Comment

Comment by Dr. Krishna Kumari Challa on Friday

New AI tool predicts protein-protein interaction mutations in hundreds of diseases

Scientists have designed a publicly-available software and web database to break down barriers to identifying key protein-protein interactions to treat with medication.

The computational tool is called PIONEER (Protein-protein InteractiOn iNtErfacE pRediction). Researchers demonstrated PIONEER's utility by identifying potential drug targets for dozens of cancers and other complex diseases in a recently published Nature Biotechnology article.

Genomic research is key in drug discovery, but it is not always enough on its own. When it comes to making medications based on genomic data, the average time between discovering a disease-causing gene and entering clinical trials is 10–15 years.

In theory, making new medicines based on genetic data is straightforward: mutated genes make mutated proteins. Scientists try to create molecules that stop these proteins from disrupting critical biological processes by blocking them from interacting with healthy proteins, but in reality, that is much easier said than done.

One protein in our body can interact with hundreds of other proteins in many different ways. Those proteins can then interact with hundreds more, forming a complex network of protein-protein interactions called the interactome.

This becomes even more complicated when disease-causing DNA mutations are introduced into the mix. Some genes can be mutated in many ways to cause the same disease, meaning one condition can be associated with many interactomes arising from just one differently mutated protein.

Drug developers are left with tens of thousands of potential disease-causing interactions to pick from—and that's only after they generate the list based on the affected protein's physical structures.

Some scientists,  especially the drug developers, are taking the help of  artificial intelligence (AI) tools  to  identify the most promising protein-protein interactions more easily and speedily.

Their resulting database allows researchers to navigate the interactome for more than 10,500 diseases, from alopecia to von Willebrand Disease.

Researchers who identified a disease-associated mutation can input it into PIONEER to receive a ranked list of protein-protein interactions that contribute to the disease and can potentially be treated with a drug. Scientists can search for a disease by name to receive a list of potential disease-causing protein interactions that they can then go on to research. PIONEER is designed to help biomedical researchers who specialize in almost any disease across categories including autoimmune, cancer, cardiovascular, metabolic, neurological and pulmonary.

Part 1

Comment by Dr. Krishna Kumari Challa on Thursday

Throat Cancer Is Becoming an Epidemic, And Oral Sex May Be Why

Over the past two decades, there has been a rapid increase in throat cancer in the west, to the extent that some have called it an epidemic. This has been due to a large rise in a specific type of throat cancer called oropharyngeal cancer (the area of the tonsils and back of the throat).

The main cause of this cancer is the human papillomavirus (HPV), which are also the main cause of cancer of the cervix. Oropharyngeal cancer has now become more common than cervical cancer in the US and the UK.

HPV is sexually transmitted. For oropharyngeal cancer, the main risk factor is the number of lifetime sexual partners, especially oral sex. Those with six or more lifetime oral-sex partners are 8.5 times more likely to develop oropharyngeal cancer than those who do not practice oral sex.

https://theconversation.com/oral-sex-is-now-the-leading-risk-factor...

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Comment by Dr. Krishna Kumari Challa on Thursday

The second is of a college student struggling with insomnia, who begins to feel a sense of hopelessness, loneliness and despair as the sleepless nights stack up.

Both scenarios can ultimately prove fatal. Suicide and self-harm are very common at nighttime. In fact, some research reports a three-fold higher risk of suicide between midnight and 6:00 am compared to any other time of day.

A study in 2020 concluded that nocturnal wakefulness is a suicide risk factor, "possibly through misalignment of circadian rhythms."

Illicit or dangerous substances are also taken more by people at night.

Some of these behaviors could be explained by sleep debt or the cover that darkness offers, but there are probably nighttime neurological changes at play, too.

https://www.frontiersin.org/journals/network-physiology/articles/10...

Footnotes:

1. https://www.frontiersin.org/journals/network-physiology/articles/10...

Part 2

Comment by Dr. Krishna Kumari Challa on Thursday

The Human Mind Isn't Meant to Be Awake After Midnight, Scientists Warn

In the middle of the night, the world can sometimes feel like a dark place. Under the cover of darkness, negative thoughts have a way of drifting through your mind, and as you lie awake, staring at the ceiling, you might start craving guilty pleasures

Plenty of evidence suggests the human mind functions differently if it is awake at nighttime. Past midnight, negative emotions tend to draw our attention more than positive ones, dangerous ideas grow in appeal and inhibitions fall away. Some researchers think the human circadian rhythm is heavily involved in these critical changes in function, as they outline in a 2022 paper(1) summarizing the evidence of how brain systems function differently after dark.

Their hypothesis, called 'Mind After Midnight', suggests the human body and the human mind follow a natural 24-hour cycle of activity that influences our emotions and behavior.

In short, at certain hours, our species is inclined to feel and act in certain ways. In the daytime, for instance, molecular levels and brain activity are tuned to wakefulness. But at night, our usual behavior is to sleep.

From an evolutionary standpoint this, of course, makes sense. Humans are much more effective at hunting and gathering in the daylight, and while nighttime is great for rest, humans were once at greater risk of becoming the hunted.

According to the researchers, to cope with this increased risk our attention to negative stimuli is unusually heightened at night. Where it might once have helped us jump at invisible threats, this hyper-focus on the negative can then feed into an altered reward/motivation system, making a person particularly prone to risky behaviours.

Add sleep loss to the equation, and this state of consciousness only becomes more problematic.

The authors of the hypothesis use two examples to illustrate their point. The first example is of a heroin user who successfully manages their cravings in the day but succumbs to their desires at night.

Part 1

Comment by Dr. Krishna Kumari Challa on Thursday

The team also experimented with different delays, connecting brains to the liver-assisted system at intervals of 30 minutes, 50 minutes, 60 minutes, and 240 minutes. The longest interval that showed the most promise was 50 minutes after being deprived of blood: the brain restarted electrical activity, and was maintained in that state for six hours until the experiment was shut off.
Remarkably, in brains that had been starved of oxygen for 60 minutes, activity only returned for three hours before fading, suggesting a critical interval in which resuscitation can be successful with the addition of a functioning liver.

These results, the researchers say, suggest the liver plays an important role in the development of brain injury following cardiac arrest. The findings suggest new avenues for research into brain injury, and may, hopefully, improve survival rates and recovery outcomes for human patients in the future.

https://www.embopress.org/doi/full/10.1038/s44321-024-00140-z

Part 3

Comment by Dr. Krishna Kumari Challa on Thursday

When the pigs were euthanized and their brains examined, the control group obviously had the least brain damage; but the group that had not been subjected to liver ischemia showed significantly less brain damage than the group that had.

The next stage of the research involved attempting to incorporate an undamaged liver into the life support system reviving a brain that had been removed from a euthanized pig entirely. This is unlikely to be a scenario used to treat humans, but it helps scientists understand the windows in which resuscitation may be viable.

The basic life support system involved an artificial heart and lungs to help pump fluid through the brain. For one group, a pig's liver was integrated into the system, known as liver-assisted brain normothermic machine perfusion.

First, brains were connected to the life support systems 10 minutes after commencement of the life support procedure. For the system without a liver, electrical activity in the brain emerged within half an hour before declining over time.
Part 2

Comment by Dr. Krishna Kumari Challa on Thursday

Scientists Revived a Pig's Brain Nearly a Whole Hour After It Died

Scientists have revived activity in the brains of pigs up to nearly an hour after circulation had ceased. In some cases, functionality was sustained for hours through a surprising discovery by researchers.

 This achievement represents a huge step forward in working out how to restore brain function after a patient has suffered a sudden cardiac arrest. It suggests that doctors may be able to widen the brief window for successful resuscitation of patients following cardiac arrest.

The trick? Incorporating the patient's unharmed liver – the organ the body uses to purify its blood – into the life support system used to revive the brain after the time had elapsed.

Sudden cardiac arrest causes a lot of problems in the body due to the rapid cessation of blood flow. The subsequent drop in circulation to parts of the body is called ischemia, and when it occurs in the brain, it can cause serious, irreparable damage within minutes. This is why the resuscitation window for cardiac arrest is so short.

It's known that multi-organ ischemia plays a role in the brain's ability to recover after a cardiac arrest, but the individual organs have not been fully investigated.

In recent years, scientists have been using pig models to test methods for limiting brain injury. Supervised by physician Xiaoshun He of Sun Yat-Sen University in China, a team of scientists has turned to the animal to try and understand the role of the liver in brain recovery after ischemia due to cardiac arrest.

Using 17 lab-raised Tibetan minipigs, the team compared the inclusion of a liver in a loss of circulation. In one set of experiments, two groups of pigs were subjected to brain ischemia for 30 minutes; one of the groups was also subjected to liver ischemia, and the other was not. Meanwhile a control group underwent no ischemia.

Part 1

Comment by Dr. Krishna Kumari Challa on Thursday

Experiments find people assume unidentified bystanders in a war zone are combatants, acceptable collateral damage

People's bias toward sacrificing unknown bystanders appears to stem from assuming the unidentified person is an enemy, according to a study published October 23, 2024, in the open-access journal PLOS ONE.

About as many civilians as soldiers die in war each year, some during strikes targeted at enemy combatants. There have been many reported cases of mistaking innocent civilians for enemy combatants, with the possibility of many more being unreported.

Researchers conducted five experiments to test when people assume unknown bystanders in a combat zone are enemies rather than civilians, reducing their concerns about collateral damage. A total of 2,204 participants were presented with a realistic moral dilemma: A military pilot must decide whether to bomb a dangerous enemy target, also killing a bystander. 

In the study, few people endorsed bombing when the bystander was known to be an innocent civilian. However, when the bystander's identity was unknown, more than twice as many people endorsed the bombing despite no evidence they were enemies.

Bombing endorsement was predicted by attitudes toward total war: the theory that there should be no distinction between military and civilian targets in wartime conflict. 

According to the authors, these findings have implications for military strategists who must decide whether to attack areas with enemy militants and unidentified bystanders. The results support a common tendency in people to assume the bystanders are enemies, with important consequences if they turn out to be innocent civilians.

The real-world cases of civilians struck by bombs could result from the same error in judgment reported in this study.

What I don't know can hurt you: Collateral combat damage seems more acceptable when bystander victims are unidentified, PLoS ONE (2024). DOI: 10.1371/journal.pone.0298842

Comment by Dr. Krishna Kumari Challa on Thursday

'Inflexible thinking style' behind why some people won't accept vaccines, says new research

An "inflexible thinking style" could explain why some people are hesitant about taking a vaccine, new research  has revealed. It is a finding that could have implications for public health policy, especially during pandemics.

Researchers  conducted the first study evaluating the relationship between COVID-19 "vaccine hesitancy and cognitive flexibility."

Cognitive flexibility is how good people are at responding to changing situations and changing feedback, and especially when rules change. Inflexibility is generally described as the incapacity to adjust one's behavior in response to changing circumstances, update one's knowledge, and maintain optimum decision-making.

This explorative study found that those with greater vaccine hesitancy persisted with the same erroneous responses during a computerized test of flexible thinking, even when they received direct feedback telling them that their responses were no longer correct. This response pattern is the hallmark of a cognitively inflexible thinking style.

Vaccine hesitancy is quite common, occurring in approximately 12% of the population and may occur for multiple underlying reasons. In this study, researchers found the relationship between it and cognitive inflexibility can be predicted through an online test. This may be of value for public health policy in identifying this specific group.

The research, conducted between June 2021 and July 2022 after lockdown from COVID-19 was eased, has just been published in the Journal of Psychiatric Research.

L. Pellegrini et al, The inflexible mind: A critical factor in understanding and addressing COVID-19 vaccine hesitancy, Journal of Psychiatric Research (2024). DOI: 10.1016/j.jpsychires.2024.09.028

Comment by Dr. Krishna Kumari Challa on Thursday

Scientists glue two proteins together, driving cancer cells to self-destruct

Our bodies divest themselves of 60 billion cells every day through a natural process of cell culling and turnover called apoptosis. These cells—mainly blood and gut cells—are all replaced with new ones, but the way our bodies rid themselves of material could have profound implications for cancer therapies in a new approach developed by  researchers.

They aim to use this natural method of cell death to trick cancer cells into disposing of themselves. Their method accomplishes this by artificially bringing together two proteins in such a way that the new compound switches on a set of cell death genes, ultimately driving tumor cells to turn on themselves.

The researchers describe their latest such compound in a paper published Oct. 4 in Science.

Apoptosis turns out to be critical for many biological processes, including proper development of all organs and the fine-tuning of our immune systems. That system retains pathogen-recognizing cells but kills off self-recognizing ones, thus preventing autoimmune disease.

Traditional treatments for cancer—namely chemotherapy and radiation—often kill large numbers of healthy cells alongside the cancerous ones. To harness cells' natural and highly specific self-destruction abilities, researchers developed a kind of molecular glue that sticks together two proteins that normally would have nothing to do with one another.

One of these proteins, BCL6, when mutated, drives the blood cancer known as diffuse large cell B-cell lymphoma. This kind of cancer-driving protein is also referred to as an oncogene. In lymphoma, the mutated BCL6 sits on DNA near apoptosis-promoting genes and keeps them switched off, helping the cancer cells retain their signature immortality.

The researchers developed a molecule that tethers BCL6 to a protein known as CDK9, which acts as an enzyme that catalyzes gene activation, in this case, switching on the set of apoptosis genes that BCL6 normally keeps off.

When the team tested the molecule in diffuse large cell B-cell lymphoma cells in the lab, they found that it indeed killed the cancer cells with high potency. They also tested the molecule in healthy mice and found no obvious toxic side effects, even though the molecule killed off a specific category of the animals' healthy B cells, a kind of immune cell, which also depends on BCL6.

They're now testing the compound in mice with diffuse large B-cell lymphoma to gauge its ability to kill cancer in a living animal.

The research team hopes that by blasting the cells with multiple different cell death signals at once, the cancer will not be able to survive long enough to evolve resistance, although this idea remains to be tested.

Roman C. Sarott et al, Relocalizing transcriptional kinases to activate apoptosis, Science (2024). DOI: 10.1126/science.adl5361

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