A minimal U(1)′U(1)^\prime extension of MSSM in light of the B decay anomaly

Motivated by the $R_K$ and $R_{K^*}$ anomalies from B decays, we extend the minimal supersymmetric model with a non-universal anomaly-free $U(1)^\prime$ gauge symmetry, coupling non-universally to the lepton sector as well as the quark sector. In particular, only the third generation quarks are charged under this $U(1)^\prime$, which can easily evade the dilepton bound from the LHC searches. An extra singlet is introduced to break this $U(1)^\prime$ symmetry allowing for the $\mu$-term to be generated dynamically. The relevant constraints of $B_s-\bar{B}_s$ mixing, $D^0-\bar{D}^0$ mixing and the LHC dilepton searches are considered. We find that in the allowed parameter space this $U(1)^\prime$ gauge interaction can accommodate the $R_K$ and $R_{K^*}$ anomalies and weaken considerably the $Z^\prime$ mass limits while remaining perturbative up to the Planck scale.Comment: 12 pages,2 figure

Multimodal estimation of distribution algorithms

Taking the advantage of estimation of distribution algorithms (EDAs) in preserving high diversity, this paper proposes a multimodal EDA. Integrated with clustering strategies for crowding and speciation, two versions of this algorithm are developed, which operate at the niche level. Then these two algorithms are equipped with three distinctive techniques: 1) a dynamic cluster sizing strategy; 2) an alternative utilization of Gaussian and Cauchy distributions to generate offspring; and 3) an adaptive local search. The dynamic cluster sizing affords a potential balance between exploration and exploitation and reduces the sensitivity to the cluster size in the niching methods. Taking advantages of Gaussian and Cauchy distributions, we generate the offspring at the niche level through alternatively using these two distributions. Such utilization can also potentially offer a balance between exploration and exploitation. Further, solution accuracy is enhanced through a new local search scheme probabilistically conducted around seeds of niches with probabilities determined self-adaptively according to fitness values of these seeds. Extensive experiments conducted on 20 benchmark multimodal problems confirm that both algorithms can achieve competitive performance compared with several state-of-the-art multimodal algorithms, which is supported by nonparametric tests. Especially, the proposed algorithms are very promising for complex problems with many local optima

Activation of Nlrp3 Inflammasomes Enhances Macrophage Lipid-Deposition and Migration: Implication of a Novel Role of Inflammasome in Atherogenesis

Although Nlrp3 inflammasome activation in macrophages has been shown to be critical for the development of atherosclerosis upon atherogenic stimuli, it remains unknown whether activated Nlrp3 inflammasomes by other non-atherogenic stimuli induce alterations in macrophages that may contribute in the concert with other factors to atherogenesis. Thus, the present study tested the hypothesis that activation of Nlrp3 inflammasomes by ATP, which is a classical non-lipid danger stimulus, enhances the migration of macrophage and increases lipids deposition in macrophages accelerating foam cell formation. We first demonstrated that extracellular ATP (2.5 mM) markedly increased the formation and activation of Nlrp3 inflammasomes in bone marrow macrophages (BMMs) from wild type (Asc+/+) mice resulting in activation of caspase-1 and IL-1β production. In these Asc+/+ macrophages, such stimulation of inflammasomes by non-lipid ATP was similar to those induced by atherogenic stimuli such as cholesterol crystals or 7-ketocholesterol. Both non-lipid and lipid forms of stimuli induced formation and activation of Nlrp3 inflammasomes, which were prevented by Asc gene deletion. Interestingly, Asc+/+ BMMs had dramatic lipids accumulation after stimulation with ATP. Further, we demonstrated that large amount of cholesterol was accumulated in lysosomes of Asc+/+ BMMs when inflammasomes were activated by ATP. Such intracellular and lysosomal lipids deposition was not observed in Asc−/− BMMs and also prevented by caspase-1 inhibitor WEHD. In addition, in vitro and in vivo experiments revealed that migration of Asc+/+ BMMs increased due to stimulation of Nlrp3 inflammasomes, which was markedly attenuated in Asc−/− BMMs. Together, these results suggest that activation of Nlrp3 inflammasomes remarkably increases the susceptibility of macrophages to lipid deposition and their migration ability. Such novel action of inflammasomes may facilitate entry or retention of macrophages into the arterial wall, where they form foam cells and ultimately induce atherosclerosis

A Common Variant in CLDN14 is Associated with Primary Biliary Cirrhosis and Bone Mineral Density.

Primary biliary cirrhosis (PBC), a chronic autoimmune liver disease, has been associated with increased incidence of osteoporosis. Intriguingly, two PBC susceptibility loci identified through genome-wide association studies are also involved in bone mineral density (BMD). These observations led us to investigate the genetic variants shared between PBC and BMD. We evaluated 72 genome-wide significant BMD SNPs for association with PBC using two European GWAS data sets (n = 8392), with replication of significant findings in a Chinese cohort (685 cases, 1152 controls). Our analysis identified a novel variant in the intron of the CLDN14 gene (rs170183, Pfdr = 0.015) after multiple testing correction. The three associated variants were followed-up in the Chinese cohort; one SNP rs170183 demonstrated consistent evidence of association in diverse ethnic populations (Pcombined = 2.43 × 10(-5)). Notably, expression quantitative trait loci (eQTL) data revealed that rs170183 was correlated with a decline in CLDN14 expression in both lymphoblastoid cell lines and T cells (Padj = 0.003 and 0.016, respectively). In conclusion, our study identified a novel PBC susceptibility variant that has been shown to be strongly associated with BMD, highlighting the potential of pleiotropy to improve gene discovery

Increase in neuroexcitability of unmyelinated C-type vagal ganglion neurons during initial postnatal development of visceral afferent reflex functions

BACKGROUND: Baroreflex gain increase up closely to adult level during initial postnatal weeks, and any interruption within this period will increase the risk of cardiovascular problems in later of life span. We hypothesize that this short period after birth might be critical for postnatal development of vagal ganglion neurons (VGNs). METHODS: To evaluate neuroexcitability evidenced by discharge profiles and coordinate changes, ion currents were collected from identified A- and C-type VGNs at different developmental stages using whole-cell patch clamping. RESULTS: C-type VGNs underwent significant age-dependent transition from single action potential (AP) to repetitive discharge. The coordinate changes between TTX-S and TTX-R Na(+) currents were also confirmed and well simulated by computer modeling. Although 4-AP or iberiotoxin age dependently increased firing frequency, AP duration was prolonged in an opposite fashion, which paralleled well with postnatal changes in 4-AP- and iberiotoxin-sensitive K(+) current activity, whereas less developmental changes were verified in A-types. CONCLUSION: These data demonstrate for the first time that the neuroexcitability of C-type VGNs increases significantly compared with A-types within initial postnatal weeks evidenced by AP discharge profiles and coordinate ion channel changes, which explain, at least in part, that initial postnatal weeks may be crucial for ontogenesis in visceral afferent reflex function

Free field realization of the exceptional current superalgebra \hat{D(2,1;\a)}_k

The free-field representations of the D(2,1;\a) current superalgebra and the corresponding energy-momentum tensor are constructed. The related screening currents of the first kind are also presented.Comment: Latex file, 10 page

Changes of monocyte human leukocyte antigen-DR expression as a reliable predictor of mortality in severe sepsis

INTRODUCTION: Many studies have shown that monocyte human leukocyte antigen-DR (mHLA-DR) expression may be a good predictor for mortality in severe septic patients. On the contrary, other studies found mHLA-DR was not a useful prognostic marker in severe sepsis. Few studies have taken changes of mHLA-DR during treatment into consideration. The objective of this study was to estimate the prognostic value of changes of mHLA-DR to predict mortality in severe sepsis. METHODS: In this prospective observational study, mHLA-DR was measured by flow cytometry in peripheral blood from 79 adult patients with severe sepsis. mHLA-DR levels were determined on day 0, 3, 7 after admission to the surgical intensive care unit (SICU) with a diagnosis of severe sepsis. ΔmHLA-DR(3 )and ΔmHLA-DR(7 )were defined as the changes in mHLA-DR value on day 3 and day 7 compared to that on day 0. Data were compared between 28-day survivors and non-survivors. Receiver operating characteristic (ROC) curves were plotted to measure the performance and discriminating threshold of ΔmHLA-DR(3), ΔmHLA-DR(7), ΔmHLA-DR(7-3), mHLA-DR(0), mHLA-DR(3 )and mHLA-DR(7 )in predicting mortality of severe sepsis. RESULTS: ROC curve analysis showed that ΔmHLA-DR(3 )and ΔmHLA-DR(7 )were reliable indicators of mortality in severe sepsis. A ΔmHLA-DR(3 )value of 4.8% allowed discrimination between survivors and non-survivors with a sensitivity of 89.0% and a specificity of 93.7%; similarly, ΔmHLA-DR(7 )value of 9% allowed discrimination between survivors and non-survivors with a sensitivity of 85.7% and a specificity of 90.0%. Patients with ΔmHLA-DR(3 )≤4.8% had higher mortality than those with ΔmHLA-DR(3 )> 4.8% (71.4% vs. 2.0%, OR 125.00, 95% CI 13.93 to 1121.67); patients with ΔmHLA-DR(7 )≤9% had higher mortality than those with ΔmHLA-DR(7 )> 9% (52.9% vs. 2.0%, OR 54.00, 95% CI 5.99 to 486.08). The mean change of mHLA-DR significantly increased in the survivor group with the passage of time; from day 0 to day 3 and day 7, changes were 6.45 and 16.90 (P < 0.05), respectively. CONCLUSIONS: The change of mHLA-DR over time may be a reliable predictor for mortality in patients with severe sepsis

Integrated analysis identifies microRNA-195 as a suppressor of Hippo-YAP pathway in colorectal cancer

Abstract Background With persistent inconsistencies in colorectal cancer (CRC) miRNAs expression data, it is crucial to shift toward inclusion of a “pre-laboratory” integrated analysis to expedite effective precision medicine and translational research. Aberrant expression of hsa-miRNA-195 (miR-195) which is distinguished as a clinically noteworthy miRNA has previously been observed in multiple cancers, yet its role in CRC remains unclear. Methods In this study, we performed an integrated analysis of seven CRC miRNAs expression datasets. The expression of miR-195 was validated in The Cancer Genome Atlas (TCGA) datasets, and an independent validation sample cohort. Colon cancer cells were transfected with miR-195 mimic and inhibitor, after which cell proliferation, colony formation, migration, invasion, and dual luciferase reporter were assayed. Xenograft mouse models were used to determine the role of miR-195 in CRC tumorigenicity in vivo. Results Four downregulated miRNAs (hsa-let-7a, hsa-miR-125b, hsa-miR-145, and hsa-miR-195) were demonstrated to be potentially useful diagnostic markers in the clinical setting. CRC patients with a decreased level of miR-195-5p in tumor tissues had significantly shortened survival as revealed by the TCGA colon adenocarcinoma (COAD) dataset and our CRC cohort. Overexpression of miR-195-5p in DLD1 and HCT116 cells repressed cell growth, colony formation, invasion, and migration. Inhibition of miR-195-5p function contributed to aberrant cell proliferation, migration, invasion, and epithelial mesenchymal transition (EMT). We identified miR-195-5p binding sites within the 3’-untranslated region (3′-UTR) of the human yes-associated protein (YAP) mRNA. YAP1 expression was downregulated after miR-195-5p treatment by qRT-PCR analysis and western blot. Conclusions Four downregulated miRNAs were shown to be prime candidates for a panel of biomarkers with sufficient diagnostic accuracy for CRC in a clinical setting. Our integrated microRNA profiling approach identified miR-195-5p independently associated with prognosis in CRC. Our results demonstrated that miR-195-5p was a potent suppressor of YAP1, and miR-195-5p-mediated downregulation of YAP1 significantly reduced tumor development in a mouse CRC xenograft model. In the clinic, miR-195-5p can serve as a prognostic marker to predict the outcome of the CRC patients