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Monday, October 31, 2022

¿ES EL SARS-Cov-2 UN VIRUS ONCOGÉNICO?


Recently, in this journal, Wu et al. () and Gao et al. () have both indicated that host genetic variation related to COVID-19 might be associated to endometrial cancer. We here add evidence from gene expression analysis supporting that the connection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and cancer could be more general, in line with several other viral infections that represent serious risks for carcinogenesis in humans. The SARS-CoV-2 has developed similar strategies to Epstein-Barr virus (EBV) and hepatitis B virus (HSV1) to control p53 by hijacking the protein via virus antigens, and ultimately leading to its degradation (,). Specifically, the Nsp2 viral protein of the SARS-CoV-2 interacts with the prohibitin 1 and 2 (PHB1, PHB2) that are primarily located in the mitochondrion and play an essential role in maintaining mitochondrial DNA activity. Their depletion triggers a chain of cell responses that lead to a leakage of reactive oxygen species (ROS) to the nucleus and oxidative damage, that ultimately provokes the impairment of the transactivation of p53-dependent genes. In addition, the Nsp3 SARS-CoV-2 protein binds and activates the RING finger and CHY zinc finger domain-cotainin protein 1 (RCHY1) and E3 ubiquitin ligase, promoting p53 degradation (). Therefore, SARS-CoV-2 has the ability to trigger external and internal apoptotic pathways of the host cells, facilitating its spread. Impairment of p53 could be seen as a strategy of the virus to take advantage of the cell pathways controlled by this protein for its own benefit during acute phase of infection, therefore evading host immune response and facilitating its replication (). In this context, a reduced expression of p53 during the acute phase of infection is also a biomarker of severe disease.

Although it has not been demonstrated yet, it has been hypothesized that a long-term inhibition of p53 by the SARS-CoV-2 could be carcinogenic. The onco-suppressive protein p53 is a key player within the apoptotic signaling pathway and regulates the expression of about 500 target genes; therefore, it plays a role in cell cycle arrest, cell aging, cell death, etc. (). We examine three gene expression datasets to demonstrate that p53 is downregulated during acute SARS-CoV-2 infection and long coronavirus-disease 19 (COVID-19); a long-term reduction of p53 could be interpreted as a risk factor in carcinogenesis.

Sunday, October 23, 2022

LA HUELLA DE ENDONUCLEASA INDICA UN ORIGEN SINTÉTICO DEL SARS-Cov-2 (II)

LA HUELLA DE ENDONUCLEASA INDICA UN ORIGEN SINTÉTICO DEL SARS-Cov-2 (I)

Abstract 

 To prevent future pandemics, it is important that we understand whether SARS-CoV-2 spilled over directly from animals to people, or indirectly in a laboratory accident. The genome of SARS-COV-2 contains a peculiar pattern of unique restriction endonuclease recognition sites allowing efficient dis- and re-assembly of the viral genome characteristic of synthetic viruses. Here, we report the likelihood of observing such a pattern in coronaviruses with no history of bioengineering. We find that SARS-CoV-2 is an anomaly, more likely a product of synthetic genome assembly than natural evolution. The restriction map of SARS-CoV-2 is consistent with many previously reported synthetic coronavirus genomes, meets all the criteria required for an efficient reverse genetic system, differs from closest relatives by a significantly higher rate of synonymous mutations in these synthetic-looking recognitions sites, and has a synthetic fingerprint unlikely to have evolved from its close relatives. We report a high likelihood that SARS-CoV-2 may have originated as an infectious clone assembled in vitro. 

Lay Summary To construct synthetic variants of natural coronaviruses in the lab, researchers often use a method called in vitro genome assembly. This method utilizes special enzymes called restriction enzymes to generate DNA building blocks that then can be “stitched” together in the correct order of the viral genome. To make a virus in the lab, researchers usually engineer the viral genome to add and remove stitching sites, called restriction sites. The ways researchers modify these sites can serve as fingerprints of in vitro genome assembly. We found that SARS-CoV has the restriction site fingerprint that is typical for synthetic viruses. The synthetic fingerprint of SARS-CoV-2 is anomalous in wild coronaviruses, and common in lab-assembled viruses. The type of mutations (synonymous or silent mutations) that differentiate the restriction sites in SARS-CoV-2 are characteristic of engineering, and the concentration of these silent mutations in the restriction sites is extremely unlikely to have arisen by random evolution. Both the restriction site fingerprint and the pattern of mutations generating them are extremely unlikely in wild coronaviruses and nearly universal in synthetic viruses. Our findings strongly suggest a synthetic origin of SARS-CoV2.

Competing Interest Statement ADW owns shares of a life insurance company and is a co-founder of Selva. 

Paper in collection COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv

 Posted October 20, 2022.

Saturday, October 22, 2022

SATYAHIT DAS: END OF EMPIRE-3 The US will join the UK as a failed first-world state



The Ukraine conflict may be important in the re-shaping of a fractured world.

Individual trajectories within the Western bloc will differ, in part because of internal divisions. The most likely to peel off are Europe and Japan.

The US strategy appears to be to weaken Russia by sacrificing Ukrainians and Europeans as actual or economic cannon fodder. Given its high dependence on imported energy and sensitivity to fuel costs, Europe, especially Germany and Italy, risk a severe economic contraction, damage of its industrial base, loss of living standards and a banking crisis. Unsurprisingly, industrial leaders have written to the European Commission warning of an "existential threat" from higher power prices. They highlighted the danger that shutdowns pose to employment, taxes and ability to repay borrowings that would be ruinous for Europe. Environmentalist are concerned variously about recommissioning nuclear power plants and restarting dirty old coal fired power plants.

(...)

If the US were to place sanctions on China, then Australia and New Zealand would find it extremely difficult to trade with their major trading partner without broad exemptions which may not be forthcoming. The cost in national income would be substantial.

The problem is not exclusively antipodean as Europe is highly dependent on Chinese trade. In 2021, China was the third largest destination for European Union goods exports (10 percent) and the largest source for European Union goods imports(22 percent).

(...)

After having spent decades championing free trade and capital movement and forcing the Washington Consensus on other countries (most recently on Sri Lanka and Argentina), the West are busily implementing the very policies they derided – trade and capital restrictions, price caps, subsidies, nationalisation and replacing market forces with state controls.

For British statesman Lord Palmerston, countries had no eternal allies or perpetual enemies just permanent interests.  It is probable that Europe, Japan and perhaps Australia and New Zealand will drift away from the alliance. The stance on Ukraine may be an indication of the long-term trajectory. Already, large protests have taken place in the Czech Republic against continued support of Kyiv and its effects on the cost of living.

(...)

The UK's position perhaps provides a guide to America's fate. There are similar economic susceptibilities -- high debt, lagging infrastructure, a hollowed out industrial structure and problems of inequality.

(...)

In The Rise and Fall of the Great Powers published in 1987, Paul Kennedy argued that great power ascendancy and decline correlates to available resources and economic durability. America's military overreach and military spending – greater than China, India, Russia, United Kingdom, Saudi Arabia, Germany, France, Japan, and South Korea combined– is unsustainable. Ungovernability, deadlocked body politic, elite looting and absence of leadership add to the problems.

America and the UK revel in the past.

But the facts suggest that the US will join the UK as a failed first-world state, a Somali with nukes. As historian Arnold Toynbee argued: "civilizations die from suicide, not by murder."

(...)

Large systems do not fail quickly. British power has been falling for a century. The roots of the demise of the USSR can be traced back Stalin committing the Soviet Union, at the end of World War 2, to an unwinnable direct competition with an economically superior US.

(...)

But the signs are that a critical point is approaching. Structures are unravelling. Economic growth is stagnating. Resource scarcity, climate problems and resultant inflationary pressures are rising. High debt levels may prove difficult to sustain. The financial system is fragile. Global political, business and cultural elites are increasingly detached from the concerns of ordinary people. Geo-political tensions are high and the American-dominated  unipolar world is under threat from within and without.

The internal contradictions of the existing order make change inevitable. The outcomes may be positive or negative. At the edge of chaos, the exact shape of any transformation is unpredictable and rarely simple. Great powers can undertake reforms, such as those America undertook during the Great Depression, to reemerge.

 

© 2022 Satyajit Das All Rights Reserved 

Satyajit Das is a former banker and author of numerous works on derivatives and several general titles: Traders, Guns & Money: Knowns and Unknowns in the Dazzling World of Derivatives  (2006 and 2010), Extreme Money: The Masters of the Universe and the Cult of Risk (2011), A Banquet of Consequences RELOADED (2021) and Fortune’s Fool: Australia’s Choices (2022).