Conventional and Unconventional Mechanisms by which Exocytosis Proteins Oversee β-cell Function and Protection

Type 2 diabetes (T2D) is one of the prominent causes of morbidity and mortality in the United States and beyond, reaching global pandemic proportions. One hallmark of T2D is dysfunctional glucose-stimulated insulin secretion from the pancreatic β-cell. Insulin is secreted via the recruitment of insulin secretory granules to the plasma membrane, where the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) and SNARE regulators work together to dock the secretory granules and release insulin into the circulation. SNARE proteins and their regulators include the Syntaxins, SNAPs, Sec1/Munc18, VAMPs, and double C2-domain proteins. Recent studies using genomics, proteomics, and biochemical approaches have linked deficiencies of exocytosis proteins with the onset and progression of T2D. Promising results are also emerging wherein restoration or enhancement of certain exocytosis proteins to β-cells improves whole-body glucose homeostasis, enhances β-cell function, and surprisingly, protection of β-cell mass. Intriguingly, overexpression and knockout studies have revealed novel functions of certain exocytosis proteins, like Syntaxin 4, suggesting that exocytosis proteins can impact a variety of pathways, including inflammatory signaling and aging. In this review, we present the conventional and unconventional functions of β-cell exocytosis proteins in normal physiology and T2D and describe how these insights might improve clinical care for T2D.     

PE—01型水玻璃砂溃散剂的研制与应用

试验研究了ＰＥ—０１溃散剂的加入量与芯砂性能的关系，并与其它同类产品进行了对比。     

Exploring the impact of software requirements on system-wide goals: a method using satisfaction arguments and i* goal modelling

This paper describes the application of requirements engineering concepts to support the analysis of the impact of new software systems on system-wide goals. Requirements on a new or revised software component of a socio-technical system not only have implications on the goals of the subsystem itself, but they also impact upon the goals of the existing integrated system. In industries such as air traffic management and healthcare, impacts need to be identified and demonstrated in order to assess concerns such as risk, safety, and accuracy. A method called PiLGRIM was developed which integrates means-end relationships within goal modelling with knowledge associated with the application domain. The relationship between domain knowledge and requirements, as described in a satisfaction argument, adds traceability rationale to help determine the impacts of new requirements across a network of heterogeneous actors. We report procedures that human analysts follow to use the concepts of satisfaction arguments in a software tool for i* goal modelling. Results were demonstrated using models and arguments developed in two case studies, each featuring a distinct socio-technical system??a new controlled airspace infringement detection tool for NATS (the UK??s air navigation service provider), and a new version of the UK??s HIV/AIDS patient reporting system. Results provided evidence towards our claims that the conceptual integration of i* and satisfaction arguments is usable and useful to human analysts, and that the PiLGRIM impact analysis procedures and tool support are effective and scalable to model and analyse large and complex socio-technical systems.     

What failure analysis can do for the machine designer,operator, diagnostician,and prognostician

A competent failure analyst can often determine whether the machine design was nominally adequate with a half hour time slot for visual examination. The use of macrofractography, a specialized type of visual examination, can allow trained personnel to determine whether improper alignment or component imperfections may have contributed to an unexpected failure. Case studies will be presented. Some examples of “learning from the graveyard” and how that can facilitate improvements in design, manufacturing, and operations will be described. Reprinted with permission from Proceeding of the 58th Meeting of the Society for Machinery Failure Prevention Technology, April 2004, p. 329.     

Organizing Sexuality: Silencing and the Push–Pull Process of Co-sexuality in the Workplace

How human beings think about, talk about, and organize around sexuality is changing. Growing social legitimization for sexual minority relationships and a more fluid social understanding of sexual identities has shifted how we bound “normal” sexuality. In the workplace, these shifting norms affect employees of all sexual identities who must make sense of new policies and complex daily practices. This paper introduces the concept of co-sexuality, the push-and-pull process of communicatively organizing around sexuality. Using this concept, we take a grounded theory approach to exploring how employees of various sexualities and in different occupations understand “normal” sexuality and subsequently organize around it. Ultimately, participants described being silenced or silencing another to maintain sexual “norms” at work.     

Similarity between class A and class B G-protein-coupled receptors exemplified through calcitonin gene-related peptide receptor modelling and mutagenesis studies

Modelling class B G-protein-coupled receptors (GPCRs) using class A GPCR structural templates is difficult due to lack of homology. The plant GPCR, GCR1, has homology to both class A and class B GPCRs. We have used this to generate a class A–class B alignment, and by incorporating maximum lagged correlation of entropy and hydrophobicity into a consensus score, we have been able to align receptor transmembrane regions. We have applied this analysis to generate active and inactive homology models of the class B calcitonin gene-related peptide (CGRP) receptor, and have supported it with site-directed mutagenesis data using 122 CGRP receptor residues and 144 published mutagenesis results on other class B GPCRs. The variation of sequence variability with structure, the analysis of polarity violations, the alignment of group-conserved residues and the mutagenesis results at 27 key positions were particularly informative in distinguishing between the proposed and plausible alternative alignments. Furthermore, we have been able to associate the key molecular features of the class B GPCR signalling machinery with their class A counterparts for the first time. These include the [K/R]KLH motif in intracellular loop 1, [I/L]xxxL and KxxK at the intracellular end of TM5 and TM6, the NPXXY/VAVLY motif on TM7 and small group-conserved residues in TM1, TM2, TM3 and TM7. The equivalent of the class A DRY motif is proposed to involve Arg^2.39, His^2.43 and Glu^3.46, which makes a polar lock with T^6.37. These alignments and models provide useful tools for understanding class B GPCR function.