Functional interaction between the ZO-1-interacting transcription factor ZONAB/DbpA and the RNA processing factor symplekin

Epithelial tight junctions participate in the regulation of gene expression by controlling the activity of transcription factors that can interact with junctional components. One such protein is the Y-box transcription factor ZONAB/DbpA that binds to ZO-1, a component of the junctional plaque. Symplekin, another nuclear protein that can associate with tight junctions, functions in the regulation of polyadenylation and thereby promotes gene expression. Here, we addressed the question of whether these two proteins interact and whether this is of functional relevance. We demonstrate that ZONAB/DbpA and symplekin form a complex in kidney and intestinal epithelial cells that can be immunoprecipitated and that exists in the nucleus. The interaction between ZONAB/DbpA and symplekin can be reconstituted with recombinant proteins. In reporter gene assays in which ZONAB/DbpA functions as a repressor, symplekin functionally interacts with ZONAB/DbpA, indicating that symplekin can also promote transcriptional repression. RNAi experiments indicate that symplekin depletion reduces the nuclear accumulation and the transcriptional activity of ZONAB/DbpA in colon adenocarcinoma cells, resulting in inhibition of proliferation and reduced expression of the ZONAB/DbpA-target gene cyclin D1. Our data thus indicate that symplekin and ZONAB/DbpA cooperate in the regulation of transcription, and that they promote epithelial proliferation and cyclin D1 expression

Southwest Research Institute assistance to NASA in biomedical areas of the technology utilization program Quarterly progress report, 1 Jul. - 30 Sep. 1968

Southwest Research Institute activites in NASA technology utilization program for biomedical use, 1 Jul. - 30 Sep. 196

Fast generation of ultrastable computer glasses by minimization of an augmented potential energy

We present a model and protocol that enable the generation of extremely stable computer glasses at minimal computational cost. The protocol consists of an instantaneous quench in an augmented potential energy landscape, with particle radii as additional degrees of freedom. We demonstrate how our glasses' mechanical stability, which is readily tunable in our approach, is reflected both in microscopic and macroscopic observables. Our observations indicate that the stability of our computer glasses is at least comparable to that of computer glasses generated by the celebrated Swap Monte Carlo algorithm. Strikingly, some key properties support even qualitatively enhanced stability in our scheme: the density of quasilocalized excitations displays a gap in our most stable computer glasses, whose magnitude scales with the polydispersity of the particles. We explain this observation, which is consistent with the lack of plasticity we observe at small stress. It also suggests that these glasses are depleted from two-level systems, similarly to experimental vapor-deposited ultrastable glasses.Comment: 11 pages, 10 figure

Monoamine oxidase A expression is vital for embryonic brain development by modulating developmental apoptosis

Monoamine oxidases (MAO-A, MAO-B) metabolize biogenic amines and have been implicated in neuronal apoptosis. Although apoptosis is an important process in embryo development, the role of MAO isoenzymes has not been investigated in detail. We found that expression of MAO-A and MAO-B can be detected early on during embryo development. Expression levels remained constant until around midgestation but then dropped to almost undetectable levels toward birth. Similar expression kinetics were observed in the brain. Isoform-specific expression silencing of MAO-A mediated by siRNA during in vitro embryogenesis induced developmental defects, as indicated by a reduction of the crown rump length and impaired cerebral development. These alterations were paralleled by elevated serotonin levels. Similar abnormalities were observed when embryos were cultured in the presence of the MAO-A inhibitor clorgyline or when the transcriptional inhibitor of MAO-A expression Rl was overexpressed. In contrast, no such alterations were detected when expression of MAO-B was knocked down. To explore the underlying mechanisms for the developmental abnormalities in MAO-A knockdown embryos, we quantified the degree of developmental apoptosis in the developing brain. MAO-A knockdown reduced the number of apoptotic cells in the neuroepithelium, which coincided with impaired activation of caspases 3 and 9. Moreover, we observed reduced cyclin Dl levels as an indicator of impaired cell proliferation in MAO-A knockdown embryos. This data highlights MAO-A as a vital regulator of embryonic brain development

Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing

Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice

Estimating union wage effects in Great Britain during 1991-2003

Using a dynamic model of unionism and wage determination we find that the unobserved factors that influence union membership also affect wages. The estimates suggest that UK trade unions still play a non-negligible, albeit diminishing, role in wage formation. It appears that the greater impact of un observables in determining individual union propensity concerning the second period under analysis, versus past unionisation experience, implies that those remaining in unions during (1997-2002) gain most from their sorting decision. The significant contribution of unobserved heterogeneity renders the total union wage differential highly variable across individuals. The endogeneity correction procedure employed yields a discernible pattern of the estimated union wage effect relative to OLS and Fixed effects. This is in line with Robinson (1989a) and Vella and Verbeek (1998) and refutes the pessimistic conclusions reached by Freeman and Medoff (1982) and Lewis (1986) that endogeneity correction methodologies do not contribute to our understanding of the union wage effect puzzle

Determinants of trade union membership in Great Britain during 1991-2003

We analyse the determinants of union membership in the UK using data from the BHPS (1991-2003). Employing three alternative methodologies to control for the problem of initial conditions we find that union membership remains persistent even after controlling for the unobserved effect. There is evidence of a considerable correlation between the unobserved individual heterogeneity and the initial membership status. Ignoring this overstates the degree of state dependence of union membership greatly. The extent of state dependence in union membership status is notably higher in the (1991-1996) period estimates and appears to be more pronounced in the case of male employees for the entire period under analysis. The second period estimates reveal that unobserved heterogeneity has a more prominent impact in determining future unionisation probability versus past union membership. Finally, the estimates suggest that an individual´s propensity to unionise is determined by a mixture of industrial and personal characteristics. This is at odds with earlier studies, such as Booth (1986) and Wright (1995), failing to control for unobservable effects and concluding that personal attributes do not have a significant impact on unionisation propensity

The Process of Wage Adjustment: An Analysis Using Establishment-Level Data

This article presents a study of the influences on the factors that shape wage adjustments. The cost of living, comparability with other firms' wages, the fulfilment of collective agreements at sector level, the need to recruit and retain employees, the performance of the organisation, and the climate of industrial relations are included as factors of interest. The analysis was carried out using a sample of Spanish manufacturing plants. Our results show that the structural characteristics of the establishment such as its size or foreign ownership, as well as the wage setting arrangements and trade unions, play a role in explaining the importance of the factors mentioned in shaping wage adjustments. The human resource management policies adopted by the employer seem to be less relevant, although the qualification of workers and the use of pay for performance have a significant impact on the process of wage adjustment.pay settlements, collective bargaining, wage negotiation

Union Decline in Britain

This paper investigates the demise of unionisation in British private sector workplaces over the last quarter century. We show that dramatic union decline has occurred across all types of workplace. Although the union wage premium persists it is quite small in 2004. Negative union effects on employment growth and financial performance are largely confined to the 1980s. Managerial perceptions of the climate of relations between managers and workers has deteriorated since the early 1980s across the whole private sector, whether the workplace is unionised or not.trade unions, employment growth, financial performance, industrialrelations