Re-Examination of the Exacerbating Effect of Inflammasome Components during Radiation Injury

Radiation can be applied for therapeutic benefit against cancer or may result in devastating harm due to accidental or intentional release of nuclear energy. In all cases, radiation exposure causes molecular and cellular damage, resulting in the production of inflammatory factors and danger signals. Several classes of innate immune receptors sense the released damage associated molecules and activate cellular response pathways, including the induction of inflammasome signaling that impacts IL-1β/IL-18 maturation and cell death. A previous report indicated inflammasomes aggravate acute radiation syndrome. In contrast, here we find that inflammasome components do not exacerbate gamma-radiation-induced injury by examining heterozygous and gene-deletion littermate controls in addition to wild-type mice. Absence of some inflammasome genes, such as caspase-1/11 and Nlrp3, enhance susceptibility of treated mice to acute radiation injury, indicating importance of the inflammasome pathway in radioprotection. Surprisingly, we discover that the survival outcome may be sex-dependent as more inflammasome-deficient male mice are susceptible to radiation-induced injury. We discuss parameters that may influence the role of inflammasomes as radioprotective or radioexacerbating factors in recovery from radiation injury including the use of littermate controls, the sex of the animals, differences in microbiota within the colonies and other experimental conditions. Under the conditions tested, inflammasome components do not exacerbate radiation injury, but rather provide protective benefit

Effects of R-parity Violation on the Charged Higgs Boson Decays

We calculate one-loop R-parity-violating couplings corrections to the processes $H^-\to \tau\bar{\nu_\tau}$ and $H^-\to b\bar{t}$. We find that the corrections to the $H^-\to \tau\bar{\nu_\tau}$ decay mode are generally about 0.1%, and can be negligible. But the corrections to the $H^-\to b\bar{t}$ decay mode can reach a few percent for the favored parameters.Comment: 17 pages,6 figures. One type error in the title correcte

Supersymmetric Electroweak Corrections to Charged Higgs Boson Production in Association with a Top Quark at Hadron Colliders

We calculate the $O(\alpha_{ew}m_{t(b)}^{2}/m_{W}^{2})$ and $O(\alpha_{ew} m_{t(b)}^4/m_W^4)$ supersymmetric electroweak corrections to the cross section for the charged Higgs boson production in association with a top quark at the Tevatron and the LHC. These corrections arise from the quantum effects which are induced by potentially large Yukawa couplings from the Higgs sector and the chargino-top(bottom)-sbottom(stop) couplings, neutralino-top(bottom)-stop(sbottom) couplings and charged Higgs-stop-sbottom couplings. They can decrease or increase the cross section depending on $\tan\beta$ but are not very sensitive to the mass of the charged Higgs boson for high $\tan\beta$. At low $\tan\beta(=2)$ the corrections decrease the total cross sections significantly, which exceed -12% for $m_{H^{\pm}}$ below $300GeV$ at both the Tevatron and the LHC, but for $m_{H^{\pm}}>300GeV$ the corrections can become very small at the LHC. For high $\tan\beta(=10,30)$ these corrections can decrease or increase the total cross sections, and the magnitude of the corrections are at most a few percent at both the Tevatron and the LHC.Comment: 28 pages including 4 eps figure

FKBP12.6 Deficiency and Defective Calcium Release Channel (Ryanodine Receptor) Function Linked to Exercise-Induced Sudden Cardiac Death

AbstractArrhythmias, a common cause of sudden cardiac death, can occur in structurally normal hearts, although the mechanism is not known. In cardiac muscle, the ryanodine receptor (RyR2) on the sarcoplasmic reticulum releases the calcium required for muscle contraction. The FK506 binding protein (FKBP12.6) stabilizes RyR2, preventing aberrant activation of the channel during the resting phase of the cardiac cycle. We show that during exercise, RyR2 phosphorylation by cAMP-dependent protein kinase A (PKA) partially dissociates FKBP12.6 from the channel, increasing intracellular Ca2+ release and cardiac contractility. FKBP12.6−/− mice consistently exhibited exercise-induced cardiac ventricular arrhythmias that cause sudden cardiac death. Mutations in RyR2 linked to exercise-induced arrhythmias (in patients with catecholaminergic polymorphic ventricular tachycardia [CPVT]) reduced the affinity of FKBP12.6 for RyR2 and increased single-channel activity under conditions that simulate exercise. These data suggest that “leaky” RyR2 channels can trigger fatal cardiac arrhythmias, providing a possible explanation for CPVT

Clustering Algorithms: Their Application to Gene Expression Data

Gene expression data hide vital information required to understand the biological process that takes place in a particular organism in relation to its environment. Deciphering the hidden patterns in gene expression data proffers a prodigious preference to strengthen the understanding of functional genomics. The complexity of biological networks and the volume of genes present increase the challenges of comprehending and interpretation of the resulting mass of data, which consists of millions of measurements; these data also inhibit vagueness, imprecision, and noise. Therefore, the use of clustering techniques is a first step toward addressing these challenges, which is essential in the data mining process to reveal natural structures and iden-tify interesting patterns in the underlying data. The clustering of gene expression data has been proven to be useful in making known the natural structure inherent in gene expression data, understanding gene functions, cellular processes, and subtypes of cells, mining useful information from noisy data, and understanding gene regulation. The other benefit of clustering gene expression data is the identification of homology, which is very important in vaccine design. This review examines the various clustering algorithms applicable to the gene expression data in order to discover and provide useful knowledge of the appropriate clustering technique that will guarantee stability and high degree of accuracy in its analysis procedure

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry–specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13–7.22) and 33.41 (95% CI = 10.86–102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17–25%) for TA heterozygotes and 38% (95% CI = 13–65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. Patient summary: We found that rs72725854, an African ancestry–specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening. © 2020 The AuthorsThe African ancestry–specific prostate cancer risk variant at 8q24, rs72725854, is enriched in men diagnosed at younger ages and men with a prostate cancer family history. Carriers of this risk allele would benefit from regular and earlier prostate cancer screening