The steroid hormone aldosterone stimulates sodium (Na ؉ ) transport in tight epithelia by altering the expression of target genes that regulate the activity and trafficking of the epithelial sodium channel (ENaC Hormone-regulated sodium (Na ϩ ) transport in tight epithelia is essential for the control of circulatory volume, blood pressure, and extracellular fluid composition in vertebrates. The epithelial Na ϩ channel, ENaC, 5 constitutes the rate-limiting step for Na ϩ transport, and its activity, trafficking, and expression are important targets of regulation, most notably by the mineralocorticoid hormone aldosterone, which acts primarily through the mineralocorticoid receptor to alter the transcription of a set of target genes (1). Several studies using candidate gene approaches (2, 3) or unbiased screens (4 -8) have been undertaken to discern the mechanistic basis of aldosterone action. As with other steroid-regulated processes (9), two major classes of target genes have been identified: early and late. Early response genes appear to be required for initiation of the response, whereas the late response genes participate in consolidation (10). The latter include components of the ion transport machinery itself (for example, ENaC subunits and subunits of the Na,KATPase) and genes that encode regulatory proteins that likely act to limit the extent of the aldosterone response (for example, activators of the mitogen-activated protein kinase cascade, such as epidermal growth factor (EGF) or its receptor, epidermal growth factor receptor (11). The former category encodes primarily signaling molecules, implicated in pathways that control ENaC activity and/or trafficking (1). The best characterized of these targets is the serine-threonine kinase serum-and glucocorticoid-induced kinase-1 (SGK1) (1), which acts to increase apical membrane ENaC, at least in part, by inhibiting the ubiquitin ligase Nedd4Ϫ2, itself a modulator of ENaC trafficking and degradation (12, 13). Recently, several lines of evidence have suggested that aldosteroneregulated mediators other than SGK1 provide stimulatory input into this system (1). Most notably, although SGK1 knock-out mice have aldosterone resistance, their phenotype is substantially less severe than that of either mineralocorticoid receptor or ␣ENaC knock-out mice (1, 14) or of adrenalectomized wild type animals (15), suggesting that renal ENaC function and renal mineralocorticoid action are partially but not completely dependent on SGK1. The observation that short term aldosterone treatment induces an accumulation of SGK1 in the entire aldosterone-sensitive distal nephron, whereas the apical insertion of ENaC takes place only in the connecting tubule and early collecting duct, indicates that other factors are probably required as well to drive ENaC cell surface expression and activity and, thus, Na ϩ reabsorption (15). It is also notable that inhibitors of phosphatidylinositol 3Ј-kinase (which is responsible for activation of SGK1) do not completely abolish aldosterone-induced Na ...

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The farnesyltransferase (FTase) inhibitor FTI-277 is highly e ective at blocking oncogenic H-Ras but not KRas4B processing and signaling. While inhibition of processing and signaling of oncogenic K-Ras4B is more sensitive to the geranylgeranyltransferase I (GGTase I) inhibitor GGTI-286 than it is to FTI-277 in K-Ras4B-transformed NIH3T3 cells, the sensitivity of K-Ras as well as H-and N-Ras to the CAAX peptidomimetics in human tumor cell lines is not known. Here, we report that a panel of ®ve human carcinoma cell lines from pancreatic, pulmonary, and bladder origins all express H-, N-, and K-Ras, and their respective prenylation sensitivities to the FTase and GGTase I inhibitors is variable. In all of the cell lines investigated, the prenylation of N-Ras was highly sensitive to FTI-277, and in two of the cell lines, N-Ras showed slight sensitivity to GGTI-298, an analog of GGTI-286. Although the prenylation of H-Ras was also sensitive to FTI-277, complete inhibition of H-Ras processing even at high concentrations of FTI-277 and/or GGTI-298 was never achieved. The prenylation of K-Ras, on the other hand, was highly resistant to FTI-277 and GGTI-298. Most signi®cantly, treatment of human tumor cell lines with both inhibitors was required for inhibition of K-Ras prenylation. In one cell line, the human lung adenocarcinoma A-549, prenylation of KRas was highly resistant even when co-treated with both inhibitors. Furthermore, soft agar experiments demonstrated that in all the human tumor cell lines tested inhibition of K-Ras prenylation was not necessary for inhibition of anchorage-independent growth. In addition, although GGTI-298 had very little e ect on soft agar growth, the combination of FTI-277 and GGTI-298 resulted in signi®cant growth inhibition. Therefore, the results demonstrate that while FTI-277 inhibits N-Ras and H-Ras processing in the human tumor cell lines evaluated, inhibition of K-Ras processing requires both an FTase inhibitor as well as a GGTase I inhibitor, and that inhibition of human tumor growth in soft agar does not require inhibition of oncogenic K-Ras processing.

25/11/14 meb. accepted version attached, I have replaced file for OA paper version available through Elsevier websit

Purpose The purpose of this paper is twofold: to examine generational differences in complaint and post-recovery behaviors after service failures and recoveries, and to investigate the key factors that relate to Generation Y consumers’ responses. Design/methodology/approach In a two-stage approach, Study 1 investigates generational differences in the complaint and repurchase behaviors of a vast sample of more than 36,000 customers. Study 2 examines which factors influence Generation Y consumers’ decisions to complain and to repurchase. Findings Across four generational cohorts (the Silent Generation, Baby Boomers, Generation X, and Generation Y), consumers in Generation Y are the most likely to complain about service failures and repurchase after a satisfactory service recovery. The service recovery paradox thus is a generational feature. Generation Y’s unique characteristics – being tech savvy, heavily influenced by peers, and untrusting of brands – relate closely to their complaint and repurchase patterns. These prolific users of social media tend to stay with a service provider after experiencing satisfactory recovery but are more inclined to complain. Originality/value This study contributes to service management literature by revealing generational differences in customers’ complaint behavior and responses to recovery efforts, while also testing repurchase behavior rather than just behavioral intentions. This study provides valuable insights into the unique factors that influence Generation Y consumers’ complaint and post-recovery responses.

To reconcile conflicting reports on the role of CD40 signaling in germinal center (GC) formation, we examined the earliest stages of murine GC B cell differentiation. Peri-follicular GC precursors first expressed intermediate levels of BCL6 while co-expressing the transcription factors RelB and IRF4, the latter known to repress Bcl6 transcription. Transition of GC precursors to the BCL6hi follicular state was associated with cell division, although the number of required cell divisions was immunogen dose dependent. Potentiating T cell help or CD40 signaling in these GC precursors actively repressed GC B cell maturation and diverted their fate towards plasmablast differentiation, whereas depletion of CD4+ T cells promoted this initial transition. Thus while CD40 signaling in B cells is necessary to generate the immediate precursors of GC B cells, transition to the BCL6hi follicular state is promoted by a regional and transient diminution of T cell help.DOI: http://dx.doi.org/10.7554/eLife.19552.001

Due to the weak screening effect, the concentration and type of charge carriers in 2D semiconductor heterostructures can be effectively tuned by electrostatic gating, enabling us to realize different types of heterojunctions in a single device. Such 'type tunable' properties are useful for designing novel electrical or optoelectrical devices. Here, we demonstrate a 'type tunable' heterojunction device construct with two pieces of ambipolar 2D semiconductors: WSe2 and black phosphorus (BP). This heterojunction could be tuned to either the p-p junction or n-n junction by gate modulation. The p-p junction shows a large current rectification ratio while the n-n junction shows a negligible current rectification ratio, indicating a large valence band offset and a small conduction band offset at the WSe2/BP interface. In the optoelectrical measurements, we found the amplitude and even the polarity of photocurrent could be modulated by electrostatic gating. Our study could further enhance the understanding of designing devices based on these 'type tunable' van der Waals heterojunctions. Moreover, the properties of the WSe2/BP interface were also experimentally identified through the electrical and optoelectrical measurements in our study.

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