1126/science.adi5379

Comment by Dr. Krishna Kumari Challa on March 9, 2024 at 10:21am

Scientists use the term horizontal gene transfer to describe how living organisms can transfer genetic material between different individuals, including those of other species. In this way, bacteria exchange extensive genetic information, often in the form of plasmids, in order to quickly adapt to changing environmental conditions or to adapt to the host. The rapid evolution of various pathogens is based on such mechanisms, among other things.

In fungi and many other so-called eukaryotic organisms, however, horizontal gene transfer in the form of entire chromosomes is very rare.

The analysis of the genetic information of the fungal strains shows that M. robertsii independently transferred a single chromosome a total of five times during the co-infection experiments, but no other genetic information from one strain to another via horizontal transfer.

Further analyses also indicated that the same chromosome can also be found in the distantly related, also insect-damaging fungus species Metarhizium guizhouense, whose common evolutionary origin with M. robertsii dates back around 15 million years.

The chromosome in M. guizhouense is significantly less altered than would be assumed for the long period of separate evolution of the two fungal species. The chromosome therefore also appears to have been passed on naturally between these different fungal species—and probably horizontally.

The experiments showed that, under certain conditions, the fungus that had received the accessory chromosome had competitive advantages over fungi of the same strain that had not received the chromosome and were able to prevail against them.

The transfer of the chromosome may therefore have advantages for the fungus, the functional basis of which is still unclear. However, one plausible possibility is the transfer of certain genes that produce chitin-cleaving enzymes and can thus improve the ability to infect the insects.

Michael Habig et al, Frequent horizontal chromosome transfer between asexual fungal insect pathogens, Proceedings of the National Academy of Sciences (2024). DOI: 10.1073/pnas.2316284121

Comment by Dr. Krishna Kumari Challa on March 9, 2024 at 10:18am

Horizontal gene transfer: How fungi improve their ability to infect insects

Researchers have investigated for the first time in detail how a fungus important for biological plant protection can pass on an advantageous chromosome horizontally, using a previously little-studied way of exchanging genetic information.

Sustainable plant protection measures that are not based on chemical pesticides rely on various organisms and biological agents to protect crops from pests. Such organisms used for biological plant protection are, for example, microscopic fungi of the genus Metarhizium, which can attack and kill a variety of plant-pathogenic insects and are used, for example, in South American sugar cane cultivation.

The molecular mechanisms of fungal infection and the immune response of insects are in an ongoing process of mutual evolutionary adaptation.

The researchers examined the genomes of different strains of the fungi Metarhizium robertsii and Metarhizium brunneum from an earlier co-infection experiment in which ants had been infected with the fungus mix.

In the study, the outgrowing spores were used to infect new ants over 10 consecutive infection cycles. When analyzing the fungal genomes from these infection series, researchers made an exciting observation:  the analyses showed that a single chromosome was very frequently exchanged horizontally between two different strains.

This chromosome contains certain genes that the scientists suspect may give the fungus an advantage in infecting its hosts. The horizontal transfer of entire chromosomes has rarely been described scientifically and has now been studied in detail for the first time. The researchers from the Kiel Evolution Center (KEC) and ISTA published their results in the journal Proceedings of the National Academy of Sciences.

Part 1

Comment by Dr. Krishna Kumari Challa on March 9, 2024 at 9:58am

Altered protein folding drives multicellular evolution

Researchers have discovered a mechanism steering the evolution of multicellular life. They identified how altered protein folding drives multicellular evolution.

In a new study led by researchers, they turned to a tool called experimental evolution. In the ongoing Multicellularity Long Term Evolution Experiment (MuLTEE), laboratory yeast are evolving novel multicellular functions, enabling researchers to investigate how they arise.

The study, published in Science Advances, puts the spotlight on the regulation of proteins in understanding evolution.

By demonstrating the effect of protein-level changes in facilitating evolutionary change, this work highlights why knowledge of the genetic code in itself does not provide a full understanding of how organisms acquire adaptive behaviours. Achieving such understanding requires mapping the entire flow of genetic information, extending all the way to the actionable states of proteins that ultimately control the behaviour of cells.

Among the most important multicellular innovations is the origin of robust bodies: over 3,000 generations, these 'snowflake yeast' started out weaker than gelatin but evolved to be as strong and tough as wood.

Researchers identified a non-genetic mechanism at the base of this new multicellular trait, which acts at the level of protein folding. The authors found that the expression of the chaperone protein Hsp90, which helps other proteins acquire their functional shape, was gradually turned down as snowflake yeast evolved larger, tougher bodies.

It turns out Hsp90 acted as a critically-important tuning knob, destabilizing a central molecule that regulates the progression of the cell cycle, causing cells to become elongated. This elongated shape, in turn, allows cells to wrap around one another, forming larger, more mechanically tough multicellular groups.

From an evolutionary perspective, this work highlights the power of non-genetic mechanisms in rapid evolutionary change.

 Kristopher Montrose et al, Proteostatic tuning underpins the evolution of novel multicellular traits, Science Advances (2024). DOI: 10.1126/sciadv.adn2706. www.science.org/doi/10.1126/sciadv.adn2706

Comment by Dr. Krishna Kumari Challa on March 9, 2024 at 9:54am

To investigate the role of water in collagen formation, researchers decided to replace water with its heavier 'twin molecule' D₂O. 

However, in interaction with proteins, D₂O is less potent than H₂O. This is because bonds between D₂O molecules (so-called hydrogen-bonds) are stronger than those between H₂O molecules. This affects the interaction with proteins such as collagen.

Researchers were keen to study the effect this would have on collagen assembly. Together with a multi-disciplinary collaborative research network, they were able to establish that the use of heavy water results in ten times faster collagen formation, and ultimately a less homogeneous, softer and less stable collagen-fiber network.

The explanation is that the reduced interaction of the heavy water with the collagen protein makes it easier for the protein to 'shake off' the D₂O molecules and reorganize itself.

This boosts the formation of the collagen network, but also results in a sloppier, less optimal collagen network. Water thus acts as a mediator between collagen molecules, slowing down the assembly to guarantee the functional properties of living tissues.

This discovery offers fresh perspectives on how water influences the characteristics of collagen, allowing for precise adjustments in the mechanical properties of living tissues. It also creates novel avenues for creating collagen-based materials where macroscopic properties can be controlled and fine-tuned by subtle variations in the composition of the solvent, rather than making significant changes to the chemical structure of the molecular building blocks.

 Giulia Giubertoni et al, Elucidating the role of water in collagen self-assembly by isotopically modulating collagen hydration, Proceedings of the National Academy of Sciences (2024). DOI: 10.1073/pnas.2313162121

Part 2

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Comment by Dr. Krishna Kumari Challa on March 9, 2024 at 9:52am

Water guides the assembly of collagen, the building block of all humans

Water determines life: humans are three-quarters water. An international research team  has now discovered how water also determines the structure of the material that holds us together: collagen.

In a paper published in PNAS, the researchers elucidate the role of water in the molecular self-assembly of collagen. They show that by replacing water with its 'twin molecule' heavy water (D₂O), one can 'tune' the interaction between collagen molecules, and thus influence the process of collagen self-assembly. The findings will help to better understand the tissue failures resulting from heritable collagen-related diseases, such as brittle bone disease (osteogenesis imperfecta).

Collagen is to a large extent 'the stuff we're made of'—around a third of all protein in our body is collagen which ensures the mechanical integrity of all human connective tissue.

For instance, our skin and arteries stretch without tearing and our bones can resist high stress without breaking. Collagen is produced by our cells as single proteins that assemble into larger structures called fibrils. These fibrils further assemble into networks that form the scaffolds for our tissues.

Since collagen is formed in the aqueous environment of human cells, water plays a crucial role in its assembly. The interaction of water molecules with proteins results in collagen that is best suited for its function. But what exactly is behind this collagen-optimizing role of water? How does water do it? And will understanding this mechanism offer insights into conditions where something is wrong with collagen, such as osteogenesis imperfecta? These were the central questions of the research published in PNAS.

Part 1

Comment by Dr. Krishna Kumari Challa on March 9, 2024 at 8:47am

Many immune checkpoints are receptors on the surface of T cells that act to translate docking information from the outside of the cell to the signaling portion of the receptor inside the cell. Connecting the outside-of-the-cell portion of PD-1 with the inside portion is the transmembrane segment. Many immune receptors function in pairs called dimers, but to date, PD-1 has been thought to function alone, not in the dimer form.

Study results showed that PD-1 forms a dimer through interactions of its transmembrane segment. Researchers say this finding is in sharp contrast to other immune receptors, which typically form dimers through the segment of the receptor that is outside the cell.

Further immune cell testing in mice showed that encouraging PD-1 to form dimers, specifically in the transmembrane domain but not in its outer or inner regions, increased its ability to suppress T cell activity, while decreasing transmembrane dimerization lowered PD-1's ability to inhibit immune cell activity.

The study reveals that the PD-1 receptor functions optimally as dimers driven by interactions within the transmembrane domain on the surface of T cells, contrary to the dogma that PD-1 is a monomer.

These findings offer new insights into the molecular workings of the PD-1 immune cell protein that have proven pivotal to the development of the current generation of anticancer immunotherapies, and which are proving essential in the design and developing of the next generation of immunotherapies for autoimmune diseases.

Among the study's other findings was that a single change in the amino acid structure of the transmembrane segment can act to either enhance or diminish the inhibitory function of PD-1 in immune responses.

The team plans further investigations of PD-1 inhibitors and agonists to see if they can tailor what they say are more effective, "rationally designed" therapies for both cancer and autoimmune disorders.

Elliot Philips et al, Transmembrane Domain Driven PD-1 Dimers Mediate T Cell Inhibition, Science Immunology (2024). DOI: 10.1126/sciimmunol.ade6256. www.science.org/doi/10.1126/sciimmunol.ade6256

Part 2

Comment by Dr. Krishna Kumari Challa on March 9, 2024 at 8:42am

'Double life' of key immune protein reveals new strategies for treating cancer and autoimmune diseases

Insights into the workings of an immune cell surface receptor, called PD-1, reveal how treatments that restrict its action can potentially be strengthened to improve their anticancer effect, a new study shows. The same findings also support experimental treatment strategies for autoimmune diseases, in which the immune system attacks the body, because stimulating the action of PD-1, as opposed to restricting it, can potentially block an overactive immune response.

The study is published  in the journal Science Immunology.

The study results revolve around the body's immune system, which is primed to attack virally infected and cancerous cells while leaving normal cells alone. To spare normal cells from immune attack, the system uses "checkpoints," sensors on the surface of immune cells, including T cells, which turn them off or dampen activation when they receive the right signal. The immune system recognizes tumors as abnormal, but cancer cells can hijack checkpoints to turn off immune responses.

Among the most important checkpoints is a protein called programmed cell death receptor 1 (PD-1), which is shut down by a relatively new drug class called checkpoint inhibitors to make tumors "visible" again to immune attack. Such drugs are at least somewhat effective in a third of patients with a variety of cancers, say the study authors, but the field is urgently seeking ways to improve their performance and scope.

At the same time, PD-1 signaling is slowed in autoimmune diseases like rheumatoid arthritis, lupus, and type 1 diabetes, such that the action of unchecked immune cells creates inflammation that can damage tissues. Agonists, drugs that stimulate PD-1, are now showing promise in clinical trials. Part 1

Comment by Dr. Krishna Kumari Challa on March 8, 2024 at 9:30am

Bull's-Eye Cancer Treatment
A promising new class of cancer drugs is gaining momentum. Antibody-drug conjugates, or ADCs, target specific hormone receptors on cancer cells and deliver growth-stopping drugs directly to tumors. Fourteen ADCs have been approved for breast, bladder, ovarian, blood, and other cancers, some difficult to treat with traditional tactics. About 100 other ADCs are in the preclinical pipeline.

How these drugs are different: Traditional chemotherapeutic drugs kill cancer cells, but also kill healthy cells in the process, leading to severe side effects in the patient. Because of the debilitating side effects, most patients cannot endure a maximum dose of chemotherapy. ADC technology could also be used to deliver radiation therapy directly to tumor cells, or deliver drugs that activate the patient’s immune system to eradicate the cancer.

What the experts say: Enhertu, a new ADC treatment for breast cancer that uses special molecules to link the antibody to the drug that targets cancer cells, has been shown to stop cancer growth for four times longer than a compound without the linker molecules. “It was a landslide in terms of how much better it was,” says oncologist Sara M. Tolaney of the Dana-Farber Cancer Institute in Boston. “It's a really nice example of how ADC technology leads to dramatic differences in outcomes.”

deliver growth-stopping drugs directly to tumors.

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