Prediction of fear acquisition in healthy control participants in a de novo fear-conditioning paradigm

Studies using fear-conditioning paradigms have found that anxiety patients are more conditionable than individuals without these disorders, but these effects have been demonstrated inconsistently. It is unclear whether these findings have etiological significance or whether enhanced conditionability is linked only to certain anxiety characteristics. To further examine these issues, the authors assessed the predictive significance of relevant subsyndromal characteristics in 72 healthy adults, including measures of worry, avoidance, anxious mood, depressed mood, and fears of anxiety symptoms (anxiety sensitivity), as well as the dimensions of Neuroticism and Extraversion. Of these variables, the authors found that the combination of higher levels of subsyndromal worry and lower levels of behavioral avoidance predicted heightened conditionability, raising questions about the etiological significance of these variables in the acquisition or maintenance of anxiety disorders. In contrast, the authors found that anxiety sensitivity was more linked to individual differences in orienting response than differences in conditioning per se. © 2007 Sage Publications

Inconsistent strategies to spin up models in CMIP5: Implications for ocean biogeochemical model performance assessment

This is the final version of the article. Available from EGU via the DOI in this record.During the fifth phase of the Coupled Model Intercomparison Project (CMIP5) substantial efforts were made to systematically assess the skill of Earth system models. One goal was to check how realistically representative marine biogeochemical tracer distributions could be reproduced by models. In routine assessments model historical hindcasts were compared with available modern biogeochemical observations. However, these assessments considered neither how close modeled biogeochemical reservoirs were to equilibrium nor the sensitivity of model performance to initial conditions or to the spin-up protocols. Here, we explore how the large diversity in spin-up protocols used for marine biogeochemistry in CMIP5 Earth system models (ESMs) contributes to model-to-model differences in the simulated fields. We take advantage of a 500-year spin-up simulation of IPSL-CM5A-LR to quantify the influence of the spin-up protocol on model ability to reproduce relevant data fields. Amplification of biases in selected biogeochemical fields (O2, NO3, Alk-DIC) is assessed as a function of spin-up duration. We demonstrate that a relationship between spin-up duration and assessment metrics emerges from our model results and holds when confronted with a larger ensemble of CMIP5 models. This shows that drift has implications for performance assessment in addition to possibly aliasing estimates of climate change impact. Our study suggests that differences in spin-up protocols could explain a substantial part of model disparities, constituting a source of model-to-model uncertainty. This requires more attention in future model intercomparison exercises in order to provide quantitatively more correct ESM results on marine biogeochemistry and carbon cycle feedbacks.We sincerely thank I. Kriest, F. Joos, the anonymous reviewer and A. Yool for their useful comments on this paper. This work was supported by H2020 project CRESCENDO “Coordinated Research in Earth Systems and Climate: Experiments, kNowledge, Dissemination and Outreach”, which received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 641816 and by the EU FP7 project CARBOCHANGE “Changes in carbon uptake and emissions by oceans in a changing climate” which received funding from the European community’s Seventh Framework Programme under grant agreement no. 264879. Supercomputing time was provided by GENCI (Grand Equipement National de Calcul Intensif) at CCRT (Centre de Calcul Recherche et Technologie), allocation 016178. Finally, we are grateful to the ESGF project which makes data available for all the community. Roland Séférian is grateful to Aurélien Ribes for his kind advices on statistics. Jerry Tjiputra acknowledges ORGANIC project (239965/F20) funded by the Research Council of Norway. Christoph Heinze and Jerry Tjiputra are grateful for support through project EVA – Earth system modelling of climate variations in the Anthropocene (229771/E10) funded by the Research Council of Norway, as well as CPU-time and mass storage provided through NOTUR project NN2345K as well as NorStore project NS2345K. Keith Lindsay and Scott C. Doney acknowledge support from the National Science Foundation

Molecular mechanism of Mad1 kinetochore targeting by phosphorylated Bub1.

Funder: Gates Cambridge Trust; Id: http://dx.doi.org/10.13039/501100005370During metaphase, in response to improper kinetochore-microtubule attachments, the spindle assembly checkpoint (SAC) activates the mitotic checkpoint complex (MCC), an inhibitor of the anaphase-promoting complex/cyclosome (APC/C). This process is orchestrated by the kinase Mps1, which initiates the assembly of the MCC onto kinetochores through a sequential phosphorylation-dependent signalling cascade. The Mad1-Mad2 complex, which is required to catalyse MCC formation, is targeted to kinetochores through a direct interaction with the phosphorylated conserved domain 1 (CD1) of Bub1. Here, we present the crystal structure of the C-terminal domain of Mad1 (Mad1CTD ) bound to two phosphorylated Bub1CD1 peptides at 1.75 Å resolution. This interaction is mediated by phosphorylated Bub1 Thr461, which not only directly interacts with Arg617 of the Mad1 RLK (Arg-Leu-Lys) motif, but also directly acts as an N-terminal cap to the CD1 α-helix dipole. Surprisingly, only one Bub1CD1 peptide binds to the Mad1 homodimer in solution. We suggest that this stoichiometry is due to inherent asymmetry in the coiled-coil of Mad1CTD and has implications for how the Mad1-Bub1 complex at kinetochores promotes efficient MCC assembly

Chitayat-Hall and Schaaf-Yang syndromes: a common aetiology: expanding the phenotype of MAGEL2-related disorders

Chitayat-Hall syndrome, initially described in 1990, is a rare condition characterised by distal arthrogryposis, intellectual disability, dysmorphic features and hypopituitarism, in particular growth hormone deficiency. The genetic aetiology has not been identified.Background Chitayat-Hall syndrome, initially described in 1990, is a rare condition characterised by distal arthrogryposis, intellectual disability, dysmorphic features and hypopituitarism, in particular growth hormone deficiency. The genetic aetiology has not been identified. Methods and results We identified three unrelated families with a total of six affected patients with the clinical manifestations of Chitayat-Hall syndrome. Through whole exome or whole genome sequencing, pathogenic variants in the MAGEL2 gene were identified in all affected patients. All disease-causing sequence variants detected are predicted to result in a truncated protein, including one complex variant that comprised a deletion and inversion. Conclusions Chitayat-Hall syndrome is caused by pathogenic variants in MAGEL2 and shares a common aetiology with the recently described Schaaf-Yang syndrome. The phenotype of MAGEL2-related disorders is expanded to include growth hormone deficiency as an important and treatable complicationhe McLaughlin Centre, University of Toronto, Toronto, Canada, and Fondation Jeanne et Jean- Louis Lévesque (JLM). The Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, Canada. FDL has a fellowship funded by FCT - Fundação para a Ciência e a Tecnologia (SFRH/BD/84650/2010)info:eu-repo/semantics/publishedVersio

Cyclic anoxia and organic rich carbonate sediments within a drowned carbonate platform linked to Antarctic ice volume changes: Late Oligocene-early Miocene Maldives

This paper reports on the newly discovered occurrence of thick sequences (∼100 m) of Late Oligocene and Early Miocene (∼24.9 to ∼20 Ma) interbedded organic-rich sediments (sapropels) and pelagic (organic poor) carbonates at Sites U1466 and U1468 drilled in the Maldives archipelago during the International Ocean Discovery Program (IODP) Expedition 359. This occurrence is unusual in that this sequence is located > 1000 m above the surrounding ocean floor within an inter-atoll basin and not linked to any known global oceanic events. Total organic content reaches as high as 35% in the darker layers, while the interbedded carbonates have concentrations of less than 0.1%. Trace elements characteristic of anoxic waters, such as Mo, V, Cr, U, and Pb, correlate positively with concentrations of organic carbon. Nitrogen isotopic data show no evidence that the intervals of high total organic carbon are related to enhanced productivity driven by upwelling. Instead, high organic carbon is associated with intervals of anoxia. We propose that sea-level fluctuations linked to changes in Antarctic ice volume restricted exchange with the open ocean causing bottom waters of the inter-atoll basin to become anoxic periodically. The architecture of the platform at the end of the Oligocene, combined with the global sea-level highstand, set the stage for orbitally-driven sea-level changes producing cyclic deposition of sapropels. The proposed mechanism may serve as an analogue for other occurrences of organic carbon-rich sediments within carbonate platform settings.</p

Axonal inclusions in spinocerebellar ataxia type 3

Protein aggregation is a major pathological hallmark of many neurodegenerative disorders including polyglutamine diseases. Aggregation of the mutated form of the disease protein ataxin-3 into neuronal nuclear inclusions is well described in the polyglutamine disorder spinocerebellar ataxia type 3 (SCA3 or Machado–Joseph disease), although these inclusions are not thought to be directly pathogenic. Neuropil aggregates have not yet been described in SCA3. We performed a systematic immunohistochemical study of serial thick sections through brains of seven clinically diagnosed and genetically confirmed SCA3 patients. Using antibodies against ataxin-3, p62, ubiquitin, the polyglutamine marker 1C2 as well as TDP-43, we analyzed neuronal localization, composition and distribution of aggregates within SCA3 brains. The analysis revealed widespread axonal aggregates in fiber tracts known to undergo neurodegeneration in SCA3. Similar to neuronal nuclear inclusions, the axonal aggregates were ubiquitinated and immunopositive for the proteasome and autophagy associated shuttle protein p62, indicating involvement of neuronal protein quality control mechanisms. Rare TDP-43 positive axonal inclusions were also observed. Based on the correlation between affected fiber tracts and degenerating neuronal nuclei, we hypothesize that these novel axonal inclusions may be detrimental to axonal transport mechanisms and thereby contribute to degeneration of nerve cells in SCA3

The “Flexi-Chamber”: A Novel Cost-Effective In Situ Respirometry Chamber for Coral Physiological Measurements

Coral reefs are threatened worldwide, with environmental stressors increasingly affecting the ability of reef-building corals to sustain growth from calcification (G), photosynthesis (P) and respiration (R). These processes support the foundation of coral reefs by directly influencing biogeochemical nutrient cycles and complex ecological interactions and therefore represent key knowledge required for effective reef management. However, metabolic rates are not trivial to quantify and typically rely on the use of cumbersome in situ respirometry chambers and/or the need to remove material and examine ex situ, thereby fundamentally limiting the scale, resolution and possibly the accuracy of the rate data. Here we describe a novel low-cost in situ respirometry bag that mitigates many constraints of traditional glass and plexi-glass incubation chambers. We subsequently demonstrate the effectiveness of our novel "Flexi-Chamber" approach via two case studies: 1) the Flexi-Chamber provides values of P, R and G for the reef-building coral Siderastrea cf. stellata collected from reefs close to Salvador, Brazil, which were statistically similar to values collected from a traditional glass respirometry vessel; and 2) wide-scale application of obtaining P, R and G rates for different species across different habitats to obtain inter- and intra-species differences. Our novel cost-effective design allows us to increase sampling scale of metabolic rate measurements in situ without the need for destructive sampling and thus significantly expands on existing research potential, not only for corals as we have demonstrated here, but also other important benthic groups

IgG2 Antibodies against a Clinical Grade Plasmodium falciparum CSP Vaccine Antigen Associate with Protection against Transgenic Sporozoite Challenge in Mice

The availability of a highly purified and well characterized circumsporozoite protein (CSP) is essential to improve upon the partial success of recombinant CSP-based malaria vaccine candidates. Soluble, near full-length, Plasmodium falciparum CSP vaccine antigen (CS/D) was produced in E. coli under bio-production conditions that comply with current Good Manufacturing Practices (cGMP). A mouse immunogenicity study was conducted using a stable oil-in-water emulsion (SE) of CS/D in combination with the Toll-Like Receptor 4 (TLR4) agonist Glucopyranosyl Lipid A (GLA/SE), or one of two TLR7/8 agonists: R848 (un-conjugated) or 3M-051 (covalently conjugated). Compared to Alum and SE, GLA/SE induced higher CS/D specific antibody response in Balb/c mice. Subclass analysis showed higher IgG2:IgG1 ratio of GLA/SE induced antibodies as compared to Alum and SE. TLR synergy was not observed when soluble R848 was mixed with GLA/SE. Antibody response of 3M051 formulations in Balb/c was similar to GLA/SE, except for the higher IgG2:IgG1 ratio and a trend towards higher T cell responses in 3M051 containing groups. However, no synergistic enhancement of antibody and T cell response was evident when 3M051 conjugate was mixed with GLA/SE. In C57Bl/6 mice, CS/D adjuvanted with 3M051/SE or GLA/SE induced higher CSP repeat specific titers compared to SE. While, 3M051 induced antibodies had high IgG2c:IgG1 ratio, GLA/SE promoted high levels of both IgG1 and IgG2c. GLA/SE also induced more potent T-cell responses compared to SE in two independent C57/BL6 vaccination studies, suggesting a balanced and productive TH1/TH2 response. GLA and 3M-051 similarly enhanced the protective efficacy of CS/D against challenge with a transgenic P. berghei parasite and most importantly, high levels of cytophilic IgG2 antibodies were associated with protection in this model. Our data indicated that the cGMP-grade, soluble CS/D antigen combined with the TLR4-containing adjuvant GLA/SE warrants further evaluation for protective responses in humans

Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma.

Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10(-8)), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.[Please see the Supplementary Note for acknowledgments.]This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.337

Plato's Cave Algorithm: Inferring Functional Signaling Networks from Early Gene Expression Shadows

Improving the ability to reverse engineer biochemical networks is a major goal of systems biology. Lesions in signaling networks lead to alterations in gene expression, which in principle should allow network reconstruction. However, the information about the activity levels of signaling proteins conveyed in overall gene expression is limited by the complexity of gene expression dynamics and of regulatory network topology. Two observations provide the basis for overcoming this limitation: a. genes induced without de-novo protein synthesis (early genes) show a linear accumulation of product in the first hour after the change in the cell's state; b. The signaling components in the network largely function in the linear range of their stimulus-response curves. Therefore, unlike most genes or most time points, expression profiles of early genes at an early time point provide direct biochemical assays that represent the activity levels of upstream signaling components. Such expression data provide the basis for an efficient algorithm (Plato's Cave algorithm; PLACA) to reverse engineer functional signaling networks. Unlike conventional reverse engineering algorithms that use steady state values, PLACA uses stimulated early gene expression measurements associated with systematic perturbations of signaling components, without measuring the signaling components themselves. Besides the reverse engineered network, PLACA also identifies the genes detecting the functional interaction, thereby facilitating validation of the predicted functional network. Using simulated datasets, the algorithm is shown to be robust to experimental noise. Using experimental data obtained from gonadotropes, PLACA reverse engineered the interaction network of six perturbed signaling components. The network recapitulated many known interactions and identified novel functional interactions that were validated by further experiment. PLACA uses the results of experiments that are feasible for any signaling network to predict the functional topology of the network and to identify novel relationships