The human Klotho VS variant: focus on the processing and function of the V, S and VS isoforms

Klotho (KL), an anti-aging protein, attracted interest in the aging field because of the dramatic phenotype of KL deficient mice and its connection to signaling pathways implicated in aging. The KLVS variant consists of the F352V (KLV) and C370S (KLS) substitutions. It was detected in genome wide association studies (GWAS) that linked it to alterations in longevity and disease risk. The molecular mechanism(s) underlying these associations are unknown. To understand how KL increases the risk of age-related diseases, the studies in this dissertation investigated whether expression of the KLVS variant, when compared to wildtype (KLWT), displays differences in processing, protein-protein interactions and enzymatic activity. Differences in processing were evaluated by studying changes in shedding, half-life and plasma membrane localization of KL variants. The decrease in KLV shedding, as measured by the intracellular: extracellular ratio, were explained by a decreased half-life. This decreased half-life is potentially due to decreased KLV plasma membrane localization, which is attenuated by co-expression of dominant negative dynamin, suggesting a role of endocytosis in these differences. To assess whether there are changes in KLVS protein-protein interactions, differences in dimerization were measured by Blue Native gel electrophoresis and cross-linking. KLV dimerization was increased while KLS and KLVS variants decreased dimerization. Co-immunoprecipitation of tagged KL assessed whether these changes were due to alterations in homodimerization. The presence of KLVS in dimers decreased the levels of immunoprecipitated KL suggesting KLVS decreases homodimerization. Changes in heterodimerization of KLVS with fibroblast growth factor receptor (FGFR) 1c were also investigated through co-immunoprecipitation. KLVS increased heterodimerization with FGFR1c. Addition of FGF23, for which KL is a co-receptor, showed that KLVS increases FGF signaling downstream of FGFR1c. To determine differences in enzymatic activity of KLVS, 4-metylumbelliferyl-beta-D-glucuronide was used to measure alterations in glucuronidase activity. Results showed that KLVS had decreased enzymatic activity compared to KLWT. These findings are the first to show that KLVS leads to differences in function as demonstrated by decreased homodimerization and enzymatic activity and increased heterodimerization with FGFR1c. Given the association of KLVS with disease and longevity, these results suggest that these functions are integral in KL's anti-aging role in humans

ER Stress and Lipid Metabolism in Adipocytes

The role of endoplasmic reticulum (ER) stress is a rapidly emerging field of interest in the pathogenesis of metabolic diseases. Recent studies have shown that chronic activation of ER stress is closely linked to dysregulation of lipid metabolism in several metabolically important cells including hepatocytes, macrophages, β-cells, and adipocytes. Adipocytes are one of the major cell types involved in the pathogenesis of the metabolic syndrome. Recent advances in dissecting the cellular and molecular mechanisms involved in the regulation of adipogenesis and lipid metabolism indicate that activation of ER stress plays a central role in regulating adipocyte function. In this paper, we discuss the current understanding of the potential role of ER stress in lipid metabolism in adipocytes. In addition, we touch upon the interaction of ER stress and autophagy as well as inflammation. Inhibition of ER stress has the potential of decreasing the pathology in adipose tissue that is seen with energy overbalance

Cryptanalyzing a discrete-time chaos synchronization secure communication system

This paper describes the security weakness of a recently proposed secure communication method based on discrete-time chaos synchronization. We show that the security is compromised even without precise knowledge of the chaotic system used. We also make many suggestions to improve its security in future versions.Comment: 11 pages, 3 figures, latex forma

Comment on some results of Erdahl and the convex structure of reduced density matrices

In J. Math. Phys. 13, 1608-1621 (1972), Erdahl considered the convex structure of the set of $N$-representable 2-body reduced density matrices in the case of fermions. Some of these results have a straightforward extension to the $m$-body setting and to the more general quantum marginal problem. We describe these extensions, but can not resolve a problem in the proof of Erdahl's claim that every extreme point is exposed in finite dimensions. Nevertheless, we can show that when $2m \geq N$ every extreme point of the set of $N$-representable $m$-body reduced density matrices has a unique pre-image in both the symmetric and anti-symmetric setting. Moreover, this extends to the quantum marginal setting for a pair of complementary $m$-body and $(N-m)$-body reduced density matrices.Comment: 19 pages, 0 figures. Comments are welcom

PLLA-PEG-TCH-labeled bioactive molecule nanofibers for tissue engineering

By mimicking the native extracellular matrix, electrospun nanofibrous scaffolds (ENSs) can provide both chemical and physical cues to modulate cell adherence and differentiation and to promote tissue regeneration while retaining bioresorbable and biocompatible properties. In this study, ENSs were developed to deliver multiple biomolecules by loading them into the core-sheath structure and/or by conjugating them to the nanofiber surfaces. In this work, poly(L-lactide)-poly(ethylene glycol)-NH2 and poly(L-lactide) were emulsion electrospun into nanofibers with a core-sheath structure. A model drug, tetracycline hydrochloride, was loaded within the nanofibers. Amino and carboxyl reactive groups were then activated on the fiber surfaces using saturated water vapor exposure and base hydrolysis, respectively. These reactive groups allowed the surface of the ENS to be functionalized with two other bioactive molecules, fluorescein isothiocyanate- and rhodamine-labeled bovine serum albumins, which were used as model proteins. The ENSs were shown to retain their antimicrobial capacity after two functionalization reactions, indicating that multifunctional nanofibers can potentially be developed into functional wound dressings or periodontal membranes or used in more complicated tissue systems where multiple growth factors and anti-infection precautions are critical for the successful implantation and regeneration of tissues

Community Sport Service Provision, Resident Satisfaction, and Participation

Advocating for the “gold medal strategy”, China has made great advancements in elite sports; however, the significant achievement in elite sports has not translated into the development of mass sport participations. To form a stronger foundation of a sport pyramid, more attention should be directed to community sports and promoting healthy lifestyles. The purpose of this study was to examine the impact of community sport service provisions on participants’ satisfaction and in turn on their sport participation behavior. In the current study, the public sport service in community includes sport facilities, sport organizations, sport programs, fitness test, and volunteer services (fitness guide). According to the hierarchy of effects model of Lavidge and Steiner (1961), both hard services and soft services were hypothesized to exert positive influences on consumer satisfaction and participation behavior in community sport (i.e., payment and participation frequency). Of the 750 copies distributed in Guangdong, China, 576 valid questionnaires were completed and returned, yielding a usable response rate of 76.8%. The first half of the sample was used to conduct exploratory factor analyses (EFA) for the provision items; the second half was used to conduct confirmatory factor analyses (CFA) of these two measures and also conduct a structural equation modeling (SEM) analysis to examine the relationships among public service provision, consumer satisfaction, and consumption behavior in community sports. The results of EFA and CFA indicated that five aspects of community sport service provision could be categorized into hard service and soft services. Specifically, hard refers to sport facility, organization building and organizing activity which can be seen and touched while soft service refers to fitness test, fitness instruction and sport information which sometimes are intangible. The results of SEM suggested that hard service provision positively influenced consumer satisfaction (β = .685, p \u3c .01), whereas soft service provision did not exert significant influence on consumer satisfaction (β = .210, p \u3e .05). Satisfaction would positively impact the frequency of participation was supported (β = .212, p \u3c .01). Consumer satisfaction would positively impact the level of payment for participating in sport organizations was rejected (β = -.298, p \u3c .01). In conclusion, the present study provided empirical evidence that hard sport service in community, as measured by the sport facility, grassroots sport organization and sport activity program, is an important element of the public sport service construct in the context of community sports. Furthermore, it highlighted that these programs have had a strong influence on resident satisfaction and participation behavior. The resulting theoretical framework is therefore applicable in this context. Lastly, the results revealed the important role of satisfaction in the prediction of residents’ future behaviors. By understanding the major drivers of residents’ behaviors, local sport councils, community managers, grassroots organizations, and residents could work together to establish a nonhierarchical and cooperative mechanism that facilitates sport participation

A Formal Framework for Modeling Trust and Reputation in Collective Adaptive Systems

Trust and reputation models for distributed, collaborative systems have been studied and applied in several domains, in order to stimulate cooperation while preventing selfish and malicious behaviors. Nonetheless, such models have received less attention in the process of specifying and analyzing formally the functionalities of the systems mentioned above. The objective of this paper is to define a process algebraic framework for the modeling of systems that use (i) trust and reputation to govern the interactions among nodes, and (ii) communication models characterized by a high level of adaptiveness and flexibility. Hence, we propose a formalism for verifying, through model checking techniques, the robustness of these systems with respect to the typical attacks conducted against webs of trust.Comment: In Proceedings FORECAST 2016, arXiv:1607.0200

Transcriptomics-Based Network Medicine Approach Identifies Metformin as a Repurposable Drug for Atrial Fibrillation

Effective drugs for atrial fibrillation (AF) are lacking, resulting in significant morbidity and mortality. This study demonstrates that network proximity analysis of differentially expressed genes from atrial tissue to drug tar-gets can help prioritize repurposed drugs for AF. Using enrichment analysis of drug-gene signatures and functional testing in human inducible pluripotent stem cell (iPSC)-derived atrial-like cardiomyocytes, we identify metformin as a top repurposed drug candidate for AF. Using the active compactor, a new design analysis of large-scale longitudinal electronic health record (EHR) data, we determine that metformin use is significantly associated with a reduced risk of AF (odds ratio = 0.48, 95%, confidence interval [CI] 0.36- 0.64, p \u3c 0.001) compared with standard treatments for diabetes. This study utilizes network medicine meth-odologies to identify repurposed drugs for AF treatment and identifies metformin as a candidate drug