TY - JOUR T1 - SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion. JF - Nature Y1 - 2021 A1 - Mlcochova, Petra A1 - Kemp, Steven A A1 - Dhar, Mahesh Shanker A1 - Papa, Guido A1 - Meng, Bo A1 - Ferreira, Isabella A T M A1 - Datir, Rawlings A1 - Collier, Dami A A1 - Albecka, Anna A1 - Singh, Sujeet A1 - Pandey, Rajesh A1 - Brown, Jonathan A1 - Zhou, Jie A1 - Goonawardane, Niluka A1 - Mishra, Swapnil A1 - Whittaker, Charles A1 - Mellan, Thomas A1 - Marwal, Robin A1 - Datta, Meena A1 - Sengupta, Shantanu A1 - Ponnusamy, Kalaiarasan A1 - Radhakrishnan, Venkatraman Srinivasan A1 - Abdullahi, Adam A1 - Charles, Oscar A1 - Chattopadhyay, Partha A1 - Devi, Priti A1 - Caputo, Daniela A1 - Peacock, Tom A1 - Wattal, Chand A1 - Goel, Neeraj A1 - Satwik, Ambrish A1 - Vaishya, Raju A1 - Agarwal, Meenakshi A1 - Mavousian, Antranik A1 - Lee, Joo Hyeon A1 - Bassi, Jessica A1 - Silacci-Fegni, Chiara A1 - Saliba, Christian A1 - Pinto, Dora A1 - Irie, Takashi A1 - Yoshida, Isao A1 - Hamilton, William L A1 - Sato, Kei A1 - Bhatt, Samir A1 - Flaxman, Seth A1 - James, Leo C A1 - Corti, Davide A1 - Piccoli, Luca A1 - Barclay, Wendy S A1 - Rakshit, Partha A1 - Agrawal, Anurag A1 - Gupta, Ravindra K KW - Antibodies, Neutralizing KW - Cell Fusion KW - Cell Line KW - COVID-19 Vaccines KW - Female KW - Health Personnel KW - Humans KW - Immune Evasion KW - India KW - Kinetics KW - Male KW - SARS-CoV-2 KW - Spike Glycoprotein, Coronavirus KW - Vaccination KW - Virus Replication AB -

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.

VL - 599 IS - 7883 ER - TY - JOUR T1 - Role of connexins in female reproductive system and endometriosis. JF - J Gynecol Obstet Hum Reprod Y1 - 2020 A1 - Kaushik, Tripti A1 - Mishra, Rakesh A1 - Singh, Rakesh K A1 - Bajpai, Surabhi KW - Connexins KW - Decidua KW - Embryo Implantation KW - Endometriosis KW - Endometrium KW - Female KW - Gap Junctions KW - Genitalia, Female KW - Humans KW - Infertility, Female KW - Oogenesis KW - Ovulation KW - Pregnancy KW - Uterus AB -

Gap junction form channels between the cells and facilitate the function of cellular cross talk. Connexins, the gap junction proteins play an essential role in female reproductive health and its expression anomalies are correlated with female reproductive disorders like polycystic ovarian syndrome, recurrent miscarriage, pre-term birth and endometriosis. Endometriosis is a chronic gynecologic disorder caused by ectopic endometrial lesions growing outside the uterine cavity. Embryonic implantation is adversely affected in case of endometriosis leading to infertility. Endometriosis also interferes with ovulatory functions, reduces fertilization and impaires blastocyst implantation. There lies a lacunae in understanding of the role of gap junctions protein connexins in endometriosis. Therefore, this study discusses the role of connexins in improving female fertility by taming the processes of oogenesis, germ line development, uterine receptivity, placental growth, implantation, decidualization and concludes by focusing the role of connexins in endometriosis.

VL - 49 IS - 6 ER - TY - JOUR T1 - Efficient allelic-drive in Drosophila. JF - Nat Commun Y1 - 2019 A1 - Guichard, Annabel A1 - Haque, Tisha A1 - Bobik, Marketta A1 - Xu, Xiang-Ru S A1 - Klanseck, Carissa A1 - Kushwah, Raja Babu Singh A1 - Berni, Mateus A1 - Kaduskar, Bhagyashree A1 - Gantz, Valentino M A1 - Bier, Ethan KW - Agriculture KW - Alleles KW - Animals KW - Animals, Genetically Modified KW - CRISPR-Cas Systems KW - DNA End-Joining Repair KW - DNA Mutational Analysis KW - Drosophila KW - Female KW - Gene Drive Technology KW - Gene Editing KW - Inheritance Patterns KW - Male KW - Mosaicism KW - RNA, Guide AB -

Gene-drive systems developed in several organisms result in super-Mendelian inheritance of transgenic insertions. Here, we generalize this "active genetic" approach to preferentially transmit allelic variants (allelic-drive) resulting from only a single or a few nucleotide alterations. We test two configurations for allelic-drive: one, copy-cutting, in which a non-preferred allele is selectively targeted for Cas9/guide RNA (gRNA) cleavage, and a more general approach, copy-grafting, that permits selective inheritance of a desired allele located in close proximity to the gRNA cut site. We also characterize a phenomenon we refer to as lethal-mosaicism that dominantly eliminates NHEJ-induced mutations and favors inheritance of functional cleavage-resistant alleles. These two efficient allelic-drive methods, enhanced by lethal mosaicism and a trans-generational drive process we refer to as "shadow-drive", have broad practical applications in improving health and agriculture and greatly extend the active genetics toolbox.

VL - 10 IS - 1 ER - TY - JOUR T1 - Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes. JF - Psychiatry Clin Neurosci Y1 - 2019 A1 - Ganesh, Suhas A1 - Ahmed P, Husayn A1 - Nadella, Ravi K A1 - More, Ravi P A1 - Seshadri, Manasa A1 - Viswanath, Biju A1 - Rao, Mahendra A1 - Jain, Sanjeev A1 - Mukherjee, Odity KW - Bipolar Disorder KW - Exome KW - Female KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Male KW - Pedigree KW - Phenotype KW - Schizophrenia AB -

AIM: Severe mental illnesses (SMI), such as bipolar disorder and schizophrenia, are highly heritable, and have a complex pattern of inheritance. Genome-wide association studies detect a part of the heritability, which can be attributed to common genetic variation. Examination of rare variants with next-generation sequencing may add to the understanding of the genetic architecture of SMI.

METHODS: We analyzed 32 ill subjects from eight multiplex families and 33 healthy individuals using whole-exome sequencing. Prioritized variants were selected by a three-step filtering process, which included: deleteriousness by five in silico algorithms; sharing within families by affected individuals; rarity in South Asian sample estimated using the Exome Aggregation Consortium data; and complete absence of these variants in control individuals from the same gene pool.

RESULTS: We identified 42 rare, non-synonymous deleterious variants (~5 per pedigree) in this study. None of the variants were shared across families, indicating a 'private' mutational profile. Twenty (47.6%) of the variant harboring genes were previously reported to contribute to the risk of diverse neuropsychiatric syndromes, nine (21.4%) of which were of Mendelian inheritance. These included genes carrying novel deleterious variants, such as the GRM1 gene implicated in spinocerebellar ataxia 44 and the NIPBL gene implicated in Cornelia de Lange syndrome.

CONCLUSION: Next-generation sequencing approaches in family-based studies are useful to identify novel and rare variants in genes for complex disorders like SMI. The findings of the study suggest a potential phenotypic burden of rare variants in Mendelian disease genes, indicating pleiotropic effects in the etiology of SMI.

VL - 73 IS - 1 ER - TY - JOUR T1 - Low Oxygen Tension Enhances Expression of Myogenic Genes When Human Myoblasts Are Activated from G0 Arrest. JF - PLoS One Y1 - 2016 A1 - Sellathurai, Jeeva A1 - Nielsen, Joachim A1 - Hejbøl, Eva Kildall A1 - Jørgensen, Louise Helskov A1 - Dhawan, Jyotsna A1 - Nielsen, Michael Friberg Bruun A1 - Schrøder, Henrik Daa KW - Adolescent KW - Cell Cycle Checkpoints KW - Cell Hypoxia KW - Cell Proliferation KW - Cell Separation KW - Cells, Cultured KW - Down-Regulation KW - Female KW - Gene Expression Regulation KW - Humans KW - Ki-67 Antigen KW - Male KW - Muscle Development KW - Muscle Proteins KW - Myoblasts KW - Oxygen KW - Receptors, Notch KW - Resting Phase, Cell Cycle KW - Transforming Growth Factor beta KW - Wnt Signaling Pathway KW - Young Adult AB -

OBJECTIVES: Most cell culture studies have been performed at atmospheric oxygen tension of 21%, however the physiological oxygen tension is much lower and is a factor that may affect skeletal muscle myoblasts. In this study we have compared activation of G0 arrested myoblasts in 21% O2 and in 1% O2 in order to see how oxygen tension affects activation and proliferation of human myoblasts.

MATERIALS AND METHODS: Human myoblasts were isolated from skeletal muscle tissue and G0 arrested in vitro followed by reactivation at 21% O2 and 1% O2. The effect was assesses by Real-time RT-PCR, immunocytochemistry and western blot.

RESULTS AND CONCLUSIONS: We found an increase in proliferation rate of myoblasts when activated at a low oxygen tension (1% O2) compared to 21% O2. In addition, the gene expression studies showed up regulation of the myogenesis related genes PAX3, PAX7, MYOD, MYOG (myogenin), MET, NCAM, DES (desmin), MEF2A, MEF2C and CDH15 (M-cadherin), however, the fraction of DES and MYOD positive cells was not increased by low oxygen tension, indicating that 1% O2 may not have a functional effect on the myogenic response. Furthermore, the expression of genes involved in the TGFβ, Notch and Wnt signaling pathways were also up regulated in low oxygen tension. The differences in gene expression were most pronounced at day one after activation from G0-arrest, thus the initial activation of myoblasts seemed most sensitive to changes in oxygen tension. Protein expression of HES1 and β-catenin indicated that notch signaling may be induced in 21% O2, while the canonical Wnt signaling may be induced in 1% O2 during activation and proliferation of myoblasts.

VL - 11 IS - 7 ER -