Description: The responses of animals and plants to recent climate change vary greatly from species to species, but attempts to understand this variation have met with limited success. This has led to concerns that predictions of responses are inherently uncertain because of the complexity of interacting drivers and biotic interactions. However, we show for an exemplar group of 155 Lepidoptera species that about 60% of the variation among species in their abundance trends over the past four decades can be explained by species-specific exposure and sensitivity to climate change. Distribution changes were less well predicted, but nonetheless, up to 53% of the variation was explained. We found that species vary in their overall sensitivity to climate and respond to different components of the climate despite ostensibly experiencing the same climate changes. Hence, species have undergone different levels of population "forcing" (exposure), driving variation among species in their national-scale abundance and distribution trends. We conclude that variation in species’ responses to recent climate change may be more predictable than previously recognized.

Description: Using a radio-quiet subsample of the Sloan Digital Sky Survey spectroscopic quasar catalogue, spanning redshifts 0.5–3.5, we derive the mean millimetre and far-infrared quasar spectral energy distributions (SEDs) via a stacking analysis of Atacama Cosmology Telescope and Herschel -Spectral and Photometric Imaging REceiver data. We constrain the form of the far-infrared emission and find 3–4 evidence for the thermal Sunyaev–Zel'dovich (SZ) effect, characteristic of a hot ionized gas component with thermal energy (6.2 ± 1.7) x 10 60  erg. This amount of thermal energy is greater than expected assuming only hot gas in virial equilibrium with the dark matter haloes of (1–5) x 10 12 h –1 M that these systems are expected to occupy, though the highest quasar mass estimates found in the literature could explain a large fraction of this energy. Our measurements are consistent with quasars depositing up to $(14.5 \pm 3.3)\tau _8^{-1}$  per cent of their radiative energy into their circumgalactic environment if their typical period of quasar activity is 8 x 10 8 yr. For high quasar host masses, ~10 13 h –1 M , this percentage will be reduced. Furthermore, the uncertainty on this percentage is only statistical and additional systematic uncertainties enter at the 40 per cent level. The SEDs are dust dominated in all bands and we consider various models for dust emission. While sufficiently complex dust models can obviate the SZ effect, the SZ interpretation remains favoured at the 3–4 level for most models.

Description: Triple-negative breast cancer (TNBC) has the worst prognosis of all breast cancers, and women diagnosed with TNBC currently lack targeted treatment options. To identify novel targets for TNBC, we evaluated phosphatase expression in breast tumors and characterized their contributions to in vitro and in vivo growth of TNBC. Using Affymetrix microarray analysis of 102 breast cancers, we identified 146 phosphatases that were significantly differentially expressed in TNBC compared with estrogen receptor (ER)-positive tumors. Of these, 19 phosphatases were upregulated (0.66-fold; FDR = 0.05) in TNBC compared with ER-positive breast cancers. We knocked down 17 overexpressed phosphatases in four triple-negative and four ER-positive breast cancer lines using specific siRNAs and found that depletion of six of these phosphatases significantly reduced growth and anchorage-independent growth of TNBC cells to a greater extent than ER-positive cell lines. Further analysis of the phosphatase PTP4A3 (also known as PRL-3) demonstrated its requirement for G1–S cell-cycle progression in all breast cancer cells, but PTP4A3 regulated apoptosis selectively in TNBC cells. In addition, PTP4A3 inhibition reduced the growth of TNBC tumors in vivo. Moreover, in silico analysis revealed the PTP4A3 gene to be amplified in 29% of basal-like breast cancers, and high expression of PTP4A3 could serve as an independent prognostic indicator for worse overall survival. Collectively, these studies define the importance of phosphatase overexpression in TNBC and lay the foundation for the development of new targeted therapies directed against phosphatases or their respective signaling pathways for TNBC patients. Cancer Res; 76(7); 1942–53. ©2016 AACR.

Description: Precise polarization measurements of the cosmic microwave background (CMB) require accurate knowledge of the instrument orientation relative to the sky frame used to define the cosmological Stokes parameters. Suitable celestial calibration sources that could be used to measure the polarimeter orientation angle are limited, so current experiments commonly ‘self-calibrate.’ The self-calibration method exploits the theoretical fact that the EB and TB cross-spectra of the CMB vanish in the standard cosmological model, so any detected EB and TB signals must be due to systematic errors. However, this assumption neglects the fact that polarized Galactic foregrounds in a given portion of the sky may have non-zero EB and TB cross-spectra. If these foreground signals remain in the observations, then they will bias the self-calibrated telescope polarization angle and produce a spurious B -mode signal. In this paper, we estimate the foreground-induced bias for various instrument configurations and then expand the self-calibration formalism to account for polarized foreground signals. Assuming the EB correlation signal for dust is in the range constrained by angular power spectrum measurements from Planck at 353 GHz (scaled down to 150 GHz), then the bias is negligible for high angular resolution experiments, which have access to CMB-dominated high modes with which to self-calibrate. Low-resolution experiments observing particularly dusty sky patches can have a bias as large as 0 $_{.}^{\circ}$ 5. A miscalibration of this magnitude generates a spurious BB signal corresponding to a tensor-to-scalar ratio of approximately r  ~ 2  x  10 –3 , within the targeted range of planned experiments.

Description: Objectives Current musculoskeletal outcome tools are fragmented across different healthcare settings and conditions. Our objectives were to develop and validate a single musculoskeletal outcome measure for use throughout the pathway and patients with different musculoskeletal conditions: the Arthritis Research UK Musculoskeletal Health Questionnaire (MSK-HQ). Setting A consensus workshop with stakeholders from across the musculoskeletal community, workshops and individual interviews with a broad mix of musculoskeletal patients identified and prioritised outcomes for MSK-HQ inclusion. Initial psychometric validation was conducted in four cohorts from community physiotherapy, and secondary care orthopaedic hip, knee and shoulder clinics. Participants Stakeholders (n=29) included primary care, physiotherapy, orthopaedic and rheumatology patients (n=8); general practitioners, physiotherapists, orthopaedists, rheumatologists and pain specialists (n=7), patient and professional national body representatives (n=10), and researchers (n=4). The four validation cohorts included 570 participants (n=210 physiotherapy, n=150 hip, n=150 knee, n=60 shoulder patients). Outcome measures Outcomes included the MSK-HQ's acceptability, feasibility, comprehension, readability and responder burden. The validation cohort outcomes were the MSK-HQ's completion rate, test–retest reliability and convergent validity with reference standards (EQ-5D-5L, Oxford Hip, Knee, Shoulder Scores, and the Keele MSK-PROM). Results Musculoskeletal domains prioritised were pain severity, physical function, work interference, social interference, sleep, fatigue, emotional health, physical activity, independence, understanding, confidence to self-manage and overall impact. Patients reported MSK-HQ items to be ‘highly relevant’ and ‘easy to understand’. Completion rates were high (94.2%), with scores normally distributed, and no floor/ceiling effects. Test–retest reliability was excellent, and convergent validity was strong (correlations 0.81–0.88). Conclusions A new musculoskeletal outcome measure has been developed through a coproduction process with patients to capture prioritised outcomes for use throughout the pathway and with different musculoskeletal conditions. Four validation cohorts found that the MSK-HQ had high completion rates, excellent test–retest reliability and strong convergent validity with reference standards. Further validation studies are ongoing, including a cohort with rheumatoid/inflammatory arthritis.

Description: In mammals the regulation of genomic instability plays a key role in tumor suppression and also controls genome plasticity, which is important for recombination during the processes of immunity and meiosis. Most studies to identify regulators of genomic instability have been performed in cells in culture or in systems that report on gross rearrangements of the genome, yet subtle differences in the level of genomic instability can contribute to whole organism phenotypes such as tumor predisposition. Here we performed a genome-wide association study in a population of 1379 outbred Crl:CFW(SW)-US_P08 mice to dissect the genetic landscape of micronucleus formation, a biomarker of chromosomal breaks, whole chromosome loss, and extranuclear DNA. Variation in micronucleus levels is a complex trait with a genome-wide heritability of 53.1%. We identify seven loci influencing micronucleus formation (false discovery rate 〈5%), and define candidate genes at each locus. Intriguingly at several loci we find evidence for sexual dimorphism in micronucleus formation, with a locus on chromosome 11 being specific to males.

Description: Enteric fever, caused by Salmonella enterica serovar Typhi, is an important public health problem in resource-limited settings and, despite decades of research, human responses to the infection are poorly understood. In 41 healthy adults experimentally infected with wild-type S. Typhi, we detected significant cytokine responses within 12 h of bacterial ingestion. These early responses did not correlate with subsequent clinical disease outcomes and likely indicate initial host–pathogen interactions in the gut mucosa. In participants developing enteric fever after oral infection, marked transcriptional and cytokine responses during acute disease reflected dominant type I/II interferon signatures, which were significantly associated with bacteremia. Using a murine and macrophage infection model, we validated the pivotal role of this response in the expression of proteins of the host tryptophan metabolism during Salmonella infection. Corresponding alterations in tryptophan catabolites with immunomodulatory properties in serum of participants with typhoid fever confirmed the activity of this pathway, and implicate a central role of host tryptophan metabolism in the pathogenesis of typhoid fever.