What do I do now? Intolerance of uncertainty is associated with discrete patterns of anticipatory physiological responding to different contexts

Heightened physiological responses to uncertainty are a common hallmark of anxiety disorders. Many separate studies have examined the relationship between individual differences in intolerance of uncertainty (IU) and physiological responses to uncertainty during different contexts. Despite this there is a scarcity of research examining the extent to which individual differences in IU are related to shared or discrete patterns of anticipatory physiological responding across different contexts. Anticipatory physiological responses to uncertainty were assessed in three different contexts (associative threat learning and extinction, threat uncertainty, decision-making) within the same sample (n = 45). During these tasks, behavioural responses (i.e. reaction times, choices), skin conductance and corrugator supercilli activity were recorded. In addition, self-reported IU and trait anxiety were measured. IU was related to both skin conductance and corrugator supercilii activity for the associative threat learning and extinction context, and decision-making context. However, trait anxiety was related to corrugator supercilii activity during the threat uncertainty context. Ultimately, this research helps us further tease apart the role of IU on different aspects of anticipation (i.e. valence and arousal) across contexts, which will be relevant for future IU-related models of psychopathology

The Mycobacterium Tuberculosis FAS-II Dehydratases and Methyltransferases Define the Specificity of the Mycolic Acid Elongation Complexes

BACKGROUND: The human pathogen Mycobacterium tuberculosis (Mtb) has the originality of possessing a multifunctional mega-enzyme FAS-I (Fatty Acid Synthase-I), together with a multi-protein FAS-II system, to carry out the biosynthesis of common and of specific long chain fatty acids: the mycolic acids (MA). MA are the main constituents of the external mycomembrane that represents a tight permeability barrier involved in the pathogenicity of Mtb. The MA biosynthesis pathway is essential and contains targets for efficient antibiotics. We have demonstrated previously that proteins of FAS-II interact specifically to form specialized and interconnected complexes. This finding suggested that the organization of FAS-II resemble to the architecture of multifunctional mega-enzyme like the mammalian mFAS-I, which is devoted to the fatty acid biosynthesis. PRINCIPAL FINDINGS: Based on conventional and reliable studies using yeast-two hybrid, yeast-three-hybrid and in vitro Co-immunoprecipitation, we completed here the analysis of the composition and architecture of the interactome between the known components of the Mtb FAS-II complexes. We showed that the recently identified dehydratases HadAB and HadBC are part of the FAS-II elongation complexes and may represent a specific link between the core of FAS-II and the condensing enzymes of the system. By testing four additional methyltransferases involved in the biosynthesis of mycolic acids, we demonstrated that they display specific interactions with each type of complexes suggesting their coordinated action during MA elongation. SIGNIFICANCE: These results provide a global update of the architecture and organization of a FAS-II system. The FAS-II system of Mtb is organized in specialized interconnected complexes and the specificity of each elongation complex is given by preferential interactions between condensing enzymes and dehydratase heterodimers. This study will probably allow defining essential and specific interactions that correspond to promising targets for Mtb FAS-II inhibitors

Mu2e Technical Design Report

The Mu2e experiment at Fermilab will search for charged lepton flavor violation via the coherent conversion process mu- N --> e- N with a sensitivity approximately four orders of magnitude better than the current world's best limits for this process. The experiment's sensitivity offers discovery potential over a wide array of new physics models and probes mass scales well beyond the reach of the LHC. We describe herein the preliminary design of the proposed Mu2e experiment. This document was created in partial fulfillment of the requirements necessary to obtain DOE CD-2 approval.Comment: compressed file, 888 pages, 621 figures, 126 tables; full resolution available at http://mu2e.fnal.gov; corrected typo in background summary, Table 3.

Psychophysiological correlates of anxious apprehension: Trait worry is associated with startle response to threat

Worry is a form of repetitive negative thought that is closely associated with anxiety disorders. Worry has been described as anxious apprehension and conceptualized as reflecting heightened anticipation of potentially threatening future events. However, it is unclear whether people who tend to worry show heightened physiological reactivity when anticipating threat, especially if the threat is uncertain. In the current study, community participants (n = 52) completed a threat anticipation task featuring uncertain threat, certain threat, and safety while the startle response to auditory probes was measured. Self-reported tendency to worry was assessed using the Penn State Worry Questionnaire, and anxiety disorder status was assessed via a clinical interview. A repeated-measures general linear model showed a main effect of threat level on the startle response, as well as a significant three-way interaction among threat level, worry, and anxiety disorder status. Follow-up tests showed that higher worry was associated with blunted startle responses to threat but particularly to uncertain threat among participants with a history of anxiety disorders. Worry did not moderate startle responding in participants without a history of anxiety disorders. These results indicate that psychophysiological correlates of worry depend on clinical status and suggest that trait worry is associated with physiological blunting to threat in individuals with a history of anxiety disorders, particularly when threat is uncertain. Implications for theoretical models of worry are discussed. •Uncertain threat elicits larger startle responses than does certain threat.•For past or current anxiety disorder: worry moderates effect of threat on startle.•Increased trait worry dampens startle response, especially when threat is uncertain.•Psychophysiological correlates of worry depend on history of anxiety disorder

1438P Trabectedin combined with hyperthermia: Characterization of enhanced drug-efficacy in human tumor cells.

Aim: Trabectedin (Yondelis) is approved for the treatment of patients with advanced soft tissue sarcoma (STS) after failure of anthracyclines and ifosfamide. Its cytostatic activity is associated with the induction of DNA double-strand breaks (DSBs). Regional hyperthermia (RHT) improves chemotherapy of patients with high-risk STS (Issels, Lancet Oncol 2010). The rationale for combined treatment is that heat-mediated degradation of BRCA2 impairs DNA homologous recombination repair (HR) which is crucial for the repair of DSBs (Krawczyk, PNAS 2011). Previously, we have demonstrated that simultaneous treatment of trabectedin and RHT resulted in enhanced cytotoxicity accompanied by elevated DNA-damage (Kampmann, CTOS 2013). Methods: For treatment, trabectedin (5-20nM) was applied for 3 hours with or without RHT (41.8°C or 43°C) for 1.5 hours. Cell cycle arrest and apoptosis were analyzed in the following human cell lines: U2Os (osteosarcoma), SW872 (liposarcoma) DLD1 (colorectal cancer) and DLD1−/-BRCA2 by Nicoletti staining and measuring caspase-activity 24h, 48h and 72h after treatment. The extent of cellular senescence was analyzed by a senescence-associated beta-galactosidase assay 72h and 144h after treatment. Results: Trabectedin treatment induced G2 arrest which was increased and prolonged after adding RHT. Furthermore, trabectedin induced apoptosis dose dependently which was also significantly augmented by RHT. However, the relative amount of apoptosis in U2Os was only half as large as in SW872 or DLD1. Interestingly, trabectedin induced a remarkable amount of senescent cells in U2Os but not in SW872 which again was significantly augmented by RHT. In BRCA2-deficient cells, thermosensitization of trabectedin was significantly reduced. Conclusions: Simultaneous treatment of trabectedin and RHT results in enhanced cytotoxicity accompanied by elevated DNA-damage. BRCA2-degradation and impairment of HR dependent DSB-repair are involved in thermosensitization. Here we discovered cell specific differences in induction of apoptosis or senescence which warrants further investigation. Disclosure: A. Tanovic: Scientific writer of PharmaMar. All other authors have declared no conflicts of interest

Intolerance of uncertainty and physiological responses during instructed uncertain threat: a multi-lab investigation

Individuals with high self-reported Intolerance of uncertainty (IU) tend to interpret uncertainty negatively. Recent research has been inconclusive on evidence of an association between IU and physiological responses during instructed uncertain threat. To address this gap, we conducted secondary analyses of IU and physiology data recorded during instructed uncertain threat tasks from two lab sites (Wisconsin-Madison; n = 128; Yale, n = 95). No IU-related effects were observed for orbicularis oculi activity (auditory startle-reflex). Higher IU was associated with: (1) greater corrugator supercilii activity to predictable and unpredictable threat of shock, compared to the safety from shock, and (2) poorer discriminatory skin conductance response between the unpredictable threat of shock, relative to the safety from shock. These findings suggest that IU-related biases may be captured differently depending on the physiological measure during instructed uncertain threat. Implications of these findings for neurobiological models of uncertainty and anticipation in anxiety are discussed