Discontinuation of antipsychotic medication in pregnancy: A cohort study.

Women prescribed antipsychotics face the dilemma on whether to continue medication in pregnancy in terms of balancing risks and benefits. Previous research on other psychotropic medications suggests that many women discontinue treatment in early pregnancy. However, very limited evidence exists on discontinuation of antipsychotic medication

Mapping the Hsp90 Genetic Interaction Network in Candida albicans Reveals Environmental Contingency and Rewired Circuitry

The molecular chaperone Hsp90 regulates the folding of diverse signal transducers in all eukaryotes, profoundly affecting cellular circuitry. In fungi, Hsp90 influences development, drug resistance, and evolution. Hsp90 interacts with ∼10% of the proteome in the model yeast Saccharomyces cerevisiae, while only two interactions have been identified in Candida albicans, the leading fungal pathogen of humans. Utilizing a chemical genomic approach, we mapped the C. albicans Hsp90 interaction network under diverse stress conditions. The chaperone network is environmentally contingent, and most of the 226 genetic interactors are important for growth only under specific conditions, suggesting that they operate downstream of Hsp90, as with the MAPK Hog1. Few interactors are important for growth in many environments, and these are poised to operate upstream of Hsp90, as with the protein kinase CK2 and the transcription factor Ahr1. We establish environmental contingency in the first chaperone network of a fungal pathogen, novel effectors upstream and downstream of Hsp90, and network rewiring over evolutionary time

Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata

The evolution of drug resistance has a profound impact on human health. Candida glabrata is a leading human fungal pathogen that can rapidly evolve resistance to echinocandins, which target cell wall biosynthesis and are front-line therapeutics for Candida infections. Here, we provide the first global analysis of mutations accompanying the evolution of fungal drug resistance in a human host utilizing a series of C. glabrata isolates that evolved echinocandin resistance in a patient treated with the echinocandin caspofungin for recurring bloodstream candidemia. Whole genome sequencing identified a mutation in the drug target, FKS2, accompanying a major resistance increase, and 8 additional non-synonymous mutations. The FKS2-T1987C mutation was sufficient for echinocandin resistance, and associated with a fitness cost that was mitigated with further evolution, observed in vitro and in a murine model of systemic candidemia. A CDC6-A511G(K171E) mutation acquired before FKS2-T1987C(S663P), conferred a small resistance increase. Elevated dosage of CDC55, which acquired a C463T(P155S) mutation after FKS2-T1987C(S663P), ameliorated fitness. To discover strategies to abrogate echinocandin resistance, we focused on the molecular chaperone Hsp90 and downstream effector calcineurin. Genetic or pharmacological compromise of Hsp90 or calcineurin function reduced basal tolerance and resistance. Hsp90 and calcineurin were required for caspofungin-dependent FKS2 induction, providing a mechanism governing echinocandin resistance. A mitochondrial respiration-defective petite mutant in the series revealed that the petite phenotype does not confer echinocandin resistance, but renders strains refractory to synergy between echinocandins and Hsp90 or calcineurin inhibitors. The kidneys of mice infected with the petite mutant were sterile, while those infected with the HSP90-repressible strain had reduced fungal burden. We provide the first global view of mutations accompanying the evolution of fungal drug resistance in a human host, implicate the premier compensatory mutation mitigating the cost of echinocandin resistance, and suggest a new mechanism of echinocandin resistance with broad therapeutic potential

Increased Local Retention of Reef Coral Larvae as a Result of Ocean Warming

Climate change will alter many aspects of the ecology of organisms, including dispersal patterns and population connectivity. Understanding these changes is essential to predict future species distributions, estimate potential for adaptation, and design effective networks of protected areas. In marine environments, dispersal is often accomplished by larvae. At higher temperatures, larvae develop faster, but suffer higher mortality, making the effect of temperature on dispersal difficult to predict. Here, we experimentally calibrate the effect of temperature on larval survival and settlement in a dynamic model of coral dispersal. Our findings imply that most reefs globally will experience several-fold increases in local retention of larvae due to ocean warming. This increase will be particularly pronounced for reefs with mean water residence times comparable to the time required for species to become competent to settle. Higher local retention rates strengthen the link between abundance and recruitment at the reef scale, suggesting that populations will be more responsive to local conservation actions. Higher rates of local retention and mortality will weaken connectivity between populations, and thus potentially retard recovery following severe disturbances that substantially deplete local populations. Conversely, on isolated reefs that are dependent on replenishment from local broodstock, increases in local retention may hasten recovery

The role of a pseudocapsula in thymic epithelial tumors: outcome and correlation with established prognostic parameters. Results of a 20-year single centre retrospective analysis

<p>Abstract</p> <p>Background</p> <p>Treatment of thymoma is often based on observation of only a few patients. Surgical resection is considered to be the most important step. Role of a pseudocapsula for surgery, its clinical significance and outcome compared with established prognostic parameters is discussed which has not been reported so far.</p> <p>Methods</p> <p>84 patients with thymoma underwent resection and analysis was carried out for clinical features, prognostic factors and long-term survival.</p> <p>Results</p> <p>Fifteen patients were classified in WHO subgroup A, 21 in AB, 29 in B and 19 patients in C. Forty two patients were classified in Masaoka stage I, 19 stage II, 9 stage III and 14 stage IV. Encapsulated thymoma was seen in 40, incomplete or missing capsula in 44 patients. In 71 complete resections, local recurrence was 5%. 5-year survival was 88.1%. Thymomas with pseudocapsula showed a significant better survival (94.9% vs. 61.1%, respectively) (p = 0.001) and was correlated with the absence of nodal or distant metastasis (p = 0.04 and 0.001, respectively). Presence of pseudocapsula as well as the Masaoka and WHO classification, and R-status were of prognostic significance. R-status and Masaoka stage appeared to be of independent prognostic significance in multivariate analysis.</p> <p>Conclusion</p> <p>Intraoperative presence of an encapsulated tumor is a good technical marker for the surgeon to evaluate resectability and estimate prognosis. Although the presence of a capsula is of strong significance in the univariate analysis, it failed in the multivariate analysis due to its correlation with clinical Masaoka stage. Masaoka stage has a stronger relevance than WHO classification to determinate long-term outcome.</p

Genetic Traces of Recent Long-Distance Dispersal in a Predominantly Self-Recruiting Coral

Understanding of the magnitude and direction of the exchange of individuals among geographically separated subpopulations that comprise a metapopulation (connectivity) can lead to an improved ability to forecast how fast coral reef organisms are likely to recover from disturbance events that cause extensive mortality. Reef corals that brood their larvae internally and release mature larvae are believed to show little exchange of larvae over ecological times scales and are therefore expected to recover extremely slowly from large-scale perturbations.Using analysis of ten DNA microsatellite loci, we show that although Great Barrier Reef (GBR) populations of the brooding coral, Seriatopora hystrix, are mostly self-seeded and some populations are highly isolated, a considerable amount of sexual larvae (up to approximately 4%) has been exchanged among several reefs 10 s to 100 s km apart over the past few generations. Our results further indicate that S. hystrix is capable of producing asexual propagules with similar long-distance dispersal abilities (approximately 1.4% of the sampled colonies had a multilocus genotype that also occurred at another sampling location), which may aid in recovery from environmental disturbances.Patterns of connectivity in this and probably other GBR corals are complex and need to be resolved in greater detail through genetic characterisation of different cohorts and linkage of genetic data with fine-scale hydrodynamic models

The search for transient astrophysical neutrino emission with IceCube-DeepCore

We present the results of a search for astrophysical sources of brief transient neutrino emission using IceCube and DeepCore data acquired between 2012 May 15 and 2013 April 30. While the search methods employed in this analysis are similar to those used in previous IceCube point source searches, the data set being examined consists of a sample of predominantly sub-TeV muon-neutrinos from the Northern Sky (-5 degrees < delta < 90 degrees) obtained through a novel event selection method. This search represents a first attempt by IceCube to identify astrophysical neutrino sources in this relatively unexplored energy range. The reconstructed direction and time of arrival of neutrino events are used to search for any significant self-correlation in the data set. The data revealed no significant source of transient neutrino emission. This result has been used to construct limits at timescales ranging from roughly 1 s to 10 days for generic soft-spectra transients. We also present limits on a specific model of neutrino emission from soft jets in core-collapse supernovae

A Tradeoff Drives the Evolution of Reduced Metal Resistance in Natural Populations of Yeast

Various types of genetic modification and selective forces have been implicated in the process of adaptation to novel or adverse environments. However, the underlying molecular mechanisms are not well understood in most natural populations. Here we report that a set of yeast strains collected from Evolution Canyon (EC), Israel, exhibit an extremely high tolerance to the heavy metal cadmium. We found that cadmium resistance is primarily caused by an enhanced function of a metal efflux pump, PCA1. Molecular analyses demonstrate that this enhancement can be largely attributed to mutations in the promoter sequence, while mutations in the coding region have a minor effect. Reconstruction experiments show that three single nucleotide substitutions in the PCA1 promoter quantitatively increase its activity and thus enhance the cells' cadmium resistance. Comparison among different yeast species shows that the critical nucleotides found in EC strains are conserved and functionally important for cadmium resistance in other species, suggesting that they represent an ancestral type. However, these nucleotides had diverged in most Saccharomyces cerevisiae populations, which gave cells growth advantages under conditions where cadmium is low or absent. Our results provide a rare example of a selective sweep in yeast populations driven by a tradeoff in metal resistance

Hypoxia and oxidative stress in breast cancer: Tumour hypoxia – therapeutic considerations

Conclusive research has shown that regions of acute/chronic hypoxia, which exist within the majority of solid tumours, have a profound influence on the therapeutic outcome of cancer chemotherapy and radiotherapy and are a strong prognostic factor of disease progression and survival. A strong argument therefore exists for assessing the hypoxic fraction of tumours, prior to patient treatment, and to tailor this treatment accordingly. Tumour hypoxia also provides a powerful physiological stimulus that can be exploited as a tumour-specific condition, allowing for the rationale design of hypoxia-activated anticancer drugs or novel hypoxia-regulated gene therapy strategies

Contrasting patterns of population structure and gene flow facilitate exploration of connectivity in two widely distributed temperate octocorals

This is the final version of the article. Available from Springer Nature via the DOI in this record.Connectivity is an important component of metapopulation dynamics in marine systems and can influence population persistence, migration rates and conservation decisions associated with Marine Protected Areas (MPAs). In this study, we compared the genetic diversity, gene flow and population structure of two octocoral species, Eunicella verrucosa and Alcyonium digitatum, in the northeast Atlantic (ranging from the northwest of Ireland and the southern North Sea, to southern Portugal), using two panels of thirteen and eight microsatellite loci, respectively. Our results identified regional genetic structure in E. verrucosa partitioned between populations from southern Portugal, northwest Ireland, and Britain/France; subsequent hierarchical analysis of population structure also indicated reduced gene flow between southwest Britain and northwest France. However, over a similar geographical area, A. digitatum showed little evidence of population structure, suggesting high gene flow and/or a large effective population size; indeed, the only significant genetic differentiation detected in A. digitatum occurred between North Sea samples and those from the English Channel/northeast Atlantic. In both species the vast majority of gene flow originated from sample sites within regions, with populations in southwest Britain being the predominant source of contemporary exogenous genetic variants for the populations studied. Unsurprisingly, historical patterns of gene flow appeared more complex, though again southwest Britain appeared an important source of genetic variation for both species. Our findings have major conservation implications, particularly for E. verrucosa, a protected species in UK waters and listed by the IUCN as ‘Vulnerable’, and for the designation and management of European MPAs.We thank Natural England (project No. RP0286, contract No. SAE 03-02-146), the NERC (grant No. NE/L002434/1) and the University of Exeter for funding this research. Additional funding for sample collection, travel and microsatellite development was provided by the EU Framework 7 ASSEMBLE programme, agreement no. 227799, and NERC grant No. NBAF-362