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Immune cell-resolved transcriptomics provides insights into the basis for variations of fish genetic resistance to viral disease
Get PDFBackground. The genetic basis of host resistance to viral infections is generally shaped by complex interactions between host genetic variations affecting antiviral immunity and the rapid evolutionary adaptability of viruses. In this study, we investigated two isogenic rainbow trout lines exhibiting extreme resistance or susceptibility to the rhabdovirus VHSV. We compared transcriptomes of the pronephros—a major lymphoid organ in fish—at steady state and following VHSV infection. By integrating bulk tissue RNA-seq with single-cell RNA-seq, we mapped the divergent transcriptomicresponses of resistant and susceptible fish to specific immune cell types. Results. At steady state, differences in antiviral pathways were minimal.However, VHSV triggered markedly distinct transcriptomic shifts between the lines. Both resistant and susceptible fish exhibited a broad transcriptional response enriched in core type I interferon (IFN) pathway genes. However, line- specific responses were enriched in genes induced by infection independently of type I IFN. In resistant fish, lymphocyte responses included type I IFN pathway, numerous transcription factors, and various cytokine receptors. In contrast, lymphocyte responses in susceptible fish involved only a limited set of type I IFN-induced genes. Monocytic cell responses also diverged: susceptible fish upregulated IFN-induced genes, while resistant fish showed increased expression of proinflammatory genes. Conclusions. This study reveals the contribution of the core set of Interferon-stimulated-genes conserved across vertebrates to the response of different immune cells, and the response of other genes in resistant and susceptible fish. It provides a comprehensive basis for evolutionary studies of resistance to viruses in vertebrates.conserved across vertebrates to the response of different immune cells, and the response of other genes in resistant and susceptible fish. It provides a comprehensive basis for evolutionary studies of resistance to viruses in vertebrates
OTX2 controls chromatin accessibility to direct somatic versus germline differentiation
Get PDFThe choice between somatic and germline fates is essential for species survival. This choice occurs in embryonic epiblast cells, as these cells are competent for both somatic and germline differentiation. The transcription factor OTX2 regulates this process, as Otx2-null epiblast-like cells (EpiLCs) form primordial germ cell-like cells (PGCLCs) with enhanced efficiency. Yet, how OTX2 achieves this function is not fully characterized. Here we show that OTX2 controls chromatin accessibility at specific chromatin loci to enable somatic differentiation. CUT&RUN for OTX2 and ATAC-seq in wild-type and Otx2-null embryonic stem cells and EpiLCs identifies regions where OTX2 binds and opens chromatin. Enforced OTX2 expression maintains accessibility at these regions and also induces opening of ~4,000 somatic-associated regions in cells differentiating in the presence of PGC-inducing cytokines. Once cells have acquired germline identity, these additional regions no longer respond to OTX2 and remain closed. Our results indicate that OTX2 works in cells with dual competence for somatic and germline differentiation to increase accessibility of somatic regulatory regions and induce the somatic fate at the expense of the germline
Southern Ocean summer warming is regulated by storm-driven mixing
No full textThe Southern Ocean absorbs most of the excess heat resulting from climate change. However, climate projections show a persistent warm summer bias in its sea surface temperatures, indicating a limited understanding of the air–sea heat exchange mechanisms governing this region. Here we examine the impact of storms on the interannual variability of Southern Ocean surface temperatures during summer using in situ observations from underwater and surface robotic vehicles, climate reanalyses and satellite data. We show that synoptic-scale storms regulate summer sea surface temperatures through alteration of the effective heat capacity of the mixed layer and the entrainment of colder water from below. Storms reduce the summer ocean heat gain by limiting solar radiation reaching the surface. This effect is partially offset by a reduction in heat loss due to turbulent air–sea exchange. We also find that interannual variations in sea surface temperature during summer in the Southern Ocean are driven by changes in storm-mean wind speeds, which are linked to the Southern Annular Mode. Our results demonstrate a causal link between storm forcing and sea surface temperature variability, which is critical for reducing warming biases in climate models and improving future climate projections
Mortality disparity by socioeconomic position in people with and without diabetes:open cohort studies in four high-income countries
No full textBackground: There have been mixed findings on whether mortality is socially patterned among people with diabetes. We compared all-cause mortality trends by socioeconomic position (SEP) among people with and without diabetes for 2004-2021 in four high-income countries.Methods: We conducted open cohort studies in Australia, Denmark, the Netherlands, and Scotland and included national or regional populations aged 35-69 years. We used the European standard population in 2013 to calculate age-standardised mortality rates (ASMRs) by calendar year, SEP quintile, diabetes status, and sex. SEP quintiles were defined using standardised disposable household income in Denmark and the Netherlands, and area-based indices in Australia and Scotland. We calculated the age-standardised slope index of inequality and age-adjusted relative index of inequality using Poisson regression as absolute and relative measures of socioeconomic inequality respectively across the study populations stratified by calendar year, diabetes status, and sex. Results: 208,011 deaths occurred during 17 million person years (py) of follow-up among 35-69 year olds with diabetes, and 1.1 million deaths during 298 million py of follow-up among people without diabetes. ASMRs generally increased with increasing deprivation and varied between 1.3 (95% CI: 1.2-1.4) deaths per 1000 py to 29.4 (95% CI: 26.0-32.8) deaths per 1000 py. We found absolute and relative mortality inequality that increased during the follow-up period among adults without diabetes. Measures of absolute and relative inequality among adults with diabetes widened in some populations by country and sex.Conclusion: Disparities in mortality by SEP increased during follow-up in most countries. Strategies are needed to reduce excess mortality associated with low SEP and diabetes and related socioeconomic inequality
Why oppose a common form of practice? A response to Parry ET Al
No full textA recent paper by Parry et al. raises questions about the utility of unopposed practice (i.e., drills or “training form” practice). In this response we critique several arguments presented, offering examples in support of a more “nuanced” and balanced approach to coach planning and practice design. We conclude by emphasizing that complex issues such as coaching will almost inevitably require a range of tools to address specific contexts, meaning that claims for and application of a single theoretical perspective can often generate sub-optimum outcomes
Determining and predicting biochemical disease trajectory in intrahepatic cholestasis of pregnancy: a longitudinal cohort study
No full textBackgroundThe severity of intrahepatic cholestasis of pregnancy (ICP) reflects peak maternal bile acid (BA) concentration. However, the course of the disease is unclear.MethodsLongitudinal observational cohort study of individuals with ICP. Serial BA and alanine aminotransferase (ALT) trajectories were determined according to starting severity. Multiple logistic regression identified variables predictive of subsequent disease severity, validated using data from a randomised controlled trial.ResultsAlthough highly variable, BA concentrations increased across gestation (p > 0.001). Normal ALT concentration at diagnosis predicted concurrent non-severe disease (negative predictive value 94.2% (91.6–96.1%)). Gestational age and BA concentration at diagnosis somewhat predicted later moderate or severe disease (BA ≥ 40 µmol/L: ROCAUC 0.64 (0.58–0.69); BA ≥ 100 µmol/L: ROCAUC 0.68 (0.62–0.73)), similarly in the validation cohort (ROCAUC 0.70 (0.65–0.76) and 0.69 (0.63–0.76), respectively).ConclusionAn earlier gestation and higher BA concentration at diagnosis increase the likelihood of more severe disease; however robust prediction is limited
Dynamic patterns of gene expression match extracellular signals through push-pull regulation
No full textCells can match gene expression to a range of a particular signal. For example, budding yeast expresses at least seven hexose-transporter (HXT) genes in different concentration ranges of extracellular glucose. Using time-lapse microscopy, microfluidics, dynamic glucose inputs, and mathematical modelling, we determine how this glucose matching of HXT expression occurs mechanistically. The glucose-sensing network generates a push-pull regulation using two pairs of regulators: rising glucose weakens, or “pulls”, repression via regulators Mth1 and Std1 while simultaneously strengthening, or “pushing”, repression via regulators Mig1 and Mig2; falling glucose reverses this push-pull. The regulators’ combined activity reports extracellular glucose. Cells match HXT expression to glucose because HXT promoters couple to the regulators in ways specific to low, medium, or high-affinity transporters. By rewiring transcription and using model-predicted perturbations, we demonstrate how an HXT encoding a medium-affinity transporter can respond as one encoding either a low- or a high-affinity transporter. Matching gene expression to a pattern of input is fundamental; we believe push-pull regulation to be widespread
Rheology of bidisperse suspensions at the colloidal-to-granular transition
No full textWe use particle-based simulation to study the rheology of dense suspensions comprising mixtures of small colloids and larger grains subject to contact, lubrication and Brownian forces. These suspensions exhibit shear thinning at low shear rates and shear thickening at high shear rates. By systematically varying the volume fraction of the two species, we demonstrate a monotonic increase in viscosity when grains are added to colloids, but, conversely, a non-monotonic response in both the viscosity and shear-thickening onset when colloids are added to grains. Both effects are most prominent at intermediate shear rates where diffusion and convection play similar roles in the dynamics. We rationalise these results by measuring the maximum flowable volume fraction as functions of the Péclet number and composition, showing that in extreme cases increasing the solids content can disrupt grain contacts and thus allow a jammed suspension to flow. These results establish a constitutive description for the rheology of bidisperse suspensions across the colloidal-to-granular transition, with implications for flow prediction and control in multicomponent particulate systems.</p
Transferability of European-derived Alzheimer’s disease polygenic risk scores across multiancestry populations
No full textA polygenic score (PGS) for Alzheimer’s disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries. A cross-ancestry polygenic risk score improved the association with the AD risk in most of the multiancestry populations tested when the APOE region was included. Finally, we found that the PGS/polygenic risk score captured AD-specific information because the association weakened as the diagnosis was broadened. In conclusion, a simple PGS captures the AD-specific genetic information that is common to populations of different ancestries, although studies of more diverse populations are still needed to better characterize the genetics of AD.</p
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