Pomalidomide for Epistaxis in Hereditary Hemorrhagic Telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is characterized by extensive telangiectasias and arteriovenous malformations. The primary clinical manifestation is epistaxis that results in iron-deficiency anemia and reduced health-related quality of life. METHODS: We conducted a randomized, placebo-controlled trial to evaluate the safety and efficacy of pomalidomide for the treatment of HHT. We randomly assigned patients, in a 2:1 ratio, to receive pomalidomide at a dose of 4 mg daily or matching placebo for 24 weeks. The primary outcome was the change from baseline through week 24 in the Epistaxis Severity Score (a validated bleeding score in HHT; range, 0 to 10, with higher scores indicating worse bleeding). A reduction of 0.71 points or more is considered clinically significant. A key secondary outcome was the HHT-specific quality-of-life score (range, 0 to 16, with higher scores indicating more limitations). RESULTS: The trial was closed to enrollment in June 2023 after a planned interim analysis met a prespecified threshold for efficacy. A total of 144 patients underwent randomization; 95 patients were assigned to receive pomalidomide and 49 to receive placebo. The baseline mean (±SD) Epistaxis Severity Score was 5.0±1.5, a finding consistent with moderate-to-severe epistaxis. At 24 weeks, the mean difference between the pomalidomide group and the placebo group in the change from baseline in the Epistaxis Severity Score was -0.94 points (95% confidence interval [CI], -1.57 to -0.31; P = 0.004). The mean difference in the changes in the HHT-specific quality-of-life score between the groups was -1.4 points (95% CI, -2.6 to -0.3). Adverse events that were more common in the pomalidomide group than in the placebo group included neutropenia, constipation, and rash. CONCLUSIONS: Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity. No unexpected safety signals were identified. (Funded by the National Heart, Lung, and Blood Institute; PATH-HHT Clinicaltrials.gov number, NCT03910244).

Race, rituximab, and relapse in TTP.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by recurring episodes of thrombotic microangiopathy, causing ischemic organ impairment. Black patients are overrepresented in iTTP cohorts in the United States, but racial disparities in iTTP outcome and response to therapy have not been studied. Using the United States Thrombotic Microangiopathies Consortium iTTP Registry, we evaluated the impact of race on mortality and relapse-free survival (RFS) in confirmed iTTP in the United States from 1995 to 2020. We separately examined the impact of rituximab therapy and presentation with newly diagnosed (de novo) or relapsed iTTP on RFS by race. A total of 645 participants with 1308 iTTP episodes were available for analysis. Acute iTTP mortality did not differ by race. When all episodes of iTTP were included, Black race was associated with shorter RFS (hazard ratio [HR], 1.60; 95% CI, 1.16-2.21); the addition of rituximab to corticosteroids improved RFS in White (HR, 0.37; 95% CI, 0.18-0.73) but not Black patients (HR, 0.96; 95% CI, 0.71-1.31). In de novo iTTP, rituximab delayed relapse, but Black patients had shorter RFS than White patients, regardless of treatment. In relapsed iTTP, rituximab significantly improved RFS in White but not Black patients. Race affects overall relapse risk and response to rituximab in iTTP. Black patients may require closer monitoring, earlier retreatment, and alternative immunosuppression after rituximab treatment. How race, racism, and social determinants of health contribute to the disparity in relapse risk in iTTP deserves further study.

Time of day does not impact spinal serotonin levels in humans.

Spinal serotonin enables neuro-motor recovery (i.e., plasticity) in patients with debilitating paralysis. While there exists time of day fluctuations in serotonin-dependent spinal plasticity, it is unknown, in humans, whether this is due to dynamic changes in spinal serotonin levels or downstream signaling processes. The primary objective of this study was to determine if time of day variations in spinal serotonin levels exists in humans. To assess this, intrathecal drains were placed in seven adults with cerebrospinal fluid (CSF) collected at diurnal (05:00 to 07:00) and nocturnal (17:00 to 19:00) intervals. High performance liquid chromatography with mass spectrometry was used to quantify CSF serotonin levels with comparisons being made using univariate analysis. From the 7 adult patients, 21 distinct CSF samples were collected: 9 during the diurnal interval and 12 during nocturnal. Diurnal CSF samples demonstrated an average serotonin level of 216.6 ± $ \pm $ 67.7 nM. Nocturnal CSF samples demonstrated an average serotonin level of 206.7 ± $ \pm $ 75.8 nM. There was no significant difference between diurnal and nocturnal CSF serotonin levels (p = .762). Within this small cohort of spine healthy adults, there were no differences in diurnal versus nocturnal spinal serotonin levels. These observations exclude spinal serotonin levels as the etiology for time of day fluctuations in serotonin-dependent spinal plasticity expression.

Dementia care landscape in Nepal: Understanding the context, barriers, and opportunities for the development of a national dementia care plan.

OBJECTIVE: This study was conducted to comprehensively understand the context, barriers, and opportunities for improving dementia care, treatment, and support. The objective is to guide the development of a national dementia care plan. METHODOLOGY: This document review was conducted by analyzing literature available in the public domain, including scientific publications, project documents/reports, media reports, and hospital records. Additionally, annual reports published by the Department of Health Services, national census and demographic and health survey reports, Old Age Homes, and other relevant government reports were examined. Firsthand information was gathered from relevant stakeholders based on the World Health Organization's situational analysis framework for dementia plans. This framework encompasses four domains: Policy context (national ministries, legislation, policies, strategies, plans related to dementia, mental health, aging, and disability), service delivery assessment (health and social care workforces, services, support and treatment programmes, and promotion of awareness and understanding), and epidemiological indicators (prevalence and incidence rates of dementia, risk factors). Ethical clearance was obtained from the Institutional Review Committee (IRC) of B.P. Koirala Institute of Health Sciences (IRC no.2658/023). RESULTS: Existing policies in Nepal inadequately address the needs of people with dementia and their caregivers. Concerning health services, the Government of Nepal provides financial subsidies to individuals diagnosed with dementia; however, numerous hurdles impede access to care. These obstacles include geographical and structural barriers, an inefficient public healthcare system, weak governance, financial constraints, low awareness levels, stigma, and inadequate workforce. Furthermore, the absence of robust nationally representative epidemiological studies on dementia in Nepal hampers the development of evidence-based plans and policies. Similarly, there are no interventions targeted at caregivers of people with dementia, and no initiatives for dementia prevention are in place. CONCLUSIONS: This review underscores the urgent need to formulate a comprehensive national dementia care plan to address the growing challenges. Key priority action areas include the integration of dementia care into primary healthcare services, training workforce to provide the care, increasing awareness, mitigating stigma, developing caregiver support programs, and initiating high-quality research to inform evidence-based policymaking.

Effect of Thromboprophylaxis on Clinical Outcomes After COVID-19 Hospitalization.

BACKGROUND: Patients hospitalized with COVID-19 have an increased incidence of thromboembolism. The role of extended thromboprophylaxis after hospital discharge is unclear. OBJECTIVE: To determine whether anticoagulation is superior to placebo in reducing death and thromboembolic complications among patients discharged after COVID-19 hospitalization. DESIGN: Prospective, randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT04650087). SETTING: Done during 2021 to 2022 among 127 U.S. hospitals. PARTICIPANTS: Adults aged 18 years or older hospitalized with COVID-19 for 48 hours or more and ready for discharge, excluding those with a requirement for, or contraindication to, anticoagulation. INTERVENTION: 2.5 mg of apixaban versus placebo twice daily for 30 days. MEASUREMENTS: The primary efficacy end point was a 30-day composite of death, arterial thromboembolism, and venous thromboembolism. The primary safety end points were 30-day major bleeding and clinically relevant nonmajor bleeding. RESULTS: Enrollment was terminated early, after 1217 participants were randomly assigned, because of a lower than anticipated event rate and a declining rate of COVID-19 hospitalizations. Median age was 54 years, 50.4% were women, 26.5% were Black, and 16.7% were Hispanic; 30.7% had a World Health Organization severity score of 5 or greater, and 11.0% had an International Medical Prevention Registry on Venous Thromboembolism risk prediction score of greater than 4. Incidence of the primary end point was 2.13% (95% CI, 1.14 to 3.62) in the apixaban group and 2.31% (CI, 1.27 to 3.84) in the placebo group. Major bleeding occurred in 2 (0.4%) and 1 (0.2%) and clinically relevant nonmajor bleeding occurred in 3 (0.6%) and 6 (1.1%) apixaban-treated and placebo-treated participants, respectively. By day 30, thirty-six (3.0%) participants were lost to follow-up, and 8.5% of apixaban and 11.9% of placebo participants permanently discontinued the study drug treatment. LIMITATIONS: The introduction of SARS-CoV-2 vaccines decreased the risk for hospitalization and death. Study enrollment spanned the peaks of the Delta and Omicron variants in the United States, which influenced illness severity. CONCLUSION: The incidence of death or thromboembolism was low in this cohort of patients discharged after hospitalization with COVID-19. Because of early enrollment termination, the results were imprecise and the study was inconclusive. PRIMARY FUNDING SOURCE: National Institutes of Health.

Designing a deep hybridized residual and SE model for MRI image-based brain tumor prediction.

Deep learning techniques have become crucial in the detection of brain tumors but classifying numerous images is time-consuming and error-prone, impacting timely diagnosis. This can hinder the effectiveness of these techniques in detecting brain tumors in a timely manner. To address this limitation, this study introduces a novel brain tumor detection system. The main objective is to overcome the challenges associated with acquiring a large and well-classified dataset. The proposed approach involves generating synthetic Magnetic Resonance Imaging (MRI) images that mimic the patterns commonly found in brain MRI images. The system utilizes a dataset consisting of small images that are unbalanced in terms of class distribution. To enhance the accuracy of tumor detection, two deep learning models are employed. Using a hybrid ResNet+SE model, we capture feature distributions within unbalanced classes, creating a more balanced dataset. The second model, a tailored classifier identifies brain tumors in MRI images. The proposed method has shown promising results, achieving a high detection accuracy of 98.79%. This highlights the potential of the model as an efficient and cost-effective system for brain tumor detection.

Antibody Responses in SARS-CoV-2-Exposed and/or Vaccinated Individuals Target Conserved Epitopes from Multiple CoV-2 Antigens.

There is a need to investigate novel strategies in order to create an effective, broadly protective vaccine for current and future severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks. The currently available vaccines demonstrate compromised efficacy against emerging SARS-CoV-2 variants of concern (VOCs), short-lived immunity, and susceptibility to immune imprinting due to frequent boosting practices. In this study, we examined the specificity of cross-reactive IgG antibody responses in mRNA-vaccinated, AstraZeneca-vaccinated, and unvaccinated donors to identify potentially conserved, cross-reactive epitopes to target in order to create a broadly protective SARS-CoV-2 vaccine. Our study provides evidence for cross-reactive IgG antibodies specific to eight different spike (S) variants. Furthermore, the specificities of these cross-variant IgG antibody titers were associated to some extent with spike S1- and S2-subunit-derived epitopes P1 and P2, respectively. In addition, nucleocapsid (N)- and membrane (M)-specific IgG antibody titers correlated with N- and M-derived epitopes conserved across beta-CoVs, P3-7. This study reveals conserved epitopes of viral antigens, targeted by natural and/or vaccine-induced human immunity, for future designs of next-generation COVID-19 vaccines.

Predictors of duodenal eosinophil counts among subjects undergoing diagnostic endoscopy.

INTRODUCTION: Duodenal eosinophilia has been implicated in the pathophysiology of functional dyspepsia. In a retrospective observational study, we previously reported that duodenal eosinophilia (as defined by a mucosal count of greater than 15 eosinophils per 5 high power fields), was associated with symptomatic erosive gastroesophageal reflux disease (GERD), concomitant co-morbidities and Chinese ethnicity but not functional dyspepsia among 289 multiracial subjects undergoing diagnostic endoscopy in 2019 before the COVID-19 pandemic. We tested the reproducibility of those findings on a larger sample that included the original cohort and another 221 subjects who underwent endoscopy in 2022 after the easing of pandemic restrictions. MATERIALS AND METHODS: Archived duodenal histology slides were assessed by a pathologist blind to demographic and clinical data gleamed retrospectively from clinical chart review. Logistic regression analysis was used to explore associations between duodenal eosinophilia and the variables age, gender, ethnicity, year of sampling (2019 vs 2022), concomitant co-morbidities, functional dyspepsia, symptomatic erosive GERD (Los Angeles Grades A to D), endoscopic oesophagitis, gallstone disease, Helicobacter pylori infection, irritable bowel syndrome and NSAID consumption. Three different thresholds for defining duodenal eosinophilia (>15, >22 and >30 eosinophils per 5 high power fields) were tested. RESULTS: Year of sampling (2019, pre-pandemic) strongly predicted duodenal eosinophilia across all thresholds (OR 11.76, 13.11 and 21.41 respectively; p = 0.000). The presence of concomitant co-morbidities was a modest predictor across all thresholds whereas Chinese ethnicity only predicted at the lowest threshold. Absolute duodenal eosinophil counts predicted symptomatic erosive GERD (OR 1.03; p = 0.015) but not functional dyspepsia (OR 1.00; p = 0.896) after adjusting for age, gender, ethnicity, concomitant comorbidities and year of endoscopy. None of the subjects reached the threshold for the diagnosis of eosinophilic duodenitis. CONCLUSION: The cumulative impact of environmental exposures on duodenal eosinophil counts may be much greater than of putative factors linked to functional dyspepsia. A signal linking duodenal eosinophil counts and symptomatic erosive GERD was detected.

A Comparative Evaluation of Three Methods of Disinfection of Gypsum Casts and the Changes in Surface Roughness and Dimensional Accuracy after Disinfection-An Ex Vivo Study.

BACKGROUND: One of the major problems of everyday dental practice is cross-contamination. It can place office personnel, dentists, and patients at risk of acquiring serious illness. Disinfection helps in controlling this cross-contamination to an extent. The evaluation was done to find the efficient disinfection method on gypsum casts. AIMS: The aim of this study is to evaluate and compare the efficacy of three methods of disinfection of gypsum casts, namely, chemical disinfection by immersion, spray method, and microwave method, and also to evaluate and compare changes in surface roughness and dimensional accuracy between the three methods after disinfection. MATERIALS AND METHODS: Ex vivo and experimental study. Thirty participants were selected, and impressions of the maxillary arch were made using polyvinyl siloxane impression material. Ninety type IV die stone gypsum casts were poured. It was divided into three groups and was subjected to chemical disinfection by immersion and spray methods, and microwave method. The disinfected casts were evaluated for microbial growth, surface roughness, and dimensional accuracy. It was performed by using the one-way analysis of variance test and paired t-test followed by the Kruskal - Wallis test and Wilcoxon signed rank test (α = 0.05). RESULTS: Microwave disinfection was more effective than both immersion and spray chemical disinfection methods (P < 0.010 and <0.001). The surface roughness of the microwave-irradiated casts had significantly increased after disinfection. However, there were no significant dimensional changes by any of the methods of disinfection. CONCLUSION: Within the limitations of the study, the microwave method of disinfection is more effective in eradicating microorganisms when compared to chemical methods of disinfection by immersion and spray methods.

Combining pairwise structural similarity and deep learning interface contact prediction to estimate protein complex model accuracy in CASP15.

Estimating the accuracy of quaternary structural models of protein complexes and assemblies (EMA) is important for predicting quaternary structures and applying them to studying protein function and interaction. The pairwise similarity between structural models is proven useful for estimating the quality of protein tertiary structural models, but it has been rarely applied to predicting the quality of quaternary structural models. Moreover, the pairwise similarity approach often fails when many structural models are of low quality and similar to each other. To address the gap, we developed a hybrid method (MULTICOM_qa) combining a pairwise similarity score (PSS) and an interface contact probability score (ICPS) based on the deep learning inter-chain contact prediction for estimating protein complex model accuracy. It blindly participated in the 15th Critical Assessment of Techniques for Protein Structure Prediction (CASP15) in 2022 and performed very well in estimating the global structure accuracy of assembly models. The average per-target correlation coefficient between the model quality scores predicted by MULTICOM_qa and the true quality scores of the models of CASP15 assembly targets is 0.66. The average per-target ranking loss in using the predicted quality scores to rank the models is 0.14. It was able to select good models for most targets. Moreover, several key factors (i.e., target difficulty, model sampling difficulty, skewness of model quality, and similarity between good/bad models) for EMA are identified and analyzed. The results demonstrate that combining the multi-model method (PSS) with the complementary single-model method (ICPS) is a promising approach to EMA.

Impact of AlphaFold on structure prediction of protein complexes: The CASP15-CAPRI experiment.

We present the results for CAPRI Round 54, the 5th joint CASP-CAPRI protein assembly prediction challenge. The Round offered 37 targets, including 14 homodimers, 3 homo-trimers, 13 heterodimers including 3 antibody-antigen complexes, and 7 large assemblies. On average ~70 CASP and CAPRI predictor groups, including more than 20 automatics servers, submitted models for each target. A total of 21 941 models submitted by these groups and by 15 CAPRI scorer groups were evaluated using the CAPRI model quality measures and the DockQ score consolidating these measures. The prediction performance was quantified by a weighted score based on the number of models of acceptable quality or higher submitted by each group among their five best models. Results show substantial progress achieved across a significant fraction of the 60+ participating groups. High-quality models were produced for about 40% of the targets compared to 8% two years earlier. This remarkable improvement is due to the wide use of the AlphaFold2 and AlphaFold2-Multimer software and the confidence metrics they provide. Notably, expanded sampling of candidate solutions by manipulating these deep learning inference engines, enriching multiple sequence alignments, or integration of advanced modeling tools, enabled top performing groups to exceed the performance of a standard AlphaFold2-Multimer version used as a yard stick. This notwithstanding, performance remained poor for complexes with antibodies and nanobodies, where evolutionary relationships between the binding partners are lacking, and for complexes featuring conformational flexibility, clearly indicating that the prediction of protein complexes remains a challenging problem.

Structural Variants Create New Topological-Associated Domains and Ectopic Retinal Enhancer-Gene Contact in Dominant Retinitis Pigmentosa.

The cause of autosomal-dominant retinitis pigmentosa (adRP), which leads to loss of vision and blindness, was investigated in families lacking a molecular diagnosis. A refined locus for adRP on Chr17q22 (RP17) was delineated through genotyping and genome sequencing, leading to the identification of structural variants (SVs) that segregate with disease. Eight different complex SVs were characterized in 22 adRP-affected families with >300 affected individuals. All RP17 SVs had breakpoints within a genomic region spanning YPEL2 to LINC01476. To investigate the mechanism of disease, we reprogrammed fibroblasts from affected individuals and controls into induced pluripotent stem cells (iPSCs) and differentiated them into photoreceptor precursor cells (PPCs) or retinal organoids (ROs). Hi-C was performed on ROs, and differential expression of regional genes and a retinal enhancer RNA at this locus was assessed by qPCR. The epigenetic landscape of the region, and Hi-C RO data, showed that YPEL2 sits within its own topologically associating domain (TAD), rich in enhancers with binding sites for retinal transcription factors. The Hi-C map of RP17 ROs revealed creation of a neo-TAD with ectopic contacts between GDPD1 and retinal enhancers, and modeling of all RP17 SVs was consistent with neo-TADs leading to ectopic retinal-specific enhancer-GDPD1 accessibility. qPCR confirmed increased expression of GDPD1 and increased expression of the retinal enhancer that enters the neo-TAD. Altered TAD structure resulting in increased retinal expression of GDPD1 is the likely convergent mechanism of disease, consistent with a dominant gain of function. Our study highlights the importance of SVs as a genomic mechanism in unsolved Mendelian diseases.

A deep dilated convolutional residual network for predicting interchain contacts of protein homodimers.

MOTIVATION: Deep learning has revolutionized protein tertiary structure prediction recently. The cutting-edge deep learning methods such as AlphaFold can predict high-accuracy tertiary structures for most individual protein chains. However, the accuracy of predicting quaternary structures of protein complexes consisting of multiple chains is still relatively low due to lack of advanced deep learning methods in the field. Because interchain residue-residue contacts can be used as distance restraints to guide quaternary structure modeling, here we develop a deep dilated convolutional residual network method (DRCon) to predict interchain residue-residue contacts in homodimers from residue-residue co-evolutionary signals derived from multiple sequence alignments of monomers, intrachain residue-residue contacts of monomers extracted from true/predicted tertiary structures or predicted by deep learning, and other sequence and structural features. RESULTS: Tested on three homodimer test datasets (Homo_std dataset, DeepHomo dataset and CASP-CAPRI dataset), the precision of DRCon for top L/5 interchain contact predictions (L: length of monomer in a homodimer) is 43.46%, 47.10% and 33.50% respectively at 6 Å contact threshold, which is substantially better than DeepHomo and DNCON2_inter and similar to Glinter. Moreover, our experiments demonstrate that using predicted tertiary structure or intrachain contacts of monomers in the unbound state as input, DRCon still performs well, even though its accuracy is lower than using true tertiary structures in the bound state are used as input. Finally, our case study shows that good interchain contact predictions can be used to build high-accuracy quaternary structure models of homodimers. AVAILABILITY AND IMPLEMENTATION: The source code of DRCon is available at https://github.com/jianlin-cheng/DRCon. The datasets are available at https://zenodo.org/record/5998532#.YgF70vXMKsB. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Alterations of adipokines, pancreatic hormones and incretins in acute and convalescent COVID-19 children.

BACKGROUND: The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), accountable for Coronavirus disease 2019 (COVID-19), may cause hyperglycemia and additional systemic complexity in metabolic parameters. It is unsure even if the virus itself causes type 1 or type 2 diabetes mellitus (T1DM or T2DM). Furthermore, it is still unclear whether even recuperating COVID-19 individuals have an increased chance to develop new-onset diabetes. METHODS: We wanted to determine the impact of COVID-19 on the levels of adipokines, pancreatic hormones, incretins and cytokines in acute COVID-19, convalescent COVID-19 and control children through an observational study. We performed a multiplex immune assay analysis and compared the plasma levels of adipocytokines, pancreatic hormones, incretins and cytokines of children presenting with acute COVID-19 infection and convalescent COVID-19. RESULTS: Acute COVID-19 children had significantly elevated levels of adipsin, leptin, insulin, C-peptide, glucagon and ghrelin in comparison to convalescent COVID-19 and controls. Similarly, convalescent COVID-19 children had elevated levels of adipsin, leptin, insulin, C-peptide, glucagon, ghrelin and Glucagon-like peptide-1 (GLP-1) in comparison to control children. On the other hand, acute COVID-19 children had significantly decreased levels of adiponectin and Gastric Inhibitory Peptide (GIP) in comparison to convalescent COVID-19 and controls. Similarly, convalescent COVID-19 children had decreased levels of adiponectin and GIP in comparison to control children. Acute COVID-19 children had significantly elevated levels of cytokines, (Interferon (IFN)) IFNγ, Interleukins (IL)-2, TNFα, IL-1α, IL-1ß, IFNα, IFNß, IL-6, IL-12, IL-17A and Granulocyte-Colony Stimulating Factors (G-CSF) in comparison to convalescent COVID-19 and controls. Convalescent COVID-19 children had elevated levels of IFNγ, IL-2, TNFα, IL-1α, IL-1ß, IFNα, IFNß, IL-6, IL-12, IL-17A and G-CSF in comparison to control children. Additionally, Principal component Analysis (PCA) analysis distinguishes acute COVID-19 from convalescent COVID-19 and controls. The adipokines exhibited a significant correlation with the levels of pro-inflammatory cytokines. CONCLUSION: Children with acute COVID-19 show significant glycometabolic impairment and exaggerated cytokine responses, which is different from convalescent COVID-19 infection and controls.

Expression analysis of pro-apoptotic BAX and anti-apoptotic BCL-2 genes in relation to lactation performance in Deoni and Holstein Friesian crossbred cows.

The study was designed with the objective of expression analysis of pro-apoptotic BAX and anti-apoptotic BCL-2 genes on lactation performance in Bos indicus and HF crossbred cows during early lactation. BAX/BCL-2 mRNA expression ratio in HF crossbreds showed a steady increase from 30th day to 90th day, but in Deoni cows the ratio exhibited a different pattern, which increased from day 30 to day 60, decreased on day 75, and then increased on day 90. BAX/BCL-2 expression ratio in Deoni and HF crossbreds were lowest on day 30 and highest on day 90. On contrary, the milk yield was highest on day 30 and lowest on day 90 suggesting BCL-2 gene favors milk production and BAX gene oppose milk production. In comparison to HF crossbreds, Deoni cows exhibited highest BAX/BCL-2 ratio at the end of early lactation, indicating Bos indicus cows were more sensitive to apoptosis than HF crossbreds. Comparison of daily milk yield with BAX/BCL-2 mRNA expression ratio revealed significant negative correlation with a correlation coefficient of -0.98 (P < 0.01) and -0.95 (P < 0.05) in Deoni and HF crossbred cows, respectively. Our study provides new insights into understanding the genetic control of mammary apoptosis between Bos indicus and HF crossbreds.

Biological methylation: redefining the link between genotype and phenotype.

The central dogma of molecular biology is responsible for the crucial flow of genetic information from DNA to protein through the transcription and translation process. Although the sequence of DNA is constant in all organs, the difference in protein and variation in the phenotype is mainly due to the quality and quantity of tissue-specific gene expression and methylation pattern. The term methylation has been defined and redefined by various scientists in the last fifty years. There is always huge excitement around this field because the inheritance of something is beyond its DNA sequence. Advanced gene methylation studies have redefined molecular genetics and these tools are considered de novo in alleviating challenges of animal disease and production. Recent emerging evidence has shown that the impact of DNA, RNA, and protein methylation is crucial for embryonic development, cell proliferation, cell differentiation, and phenotype production. Currently, many researchers are focusing their work on methylation to understand its significant role in expression, disease-resistant traits, productivity, and longevity. The main aim of the present review is to provide an overview of DNA, RNA, and protein methylation, current research output from different sources, methodologies, factors responsible for methylation of genes, and future prospects in animal genetics.

The mucormycosis and stroke: The learning curve during the second COVID-19 pandemic.

BACKGROUND: The Angio-invasive Rhino-orbito-cerebral mucormycosis (ROCM) producing strokes is a less explored entity. Our hospital, a stroke-ready one, had an opportunity to manage mucormycosis when it was identified as the nodal center for mucormycosis management. We are sharing our experiences and mistakes in managing the cerebrovascular manifestations of ROCM. METHODS: We conducted a prospective observational study during the second wave of the COVID-19 pandemic from 1st May 2021 to 30th September 2021, where consecutive patients aged more than 18 years with microbiologically confirmed cases of ROCM were included. Clinical details (timing of stroke onset after ROCM symptoms, GCS, NIHSS), imaging findings (ASPECTS, the territory of stroke, the pattern of infarct, hemorrhagic transformation, cavernous sinus thrombosis), angiogram findings, management details (IV thrombolysis), and outcomes (mRS at discharge and duration of hospital stay) were documented. We also compared the demographics, clinical features (NIHSS), radiological findings, treatment details, duration of hospital stay, and functional outcome at the discharge of the ROCM stroke patients with stroke patients without ROCM. RESULTS: Stroke developed in 42% of patients with ROCM, predominantly anterior circulation border zone ischemic infarcts. Strokes occurred after a median of five days from the onset of ROCM symptoms. The most common vessel involved was the ophthalmic artery, followed by the cavernous ICA. We could not thrombolyse ROCM stroke patients. ROCM patients who developed stroke compared with patients without stroke had a more infiltrative fungal infection and higher inflammatory markers. Mucormycosis associated stroke patients had higher in-hospital mortality and poor functional outcomes. T CONCLUSION: Due to delayed recognition of stroke symptoms, none received reperfusion strategies, leading to poor functional outcomes. For early stroke detection, ROCM cases need frequent monitoring and education of patients and their relatives about the ALS acronym (loss of ambulation, limb weakness, and loss of speech).

Distance-based reconstruction of protein quaternary structures from inter-chain contacts.

Predicting the quaternary structure of protein complex is an important problem. Inter-chain residue-residue contact prediction can provide useful information to guide the ab initio reconstruction of quaternary structures. However, few methods have been developed to build quaternary structures from predicted inter-chain contacts. Here, we develop the first method based on gradient descent optimization (GD) to build quaternary structures of protein dimers utilizing inter-chain contacts as distance restraints. We evaluate GD on several datasets of homodimers and heterodimers using true/predicted contacts and monomer structures as input. GD consistently performs better than both simulated annealing and Markov Chain Monte Carlo simulation. Starting from an arbitrarily quaternary structure randomly initialized from the tertiary structures of protein chains and using true inter-chain contacts as input, GD can reconstruct high-quality structural models for homodimers and heterodimers with average TM-score ranging from 0.92 to 0.99 and average interface root mean square distance from 0.72 Å to 1.64 Å. On a dataset of 115 homodimers, using predicted inter-chain contacts as restraints, the average TM-score of the structural models built by GD is 0.76. For 46% of the homodimers, high-quality structural models with TM-score ≥ 0.9 are reconstructed from predicted contacts. There is a strong correlation between the quality of the reconstructed models and the precision and recall of predicted contacts. Only a moderate precision or recall of inter-chain contact prediction is needed to build good structural models for most homodimers. Moreover, GD improves the quality of quaternary structures predicted by AlphaFold2 on a Critical Assessment of Techniques for Protein Structure Prediction-Critical Assessments of Predictions of Interactions dataset.

Cancer Therapy-Associated Thrombosis.

[Figure: see text].

Utility of high-resolution ultrasound in measuring subcutaneous fat thickness.

OBJECTIVE: Previous studies conclude that high-resolution ultrasound (HRUS) enables noninvasive and accurate measurements of subcutaneous fat thickness. The primary objective of this cross-sectional study was to better characterize subcutaneous fat thickness measurements in a diverse patient population using HRUS. Secondarily, we sought to correlate these measurements with patients' body image. METHODS: A cross-sectional study to measure subcutaneous fat measurements at seven distinct anatomic sites, including upper and lower extremities, submental, and torso regions, in 40 men and women of different ages and races using HRUS. Independent t-tests and analysis of variance were performed to analyze findings. RESULTS: In our patient population, on average, women had thicker subcutaneous fat than men at all anatomic sites. Asian patients had significantly reduced fat thickness at peripheral anatomic sites, such as arms when compared to patients who identified as Black and Other (p = 0.05 and p = 0.008, respectively). Lastly, women reported decreased total body satisfaction at all anatomic sites when compared to men. CONCLUSION: The information obtained and methods developed in this study may be utilized clinically during patient selection for fat reduction procedures, including for estimating the degree of likely benefit; for managing pathologies involving subcutaneous fat thickness alteration; and to monitor the progression of lipodystrophy secondary to disease or drugs.