The Space Omics and Medical Atlas (SOMA) and international astronaut biobank

Spaceflight induces molecular, cellular and physiological shifts in astronauts and poses myriad biomedical challenges to the human body, which are becoming increasingly relevant as more humans venture into spac

What clonal hematopoiesis can teach us about MDS

Clonal hematopoiesis (CH), defined as the clonal expansion of mutated hematopoietic stem and progenitor cells (HSPCs), is a common aging process. CH is a risk factor for the development of hematologic malignancies, most commonly myeloid neoplasms (MNs) including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN). Recent work has elucidated how the development and cellular fitness of CH is shaped by aging, environmental exposures, and the germline (inherited) genetic background of an individual. This in turn has provided valuable insights into the pathogenesis of MNs including MDS. Here, in this review, we discuss the genetic origins of CH, the environmental stressors that influence CH, and the implications of CH on health outcomes including MDS. Since MNs have shared risk factors and underlying biology, most of our discussion regarding the implications of CH surrounds MN in general rather than focusing specifically on MDS. We conclude with future directions and areas of investigation including how intervention studies of CH might inform future therapeutic approaches to MN including MDS

Molecular subclasses of clear cell ovarian carcinoma and their impact on disease behavior and outcomes

PURPOSE: To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes. EXPERIMENTAL DESIGN: We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival. RESULTS: We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance; the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy. CONCLUSIONS: Our study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness. See related commentary by Lheureux, p. 4838

The Sloan Lens ACS Survey. X. Stellar, Dynamical, and Total Mass Correlations of Massive Early-type Galaxies

We use stellar masses, photometry, lensing, and velocity dispersions to investigate empirical correlations for the final sample of 73 early-type lens galaxies (ETGs) from the SLACS survey. The traditional correlations (Fundamental Plane [FP] and its projections) are consistent with those found for non-lens galaxies, supporting the thesis that SLACS lens galaxies are representative of massive ETGs. The addition of strong lensing estimates of the total mass allows us to gain further insights into their internal structure: i) the mean slope of the total mass density profile is = 2.078+/-0.027 with an intrinsic scatter of 0.16+/-0.02; ii) gamma' correlates with effective radius and central mass density, in the sense that denser galaxies have steeper profiles; iii) the dark matter fraction within reff/2 is a monotonically increasing function of galaxy mass and size; iv) the dimensional mass M_dim is proportional to the total mass, and both increase more rapidly than stellar mass M*; v) the Mass Plane (MP), obtained by replacing surface brightness with surface mass density in the FP, is found to be tighter and closer to the virial relation than the FP and the M*P, indicating that the scatter of those relations is dominated by stellar population effects; vi) we construct the Fundamental Hyper-Plane by adding stellar masses to the MP and find the M* coefficient to be consistent with zero and no residual intrinsic scatter. Our results demonstrate that the dynamical structure of ETGs is not scale invariant and that it is fully specified by the total mass, r_eff, and sigma. Although the basic trends can be explained qualitatively in terms of varying star formation efficiency as a function of halo mass and as the result of dry and wet mergers, reproducing quantitatively the observed correlations and their tightness may be a significant challenge for galaxy formation models.Comment: 16 pages, 9 figures; submitted to ApJ after responding to the referee comment

Semi-numeric simulations of helium reionization and the fluctuating radiation background

Recent He II Lyman-alpha forest observations from 2.0 2.7. These results point to a fluctuating He-ionizing background, which may be due to the end of helium reionization of this era. We present a fast, semi-numeric procedure to approximate detailed cosmological simulations. We compute the distribution of dark matter halos, ionization state of helium, and density field at z = 3 in broad agreement with recent simulations. Given our speed and flexibility, we investigate a range of ionizing source and active quasar prescriptions. Spanning a large area of parameter space, we find order-of-magnitude fluctuations in the He II ionization rate in the post-reionization regime. During reionization, the fluctuations are even stronger and develop a bimodal distribution, in contrast to semi-analytic models and the hydrogen equivalent. These distributions indicate a low-level ionizing background even at significant He II fractions

Assessing the perceived value of Reflexive Groups for supporting Clergy in the Church of England

This is an Accepted Manuscript of an article published by Taylor & Francis in Mental Health, Religion and Culture on 18-7-16, available online: http://dx.doi.org/10.1080/13674676.2016.1197194Little research has been conducted to assess the effectiveness of reflexive groups in supporting clergy. For this research, eight Church of England Bishops’ Advisors for Pastoral Care and Counselling were interviewed to ascertain the value of reflexive groups. These data were analysed using a thematic analysis. Two superordinate themes emerged: Contextual issues and Benefits, along with 20 subordinate themes. An online survey, consisting of questions that came from the Bishops’ Advisors data, was then sent to reflexive group participants (n=64), to see if their experiences matched those benefits identified by the Bishops’ Advisors. The data from 37 participants was statistically analysed. The data from both sets of participants reveal that reflexive groups are psychologically beneficial to clergy. The research concludes that the implementation of reflexive groups as a way of developing self-awareness and enculturating attitudes towards resilience and self-care is important to foster psychologically and spiritually healthy practice

New constraints on the free-streaming of warm dark matter from intermediate and small scale Lyman-α forest data

We present new measurements of the free-streaming of warm dark matter (WDM) from Lyman-α flux-power spectra. We use data from the medium resolution, intermediate redshift XQ-100 sample observed with the X-shooter spectrograph (z=3–4.2) and the high-resolution, high-redshift sample used in Viel et al. (2013) obtained with the HIRES/MIKE spectrographs (z=4.2 – 5.4 ). Based on further improved modelling of the dependence of the Lyman- α flux-power spectrum on the free-streaming of dark matter, cosmological parameters, as well as the thermal history of the intergalactic medium (IGM) with hydrodynamical simulations, we obtain the following limits, expressed as the equivalent mass of thermal relic WDM particles. The XQ-100 flux power spectrum alone gives a lower limit of 1.4 keV, the re-analysis of the HIRES/MIKE sample gives 4.1 keV while the combined analysis gives our best and significantly strengthened lower limit of 5.3 keV (all 2 σ C.L.). The further improvement in the joint analysis is partly due to the fact that the two data sets have different degeneracies between astrophysical and cosmological parameters that are broken when the data sets are combined, and more importantly on chosen priors on the thermal evolution. These results all assume that the temperature evolution of the IGM can be modeled as a power law in redshift. Allowing for a nonsmooth evolution of the temperature of the IGM with sudden temperature changes of up to 5000 K reduces the lower limit for the combined analysis to 3.5 keV. A WDM with smaller thermal relic masses would require, however, a sudden temperature jump of 5000 K or more in the narrow redshift interval z = 4.6 – 4.8 , in disagreement with observations of the thermal history based on high-resolution resolution Lyman- α forest data and expectations for photo-heating and cooling in the low density IGM at these redshifts.V. I. is supported by U.S. NSF Grant No. AST-1514734. V. I. also thanks M. McQuinn for useful discussions, and IAS, Princeton, for hospitality during his stay where part of this work was completed. M. V. and T. S. K. are supported by ERC-StG “cosmoIGM”. S. L. has been supported by FONDECYT grant number 1140838 and partially by PFB-06 CATA. V. D., M. V., S. C. acknowledge support from the PRIN INAF 2012 “The X-Shooter sample of 100 quasar spectra at z ∼ 3.5 : Digging into cosmology and galaxy evolution with quasar absorption lines. G. B. is supported by the NSF under award AST-1615814. S. L. E. acknowledges the receipt of an NSERC Discovery Grant. M. H. acknowledges support by ERC ADVANCED GRANT 320596 “The Emergence of Structure during the epoch of Reionization”. L. C. is supported by YDUN DFF 4090-00079. K. D. D. is supported by an NSF AAPF fellowship awarded under NSF grant AST-1302093. J. S. B. acknowledges the support of a Royal Society University Research Fellowship. Based on observations collected at the European Organisation for Astronomical Research in the Southern Hemisphere under ESO programme 189.A-0424. This work made use of the DiRAC High Performance Computing System (HPCS) and the COSMOS shared memory service at the University of Cambridge. These are operated on behalf of the STFC DiRAC HPC facility. This equipment is funded by BIS National E-infrastructure capital grant ST/J005673/1 and STFC grants ST/H008586/1, ST/K00333X/1

ArCH: Improving the performance of clonal hematopoiesis variant calling and interpretation

MOTIVATION: The acquisition of somatic mutations in hematopoietic stem and progenitor stem cells with resultant clonal expansion, termed clonal hematopoiesis (CH), is associated with increased risk of hematologic malignancies and other adverse outcomes. CH is generally present at low allelic fractions, but clonal expansion and acquisition of additional mutations leads to hematologic cancers in a small proportion of individuals. With high depth and high sensitivity sequencing, CH can be detected in most adults and its clonal trajectory mapped over time. However, accurate CH variant calling is challenging due to the difficulty in distinguishing low frequency CH mutations from sequencing artifacts. The lack of well-validated bioinformatic pipelines for CH calling may contribute to lack of reproducibility in studies of CH. RESULTS: Here, we developed ArCH, an Artifact filtering Clonal Hematopoiesis variant calling pipeline for detecting single nucleotide variants and short insertions/deletions by combining the output of four variant calling tools and filtering based on variant characteristics and sequencing error rate estimation. ArCH is an end-to-end cloud-based pipeline optimized to accept a variety of inputs with customizable parameters adaptable to multiple sequencing technologies, research questions, and datasets. Using deep targeted sequencing data generated from six acute myeloid leukemia patient tumor: normal dilutions, 31 blood samples with orthogonal validation, and 26 blood samples with technical replicates, we show that ArCH improves the sensitivity and positive predictive value of CH variant detection at low allele frequencies compared to standard application of commonly used variant calling approaches. AVAILABILITY AND IMPLEMENTATION: The code for this workflow is available at: https://github.com/kbolton-lab/ArCH