Essential role of Cp190 in physical and regulatory boundary formation.

Boundaries in animal genomes delimit contact domains with enhanced internal contact frequencies and have debated functions in limiting regulatory cross-talk between domains and guiding enhancers to target promoters. Most mammalian boundaries form by stalling of chromosomal loop-extruding cohesin by CTCF, but most Drosophila boundaries form CTCF independently. However, how CTCF-independent boundaries form and function remains largely unexplored. Here, we assess genome folding and developmental gene expression in fly embryos lacking the ubiquitous boundary-associated factor Cp190. We find that sequence-specific DNA binding proteins such as CTCF and Su(Hw) directly interact with and recruit Cp190 to form most promoter-distal boundaries. Cp190 is essential for early development and prevents regulatory cross-talk between specific gene loci that pattern the embryo. Cp190 was, in contrast, dispensable for long-range enhancer-promoter communication at tested loci. Cp190 is thus currently the major player in fly boundary formation and function, revealing that diverse mechanisms evolved to partition genomes into independent regulatory domains.

Dosimetry of indoor alpha flux belonging to seasonal radon, thoron and their EECs.

Radon (222Rn) and thoron (220Rn) are ubiquitous radioactive noble gases present in the earth's crust. The source term for these gases includes soil and building materials as well. The radiological impact of radon/thoron gases and their decay products on human life is a matter of concern and has been given due attention in research and policy. The present study aims to measure and quantify residential radon/thoron gas and the decay product's concentration and to discuss the associated interpretations for Ludhiana district of Punjab, India. Passive measurement techniques employing a single-entry pinhole dosimeter for gases and direct progeny sensors for the decay product's concentration have been used in this work. The obtained data from these measurements have been analysed using appropriate statistical techniques. The variations have been linked with the changes in the ventilation conditions, building material, room type and altitude. A higher concentration of radon and thoron gas was observed in the winter season for the study region. It was estimated that the contribution of radon and thoron decay products towards the annual average inhalation dose is 75% and 25%, respectively.

Anticancer potential of spirocompounds in medicinal chemistry: A pentennial expedition.

Spirocompounds constitute an important class of organic frameworks enveloping numerous pharmacological activities, among them, the promising anticancer potential of spirocompounds have enthused medicinal chemists to explore new spiro derivatives with significantly improved pharmacodynamic and pharmacokinetic profile along with their mechanism of action. The current review intends to provide a sketch of the anticancer activity of various spirocompounds like spirooxindole, spiroisoxazole, spiroindole etc, from the past five years unfolding various aspects of pharmacological activities and their structure-activity relationships (SARs). This literature analysis may provide future direction for the efficient design of novel spiromolecules with enhanced safety and efficacy.

CTCF loss has limited effects on global genome architecture in Drosophila despite critical regulatory functions.

Vertebrate genomes are partitioned into contact domains defined by enhanced internal contact frequency and formed by two principal mechanisms: compartmentalization of transcriptionally active and inactive domains, and stalling of chromosomal loop-extruding cohesin by CTCF bound at domain boundaries. While Drosophila has widespread contact domains and CTCF, it is currently unclear whether CTCF-dependent domains exist in flies. We genetically ablate CTCF in Drosophila and examine impacts on genome folding and transcriptional regulation in the central nervous system. We find that CTCF is required to form a small fraction of all domain boundaries, while critically controlling expression patterns of certain genes and supporting nervous system function. We also find that CTCF recruits the pervasive boundary-associated factor Cp190 to CTCF-occupied boundaries and co-regulates a subset of genes near boundaries together with Cp190. These results highlight a profound difference in CTCF-requirement for genome folding in flies and vertebrates, in which a large fraction of boundaries are CTCF-dependent and suggest that CTCF has played mutable roles in genome architecture and direct gene expression control during metazoan evolution.

RAD51C/XRCC3 Facilitates Mitochondrial DNA Replication and Maintains Integrity of the Mitochondrial Genome.

Mechanisms underlying mitochondrial genome maintenance have recently gained wide attention, as mutations in mitochondrial DNA (mtDNA) lead to inherited muscular and neurological diseases, which are linked to aging and cancer. It was previously reported that human RAD51, RAD51C, and XRCC3 localize to mitochondria upon oxidative stress and are required for the maintenance of mtDNA stability. Since RAD51 and RAD51 paralogs are spontaneously imported into mitochondria, their precise role in mtDNA maintenance under unperturbed conditions remains elusive. Here, we show that RAD51C/XRCC3 is an additional component of the mitochondrial nucleoid having nucleus-independent roles in mtDNA maintenance. RAD51C/XRCC3 localizes to the mtDNA regulatory regions in the D-loop along with the mitochondrial polymerase POLG, and this recruitment is dependent upon Twinkle helicase. Moreover, upon replication stress, RAD51C and XRCC3 are further enriched at the mtDNA mutation hot spot region D310. Notably, the absence of RAD51C/XRCC3 affects the stability of POLG on mtDNA. As a consequence, RAD51C/XRCC3-deficient cells exhibit reduced mtDNA synthesis and increased lesions in the mitochondrial genome, leading to overall unhealthy mitochondria. Together, these findings lead to the proposal of a mechanism for a direct role of RAD51C/XRCC3 in maintaining mtDNA integrity under replication stress conditions.

Prevention and management of ventilator-associated pneumonia: A survey on current practices by intensivists practicing in the Indian subcontinent.

Implementation of evidence-based guidelines to prevent and manage ventilator-associated pneumonia (VAP) in the clinical setting may not be adequate. We aimed to assess the implementation of selected VAP prevention strategies, and to learn how VAP is managed by the intensivists practicing in the Indian Subcontinent. Three hundred 10-point questionnaires were distributed during an International Critical Care Conferenceheld at New Delhi in 2009. A total of 126 (42%) questionnaires distributed among delegates from India, Nepal and Sri Lanka were analyzed. Majority (96.8%) reported using VAP bundles with a high proportion including head elevation (98.4%), chlorhexidine mouthcare (83.3%), stress ulcer prophylaxis (96.8%), heat and moisture exchangers (HME, 92.9%), early weaning (94.4%), and hand washing (97.6%) as part of their VAP bundle. Use of subglottic secretion drainage (SSD, 45.2%) and closed suction systems (CSS, 74.6%) was also reported by many intensivists, whereas use of selective gut decontamination was reported by only 22.2%. Commonest method for sampling was endotracheal suction by 68.3%. Gram negative organisms were reported to be the most commonly isolated. Majority (39.7%) reported using proton pump inhibitors for stress ulcer prophylaxis and 84.1% believed that VAP contributed to increased mortality. De-escalating therapy was considered in patients responding to treatment by 57.9% and 65.9% considered adding empirical methicillin resistant Staphylococcus aureus (MRSA)coverage, while 63.5% considered adding nebulized antibiotics in certain high-risk patients. There was good concordance regarding VAP prophylaxis among the intensivists with a majority adhering to evidence-based guidelines. We could identify certain issues like the choice of agent for stress ulcer prophylaxis, use of HME filters, SSD and CSS, where there still exists some practice variability and opportunities for improvement.