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 18,2020

China, where the novel coronavirus originated, has reported 111 cases since beginning of May, which shows the infection rate has dipped, and 3 deaths since April 27, according to the WHO. A Shanghai-based Noida doctor says China is close to winning the battle against COVID-19, and the combination of zinc, hydroxychloroquine (HCQ) and antibiotic azithromycin has been able to save the lives of coronavirus patients.

Speaking to media persons, Dr Sanjeev Choubey, Medical Director Internal Medicine at St. Michael Hospital said this combination has been adopted as a line of treatment for patients infected with coronavirus, and as a result patients are recovering, decreasing their need for intensive care.

What is the line of treatment for COVID-19 patients, which also include asymptomatic patients?

The combination of zinc, hydroxychloroquine and antibiotic azithromycin has produced positive results, and it helped in the recovery of many COVID-19 patients. The combination -- Ascorbic Acid, B-complex, Zinc, Selenium, L-carnitine, Vitamin B-12 and Glutathione normal saline should be administered on patients twice a week for at least 6 weeks. This is COVID-19 treatment protocol for prophylaxis, and it implies both asymptomatic and symptomatic along with other medicine support.

Based on your experience on COVID-19 in China, after how many tests, is it safe to call a person coronavirus free?

The coronavirus should be performed at least 9 times, before terming a patient COVID-19 free. It is a standard in China. This procedure has worked in China and it will also work in India. Minimum five tests should be mandatory through RT-PCR.

Does coronavirus majorly attack the respiratory system or it could lead to organ failure too?

Line of treatment should not be just looking at the respiratory system, as the problem lies somewhere else. COVID-19 attacks many vital organs in the body. In China, a coronavirus patient died from a stroke. In the autopsy it was found that the innermost layer in the arteries was swollen. It was concluded that coronavirus had inflamed the layer of the arteries leading to clotting, which was a factor in generating a heart attack. Therefore, COVID-19 is not just a respiratory problem.

Amid the coronavirus pandemic, should autopsy be made mandatory in the case of unpredictable death or where reasons for death are not unknown?

Patients below 50 years, who die suddenly and the reasons are not known, then it should be mandatory to conduct the autopsy. After death, coronavirus is active in the body for five days, and it fades away on day 6. Therefore, if an autopsy is done then it will help in understanding this disease. In China, we have seen young COVID-19 patients, aged 22 and 28, succumbed to strokes.

Since the beginning of May, India has recorded more than 2,000 cases everyday in the first week, then it jumped past 3,000 mark in the second week. Finally, the tally is 4,987 on May 17. At 90,927 cases, has India progressed into community transmission or Stage3?

Yes, India has moved into Stage 3. The data suggests that 3,000 to 4,000 active COVID-19 cases, who are asymptomatic, are moving around and spreading the infection. The research has indicated that COVID-19 from an infected person spreads in 30 minutes to non-infected persons. The relaxation on the lockdown will certainly contribute to a high infection rate.

Do you think India has reached its peak in COVID-19 cases, or the sharp rise will continue till July end?

It seems India has already reached its peak and cases will begin to come down from June end or beginning of July first week. If social distancing norms are followed then certainly things can improve, but if not followed then it may get worse. High population density is a major contributor for the increase in cases. The government should continue to focus on finding hotspots, and urge people to follow the rules, eventually it is for people’s own benefit.

Has China won the battle against COVID-19?

It seems China has won the battle by not opening up Wuhan. The Chinese are following a COVID-19 patient’s engagement program, where the authorities continuously interact with people infected with the disease. The Government of India should reward people who follow the guidelines; it will help in setting up a positive trend in the society.

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Agencies
February 20,2020

The health and future of every child and adolescent worldwide is under immediate threat from ecological degradation, climate change and exploitative marketing practices that push fast food, sugary drinks, alcohol and tobacco at children, said a new report on Wednesday.

No single country is adequately protecting children's health, their environment and their futures, according to the report by a commission of over 40 child and adolescent health experts from around the world.

The commission, convened by the World Health Organization (WHO), the United Nations children's agency, Unicef, and medical journal the Lancet, found that while the poorest countries need to do more to support their children's ability to live healthy lives, excessive carbon emissions --disproportionately from wealthier countries -- threaten the future of all children.

"Despite improvements in child and adolescent health over the past 20 years, progress has stalled, and is set to reverse," said former Prime Minister of New Zealand and Co-Chair of the Commission, Helen Clark.

"It has been estimated that around 250 million children under five years old in low- and middle-income countries are at risk of not reaching their developmental potential, based on proxy measures of stunting and poverty. But of even greater concern, every child worldwide now faces existential threats from climate change and commercial pressures," Clark said.

The report, titled "A Future for the World's Children?", includes a new global index of 180 countries, comparing performance on child flourishing and sustainability, with a proxy for greenhouse gas emissions, and equity, or income gaps.

India ranked 131 among the 180 countries in the index.

The index shows that children in Norway, the Republic of Korea, and the Netherlands have the best chance at survival and well-being, while children in the Central African Republic, Chad, Somalia, Niger and Mali face the worst odds.

However, when the authors took per capita CO2 emissions into account, the top countries trail behind: Norway ranked 156, the Republic of Korea 166, and the Netherlands 160.

Each of the three emits 210 per cent more CO2 per capita than their 2030 target.

The US, Australia, and Saudi Arabia are among the ten worst emitters.

If global warming exceeds 4 degree Celsius by the year 2100 in line with current projections, this would lead to devastating health consequences for children, due to rising ocean levels, heatwaves, proliferation of diseases like malaria and dengue, and malnutrition, said the report.

The only countries on track to beat CO2 emission per capita targets by 2030, while also performing fairly (within the top 70) on child flourishing measures are: Albania, Armenia, Grenada, Jordan, Moldova, Sri Lanka, Tunisia, Uruguay and Vietnam.

The report also revealed the distinct threat posed to children from harmful marketing. Evidence suggests that children in some countries see as many as 30,000 advertisements on television alone in a single year, while youth exposure to vaping (e-cigarettes) advertisements increased by more than 250 per cent in the US over two years, reaching more than 24 million young people.

Children's exposure to commercial marketing of junk food and sugary beverages is associated with purchase of unhealthy foods and overweight and obesity, linking predatory marketing to the alarming rise in childhood obesity, said the report.

The number of obese children and adolescents increased from 11 million in 1975 to 124 million in 2016 - an 11-fold increase, with dire individual and societal costs.

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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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