@article {2363,
	title = {SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion.},
	journal = {Nature},
	volume = {599},
	year = {2021},
	month = {2021 11},
	pages = {114-119},
	abstract = {<p>The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha). In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era.</p>
},
	keywords = {Antibodies, Neutralizing, Cell Fusion, Cell Line, COVID-19 Vaccines, Female, Health Personnel, Humans, Immune Evasion, India, Kinetics, Male, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Vaccination, Virus Replication},
	issn = {1476-4687},
	doi = {10.1038/s41586-021-03944-y},
	author = {Mlcochova, Petra and Kemp, Steven A and Dhar, Mahesh Shanker and Papa, Guido and Meng, Bo and Ferreira, Isabella A T M and Datir, Rawlings and Collier, Dami A and Albecka, Anna and Singh, Sujeet and Pandey, Rajesh and Brown, Jonathan and Zhou, Jie and Goonawardane, Niluka and Mishra, Swapnil and Whittaker, Charles and Mellan, Thomas and Marwal, Robin and Datta, Meena and Sengupta, Shantanu and Ponnusamy, Kalaiarasan and Radhakrishnan, Venkatraman Srinivasan and Abdullahi, Adam and Charles, Oscar and Chattopadhyay, Partha and Devi, Priti and Caputo, Daniela and Peacock, Tom and Wattal, Chand and Goel, Neeraj and Satwik, Ambrish and Vaishya, Raju and Agarwal, Meenakshi and Mavousian, Antranik and Lee, Joo Hyeon and Bassi, Jessica and Silacci-Fegni, Chiara and Saliba, Christian and Pinto, Dora and Irie, Takashi and Yoshida, Isao and Hamilton, William L and Sato, Kei and Bhatt, Samir and Flaxman, Seth and James, Leo C and Corti, Davide and Piccoli, Luca and Barclay, Wendy S and Rakshit, Partha and Agrawal, Anurag and Gupta, Ravindra K}
}
@article {2248,
	title = {Allosteric inhibition of MTHFR prevents futile SAM cycling and maintains nucleotide pools in one-carbon metabolism.},
	journal = {J Biol Chem},
	volume = {295},
	year = {2020},
	month = {2020 11 20},
	pages = {16037-16057},
	abstract = {<p>Methylenetetrahydrofolate reductase (MTHFR) links the folate cycle to the methionine cycle in one-carbon metabolism. The enzyme is known to be allosterically inhibited by SAM for decades, but the importance of this regulatory control to one-carbon metabolism has never been adequately understood. To shed light on this issue, we exchanged selected amino acid residues in a highly conserved stretch within the regulatory region of yeast MTHFR to create a series of feedback-insensitive, deregulated mutants. These were exploited to investigate the impact of defective allosteric regulation on one-carbon metabolism. We observed a strong growth defect in the presence of methionine. Biochemical and metabolite analysis revealed that both the folate and methionine cycles were affected in these mutants, as was the transsulfuration pathway, leading also to a disruption in redox homeostasis. The major consequences, however, appeared to be in the depletion of nucleotides. C isotope labeling and metabolic studies revealed that the deregulated MTHFR cells undergo continuous transmethylation of homocysteine by methyltetrahydrofolate (CHTHF) to form methionine. This reaction also drives SAM formation and further depletes ATP reserves. SAM was then cycled back to methionine, leading to futile cycles of SAM synthesis and recycling and explaining the necessity for MTHFR to be regulated by SAM. The study has yielded valuable new insights into the regulation of one-carbon metabolism, and the mutants appear as powerful new tools to further dissect out the intersection of one-carbon metabolism with various pathways both in yeasts and in humans.</p>
},
	keywords = {Adenosine Triphosphate, Allosteric Regulation, Humans, Methylation, Methylenetetrahydrofolate Reductase (NADPH2), S-Adenosylmethionine, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins},
	issn = {1083-351X},
	doi = {10.1074/jbc.RA120.015129},
	author = {Bhatia, Muskan and Thakur, Jyotika and Suyal, Shradha and Oniel, Ruchika and Chakraborty, Rahul and Pradhan, Shalini and Sharma, Monika and Sengupta, Shantanu and Laxman, Sunil and Masakapalli, Shyam Kumar and Bachhawat, Anand Kumar}
}
