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
June 12,2020

Global poverty could rise to over one billion people due to the COVID-19 pandemic and more than half of the 395 million additional extreme poor would be located in South Asia, which would be the hardest-hit region in the world, according to a new report.

Researchers from King's College London and Australian National University published the new paper with the United Nations University World Institute for Development Economics Research (UNU-WIDER) said that poverty is likely to increase dramatically in middle-income developing countries and there could be a significant change in the distribution of global poverty.

The location of global poverty could shift back towards developing countries in South Asia and East Asia, the report said.

The paper, 'Precarity and the Pandemic: COVID-19 and Poverty Incidence, Intensity and Severity in Developing Countries,' finds that extreme poverty could rise to over one billion people globally as a result of the crisis.

The cost of the crisis in lost income could reach USD 500 million per day for the world's poorest people, and the intensity and severity of poverty are likely to be exacerbated dramatically.

The report said that based on the USD 1.90 a day poverty line and a 20 per cent contraction, more than half of the 395 million additional extreme poor would be located in South Asia, which would become the hardest hit region in the world mainly driven by the weight of populous India followed by sub-Saharan Africa which would comprise 30 per cent, or 119 million, of the additional poor.

The report added that as the value of the poverty line increases, a larger share of the additional poor will be concentrated in regions where the corresponding poverty line is more relevant given the average income level.

For instance, the regional distribution of the world's poor changes drastically when looking at the USD 5.50 a day poverty line the median poverty line among upper-middle-income countries.

At this level, almost 41 per cent of the additional half a billion poor under a 20 per cent contraction scenario would live in East Asia and the Pacific, chiefly China; a fourth would still reside in South Asia; and a combined 18 per cent would live in the Middle East and North Africa (MENA) and in Latin America and the Caribbean (LAC), whose individual shares are close to that recorded for sub-Saharan Africa.

India plays a significant role in driving the potential increases in global extreme poverty documented previously, comprising almost half the estimated additional poor regardless of the contraction scenario, the report said.

Nonetheless, there are other populous, low and lower-middle- income countries in South Asia, sub-Saharan Africa, and East Asia and the Pacific accounting for a sizeable share of the estimates: Nigeria, Ethiopia, Bangladesh, and Indonesia come next, in that order, concentrating a total of 18 19 per cent of the new poor, whereas the Democratic Republic of Congo, Tanzania, Pakistan, Kenya, Uganda, and the Philippines could jointly add 11 12 per cent.

Taken together, these figures imply that three quarters of the additional extreme poor globally could be living in just ten populous countries.

The report added that this high concentration of the additional extreme poor is staggering , although not necessarily unexpected given the size of each country's population.

On one hand, data shows that three of these ten countries (Ethiopia, India, and Nigeria) were among the top ten by number of extreme poor people in 1990 and remained within the ranks of that group until 2018.

Despite this crude fact, two of these countries have managed to achieve a sustained reduction in their incidence of poverty since the early 1990s, namely Ethiopia and India, reaching their lowest poverty headcount ratio ever recorded at about 22 and 13 per cent, respectively. Nonetheless, the potential contraction in per capita income/consumption imposed by the pandemic's economic effects could erase some of this progress.

The researchers are now calling for urgent global leadership from the G7, G20, and the multilateral system, and propose a three-point plan to address the impact of the COVID-19 on global poverty quickly.

Professor of International Development at King's College London and a Senior Non-Resident Research Fellow at UNU-WIDER Andy Sumner said the COVID-19 crisis could take extreme poverty back over one billion people because millions of people live just above poverty.

Millions of people live in a precarious position one shock away from poverty. And the current crisis could be that shock that pushes them into poverty.

Professor Kunal Sen, Director of UNU-WIDER said the new estimates about the level of poverty in the world and the cost of the COVID-19 pandemic to the world's poor are sobering.

We cannot stand by and see the hard work and effort of so many be eradicated. We will know what the real impact is in time, but the necessary action to ensure we achieve the Sustainable Development Goals by 2030 needs to be planned now, Sen said.

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Agencies
May 20,2020

Washington D.C., May 20: While a dairy-rich diet is helpful in meeting the body's calcium requirement, outcomes of a large international study links eating at least two daily servings of dairy with lower risks of diabetes and high blood pressure.

The dairy-rich diet also proved to lower the cluster of factors that heighten cardiovascular disease risk (metabolic syndrome). The study was published online in journal BMJ Open Diabetes Research & Care.

The observed associations were strongest for full-fat dairy products, the findings indicated.

Previously published research has suggested that higher dairy intake is associated with a lower risk of diabetes, high blood pressure, and metabolic syndrome. But these studies have tended to focus on North America and Europe to the exclusion of other regions of the world.

To see whether these associations might also be found in a broader range of countries, the researchers drew on people taking part in the Prospective Urban Rural Epidemiology (PURE) study.

Participants were all aged between 35 and 70 and came from 21 countries: Argentina; Bangladesh; Brazil; Canada; Chile; China; Colombia; India; Iran; Malaysia; Palestine; Pakistan; Philippines, Poland; South Africa; Saudi Arabia; Sweden; Tanzania; Turkey; United Arab Emirates; and Zimbabwe.

Usual dietary intake over the previous 12 months was assessed by means of Food Frequency Questionnaires. Dairy products included milk, yogurt, yogurt drinks, cheese and dishes prepared with dairy products, and were classified as full or low fat (1-2 percent).

Butter and cream were assessed separately as these are not commonly eaten in some of the countries studied.

Information on personal medical history, use of prescription medicines, educational attainment, smoking and measurements of weight, height, waist circumference, blood pressure and fasting blood glucose were also collected.

Data on all five components of the metabolic syndrome were available for nearly 113,000 people: blood pressure above 130/85 mm Hg; waist circumference above 80 cm; low levels of (beneficial) high-density cholesterol (less than 1-1.3 mmol/l); blood fats (triglycerides) of more than 1.7 mmol/dl; and fasting blood glucose of 5.5 mmol/l or more.

Average daily total dairy consumption was 179 g, with full-fat accounting for around double the amount of low fat: 124.5+ vs 65 g.

Some 46, 667 people had metabolic syndrome--defined as having at least 3 of the 5 components.

Total dairy and full-fat dairy, but not low-fat dairy, was associated with a lower prevalence of most components of metabolic syndrome, with the size of the association greatest in those countries with normally low dairy intakes.

At least 2 servings a day of total dairy were associated with a 24 percent lower risk of metabolic syndrome, rising to 28 percent for full-fat dairy alone, compared with no daily dairy intake.

The health of nearly 190,000 participants was tracked for an average of nine years, during which time 13,640 people developed high blood pressure and 5351 developed diabetes.

At least 2 servings a day of total dairy was associated with a 11-12 percent lower risk of both conditions, rising to a 13-14 percent lower risk for 3 daily servings. The associations were stronger for full fat than they were for low-fat dairy.

This is an observational study, and as such can't establish the cause. Food frequency questionnaires are also subject to recall, and changes in metabolic syndrome weren't measured over time, all of which may have influenced the findings.

Nevertheless, the researchers suggest: "If our findings are confirmed in sufficiently large and long term trials, then increasing dairy consumption may represent a feasible and low-cost approach to reducing [metabolic syndrome], hypertension, diabetes, and ultimately cardiovascular disease events worldwide."

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Agencies
July 4,2020

The Union health ministry on Friday revised the dosage of anti-viral drug remdesivir to be administered to coronavirus patients in the moderate stage of illness from the earlier six days to five days as it issued an updated 'Clinical Management Protocols for COVID-19'.

The drug, administered in the form of injection, should be given at a dose of 200 mg on day one followed by 100 mg daily for four days (total five days), the new treatment protocols stated.

The Health Ministry on June 13 had allowed the use of remdesivir for restricted emergency use in moderate cases under "investigational therapies".

"Under emergency use authorisation, remdesivir may be considered for patients in moderate stage requiring oxygen support," the document stated.

It is not recommended for those with severe renal impairment and high level of liver enzymes, pregnant and lactating women, and those below 12 years, it said.

The ministry also okayed off-label application of tocilizumab, a drug that modifies the immune system or its functioning, and convalescent plasma for treating COVID-19 patients in the moderate stage of illness as "investigational therapies".

It also recommended hydroxychloroquine for patients during the early course of the disease and not for critically-ill patients.

On June 27, the ministry had included an inexpensive, widely used steroid dexamethasone in treatment protocols for COVID-19 patients in the moderate to severe stages of their illness among other therapeutic measures.

The ministry advised use of dexamethasone, which is already used in a wide range of conditions for its anti-inflammatory and immunosuppressant effects, as an alternative choice to methylprednisolone for managing moderate to severe cases of coronavirus infection.

India's COVID-19 cases soared by over 20,000 in a day for the first time taking the country's total tally to 6,25,544 on Friday while the death toll climbed to 18,213 with 379 new fatalities, according to the Union Health Ministry data updated at 8 am.

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