A dual role of Cohesin in DNA DSB repair.

Cells undergo tens of thousands of DNA-damaging events each day. Defects in repairing double-stranded breaks (DSBs) can lead to genomic instability, contributing to cancer, genetic disorders, immunological diseases, and developmental defects. Cohesin, a multi-subunit protein complex, plays a crucial role in both chromosome organization and DNA repair by creating architectural loops through chromatin extrusion.

Extraction of Spectra in the Shell Model Monte Carlo Method Using Imaginary-Time Correlation Matrices.

Nuclear energy levels are usually calculated using conventional diagonalization methods in the framework of the configuration-interaction (CI) shell model but these methods are prohibited in very large model spaces. The shell model Monte Carlo (SMMC) method is a powerful technique for calculating thermal and ground-state observables of nuclei in very large model spaces, but it is challenging to extract nuclear spectra in this approach. We present a novel method to extract within SMMC low-lying energy levels for given values of a set of good quantum numbers such as spin and parity.

An IDR-dependent mechanism for nuclear receptor control of Mediator interaction with RNA polymerase II.

The essential Mediator (MED) coactivator complex plays a well-understood role in regulation of basal transcription in all eukaryotes, but the mechanism underlying its role in activator-dependent transcription remains unknown. We investigated modulation of metazoan MED interaction with RNA polymerase II (RNA Pol II) by antagonistic effects of the MED26 subunit and the CDK8 kinase module (CKM). Biochemical analysis of CKM-MED showed that the CKM blocks binding of the RNA Pol II carboxy-terminal domain (CTD), preventing RNA Pol II interaction.

"Stripe" transcription factors provide accessibility to co-binding partners in mammalian genomes.

Regulatory elements activate promoters by recruiting transcription factors (TFs) to specific motifs. Notably, TF-DNA interactions often depend on cooperativity with colocalized partners, suggesting an underlying cis-regulatory syntax. To explore TF cooperativity in mammals, we analyze ∼500 mouse and human primary cells by combining an atlas of TF motifs, footprints, ChIP-seq, transcriptomes, and accessibility.

Clinical Profile and Outcome of Hospitalized Confirmed Cases of Omicron Variant of SARS-CoV-2 Among Children in Pune, India.

Background The Omicron variant of SARS-CoV-2 infection was seen to be more infectious but less severe in children than adults with reduced hospitalization rates. There is a paucity of data on hospitalized children with confirmed Omicron variant. Objective We describe demographic, epidemiologic, clinical, radiological, laboratory features and outcomes of children with confirmed Omicron variant of SARS-CoV-2 infection admitted to a tertiary care teaching hospital in Pune, India.

G4 DNA present at human telomeric DNA contributes toward reduced sensitivity to γ-radiation induced oxidative damage, but not bulky adduct formation.

Purpose: DNA, the hereditary material of a human cell generally exists as Watson-Crick base paired double-stranded B-DNA. Studies suggest that DNA can also exist in non-B forms, such as four stranded G-quadruplexes (G4 DNA). Recently, our studies revealed that the regions of DNA that can fold into G-quadruplex structures are less sensitive to ionizing radiation (IR) compared to B-DNA.

NHEJ inhibitor SCR7 and its different forms: Promising CRISPR tools for genome engineering.

The CRISPR-Cas system currently stands as one of the best multifaceted tools for site-specific genome engineering in mammals. An important aspect of research in this field focusses on improving the specificity and efficacy of precise genome editing in multiple model systems. The cornerstone of this mini-review is one of the extensively investigated small molecule inhibitor, SCR7, which abrogates NHEJ, a Ligase IV-dependent DSB repair pathway, thus guiding integration of the foreign DNA fragment via the more precise homology directed repair during genome editing.

Early-onset symptomatic neonatal COVID-19 infection with high probability of vertical transmission.

Background: There are few reports of COVID-19 in neonates and most are suspected to be due to postnatal transmission. Vertical transmission has been proven in only a couple of cases so far.

Methods: We describe early-onset, severe COVID-19 disease in a neonate with very strong evidence of vertical transmission of SARS-CoV-2.

Correction to: Comparative Study to Evaluate Tolerability of Topical 5% Minoxidil Novel Formulation and Alcohol-Based Conventional Solutions in Treatment of Androgenetic Alopecia in Indian Men: Randomized Double-Blind Study.

In Methods section under Study Design and Patients.

Comparative Study to Evaluate Tolerability of Topical 5% Minoxidil Novel Formulation and Alcohol-Based Conventional Solutions in Treatment of Androgenetic Alopecia in Indian Men: Randomized Double-Blind Study.

Introduction: Patients with androgenetic alopecia treated with alcohol-based minoxidil topical solutions often report local irritation, dryness, and redness of the scalp. We evaluate the in-use tolerance of 5% minoxidil novel formulation topical solution-test product (TP)-compared with 5% minoxidil alcohol-based topical solutions-reference product 1 (RP1) and reference product 2 (RP2)-in Indian men with androgenetic alopecia.

Methods: In this randomized double-blind study, patients aged ≥ 18 years with androgenetic alopecia were randomized 1:1:1 to apply TP, RP1, and RP2 twice daily for 30 days.

G-quadruplex Structures Contribute to Differential Radiosensitivity of the Human Genome.

DNA, the fundamental unit of human cell, generally exists in Watson-Crick base-paired B-DNA form. Often, DNA folds into non-B forms, such as four-stranded G-quadruplexes. It is generally believed that ionizing radiation (IR) induces DNA strand-breaks in a random manner.

Autocyclized and oxidized forms of SCR7 induce cancer cell death by inhibiting nonhomologous DNA end joining in a Ligase IV dependent manner.

Nonhomologous DNA end joining (NHEJ) is the major DNA double-strand break (DSB) repair pathway in mammals. Previously, we have described a small molecule inhibitor, SCR7, which can inhibit NHEJ in a Ligase IV-dependent manner. Administration of SCR7 within the cells resulted in the accumulation of DNA breaks, cell death, and inhibition of tumor growth in mice.

A Benzothiazole Derivative (5g) Induces DNA Damage And Potent G2/M Arrest In Cancer Cells.

Chemically synthesized small molecules play important role in anticancer therapy. Several chemical compounds have been reported to damage the DNA, either directly or indirectly slowing down the cancer cell progression by causing a cell cycle arrest. Direct or indirect reactive oxygen species formation causes DNA damage leading to cell cycle arrest and subsequent cell death.

Novel BCL2 inhibitor, Disarib induces apoptosis by disruption of BCL2-BAK interaction.

Apoptosis is a highly regulated pathway of programmed cell death relying on the fine balance between pro and antiapoptotic binding partners. Overexpression of the antiapoptotic protein BCL2 in several cancers makes it an ideal target for chemotherapy, with minimum side effects. In one of our previous studies, we designed, synthesized and characterized Disarib, a BCL2-specific small molecule inhibitor.

A novel inhibitor of BCL2, Disarib abrogates tumor growth while sparing platelets, by activating intrinsic pathway of apoptosis.

Antiapoptotic protein BCL2, serves as an excellent target for anticancer therapy owing to its increased level in cancers. Previously, we have described characterization of a novel BCL2 inhibitor, Disarib, which showed selective cytotoxicity in BCL2 'high' cancer cells and CLL patient cells. Here, we have investigated the mechanism of Disarib-induced cytotoxicity, and compared its efficacy with a well-established BCL2 inhibitor, ABT199.

Monte Carlo Study of Real Time Dynamics on the Lattice.

Monte Carlo studies involving real time dynamics are severely restricted by the sign problem that emerges from a highly oscillatory phase of the path integral. In this Letter, we present a new method to compute real time quantities on the lattice using the Schwinger-Keldysh formalism via Monte Carlo simulations. The key idea is to deform the path integration domain to a complex manifold where the phase oscillations are mild and the sign problem is manageable.

Identification of a novel BCL2-specific inhibitor that binds predominantly to the BH1 domain.

The antiapoptotic protein BCL2 is overexpressed in several cancers and contributes to prolonged cell survival and chemoresistance, lending itself as an excellent target for cancer therapy. Here, we report the design, synthesis, and characterization of Disarib, a novel BCL2 inhibitor. Disarib showed selective cytotoxicity in BCL2 high cancer cell lines, and CLL patient primary cells, as compared to BCL2 low cell lines.

Inhibition of nonhomologous end joining to increase the specificity of CRISPR/Cas9 genome editing.

DNA repair, one of the fundamental processes occurring in a cell, safeguards the genome and maintains its integrity. Among various DNA lesions, double-strand breaks are considered to be the most deleterious, as they can lead to potential loss of genetic information, if not repaired. Nonhomologous end joining (NHEJ) and homologous recombination are two major double-strand break repair pathways.

Enhanced efficacy of pluronic copolymer micelle encapsulated SCR7 against cancer cell proliferation.

5,6-Bis(benzylideneamino)-2-mercaptopyrimidin-4-ol (SCR7) is a new anti cancer molecule having capability to selectively inhibit non-homologous end joining (NHEJ), one of the DNA double strand break (DSB) repair pathways inside the cells. In spite of the promising potential as an anticancer agent, hydrophobicity of SCR7 decreases its bioavailability. Herein the entrapment of SCR7 in Pluronic copolymer is reported.

Ab initio metadynamics study on hydronium ion dynamics at acid-functionalized interfaces: effect of surface group density.

This article presents an ab initio metadynamics study of elementary hydronium ion transitions at dense arrays of surface groups with sulfonic acid head groups. Calculations simulate minimally hydrated conditions of the interfacial ionic system. The specific focus is on the influence of the surface group density on hydronium ion transport.

Evidence-based health care management: what is the research evidence available for health care managers?

In light of increasing interest in evidence-based management, we conducted a scoping review of systematic reviews (SRs) and meta-analyses (MAs) to determine the availability and accessibility of evidence for health care managers; 14 MAs and 61 SRs met the inclusion criteria. Most reviews appeared in medical journals (53%), originated in the United States (29%) or United Kingdom (22%), were hospital-based (55%), and targeted clinical providers (55%). Topics included health services organization (34%), quality/patient safety (17%), information technology (15%), organization/workplace management (13%), and health care workforce (12%).

Perforation of the hard palate due to tuberculosis.

Tuberculosis (TB) of the hard palate is rare and usually secondary to pulmonary TB. We present a case of a 7-year-old boy who presented with difficulty in swallowing solid foods, low-grade fever and loss of weight. Oral cavity examination showed perforation of the hard palate with an irregular, undermined margin and a necrotic base.

Collective proton dynamics at highly charged interfaces studied by ab initio metadynamics.

Surface proton conduction is of utmost importance in biology, materials science, and electrochemistry; yet experimental findings of ultrafast proton transport at densely packed arrays of anionic surface groups have remained controversial and unexplained. We present an ab initio molecular dynamics study of proton dynamics at sulfonic-acid terminated surface groups. Results furnish a highly efficient collective mechanism of hydronium ion translocations at a critical surface group separation of ~6.