Protein complex clears potential traffic jams in RNA production, finds research

Agencies
April 6, 2019

April 6: A new research has found that a protein complex plays a key role in clearing potential traffic jams in the production of RNA.

The research was published in the journal Genes & Development.

"The 'Ccr4-Not' complex is involved in nearly every step of this process from start to finish. Our new research shows that this complex has an additional function that helps maintain normal cellular function when something goes wrong during transcription," said Joseph C. Reese, a researcher.

During the transcription of RNA from DNA, RNAPII, itself a large complex made up of multiple protein subunits, travels along the strand of DNA reading the ATCG sequence and producing a complementary strand of RNA.

If the RNAPII encounters DNA damage, which can be caused by UV radiation and other sources, it can become stuck and prevent trailing polymerases from completing transcription of the gene, similar to how a stalled car prevents traffic behind it from flowing.

If this jam cannot be cleared, multiple RNAPIIs transcribing the same gene can start to pile up in a sort of traffic jam preventing the DNA from being repaired and hampering cell function.

"Defects in this pathway have been associated with a number of diseases and human syndromes, such as Cockayne syndrome- a neurodegenerative disorder that results in growth failure, neurological developmental defects, and sensitivity to UV light," Reese added.

RNA polymerase II (RNAPII), the enzyme that produces RNA from a DNA template, can become stuck due to damage to the DNA template, and these jams must be cleared to restore gene expression and normal cell function.

New research shows that the master regulatory complex, 'Ccr4-Not' performs this task, associating with RNAPII during the transcription of RNA from DNA and marking RNAPII for degradation when it becomes stuck, allowing the DNA to be repaired and normal cell function to resume.

"Normal cellular functions rely on what is sometimes called the 'central dogma of biology,'" said Reese.

The researchers used genetic methods and reconstitution biochemistry- a method whereby purified components of a cellular process can be added- taken away, and mixed in a precisely controlled manner to identify exactly how they function to show that 'Ccr4-Not' recruits factors that mark RNAPII with a small signalling molecule called ubiquitin.Attachment of ubiquitin to RNAPII triggers other cellular components to degrade the enzyme, clearing the jam.

"Mutating members of the 'Ccr4-Not' complex makes cells more sensitive to agents that damage the genome, but because 'Ccr4-Not' is involved in so many aspects of gene regulation it wasn't clear until now what its precise role was," said Reese.

"The fact that 'Ccr4-Not' recruited the destruction machinery to RNAPII was a surprising result, and suggests it acts as a tow truck to remove traffic jams throughout the genome," he added.

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Agencies
May 2,2020

Clinician-scientists have found that Irish patients admitted to hospital with severe coronavirus (COVID-19) infection are experiencing abnormal blood clotting that contributes to death in some patients.

The research team from the Royal College of Surgeons in Ireland found that abnormal blood clotting occurs in Irish patients with severe COVID-19 infection, causing micro-clots within the lungs.

According to the study, they also found that Irish patients with higher levels of blood clotting activity had a significantly worse prognosis and were more likely to require ICU admission.

"Our novel findings demonstrate that COVID-19 is associated with a unique type of blood clotting disorder that is primarily focussed within the lungs and which undoubtedly contributes to the high levels of mortality being seen in patients with COVID-19," said Professor James O'Donnell from St James's Hospital in Ireland.

In addition to pneumonia affecting the small air sacs within the lungs, the research team has also hundreds of small blood clots throughout the lungs.

This scenario is not seen with other types of lung infection and explains why blood oxygen levels fall dramatically in severe COVID-19 infection, the study, published in the British Journal of Haematology said.

"Understanding how these micro-clots are being formed within the lung is critical so that we can develop more effective treatments for our patients, particularly those in high-risk groups," O'Donnell said.

"Further studies will be required to investigate whether different blood-thinning treatments may have a role in selected high-risk patients in order to reduce the risk of clot formation," Professor O'Donnell added.

According to the study, emerging evidence also shows that the abnormal blood-clotting problem in COVID-19 results in a significantly increased risk of heart attacks and strokes.

As of Friday morning, the cases increased to 20,612 cases in Ireland, with 1,232 deaths so far, according to the Johns Hopkins University.

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Agencies
January 26,2020

High-protein diets may help people lose weight and build muscle, but there is a downside to it --a greater heart attack risk. Researchers now report that high-protein diets boost artery-clogging plaque.

The research in mice showed that high-protein diets spur unstable plaque -- the kind most prone to rupturing and causing blocked arteries.

More plaque buildup in the arteries, particularly if it's unstable, increases the risk of heart attack.

"There are clear weight-loss benefits to high-protein diets, which has boosted their popularity in recent years," said senior author Babak Razani, associate professor at Washington University School of Medicine in St. Louis, Missouri.

"But animal studies and some large epidemiological studies in people have linked high dietary protein to cardiovascular problems. We decided to take a look at whether there is truly a causal link between high dietary protein and poorer cardiovascular health," Razani added.

The researchers studied mice who were fed a high-fat diet to deliberately induce atherosclerosis, or plaque buildup in the arteries.

Some of the mice received a high-fat diet that was also high in protein. And others were fed a high-fat, low-protein diet for comparison.

The mice on the high-fat, high-protein diet developed worse atherosclerosis -- about 30 per cent more plaque in the arteries -- than mice on the high-fat, normal-protein diet, despite the fact that the mice eating more protein did not gain weight, unlike the mice on the high-fat, normal-protein diet.

"A couple of a scoop of protein powder in a milkshake or smoothie adds something like 40 grams of protein -- almost equivalent to the daily recommended intake," Razani said.

"To see if protein has an effect on cardiovascular health, we tripled the amount of protein that the mice receive in the high-fat, high-protein diet -- keeping the fat constant. Protein went from 15 per cent to 46 per cent of calories for these mice".

Plaque contains a mix of fat, cholesterol, calcium deposits and dead cells. Past work by Razani's team and other groups has shown that immune cells called macrophages work to clean up plaque in the arteries.

But the environment inside plaque can overwhelm these cells, and when such cells die, they make the problem worse, contributing to plaque buildup and increasing plaque complexity.

"In mice on the high-protein diet, their plaques were a macrophage graveyard," Razani informed.

To understand how high dietary protein might increase plaque complexity, Razani and his colleagues also studied the path protein takes after it has been digested -- broken down into its original building blocks, called amino acids.

"This study is not the first to show a telltale increase in plaque with high-protein diets, but it offers a deeper understanding of the impact of high protein with the detailed analysis of the plaques," said Razani.

"This work not only defines the critical processes underlying the cardiovascular risks of dietary protein but also lays the groundwork for targeting these pathways in treating heart disease," he added.

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Agencies
June 28,2020

As the COVID-19 wave sweeps strongly across the country, including in Tamil Nadu, mental health experts say the pandemic has triggered panic attacks among those who tested positive for the virus, causing bouts of depression and even driving some to the brink of suicide.

According to experts, nervousness, fear of contamination, panic attacks, constant reassurance seeking behaviour, sleep disturbance, excessive worry, feelings of helplessness and probability of an economic slowdown are the major factors leading to depression and anxiety among the people.

Potential job losses, financial burden, uncertainty about the future and fears of running out of food and necessities add to the worries.

Online platforms too have seen a growing number of people seeking help for mental health issues, ranging from anxiety and loneliness to concerns over productivity and job loss since the outbreak of COVID-19.

Director of Institute of Mental Health here, Dr R Purna Chandrika said towards April end about 3,632 calls were received and psychiatric counselling was provided to 2,603 callers.

"We have dedicated services at our centres in the districts and the calls meant for government medical college hospitals are routed to the respective institutions," she said.

Due to heavy virus caseloads, making this city the major contributor to the state's tally, the Greater Chennai Corporation too started a free helpline to help residents cope up with stress during the pandemic.

"From the psychological perspective, we don't find a single human being who is not feeling some degree of stress or anxiety due to coronavirus. The intensity and impact varies from person to person," said Lt Col N T Rajan, director of Chennai-based Mastermind Foundation.

The organisation is involved in free counselling throughout India ever since the first case of the deadly virus was reported in the country.

The foundation's recommendation on not to deploy the vulnerable in the police force, especially those above 50 years and women personnel with children below five years for COVID-19 related duty, was accepted and implemented by the Punjab government.

Psychiatrists feel that further worsening situations could lead to severe mental health issues, even triggering suicidal tendencies.

"Further worsening depression may lead to severe mental health issues and suicidal tendencies," said Dr S Senthil Kumar, a psychiatrist.

However, not all of them require medicines, he added.

"The situation is serious. There should be counselling at three stages--on coping with the virus, how to face it if tested positive and how to face life once treated and discharged from the hospital," Rajan said.

Awareness was of paramount importance, he said and warned the pandemic could cause panic attacks while in hospital or drive them to the brink of suicide.

Tamil Nadu, one of the worst affected states with a virus count in excess of 74,000 as of Friday, has witnessed a few instances of suicides allegedly related to COVID-19.

Hari Singh, owner of popular 'Iruttu Kadai' halwa shop in Tirunelveli, allegedly died by committing suicide on Thursday after being tested positive for COVID-19. He was 80.

Earlier in May, two COVID-19 patients in their 50s allegedly committed suicide in separate instances, at the government hospitals they were admitted to for treatment.

In the city corporation limits, a three-member team comprising a psychiatrist, counsellor and a social worker work for the respective zones.

"We direct certain sections of people like those with withdrawal symptoms and people requiring pills, to visit the doctor at their corporation zonal at a specific time, for medicines," a health worker of the civic body said.

Health platform, Lybrate reported an increase of 180 per cent in online patient consultations related to mental health on its platform between March 1 and June 20 across the country.

The largest increase came from Mumbai and Delhi, followed by Pune, Ahmedabad, Chennai and Bengaluru.

The biggest jump was witnessed in the age group of 25 and 45 years.

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