Seasonality influences cuticle melanization and immune defense in a cricket: support for a temperature-dependent immune investment hypothesis in insects

To improve thermoregulation in colder environments, insects are expected to darken their cuticles with melanin via the phenoloxidase cascade, a phenomenon predicted by the thermal melanin hypothesis. However, the phenoloxidase cascade also plays a significant role in insect immunity, leading to the additional hypothesis that the thermal environment indirectly shapes immune function via direct selection on cuticle color. Support for the latter hypothesis comes from the cricket Allonemobius socius, where cuticle darkness and immune-related phenoloxidase activity increase with latitude. However, thermal environments vary seasonally as well as geographically, suggesting that seasonal plasticity in immunity may also exist. Although seasonal fluctuations in vertebrate immune function are common (because of flux in breeding or resource abundance), seasonality in invertebrate immunity has not been widely explored. We addressed this possibility by rearing crickets in simulated summer and fall environments and assayed their cuticle color and immune function. Prior to estimating immunity, crickets were placed in a common environment to minimize metabolic rate differences. Individuals reared under fall-like conditions exhibited darker cuticles, greater phenoloxidase activity and greater resistance to the bacteria Serratia marcescens. These data support the hypothesis that changes in the thermal environment modify cuticle color, which indirectly shapes immune investment through pleiotropy. This hypothesis may represent a widespread mechanism governing immunity in numerous systems, considering that most insects operate in seasonally and geographically variable thermal environments

Bacterial artificial chromosomes as analytical basis for gene transcriptional machineries

Bacterial Artificial Chromosomes (BACs) had been minimal components of various genome-sequencing projects, constituting perfect analytical basis for functional genomics. Here we describe an enhancer screening strategy in which BAC clones that cover any genomic segments of interest are modified to harbor a reporter cassette by transposon tagging, then processed to carry selected combinations of gene regulatory modules by homologous recombination mediated systematic deletions. Such engineered BAC-reporter constructs in bacterial cells are ready for efficient transgenesis in mice to evaluate activities of gene regulatory modules intact or absent in the constructs. By utilizing the strategy, we could speedily identify a critical genomic fragment for spatio-temporally regulated expression of a mouse cadherin gene whose structure is extraordinarily huge and intricate. This BAC-based methodology would hence provide a novel screening platform for gene transcriptional machineries that dynamically fluctuate during development, pathogenesis and/or evolution

Association between body mass index and cardiovascular disease mortality in east Asians and south Asians: pooled analysis of prospective data from the Asia Cohort Consortium

Objective: To evaluate the association between body mass index and mortality from overall cardiovascular disease and specific subtypes of cardiovascular disease in east and south Asians. Design: Pooled analyses of 20 prospective cohorts in Asia, including data from 835 082 east Asians and 289 815 south Asians. Cohorts were identified through a systematic search of the literature in early 2008, followed by a survey that was sent to each cohort to assess data availability. Setting: General populations in east Asia (China, Taiwan, Singapore, Japan, and Korea) and south Asia (India and Bangladesh). Participants: 1 124 897 men and women (mean age 53.4 years at baseline). Main outcome measures: Risk of death from overall cardiovascular disease, coronary heart disease, stroke, and (in east Asians only) stroke subtypes. Results: 49 184 cardiovascular deaths (40 791 in east Asians and 8393 in south Asians) were identified during a mean follow-up of 9.7 years. East Asians with a body mass index of 25 or above had a raised risk of death from overall cardiovascular disease, compared with the reference range of body mass index (values 22.5-24.9; hazard ratio 1.09 (95% confidence interval 1.03 to 1.15), 1.27 (1.20 to 1.35), 1.59 (1.43 to 1.76), 1.74 (1.47 to 2.06), and 1.97 (1.44 to 2.71) for body mass index ranges 25.0-27.4, 27.5-29.9, 30.0-32.4, 32.5-34.9, and 35.0-50.0, respectively). This association was similar for risk of death from coronary heart disease and ischaemic stroke; for haemorrhagic stroke, the risk of death was higher at body mass index values of 27.5 and above. Elevated risk of death from cardiovascular disease was also observed at lower categories of body mass index (hazard ratio 1.19 (95% confidence interval 1.02 to 1.39) and 2.16 (1.37 to 3.40) for body mass index ranges 15.0-17.4 and less than 15.0, respectively), compared with the reference range. In south Asians, the association between body mass index and mortality from cardiovascular disease was less pronounced than that in east Asians. South Asians had an increased risk of death observed for coronary heart disease only in individuals with a body mass index greater than 35 (hazard ratio 1.90, 95% confidence interval 1.15 to 3.12). Conclusions: Body mass index shows a U shaped association with death from overall cardiovascular disease among east Asians: increased risk of death from cardiovascular disease is observed at lower and higher ranges of body mass index. A high body mass index is a risk factor for mortality from overall cardiovascular disease and for specific diseases, including coronary heart disease, ischaemic stroke, and haemorrhagic stroke in east Asians. Higher body mass index is a weak risk factor for mortality from cardiovascular disease in south Asians

A Common Variant Associated with Dyslexia Reduces Expression of the KIAA0319 Gene

Numerous genetic association studies have implicated the KIAA0319 gene on human chromosome 6p22 in dyslexia susceptibility. The causative variant(s) remains unknown but may modulate gene expression, given that (1) a dyslexia-associated haplotype has been implicated in the reduced expression of KIAA0319, and (2) the strongest association has been found for the region spanning exon 1 of KIAA0319. Here, we test the hypothesis that variant(s) responsible for reduced KIAA0319 expression resides on the risk haplotype close to the gene's transcription start site. We identified seven single-nucleotide polymorphisms on the risk haplotype immediately upstream of KIAA0319 and determined that three of these are strongly associated with multiple reading-related traits. Using luciferase-expressing constructs containing the KIAA0319 upstream region, we characterized the minimal promoter and additional putative transcriptional regulator regions. This revealed that the minor allele of rs9461045, which shows the strongest association with dyslexia in our sample (max p-value = 0.0001), confers reduced luciferase expression in both neuronal and non-neuronal cell lines. Additionally, we found that the presence of this rs9461045 dyslexia-associated allele creates a nuclear protein-binding site, likely for the transcriptional silencer OCT-1. Knocking down OCT-1 expression in the neuronal cell line SHSY5Y using an siRNA restores KIAA0319 expression from the risk haplotype to nearly that seen from the non-risk haplotype. Our study thus pinpoints a common variant as altering the function of a dyslexia candidate gene and provides an illustrative example of the strategic approach needed to dissect the molecular basis of complex genetic traits

A Project Portfolio Management Approach to Tacklingthe Exploration/Exploitation Trade-off

Organizational ambidexterity (OA) is an essen-tial capability for surviving in dynamic business environ-ments that advocates the simultaneous engagement inexploration and exploitation. Over the last decades,knowledge on OA has substantially matured, coveringinsights into antecedents, outcomes, and moderators of OA.However, there is little prescriptive knowledge that offersguidance on how to put OA into practice and to tackle thetrade-off between exploration and exploitation. To addressthis gap, the authors adopt the design science researchparadigm and propose an economic decision model asartifact. The decision model assists organizations inselecting and scheduling exploration and exploitation pro-jects to become ambidextrous in an economically reason-able manner. As for justificatory knowledge, the decisionmodel draws from prescriptive knowledge on projectportfolio management and value-based management, andfrom descriptive knowledge related to OA to structure thefield of action. To evaluate the decision model, its designspecification is discussed against theory-backed designobjectives and with industry experts. The paper alsoinstantiates the decision model as a software prototype andapplies the prototype to a case based on real-world data

Determinants of recovery from post-COVID-19 dyspnoea: analysis of UK prospective cohorts of hospitalised COVID-19 patients and community-based controls

Background The risk factors for recovery from COVID-19 dyspnoea are poorly understood. We investigated determinants of recovery from dyspnoea in adults with COVID-19 and compared these to determinants of recovery from non-COVID-19 dyspnoea. Methods We used data from two prospective cohort studies: PHOSP-COVID (patients hospitalised between March 2020 and April 2021 with COVID-19) and COVIDENCE UK (community cohort studied over the same time period). PHOSP-COVID data were collected during hospitalisation and at 5-month and 1-year follow-up visits. COVIDENCE UK data were obtained through baseline and monthly online questionnaires. Dyspnoea was measured in both cohorts with the Medical Research Council Dyspnoea Scale. We used multivariable logistic regression to identify determinants associated with a reduction in dyspnoea between 5-month and 1-year follow-up. Findings We included 990 PHOSP-COVID and 3309 COVIDENCE UK participants. We observed higher odds of improvement between 5-month and 1-year follow-up among PHOSP-COVID participants who were younger (odds ratio 1.02 per year, 95% CI 1.01–1.03), male (1.54, 1.16–2.04), neither obese nor severely obese (1.82, 1.06–3.13 and 4.19, 2.14–8.19, respectively), had no pre-existing anxiety or depression (1.56, 1.09–2.22) or cardiovascular disease (1.33, 1.00–1.79), and shorter hospital admission (1.01 per day, 1.00–1.02). Similar associations were found in those recovering from non-COVID-19 dyspnoea, excluding age (and length of hospital admission). Interpretation Factors associated with dyspnoea recovery at 1-year post-discharge among patients hospitalised with COVID-19 were similar to those among community controls without COVID-19. Funding PHOSP-COVID is supported by a grant from the MRC-UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research (NIHR) rapid response panel to tackle COVID-19. The views expressed in the publication are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health and Social Care. COVIDENCE UK is supported by the UK Research and Innovation, the National Institute for Health Research, and Barts Charity. The views expressed are those of the authors and not necessarily those of the funders

Planck 2015 results. XIII. Cosmological parameters

We present results based on full-mission Planck observations of temperature and polarization anisotropies of the CMB. These data are consistent with the six-parameter inflationary LCDM cosmology. From the Planck temperature and lensing data, for this cosmology we find a Hubble constant, H0= (67.8 +/- 0.9) km/s/Mpc, a matter density parameter Omega_m = 0.308 +/- 0.012 and a scalar spectral index with n_s = 0.968 +/- 0.006. (We quote 68% errors on measured parameters and 95% limits on other parameters.) Combined with Planck temperature and lensing data, Planck LFI polarization measurements lead to a reionization optical depth of tau = 0.066 +/- 0.016. Combining Planck with other astrophysical data we find N_ eff = 3.15 +/- 0.23 for the effective number of relativistic degrees of freedom and the sum of neutrino masses is constrained to < 0.23 eV. Spatial curvature is found to be |Omega_K| < 0.005. For LCDM we find a limit on the tensor-to-scalar ratio of r <0.11 consistent with the B-mode constraints from an analysis of BICEP2, Keck Array, and Planck (BKP) data. Adding the BKP data leads to a tighter constraint of r < 0.09. We find no evidence for isocurvature perturbations or cosmic defects. The equation of state of dark energy is constrained to w = -1.006 +/- 0.045. Standard big bang nucleosynthesis predictions for the Planck LCDM cosmology are in excellent agreement with observations. We investigate annihilating dark matter and deviations from standard recombination, finding no evidence for new physics. The Planck results for base LCDM are in agreement with BAO data and with the JLA SNe sample. However the amplitude of the fluctuations is found to be higher than inferred from rich cluster counts and weak gravitational lensing. Apart from these tensions, the base LCDM cosmology provides an excellent description of the Planck CMB observations and many other astrophysical data sets

Treatments for people who use anabolic androgenic steroids: a scoping review.

BACKGROUND: A growing body of evidence suggests that anabolic androgenic steroids (AAS) are used globally by a diverse population with varying motivations. Evidence has increased greatly in recent years to support understanding of this form of substance use and the associated health harms, but there remains little evidence regarding interventions to support cessation and treat the consequences of use. In this scoping review, we identify and describe what is known about interventions that aim to support and achieve cessation of AAS, and treat and prevent associated health problems. METHODS: A comprehensive search strategy was developed in four bibliographic databases, supported by an iterative citation searching process to identify eligible studies. Studies of any psychological or medical treatment interventions delivered in response to non-prescribed use of AAS or an associated harm in any setting were eligible. RESULTS: In total, 109 eligible studies were identified, which included case reports representing a diverse range of disciplines and sources. Studies predominantly focussed on treatments for harms associated with AAS use, with scant evidence on interventions to support cessation of AAS use or responding to dependence. The types of conditions requiring treatment included psychiatric, neuroendocrine, hepatic, kidney, cardiovascular, musculoskeletal and infectious. There was limited evidence of engagement with users or delivery of psychosocial interventions as part of treatment for any condition, and of harm reduction interventions initiated alongside, or following, treatment. Findings were limited throughout by the case report study designs and limited information was provided. CONCLUSION: This scoping review indicates that while a range of case reports describe treatments provided to AAS users, there is scarce evidence on treating dependence, managing withdrawal, or initiating behaviour change in users in any settings. Evidence is urgently required to support the development of effective services for users and of evidence-based guidance and interventions to respond to users in a range of healthcare settings. More consistent reporting in articles of whether engagement or assessment relating to AAS was initiated, and publication within broader health- or drug-related journals, will support development of the evidence base

Planck 2015 results. XX. Constraints on inflation

We present the implications for cosmic inflation of the Planck measurements of the cosmic microwave background (CMB) anisotropies in both temperature and polarization based on the full Planck survey. The Planck full mission temperature data and a first release of polarization data on large angular scales measure the spectral index of curvature perturbations to be n s = 0.968 ± 0.006 and tightly constrain its scale dependence to dn s /dlnk = −0.003 ± 0.007 when combined with the Planck lensing likelihood. When the high-ℓ polarization data is included, the results are consistent and uncertainties are reduced. The upper bound on the tensor-to-scalar ratio is r 0.002 <0.11 (95% CL), consistent with the B-mode polarization constraint r<0.12 (95% CL) obtained from a joint BICEP2/Keck Array and Planck analysis. These results imply that V(ϕ)∝ϕ 2 and natural inflation are now disfavoured compared to models predicting a smaller tensor-to-scalar ratio, such as R 2 inflation. Three independent methods reconstructing the primordial power spectrum are investigated. The Planck data are consistent with adiabatic primordial perturbations. We investigate inflationary models producing an anisotropic modulation of the primordial curvature power spectrum as well as generalized models of inflation not governed by a scalar field with a canonical kinetic term. The 2015 results are consistent with the 2013 analysis based on the nominal mission data