Characterization of the role of the RNA-binding protein FUS in the DNA damage response

FUS/TLS (fused in sarcoma/translocated in liposarcoma), a ubiquitously expressed RNA-binding protein, has been linked to a variety of cellular processes, including RNA metabolism, microRNA biogenesis and DNA repair. However, the precise cellular function of FUS remains unclear. Recently, mutations in the FUS gene have been found in ∼5% of familial Amyotrophic Lateral Sclerosis, a neurodegenerative disorder characterized by the dysfunction and death of motor neurons. Since MEFs and B-lymphocytes derived from FUS knockdown mice display major sensitivity to ionizing radiation and chromosomal aberrations [1,2], we are investigating the effects of DNA damage both in the presence or in the absence of FUS. To this purpose, we have generated a SH-SY5Y human neuroblastoma cell line expressing a doxycycline-induced shRNA targeting FUS, which specifically depletes the protein. We have found that FUS depletion induces an activation of the DNA damage response (DDR). However, treatment with genotoxic agents did not induce any strong changes in ATM (Ataxia Telangiectasia Mutated)-mediated DDR signaling. Interestingly, genotoxic treatment results in changes in the subcellular localization of FUS in normal cells. We are currently exploring on one hand the mechanism by which FUS depletion leads to DNA damage, and on the other the functional significance of FUS relocalization after genotoxic stress.

The role of the state in investor-state arbitration

The Role of the State in Investor-State Arbitration is a collection of contributions from lawyers, arbitrators and political scientists on the development of the concept of the “State” in a field that currently presents an increasing number of controversial disputes: Investor-State Arbitration. The book analyzes the limits of the host State as a regulator, studying issues such as attribution and the role of State-Owned Enterprises and sub-State entities; the changing role of the home State in Investor-State disputes, including its direct participation in Investor-State arbitration and State to State dispute settlement; and the overall role that both home and host States can play in the improvement of Investor-State Dispute Settlement.

The role of the right frontal eye field in overt visual attention deployment as assessed by free visual exploration

The frontal eye field (FEF) is known to be involved in saccade generation and visual attention control. Studies applying covert attentional orienting paradigms have shown that the right FEF is involved in attentional shifts to both the left and the right hemifield. In the current study, we aimed at examining the effects of inhibitory continuous theta burst (cTBS) transcranial magnetic stimulation over the right FEF on overt attentional orienting, as measured by a free visual exploration paradigm. In forty-two healthy subjects, free visual exploration of naturalistic pictures was tested in three conditions: (1) after cTBS over the right FEF; (2) after cTBS over a control site (vertex); and, (3) without any stimulation. The results showed that cTBS over the right FEF-but not cTBS over the vertex-triggered significant changes in the spatial distribution of the cumulative fixation duration. Compared to the group without stimulation and the group with cTBS over the vertex, cTBS over the right FEF decreased cumulative fixation duration in the left and in the right peripheral regions, and increased cumulative fixation duration in the central region. The present study supports the view that the right FEF is involved in the bilateral control of not only covert, but also of overt, peripheral visual attention.

Hypofibrinolysis in type 2 diabetes: the role of the inflammatory pathway and complement C3

AIMS/HYPOTHESIS Plasminogen activator inhibitor-1 (PAI-1) has been regarded as the main antifibrinolytic protein in diabetes, but recent work indicates that complement C3 (C3), an inflammatory protein, directly compromises fibrinolysis in type 1 diabetes. The aim of the current project was to investigate associations between C3 and fibrinolysis in a large cohort of individuals with type 2 diabetes. METHODS Plasma levels of C3, C-reactive protein (CRP), PAI-1 and fibrinogen were analysed by ELISA in 837 patients enrolled in the Edinburgh Type 2 Diabetes Study. Fibrin clot lysis was analysed using a validated turbidimetric assay. RESULTS Clot lysis time correlated with C3 and PAI-1 plasma levels (r = 0.24, p < 0.001 and r = 0.22, p < 0.001, respectively). In a multivariable regression model involving age, sex, BMI, C3, PAI-1, CRP and fibrinogen, and using log-transformed data as appropriate, C3 was associated with clot lysis time (regression coefficient 0.227 [95% CI 0.161, 0.292], p < 0.001), as was PAI-1 (regression coefficient 0.033 [95% CI 0.020, 0.064], p < 0.05) but not fibrinogen (regression coefficient 0.003 [95% CI -0.046, 0.051], p = 0.92) or CRP (regression coefficient 0.024 [95% CI -0.008, 0.056], p = 0.14). No correlation was demonstrated between plasma levels of C3 and PAI-1 (r = -0.03, p = 0.44), consistent with previous observations that the two proteins affect different pathways in the fibrinolytic system. CONCLUSIONS/INTERPRETATION Similarly to PAI-1, C3 plasma levels are independently associated with fibrin clot lysis in individuals with type 2 diabetes. Therefore, future studies should analyse C3 plasma levels as a surrogate marker of fibrinolysis potential in this population.

Role of the Salmonella pathogenicity island 1 effector proteins SipA, SopB, SopE, and SopE2 in Salmonella enterica subspecies 1 serovar Typhimurium colitis in streptomycin-pretreated mice.

Salmonella enterica subspecies 1 serovar Typhimurium (serovar Typhimurium) induces enterocolitis in humans and cattle. The mechanisms of enteric salmonellosis have been studied most extensively in calf infection models. The previous studies established that effector protein translocation into host cells via the Salmonella pathogenicity island 1 (SPI-1) type III secretion system (TTSS) is of central importance in serovar Typhimurium enterocolitis. We recently found that orally streptomycin-pretreated mice provide an alternative model for serovar Typhimurium colitis. In this model the SPI-1 TTSS also plays a key role in the elicitation of intestinal inflammation. However, whether intestinal inflammation in calves and intestinal inflammation in streptomycin-pretreated mice are induced by the same SPI-1 effector proteins is still unclear. Therefore, we analyzed the role of the SPI-1 effector proteins SopB/SigD, SopE, SopE2, and SipA/SspA in elicitation of intestinal inflammation in the murine model. We found that sipA, sopE, and, to a lesser degree, sopE2 contribute to murine colitis, but we could not assign an inflammation phenotype to sopB. These findings are in line with previous studies performed with orally infected calves. Extending these observations, we demonstrated that in addition to SipA, SopE and SopE2 can induce intestinal inflammation independent of each other and in the absence of SopB. In conclusion, our data corroborate the finding that streptomycin-pretreated mice provide a useful model for studying the molecular mechanisms of serovar Typhimurium colitis and are an important starting point for analysis of the molecular events triggered by SopE, SopE2, and SipA in vivo.

The Strategic Role of the Sales Force: Perceptions of Senior Sales Executives

Current models of sales force strategy imply formidable information processing demands, which leads us to take a cognitive approach to studying the issue of sales force strategy. We focus on how top-level executives use mental models of sales force performance to simplify the issue of sales force strategy. We interviewed 74 senior executives responsible for their firms’ selling function using the repertory grid approach, as this methodology has been shown to be particularly effective at uncovering the collective cognitive maps on which executives’ decisions and behaviors are based. Executives identified a broad set of 37 strategic concepts that they felt distinguish the sales force efforts of directly competing companies. A second set of sales executives classified the 37 concepts into capabilities, resources, and organizational context concepts. Based on the classification results and feedback from both sets of executives, we developed research propositions for examining sales force strategy and provide directions for future research.

A novel CYP17A1 deletion causes a functional knockout of the steroid enzyme 17-hydroxylase and 17,20-lyase in a Turkish family and illustrates the precise role of the CYP17A1 gene

A novel homozygous long-range deletion of the CYP17A1 gene abolished protein expression and caused the severest form of 17-hydroxylase deficiency in one kindred of a Turkish family. The affected subjects presented with 46,XY sex reversal and 46,XX lack of pubertal development as well as severe hypertension.

The Role of the European Imperial Powers throughout the Armenian Schism in the 1870s

The Bull "Reversurus" (1867) and its dogmatic legitimization at the First Vatican Council in 1870 caused not only ecclesiastical controversy and Schism in the Armenian Catholic Church, but it had also wide political consequences for the Armenian Catholics in the Ottoman Empire. The conflict originally between the Armenian Catholics and Rome attracted very soon the attention of the European imperial Powers. France, the British Empire, the German Empire, Austria-Hungary and Russia were the main political powers who were involved in the Armenian affair. A full picture of the role of all these powers for the course of the Armenian Schism is missing. Mostly the role of France is foregrounded in the printed sources, as the main power, which supported the papacy to win during the Armenian affair. The role and the motives of the other imperial powers is almost missing. This article will try to describe as completely as possible the historical and political background, which brought to the escalation of the Armenian conflict beyond the national frontiers and led to number of conflicts at the international and transnational level. It will be shown that the imperial policy in Europe in the 19th century have played an enormous role throughout the Armenian Schism. It will be explained that several historical circumstances in Europe, especially the relation of the European imperial powers to each other as well as their expectations from the Ottoman Empire and its Armenian subjects were decisive for the duration and conclusion of the Armenian Schism.