Understanding the Role of Regulators of Homologous Recombination

DNA double strand breaks (DSB) are the most genotoxic lesions because they affect the integrity of the genome. DSBs can be caused by exogenous factors such as ionizing radiation or induced during meiosis. Failure to repair DSBs can cause genome instability, cancer and cell death. DSBs can be repaired by one of three main pathways, homologous recombination (HR), non-homologous end joining (NHEJ) and microhomology mediated end joining (MMEJ). NHEJ and MMEJ are error-prone but HR is relatively error-free since it relies on a homologous DNA sequence. Studies have shown that HR accounts for repair of about 50% of induced DSBs. HR is also essential for proper segregation of chromosomes and telomere maintenance in eukaryotes. Impaired HR is implicated in diseases like Bloom’s syndrome, Fanconi’s anemia and breast and ovarian cancer. In eukaryotes, the mechanism of HR is largely governed by two recombinases, Rad51 and Dmc1, the homologs of E. coli RecA. Dmc1 is meiosis-specific whereas Rad51 functions in mitosis and meiosis. Rad51 and Dmc1 mediate ATP-dependent DNA strand exchange and require recombination mediators and accessory factors to assist them in forming a presynaptic filament on single-stranded DNA and search for homology. This study involved examining the biochemical properties of a set of proteins with respect to their function in RAD51-mediated homologous recombination. The results indicated that HELLS, BCCIPα and BCCIPβ interact with RAD51 and bind single-stranded DNA. Further, these proteins function in HR by stabilizing the RAD51 presynaptic filament and preventing it from dissociation, thus promoting efficient recombination

Role of atmospheric stability over the Arabian Sea and the unprecedented failure of monsoon 2002

The anomalous behaviour of the monsoon 2002 has been studied. We have made an attempt to combine satellite and other data sources to characterize the thermal stratification over the Arabian Sea during different phases of monsoon 2002. Using NOAA-ATOVSderived atmospheric temperature and moisture profiles, we have calculated a daily stability index (SI) over the entire Indian region and surrounding oceans. The time series of SI clearly brings out the three major significant epochs of monsoon 2002. The relatively dry atmosphere west of 65° E, signifying lack of convection and an unstable atmosphere over the southeast Arabian Sea with west-to-east gradients in water vapour, SI and cloud liquid water content are noted. The unfavourable stratification during July over the entire Arabian Sea has been investigated in detail. The dominant modes of instability oscillations have been seen to be ~ 30 days both over the western and eastern Arabian Sea, while for the high-frequency modes preference was seen over the eastern part. Using the analysed fields of the National Centre for Medium Range Weather Forecasts, the relative contributions of advective and subsidence components in the maintenance of stratification have been investigated. The latter has been found to have played a more dominant role in the deficit monsoon 2002

The β-isoform of BCCIP promotes ADP release from the RAD51 presynaptic filament and enhances homologous DNA pairing

Homologous recombination (HR) is a template-driven repair pathway that mends DNA double-stranded breaks (DSBs), and thus helps to maintain genome stability. The RAD51 recombinase facilitates DNA joint formation during HR, but to accomplish this task, RAD51 must be loaded onto the single-stranded DNA. DSS1, a candidate gene for split hand/split foot syndrome, provides the ability to recognize RPA-coated ssDNA to the tumor suppressor BRCA2, which is complexed with RAD51. Together BRCA2-DSS1 displace RPA and load RAD51 onto the ssDNA. In addition, the BRCA2 interacting protein BCCIP normally colocalizes with chromatin bound BRCA2, and upon DSB induction, RAD51 colocalizes with BRCA2-BCCIP foci. Down-regulation of BCCIP reduces DSB repair and disrupts BRCA2 and RAD51 foci formation. While BCCIP is known to interact with BRCA2, the relationship between BCCIP and RAD51 is not known. In this study, we investigated the biochemical role of the β-isoform of BCCIP in relation to the RAD51 recombinase. We demonstrate that BCCIPβ binds DNA and physically and functionally interacts with RAD51 to stimulate its homologous DNA pairing activity. Notably, this stimulatory effect is not the result of RAD51 nucleoprotein filament stabilization; rather, we demonstrate that BCCIPβ induces a conformational change within the RAD51 filament that promotes release of ADP to help maintain an active presynaptic filament. Our findings reveal a functional role for BCCIPβ as a RAD51 accessory factor in HR

Reporting trends, practices, and resource utilization in neuroendocrine tumors of the prostate gland: a survey among thirty-nine genitourinary pathologists

Background: Neuroendocrine differentiation in the prostate gland ranges from clinically insignificant neuroendocrine differentiation detected with markers in an otherwise conventional prostatic adenocarcinoma to a lethal high-grade small/large cell neuroendocrine carcinoma. The concept of neuroendocrine differentiation in prostatic adenocarcinoma has gained considerable importance due to its prognostic and therapeutic ramifications and pathologists play a pivotal role in its recognition. However, its awareness, reporting, and resource utilization practice patterns among pathologists are largely unknown. Methods: Representative examples of different spectrums of neuroendocrine differentiation along with a detailed questionnaire were shared among 39 urologic pathologists using the survey monkey software. Participants were specifically questioned about the use and awareness of the 2016 WHO classification of neuroendocrine tumors of the prostate, understanding of the clinical significance of each entity, and use of different immunohistochemical (IHC) markers. De-identified respondent data were analyzed. Results: A vast majority (90%) of the participants utilize IHC markers to confirm the diagnosis of small cell neuroendocrine carcinoma. A majority (87%) of the respondents were in agreement regarding the utilization of type of IHC markers for small cell neuroendocrine carcinoma for which 85% of the pathologists agreed that determination of the site of origin of a high-grade neuroendocrine carcinoma is not critical, as these are treated similarly. In the setting of mixed carcinomas, 62% of respondents indicated that they provide quantification and grading of the acinar component. There were varied responses regarding the prognostic implication of focal neuroendocrine cells in an otherwise conventional acinar adenocarcinoma and for Paneth cell-like differentiation. The classification of large cell neuroendocrine carcinoma was highly varied, with only 38% agreement in the illustrated case. Finally, despite the recommendation not to perform neuroendocrine markers in the absence of morphologic evidence of neuroendocrine differentiation, 62% would routinely utilize IHC in the work-up of a Gleason score 5 + 5 = 10 acinar adenocarcinoma and its differentiation from high-grade neuroendocrine carcinoma. Conclusion: There is a disparity in the practice utilization patterns among the urologic pathologists with regard to diagnosing high-grade neuroendocrine carcinoma and in understanding the clinical significance of focal neuroendocrine cells in an otherwise conventional acinar adenocarcinoma and Paneth cell-like neuroendocrine differentiation. There seems to have a trend towards overutilization of IHC to determine neuroendocrine differentiation in the absence of neuroendocrine features on morphology. The survey results suggest a need for further refinement and development of standardized guidelines for the classification and reporting of neuroendocrine differentiation in the prostate gland

The Diabetes Technology Society Error Grid and Trend Accuracy Matrix for Glucose Monitors.

INTRODUCTION: An error grid compares measured versus reference glucose concentrations to assign clinical risk values to observed errors. Widely used error grids for blood glucose monitors (BGMs) have limited value because they do not also reflect clinical accuracy of continuous glucose monitors (CGMs). METHODS: Diabetes Technology Society (DTS) convened 89 international experts in glucose monitoring to (1) smooth the borders of the Surveillance Error Grid (SEG) zones and create a user-friendly tool-the DTS Error Grid; (2) define five risk zones of clinical point accuracy (A-E) to be identical for BGMs and CGMs; (3) determine a relationship between DTS Error Grid percent in Zone A and mean absolute relative difference (MARD) from analyzing 22 BGM and nine CGM accuracy studies; and (4) create trend risk categories (1-5) for CGM trend accuracy. RESULTS: The DTS Error Grid for point accuracy contains five risk zones (A-E) with straight-line borders that can be applied to both BGM and CGM accuracy data. In a data set combining point accuracy data from 18 BGMs, 2.6% of total data pairs equally moved from Zones A to B and vice versa (SEG compared with DTS Error Grid). For every 1% increase in percent data in Zone A, the MARD decreased by approximately 0.33%. We also created a DTS Trend Accuracy Matrix with five trend risk categories (1-5) for CGM-reported trend indicators compared with reference trends calculated from reference glucose. CONCLUSION: The DTS Error Grid combines contemporary clinician input regarding clinical point accuracy for BGMs and CGMs. The DTS Trend Accuracy Matrix assesses accuracy of CGM trend indicators

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Effect of salivary contamination on shear bond strength of two adhesives: An in vitro study

Introduction: Composite material used with bonding system are technique sensitive and contamination of an etched surface by saliva or blood plays a key role in bonding efficacy. Achieving good moisture control is a common problem encountered and is of importance while treating a pediatric age group since rubber dam in dental office is commonly applied in fewer than 10% of restorative treatment. Despite the advantage of rubber dam application, usage of rubber dam depends on child′s behavior and its level of co-operation for which pediatric dentists compromise with its usage. This study was conducted to evaluate the effect of salivary contamination of enamel and dentin on bond strength of two adhesives. Materials and Methods: An in vitro study comprised of test group of 112 central incisors divided into 4 groups for testing on enamel and dentin separately. These are Group I: Control group without salivary contamination; Group II: Contaminated with saliva and air-dried; Group III: Contaminated with saliva, rinsed and air-dried; Group IV: Coated with adhesive, light cured and then contaminated. Shear bond strength was calculated using universal testing machine. Results: For testing on enamel and dentin, significantly decreased bond strength was seen with Group II (P < 0.05) and Group IV (P < 0.01) showed decreased bond strength, whereas bond strength of group III was not significant (P > 0.05), when compared with control Group I. Conclusion: The decontamination method used in this study by rinsing the contaminated cured adhesive layer that did not reverse the harmful effect of salivary contamination. As most of the children are active and restless with swinging mood, it is important not to negotiate with the procedural steps during treatment

Effect of single dose intraoperative IV acetaminophen in pediatric tonsillectomy or adenotonsillectomy

Background: A number of different treatment regimens have been described for post-operative pain management for pediatric tonsillectomy following the widespread discontinuation of the use of codeine due to safety concerns. However, the literature is lacking with regard to the relative efficacy of the treatment regimens. This study is designed to determine the effectiveness of an intraoperative dose of intravenous acetaminophen for pediatric tonsillectomy pain management. Methods: Records were reviewed for pediatric patients undergoing tonsillectomy with a single surgeon between 2012 and 2014. Pain scores, need for narcotic analgesics, and recovery times were reviewed for up to 24 postoperative hours. Patients were grouped based on whether they received an intraoperative dose of intravenous acetaminophen (Group 1) or did not receive it (Group 2). The primary outcome measure was pain score during the 24-h post-operative period. Secondary outcome measures include need for narcotic medications for breakthrough pain in the recovery room and time spent in the recovery room and hospital. Results: 350 patients were included, of which 116 received an intraoperative dose of intravenous acetaminophen. Patients in Group 1 had lower pain scores during the second postoperative hour (1.27 vs. 2.06, p = 0.008). No significant differences were noted for pain scores during postoperative hours 1 or 3–24. Patients in Group 1 spent less time in the Recovery Room (59.08 min vs. 69.5 min, p = 0.016) but more time in the hospital (24.54 h vs. 19.66 h, p = 0.030). There was no difference between the groups based on whether the patients received narcotics for breakthrough pain in the recovery room (79.3% vs. 70.9%, p = 0.094). Conclusion: Intraoperative intravenous acetaminophen may lead to improved pain scores in the early postoperative period and decreased time in the recovery room, but this group also had a longer hospital stay. This information should instigate randomized controlled trials of this intervention

Image Search Re ranking based on Topic Diversity Using K-NN Algorithm

The developing measure of client labeled sight and sound has driven social picture examination and recovery gain significance which has helped individuals arrange and get to client labeled mixed media. Client labeling is uncontrolled, includes uncertainty and profoundly customized thus a crucial inquiry emerges how to decipher the importance of client contributed tag&nbsp; concerning the visual substance depicted by the tag. Picture’s significance and decent variety are considered and a social re-ranking framework for tag-&nbsp;based picture recovery. As per individual visual data, semantic data and social pieces of information the pictures are re-positioned. The underlying outcomes incorporate pictures contributed by various social clients. Every client may contribute a few pictures. Consequently, first, these pictures are arranged by between clients re-positioning. The clients that have a higher commitment to the given question&nbsp;are positioned higher. At that point, consecutive checking time stamp positioning is performed in which the ideal yield is acquired on the premise of title data and the ongoing time stamp which improves the decent variety execution of picture positioning framework. It additionally checks a number of perspectives used to enhance the importance execution of the picture recovery results. The last recovered outcomes are made out of the chose pictures. Catchphrase importance coordinates the information is recovered for the social picture dataset to quicken the seeking procedure