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Immunology

Trinity researchers in potential MS treatment breakthrough – The Irish Times

An important discovery that could lead to more effective treatments for people living with multiple sclerosis (MS) and other autoimmune diseases such as psoriasis and rheumatoid arthritis, has been made by scientists from Trinity College Dublin.

The researchers have identified the role played by a specific immune molecule, known as IL-17, in priming cells that cause the disease. Rather than being directly involved in damaging the nervous system, IL-17 kick-starts the disease-causing immune response that mediates the damage, they believe

Their work, published in Immunity scientific journal, also suggested there is significant potential in drugs that target the IL-17 molecule, both for MS and psoriasis/rheumatoid arthritis.

MS is a debilitating disease that affects some 2.3 million people globally and over 9,000 people in Ireland. It is associated with infiltration of immune cells into the brain and spinal cord that cause damage to nerves, leading to neurological disabilities.

However, the cause and precise immunological basis to this autoimmune disease is still unclear.

Studies in a mouse model of MS, called experimental autoimmune encephalomyelitis (EAE), have shown that immune T cells, which secrete IL-17, cause damage to the myelin sheath that surrounds nerves in the central nervous system (CNS).

Early clinical trials with antibody-based drugs that block IL-17 are showing promise in the treatment of relapsing-remitting MS and have already been licensed for the treatment of psoriasis.

The Irish research outlines a new role for IL-17 in EAE and, potentially, in MS. The new research shows that, instead of playing a direct part in CNS pathology, a key role of IL-17 is to mobilise and activate an army of disease-causing immune cells in the lymph nodes that then migrate to the CNS to cause the nerve damage, said Prof Kingston Mills, professor of experimental immunology at TCD.

Crucially, our findings suggest that drugs that block IL-17 may not need to get across the blood-brain-barrier to be effective in treating MS, add Dr Aoife McGinley, another member of the research team.

So, as well as shedding new light on the importance of IL-17 as a drugs target in RR MS, our research highlights the huge potential of drugs that block IL-17 in the treatment of other autoimmune diseases.

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Trinity researchers in potential MS treatment breakthrough - The Irish Times

Cell Biology

‘Stench of death’ compound helps your body feast on its own rotting cells – Livescience.com

The scent wafts from busy roadsides, broken meat lockers and grisly crime scenes; it's the signature stink of rotting flesh. Despite its putrid aroma, the chemical compound may serve an important purpose in the living human body, new research suggests.

The compound, known as putrescine, flips a switch in certain immune cells that helps them gobble up dead tissues in the body, according to a new study published online Jan. 30 in the journal Cell Metabolism. That, in turn, could help the body stave off heart disease.

The authors studied both human and mouse cells, as well as live mice, to reveal how these corpse-crunching immune cells, called macrophages, concoct putrescine from the digested remains swirling around in their bellies.

If their putrescine supply runs short, macrophages struggle to consume additional cells, leaving corpses to pile up, break down and ooze harmful substances into the body. Dead tissues that leak toxic substances can trigger inflammation and contribute to diseases, including atherosclerosis, in which fatty plaques build up in the arteries and can burst, triggering heart attacks or stroke.

These leaky, "necrotic" cells are "really a hallmark of what distinguishes relatively benign athersclerotic lesions from those that cause disease," senior author Dr. Ira Tabas, a professor of pathology and cell biology at Columbia University Vagelos College of Physicians and Surgeons, told Live Science. Putrescine is just one member of the body's housekeeping team, but understanding its role in cellular cleanup could someday help doctors treat atherosclerosis and many other ailments, such as autoimmune diseases and cancer, Tabas added.

"The ability of macrophages to eat multiple dead cells each is very, very important to avoiding these problems," he said. An estimated billions, "if not trillions," of cells die in our bodies every day, making corpse cleanup an absolutely critical component of our everyday health. "The basis of this study was to figure out what happens after [a macrophage] eats its first dead cell," Tabas said.

Related: The science of death: 10 tales from the crypt and beyond

The process of clearing dead cells from the body is called efferocytosis, a term derived from the Latin phrase "to carry to the grave," according to a statement describing the new study. Macrophages excel at engulfing and digesting cellular corpses. Other cells help remove dying and diseased tissue when necessary, but macrophages make their living gobbling up cellular debris.

An individual macrophage often has to clear dozens of cells, if not more, to keep efferocytosis running smoothly, said Dr. Nicholas Leeper, a professor of vascular surgery at Stanford University School of Medicine who was not involved in the study. But no one knew how a single macrophage could take on such a workload. "It's always been a mystery," he said.

Unraveling this mystery could be critical to treating people with atherosclerosis, Leeper told Live Science. Evidence suggests that efferocytosis becomes defective in diseased arteries, leaving mounting plaques to become unstable and leaky, according to a 2017 review in the journal Circulation. Once a plaque ruptures, proteins sequestered inside the structure burst out and signal an army of platelets to assemble at the site. The platelets perceive the rupture as a wound that needs to clot, but in effect, the platelets themselves end up clogging the artery, leading to stroke, heart attack or sudden cardiac arrest, Tabas said.

"It's the platelet plug that does us in," Tabas noted. Restoring efferocytosis to healthy levels could theoretically prevent tissue death and plaque rupture, but scientists must first understand how fully functional macrophages consume so many cells.

Related: Top 10 leading causes of death

So Tabas and his colleagues arranged a dinner party for human macrophages, complete with a buffet of dead cells.

To grab hold of a meal, macrophages use a protein called Rac1 to construct wiry filaments that extend from their cell body. The filaments latch onto cellular corpses and reel them into the macrophage, where the deceased cells then get broken down into their component parts. While consuming this snack, the macrophage also digests some of its own Rac1 proteins. The remaining Rac1 must be revitalized before the macrophage can take on another meal, the team found but first, the cell requires something to stoke its appetite.

Turns out, the first meal devoured by a macrophage helps spur the cell to eat more and more. Proteins in the dead cells get broken down into individual amino acids, including one called arginine. An enzyme takes up the arginine, transforms it into a molecule called ornithine and then passes that product off to a second enzyme. Ornithine gets turned into putrescine, which, in turn, sets off a chain reaction that drives any remaining Rac1 to flip into overdrive and build filaments more efficiently than before. The ramped-up Rac1 enables the macrophage to go after more food.

The team tried blocking the production of putrescine in both human and mouse macrophages and found that the cells could no longer consume multiple meals in one sitting. The researchers wondered how low putrescine levels might contribute to atherosclerosis. In a mouse model of the disease, the team found that animals with advanced symptoms lacked a key component in the putrescine production line: the enzyme that transforms arginine into ornithine, known as arginase-1.

In an attempt to treat the animals, the team added low doses of putrescine directly to the animals' drinking water. (When dissolved and delivered in low doses, the super-stinky compound no longer gives off an offensive odor.) After the treatment, the mouse macrophages appeared to consume cells more efficiently, and the animals' plaques began to shrink.

To connect the dots from mice to humans, the team also sampled macrophages from people with early and advanced atherosclerosis and noted a similar pattern: Macrophages from those with the more advanced disease were equipped with less arginase-1. Given that the formation of putrescine works very similarly in mice and humans, theoretically, treatments that manipulate that formation could treat atherosclerosis.

"I wouldn't push putrescine as a treatment," specifically, but other therapies could be developed to boost efferocytosis in other ways, Tabas said. At high doses, putrescine can be toxic to people and animals and cause gastrointestinal distress, he said. The main point is that efferocytosis, when unfolding properly, helps maintain human health and prevent disease, Tabas said.

It may be possible that "one could drive the conversion of cells to a situation that would induce more efferocytosis and repair of damaged arteries," Dr. Ira Goldberg, director of the Division of Endocrinology, Diabetes and Metabolism at NYU Langone Health, told Live Science in an email. "More important, this process is likely to be similar to that which occurs in other situations that [involve] cell death," said Goldberg, who was not involved in the new study.

For example, research suggests that efferocytosis goes awry in autoimmune diseases like lupus, in which dead cells accumulate in the lymph nodes and disrupt immune cell function. Cancer cells avoid being eaten by macrophages by sending out so-called "don't eat me" signals, so boosting efferocytosis at tumor sites could serve as a targeted form of cancer treatment. For now, though, insight into efferocytosis could mark a "major advance" in the treatment of heart disease, Leeper said.

"The importance of a pathway linked to cardiovascular disease can't be overstated Basically all adults in the Western world have some sort of atherosclerosis," Leeper said. Plagues can begin developing as early as adolescence, he said. Leeper himself recently developed a medication that helps macrophages recognize and eat dying cells in mice with atherosclerosis. As scientists continue to uncover the various chemical reactions involved in efferocytosis, drug developers can learn to promote the process through various therapies.

Leeper said the line of research could someday result in treatments to address "several of the top killers in the world."

Originally published on Live Science.

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'Stench of death' compound helps your body feast on its own rotting cells - Livescience.com

Cell Biology

As bioengineering progresses, regulation will need to follow – Highlander Newspaper

Courtesy of YouTube

The first annual conference of Please Try This at Home took place in September 2019. At the cross section of biotechnology, body autonomy and anarchy, the conference represents an inclusive group of scientists concerned with using and discussing biotechnology in the hopes of moving the field in a more progressive direction. That being said, it is indeed a solid step in the right direction, especially when one takes into consideration how misunderstood the bioengineering field has become.

To get a sense of the state of bioengineering, a biohacker by the name of Josiah Zayner livestreamed an attempt to splice his DNA to give himself bigger muscles. If it was inserted in the wrong place in his body, or in the wrong place for the code, his DNA could end up producing weakened or ineffective proteins that could affect his body functionality. While that attempt was misguided and Zayner later regretted the stunt, the implication was that this technology should be safe and easy, which is a dangerous and untrue belief to hold. As biotechnology continues to improve, more research and regulation will be needed to ensure the safety of its use.

Ensuring said safety requires a basic understanding of cellular biology, and at its core is the central dogma of molecular biology. Simply put, most genetic material is encoded in DNA, DNA transcribes to RNA and RNA translates to proteins and those proteins are responsible for most functions in the body. Generally, bioengineering works by taking a segment of foreign DNA and inserting it into the rest of the genetic code, resulting in a production of proteins that will carry out a function specific to that DNA code. The described process is extremely complex and delicate, but despite that, genetic engineering has been used to treat Parkinsons disease and sickle cell disease among others.

That said, genetic engineering has a promising future outside of simple disease treatment. To reaffirm the purpose of Please Try This at Home, genetic engineering could be used for a different form of hormone therapy for transgender individuals. In a mostly speculative procedure, a geneticist could activate the necessary genes responsible for production of a specific hormone. That being said, it is important to keep in mind that this is a hypothetical experiment, and could result in potentially greater health problems later in life. These potential problems necessitate the need for greater experimentation and regulation in order to work out the difficulties.

Experiments in gene editing on a larger scale have already been proposed to fight Lyme disease. Normally, the disease spreads when a tick bites a mouse, followed by that tick biting a human. On Nantucket Island and Marthas Vineyard, where Lyme disease is particularly virulent, a project called Mice Against Ticks is under consideration, in which mice would be genetically modified to be able to resist and prevent the spread of Lyme disease. Kevin Esvelt, the scientist spearheading this operation is also acutely aware of the potential ecological ramifications of this project, cautiously choosing an isolated island with a low human population and low chances of dispersal if the project goes awry.

Esvelts caution in choosing an experimental site calls to mind the dangers of genetic engineering: the long term effects are not yet fully known, and it is understandable to be afraid of something that is not entirely explored. The chances of cascading ecological effects from genetic engineering is as present as the possibility for abuse of genetic engineering via eugenics. Simultaneously, those possibilities are also matched by the potential to eradicate Lyme disease, malaria or leukemia.

The best way to ensure safer practices and better opportunities for the future of genetic engineering is to regulate its practice. Clear distinctions need to be made between biohackers, like Zayner and practical, controlled applications like Mice Against Ticks. Genetic engineering could have world changing effects; it just needs to be regulated and perfected.

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As bioengineering progresses, regulation will need to follow - Highlander Newspaper

Cell Biology

UH professor examines life cycle of drug-resistant persister cells in recurrent infections – News-Medical.net

A University of Houston engineering professor is examining the life cycle of stubborn, drug-resistant persister cells in recurrent infections to find a way to destroy them. Persister cells are non-growing cell subpopulations observed in many pathogenic bacteria and they certainly live up to their name - they persist, and are not phased in the least by current medications. Scientists believe they cause the recurrence of chronic health issues like airway infections in cystic fibrosis patients, urinary tract infections and tuberculosis.

"If we know how persister cells are formed, we can target their formation mechanisms to eliminate these dangerous cell types," said Mehmet Orman, assistant professor of chemical and biomolecular engineering, who is using a $1.9 million grant from the National Institute of Allergy and Infectious Diseases to explore persister cells.

Orman believes that self-digestion, or autophagy, stimulates persister formation. In self-digestion, cells recycle essential energy molecules by eating their own protein, lipids or other bits to stay alive or temporarily survive under starvation conditions. Self-digestion is triggered by extracellular stress conditions, such as nutrient depletion, hypoxia and overpopulation.

Orman will map the self-digestion-related mechanisms in E. coli to understand how self-digestion is linked to persister cell formation. Then, he will therapeutically explore these mechanisms to identify chemical compounds that can eliminate persister cells.

Mapping of this comprehensive bacterial pathway from its initial exogenous trigger, through its signal transduction, to the source of antibiotic tolerance, will enable us to develop affective anti-persister therapeutics."

Mehmet Orman, assistant professor of chemical and biomolecular engineering,University of Houston

Self-digestion inflicts damage on the cells and can make the cells dormant, putting them in a sleeping mode, and these dormant cells are not effected by antibiotics. The bacterium is less fit to produce protein and resume growth upon exposure to fresh nutrients, providing temporary protection against antibiotics until the self-inflicted damage is repaired.

From an evolutionary perspective, self-digestion is an important survival mechanism. This complex process, which is orchestrated by many regulatory proteins and enzymes, has been well documented in mammalian cells, but largely ignored in bacteria. "By integrating our expertise in bacterial cell biology with advanced current technologies, we aim to decipher the key components of this pathway to provide a clear and much-needed picture of bacterial self-digestion mechanisms," said Orman.

Orman, himself, is persistent. Previously he developed methods to directly measure the metabolism of persister cells. He has also discovered that persisters are mostly derived from stationary-phase cells with high metabolic activities maintained by self-digestion.

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UH professor examines life cycle of drug-resistant persister cells in recurrent infections - News-Medical.net

Cell Biology

Bernard Robaire honoured by Society for the Study of Reproduction – McGill Reporter

The Society For The Study Of Reproduction (SSR) unveiled its 2020 award winners today, honouring seven individualswho have made outstanding contributions to the scientific discipline ofreproductive biology. BernardRobaire, cross appointed in both the Departments of Pharmacology & Therapeutics; and Obstetrics & Gynaecology, was named recipient of the SSR Jansen Distinguished Service Award. The Jansen Award recognizes an individual for their unselfish service and leadership in advancing the discipline of reproductive biology.

Robaires research interests focus on aging of the male reproductive system, male-mediated reproductive toxicology, mechanisms of androgen actions, and the structure, function, and regulation of the epididymis.

The scientific research conducted by theseseven biology scientists, physicians and professors have significantly advanced thescience of reproduction, fertility and development, said Saima Hedrick, executive director, SSR, Their original researchon a broad range of topics in the field of reproductive biologyis helping lead us toward new discoveries, more mentorship opportunities and greater professionalism in the discipline. Their work has improved the lives of millions of humans and animals.

SSRsupports the scientific study of reproductive processes in animals and humans. Pioneering scientific contributions from SSR members have been made in areas such as stem cell biology; transgenesis; treatment of infertility; contraception; livestock production; pregnancy health; treatment of reproductive system cancers; and identification of environmental contaminants.

The annual award program recognizes significant achievements and contributions to advancing the science of reproductive biology in research, academic scholarship, professional leadership, mentoring and service. Award winners will be recognized at SSRs 2020 annual conference in Ottawa, Canada from July 912.

For a description of each award winners achievements and contributions click here.

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Bernard Robaire honoured by Society for the Study of Reproduction - McGill Reporter

Cell Biology

If cancer were easy, every cell would do it – Newswise

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Newswise A new Scientific Reports paper puts an evolutionary twist on a classic question. Instead of asking why we get cancer, Leonardo Oa of Osnabrck University and Michael Lachmann of the Santa Fe Institute use signaling theory to explore how our bodies have evolved to keep us from getting more cancer.

It isnt obvious why, when any cancer arises, it doesnt very quickly learn to take advantage of the bodys own signaling mechanisms for quick growth. After all, unlike an infection, cancers can easily use the bodys own chemical language. Any signal that the body uses, an infection has to evolve to make, says Lachmann. If a thief wants to unlock your house, they have to figure out how to pick the lock on the door. But cancer cells have the keys to your house. How do you protect against that? How do you protect against an intruder who knows everything you know, and has all the tools and keys you have? Their answer: You make the keys very costly to use.

Oa and Lachmanns evolutionary model reveals two factors in our cellular architecture that thwart cancer: the expense of manufacturing growth factors (keys) and the range of benefits delivered to cells nearby. Individual cancer cells are kept in check when theres a high energetic cost for creating growth factors that signal cell growth. To understand the evolutionary dynamics in the model, the authors emphasize the importance of thinking about the competition between a mutant cancerous cell and surrounding cells. When a mutant cell arises and puts out a signal for growth, that signal also provides resources to adjacent, non-mutated cells. Thus, when the benefits are distributed to a radius around the signaling cell, the mutant cells have a hard time out-competing their neighbors and cant get established. The cancer loses the ability to give the signal.

The work represents a novel application of evolutionary biology toward a big-picture understanding of cancer. Oa and Lachmann draw from the late biologist Amotz Zahavis handicap principle, which explains how evolutionary systems are stabilized against cheaters when dishonest signals are costlier to produce than the benefit they provide. The male peacocks elaborate tail is the classic example of a costly signal an unhealthy bird would not have the energetic resources to grow an elaborate tail, and thus could not fake a signal of their evolutionary fitness. By the handicap principle, a cancer cell would be analogous to the unhealthy peacock that cant afford to signal for attention.

So how do some cancer cells overcome these evolutionary constraints? The authors point out that their model only addresses the scenario of an individual cancer trying to invade a healthy population. Once cancer has overcome the odds of extinction and reached a certain critical size, other dynamics prevail.

Many mechanisms seem to have evolved to prevent cancer from immune system control, cell death, limits on cell proliferation, to tissue architecture, the authors write. Our model only studies the reduced chance for invasion.

Cancer is incredibly complex, Lachmann says, and our model is relatively simple. Still, we believe its an important step toward understanding cancer and cancer prevention in evolutionary terms.

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If cancer were easy, every cell would do it - Newswise

Cell Biology

Chemists Discovered the Structure of a Key Influenza Protein Breakthrough Could Lead to Flu Treatment – SciTechDaily

This digitally-colorized transmission electron microscopic image depicts the ultrastructural details of an influenza virus particle. Credit: CDC, Frederick Murphy

A team of MIT chemists has discovered the structure of a key influenza protein, a finding that could help researchers design drugs that block the protein and prevent the virus from spreading.

The protein, known as BM2, is a proton channel that controls acidity within the virus, helping it to release its genetic material inside infected cells.

If you can block this proton channel, you have a way to inhibit influenza infection, says Mei Hong, an MIT professor of chemistry and senior author of the study. Having the atomic-resolution structure for this protein is exactly what medicinal chemists and pharmaceutical scientists need to start designing small molecules that can block it.

MIT graduate student Venkata Mandala is the lead author of the paper, which was published on February 3, 2020, in Nature Structural and Molecular Biology. Other authors include graduate students Alexander Loftis and Alexander Shcherbakov and associate professor of chemistry Bradley Pentelute.

There are three classes of influenza virus A, B, and C and each of them produces a different version of the M2 protein. M2 is an ion channel that carries protons through the viruss outer membrane, known as the lipid envelope. These protons usually flow into the virus, making the interior more acidic. This acidity helps the virus to merge its lipid envelope with the membrane of a cellular compartment called an endosome, allowing it to release its DNA into the infected cell.

Until now, most structural studies of the M2 protein have focused on the version of M2 found in influenza A, which is usually the most common form, especially earlier in the flu season. In this study, the researchers focused on the version of M2 found in influenza B viruses, which usually dominate in March and April. However, in contrast to previous patterns of seasonal flu infections, this winter, influenza B has been unusually dominant, accounting for 67 percent of all flu cases reported to the U.S. Centers for Disease Control since last September.

The A and B versions of M2 vary significantly in their amino acid sequences, so Hong and her colleagues set out to study what structural differences these proteins might have, and how those differences influence their functions. One key difference is that the BM2 channel can allow protons to flow in either direction, whereas the AM2 channel only allows protons to flow into the viral envelope.

To investigate the structure of BM2, the researchers embedded it into a lipid bilayer, similar to a cell membrane, and then used nuclear magnetic resonance (NMR) spectroscopy to analyze the structure with atomic-scale resolution. Very few ion channels have been studied at such high resolution because of the difficulty of studying proteins embedded within membranes. However, Hong has previously developed several NMR techniques that allow her to obtain accurate structural information from membrane-embedded proteins, including their orientation and the distances between atoms of the protein.

The M2 channel is made of four helices that run parallel to each other through the membrane, and Hong found that the alignment of these helices changes slightly depending on the pH of the environment outside the viral envelope. When the pH is high, the helices are tilted by about 14 degrees, and the channel is closed. When the pH goes down, the helices increase their tilt to about 20 degrees, opening up like a pair of scissors. This scissoring motion creates more space between the helices and allows more water to get into the channel.

Previous studies have found that as water flows into the M2 channel, the amino acid histidine grabs protons from the water in the top half of the channel and passes them to water molecules in the lower half of the channel, which then deliver the excess protons into the virion.

Unlike the AM2 channel, the BM2 channel has an extra histidine at the virion-facing end of the channel, which the MIT team believes to explain why protons can flow in either direction through the channel. More study is needed to determine what kind of advantage this may provide for influenza B viruses, the researchers say.

Now that chemists know the structure of both the open and closed states of the BM2 channel at atomic resolution, they can try to come up with ways to block it. There is precedent for this type of drug development: Amantadine and rimantadine, both used to treat influenza A, work by wedging themselves into the AM2 channel pore and cutting off the flow of protons. However, these drugs do not affect the BM2 channel.

Hongs research group is now investigating another one of BM2s functions, which is generating curvature in lipid membranes in order to allow progeny viruses to be released from cells. Preliminary studies suggest that a portion of the protein that sticks out from the membrane forms a structure called a beta sheet that plays a role in inducing the membrane to curve inward.

Reference: Atomic structures of closed and open influenza B M2 proton channel reveal the conduction mechanism by Venkata S. Mandala, Alexander R. Loftis, Alexander A. Shcherbakov, Bradley L. Pentelute and Mei Hong, 3 February 2020, Nature Structural and Molecular Biology.DOI: 10.1038/s41594-019-0371-2

The research was funded by the National Institutes of Health.

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Chemists Discovered the Structure of a Key Influenza Protein Breakthrough Could Lead to Flu Treatment - SciTechDaily

Cell Biology

Unveiling the structure of the influenza virus – News-Medical.net

The flu season is coming, and the frigid temperatures make it worse. The influenza B virus is the causative agent of the common flu, but over the past years, it has become more potent in causing disease. Now, a team of MIT scientists has found and unveiled the structure of the virus, particularly the key influenza protein, in the hopes to develop new drugs to combat influenza.

The Centers for Disease Control and Prevention (CDC) reports that the overall hospitalizations related to influenza this season increased to 29.7 percent per 100,000, which is similar to what happened over the past seasons. Further, a total of 68 children had died due to influenza this season, with 14 deaths occurring during the 2019-2020 season. Overall, pneumonia and influenza mortality have been low while CDC estimates that for this season, there had been 19 million flu illnesses, 180,000 hospitalizations, and 10,000 deaths from flu.

This digitally-colorized transmission electron microscopic image depicts the ultrastructural details of an influenza virus particle. Image: CDC, Frederick Murphy

Known as BM2, the protein is a proton channel that regulates the acidity in the virus to aid in releasing its genetic material in infected cells.

The researchers believe that blocking the proton channel can help combat infection and block the effects of the virus. Knowing the structure of the protein, particularly its atomic-resolution structure, can help doctors, medicinal chemists, and pharmaceutical scientists to develop compounds and drugs to block its function.

Published in the journal Nature Structural and Molecular Biology, the study sheds light on the structure of the influenza B protein to help in the development of compounds to block its effect on the infected cell.

The three types of influenza virus influenza A, B, and C, produce a different kind of the M2 protein, which is an ion channel carrying protons through the outer membrane of the virus, known as the lipid envelope. The proteins go inside the virus and will create the internal environment more acidic. If the interior of the virus becomes acidic, it helps the virus release its DNA into the infected cell.

The M2 proteins are very interesting focuses for scientists, in the hopes of finding a cure for flu or treatment modalities to prevent further deaths. There had been many studies about the structure of the M2 protein, but most focused on the type A of the virus.

In the study, however, the team focused on the influenza B M2 protein, which usually dominates the March to April flu season, which accounts for about 67 percent of all flu cases reported by the CDC since September 2019.

The researchers aimed to study what structural differences in the proteins of A and B influenza viruses have. They found that one key difference between the two is that the BM2 channel allows the protons to flow in either direction, while the AM2 only allows the protons to flow into the envelope of the virus.

To land to their findings, the researchers studied BM2s structure by embedding it into a lipid bilayer, which is akin to a cell membrane. They used nuclear magnetic resonance (NMR) spectroscopy to investigate the structure with atomic-scale resolution.

They discovered that the M2 channel is made of four helices, wherein the alignment chances depending on how acidic or alkaline the environment outside the viral envelope is. If the pH is high, the helices begin to tilt by approximately 14 degrees, and if it decreases, the tilt increases to about 20 degrees. With the motion of the helices, mimicking a pair of scissors, it allows water to enter the channel.

They found that the BM2, unlike the AM2, has an extra histidine at the virion-facing end of the channel. The scientists believe that this explains why the protons can flow in both directions through the channel.

These results indicate that asymmetric proton conduction requires a backbone hinge motion, whereas bidirectional conduction is achieved by a symmetric scissor motion. The proton-selective histidine and gating tryptophan in the open BM2 reorient on the microsecond timescale, similar to AM2, indicating that side-chain dynamics are the essential driver of proton shuttling, the researchers concluded.

Funded by the National Institutes of Health, the study has revealed the structure of BM2 in its open and closed state, paving the way for finding a compound to finally block it.

Source:

Journal reference:

Mandala, V.S., Loftis, A.R., Shcherbakov, A.A. et al. Atomic structures of closed and open influenza B M2 proton channel reveal the conduction mechanism. Nat Struct Mol Biol (2020). https://doi.org/10.1038/s41594-019-0371-2

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Unveiling the structure of the influenza virus - News-Medical.net

Cell Biology

Study uncovers more pieces of the autism puzzle – News-Medical.net

A major international study from the Autism Sequencing Consortium with participation of researchers from the Danish iPSYCH psychiatry project, has recently mapped 102 new autism genes. The new findings provide a new understanding of the biology behind autism, which could in the future be utilised to provide an earlier and more precise diagnosis and better treatment options.

Ever since the first autism diagnosis was made in 1938, researchers have been trying to clarify where the disorder originates. There have been many suggestions - along with many disagreements. But one thing has been clear for a while: Genetics play a major role with a heritability of up to eighty per cent.

The largest study so far of rare genetic variants has now identified 102 new so-called risk genes for autism. The results have just been published in the international journal Cell.

"Broadly speaking, there are two types of genetic variants which play a role in autism. There are uncommon genetic variants that few people have, although these may have a big effect, and then there are frequent variants which we all carry some of, and which each contribute in a very small way to the risk," says Associate Professor Jakob Grove from Aarhus University, who is one of the driving forces behind the Danish contribution and a member of the iPSYCH research project.

In the study, the researchers mapped the DNA building blocks in the genes of 35,584 individuals, of whom 11,986 had autism. The researchers then determined how many times each gene is affected by variants with "protein disrupting consequences", as the researcher puts it. "If a gene is more often hit by these mutations among people with autism than among people without it, this indicates that the gene is involved in the processes that lead to autism, and is thus designated as a risk gene," explains Jakob Grove. The majority of the identified gene-destroying mutations are new mutations that are only found in the person with autism and not in their parents.

The genetic findings provide an entirely new insight into the biological processes that are involved in the development of autism. Some of the genes identified alter early development broadly, while others appear to be more specific to autism. Most of the genes help determine how neurones communicate with each other or they regulate the expression of other genes.

This new knowledge could provide a better basis for understanding autism. For example, it may help us to make a diagnosis earlier, which we already know makes life easier for people with autism and their relatives. It's also conceivable it could contribute to the development of personalized medicine for those who may want this."

Jakob Grove, Associate Professor, Aarhus University

In other words, the results of the study may turn out to be crucial for the treatment of psychiatric disorders in the future.

However, he also emphasizes that the new findings can only explain a few cases of autism as these genetic variants are only present in few individuals. "For this reason, iPSYCH continues to study both rare and more frequent genetic variants," he says.

The research has been carried out in collaboration with the Autism Sequencing Consortium (ASC) and the project is anchored at Mount Sinai in New York. In addition to researchers from Aarhus University, the Broad Institute in Boston, UCSF in San Francisco and Carnegie Mellon University in Pittsburgh have also participated along with researchers from altogether more than 50 sites.

Source:

Journal reference:

Satterstrom, F.K., et al. (2020) Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism. Cell. doi.org/10.1016/j.cell.2019.12.036.

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Study uncovers more pieces of the autism puzzle - News-Medical.net

Human Behavior

What science teaches us about free will – Science 101

In ancient times, debates around free will centered on the concept of destiny. Stories like Oedipus Rex asked whether humans could escape the fate the gods had bestowed upon them. But as science has taught us more about our brains, bodies, and environment, thinkers have shifted from theological questions to scientific ones like: If our actions are determined by a combination of genes and upbringing, does that leave any room for free will? Does someone have free will if their brain functioning is compromised? And does quantum physics, with its nondeterministic forms of causation, provide an explanation for how conscious choice could occur? Neuroscientists, physicists, and even legal experts are now in on the debate, inspiring the rest of us to question and refine our own definitions of free will.

A conversation about free will broke out within the field of neuroscience after neurologist Benjamin Libet conducted a famous experiment addressing the issue in the 1980s. The studys participants were instructed to press a button with their fingers whenever they wanted and to note exactly what time they saw on a stopwatch in front of them when they made the decision to press it. Libet found that the neural activity initiating this action, as indicated by brain scanners, started about half a second before people consciously made the choice.

This finding brought up the question of whether conscious thought plays a role in our behavior, or whether were essentially biological automatons acting according to predetermined patterns of neural firing. Perhaps we think were choosing an action before we perform it, but that choice is simply an illusion that emerges once that actions already being performed.

The idea that peoples behavior is determined by their brain activity, which is in turn determined by other physical processes outside our control, is known as determinism. Determinists argue that if you could go all the way back to the Big Bang with an extremely advanced computer that could track the states of every particle and follow the effects of all these states, you could predict everything thats happening today, including everything that happens in our minds.

One counterargument to this theory is that, if something could actually determine every position of every particle at the time of the Big Bang, whatever is capable of doing that would be so powerful, it may be able to interfere with that system, says mathematician Jonathan Farley. And if that powerful entity were human consciousness, that might mean we do have free will.

The merits of determinism have also been called into question by some interpretations of quantum physics, which has shown that, down at the level of subatomic particles, things look more like waves of possibilities than definite events. For example, the famous double-slit experiment showed that electrons can exist in multiple places at once. Its results suggested that human observation is what collapses quantum particles into one state: The interference pattern of electrons on a wall after they were fired through a slit changed based on whether they were measured. This seems to suggest that there may be something special about the human brain that allows it to exert control over the physical universe, says Farley.

But because its unclear whether the outcomes of quantum events are the products of conscious choice or simply random, quantum physics doesnt necessarily prove that free will exists. In fact, many scientists concerned with free will actually consider questions about determinism to be irrelevant.

Those who believe free will and determinism can coexist are known as compatibilists, and studies show that most people actually have a compatibilist view of free will. That is, people appear to be less concerned with the behavior of small particles and more concerned with the constraints placed on people as a whole, such as whether someone else has forced them to do anything or whether some physical or psychological limitation is affecting their behavior.

This is reflected in the legal system, which tends to consider someones free will constrained only if they have a relevant brain injury, disease, or disability, says James Giordano, professor of neurology and biochemistry and chief of neuroethics studies at Georgetown University Medical Center. Legal debates tend not to touch on physics because that would be a moot point: Everyones actions stem from an amalgamation of physical particles, so if physical causation precluded moral responsibility, it would for everyone.

The way Giordano puts it is that free will is less important than free wont. It matters less, for example, whether the brain activity leading someone to push a button starts before they make the decision, and more whether they can decide against pushing that button if there is a disadvantage to doing so. In a legal context, this would involve someones ability to resist the temptation of committing a crime. This is likely related to the connectivity between brain areas involved in things like memory, emotion, and rational thought, says Giordano.

Many physical traits have actually been shown to correlate with someones likelihood of committing a crime, such as their genes, deficits in brain areas that inhibit impulsive behavior, IQ, health conditions, and even heart rate (the theory being that people with low resting heart rates are more prone to risk-taking because its harder for them to feel stimulated), says criminologist Margit Averdijk.

Some of these factors actually are taken into consideration in court. Typically, evidence that someones capacity to make ethical decisions is compromised wont absolve them of guilt, but it may make them more likely to be put in a psychiatric institution rather than prison, says Giordano. A 2016 analysis found that brain scans had been used as mitigating evidence in 5% of appellate murder cases and 25% of death penalty trials.

Social scientists have also posed questions about free will, often in the broader context of asking how much society is influencing human behavior. For example, some argue that someones culture and even the physical environment they grow up in will have a major effect on their lives.

A slightly different way to approach the question of how much free will society affords people is to ask how much external factors constrain our decisions. In that vein, its actually rather difficult to sway peoples choices, says MD-technologist and behavioral economics consultant Drea Burbank. Changes to things like prices and stores that attempt to get people to buy fewer cigarettes, for example, only account for around 10%-20% of variance in human behavior.

So, in short, theres no proven answer to the question of whether free will in any metaphysical sense exists. Clearer working definitions of free will have been developed for more pragmatic purposes like determining legal sentences and getting people to make healthier decisions. Under these definitions, people do appear to have free will, but the extent of the freedom varies from person to person.

While more abstract definitions of free will are interesting to ponder, its difficult to make them the lens through which we make moral judgments or attempt to understand human behavior. Still, questions about quantum states and physical determinism, like those about ethereal souls and deities, are fascinating enough that scientists, philosophers, and artists alike will unlikely stop thinking about them any time soon.

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What science teaches us about free will - Science 101