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In almost every natural environment, sounds are reflected by nearby objects, producing many delayed and distorted copies of the original sound, known as reverberation. Our brains usually cope well with reverberation, allowing us to recognize sound sources regardless of their environments. In contrast, reverberation can cause severe difficulties for speech recognition algorithms and hearing-impaired people. The present study examines how the auditory system copes with reverberation. We trained a linear model to recover a rich set of natural, anechoic sounds from their simulated reverberant counterparts. The model neurons achieved this by extending the inhibitory component of their receptive filters for more reverberant spaces, and did so in a frequency-dependent manner. These predicted effects were observed in the responses of auditory cortical neurons of ferrets in the same simulated reverberant environments. Together, these results suggest that auditory cortical neurons adapt to reverberation by adjusting their filtering properties in a manner consistent with dereverberation. We have provided our Matlab scripts for generating our figures on Github: https://github.com/PhantomSpike/DeReverb Spike data were recorded using Neuropixels electrodes in the auditory cortex of anaesthetised ferrets.

Obesity is a world wide problem and evidence suggests, that early lifetime undernourishment of caloric restirction predispose an organism for obesity and metabolic syndrome. We have raised two cohorts of zebrafish in an obesogenic environment (DIO) and compared several metabolic markers with fish raised under caloric restriction (CR) or fish shifted from CR to DIO at different periods in their life. We have looked morphologically at standard length and weight and found that fish on DIO grow faster in both axes. Fish shifted from CR to DIO show catch-up growth and not compensatory growth when shifted at one month, 3 months or 9 months of age. We have further characterized central agrp expression and hyperphagia, adipose tissue by histology as well as uCT imaging, hepatic histology, metabolic rate mitochondrial function as well as feeding induced glucose levels. We find that fish in an obesogenic environment develop markers of obesity which are not exacerbated by ealry lifetime food restriction.

For µCT imaging, adult zebrafish were fixed and decalcified in Bouin's solution at room temperature for 7 days, stored in PBS and imaged using a micro-computed tomography (µCT) device (SkyScan1272, Bruker BioSpin GmbH, Ettlingen, Germany). Zebrafish were placed individually in 1.5ml Eppendorf tubes using and an ultra-focus scan over the whole body was performed in a full-rotation in step-and-shoot mode. 322 projections (1008x672 pixels, 4x4 binning) were acquired per subscan with an x-ray tube voltage of 60 kV, power 0.166 mA, aluminum filter 0.25 mm,exposure time of 363 ms, 6 averages and a object-source distance of 86 mm. All CT images were reconstructed at an isotropic voxel size of 18 µm using a Feldkamp type algorithm (filtered back-projection). Fat-containing regions were appear hypo intense in µCT data and were segmented using Imalytics Preclinical (Gremse-IT GmbH, Aachen, Germany (Gremse et al., 2016; doi:10.7150/thno.13624). The volumetric fat percentage was calculated as the ratio of subcutaneous adipose tissue (SAT) or visceral adipose tissue (VAT) fat volume compared to the entire volume of the body cavity anterior of the anal fin and expressed per skeletal segment. Fish were raised as previously reported (Leibold and Hammerschmidt, 2015) for the following conditions:CG1: compensatory or catch up growth shifted at 1 month of ageCG3: compensatory or catch up growth shifted at 3 months of ageCG9: compensatory or catch up growth shifted at 9 months of ageCR: caloric restrictionDIO: diet induced obesityThe CT .nii files correlate to the groups as follows: Group 2: CG1; Group 3: DIO1; Group 6: CG3; Group 7 DIO3; Group 10: CG9; Group 11: DIO9; Group 1: CR1; Group 5: CR3; Group 9: CR9

Northern Australia’s unique and rich biodiversity faces numerous threatening processes. Currently, there is limited knowledge of i) the distribution of species of conservation concern across northern Australia, ii) their level of exposure to various threats and iii) their vulnerability as a result of exposure and differential sensitivity to threats. These knowledge gaps severely limit the efficiency and adequacy of conservation actions and simultaneously create uncertainty for sustainable development in the North. This project aimed to fill these knowledge gaps by creating spatially explicit data that can be used to inform species conservation policy, assessments of species’ conservation status and decision-making about threat mitigation and management. The data can also be used to guide where further research may be needed about species of conservation concern, as part of regional planning processes governing land-use and water resources in northern Australia. The user guide has been prepared to assist stakeholders with the appropriate use of data created for the National Environmental Science Program (NESP) Northern Australia Environmental Resources (NAER) Hub, through Project 3.3 Prioritising threatened species and threatening processes across northern Australia. The project has generated the following data sets: 1. High-resolution maps of the distributions of >1,400 ‘species of conservation concern’,i.e. rare, range-restricted, threatened or near threatened species or populations of plants and animals that occupy terrestrial or freshwater ecosystems, developed based on habitat suitability models and expert knowledge; 2. Hotspot maps that show concentrations, or richness, of species of conservation concern for different taxonomic groups; 3. Maps of the key threatening processes that impact northern Australian biodiversity; and 4. Maps of vulnerability: These combine maps of species of conservation concern distributions with maps of threatening processes and information on how sensitive the species are to those threats. The resulting maps identify areas of high vulnerability – areas, where species of conservation concern coincide with significant threats and thus should be considered for targeted management. The user guide briefly describes the rationale for, and data files associated with, all four data sets described above. It also provides practical guidance on appropriate interpretation of the data, as well as important methodological caveats and limitations. It does not replace the need for ground-truthing, regional and site-based ecological surveys and/or taxa-specific research, but can help frame where this survey effort might occur and for which species.

To test associations between DNA methylation levels and gene expression levels in cis (cis eQTMs), we paired each Gene to CpGs closer than 500 kb from its TSS, either upstream or downstream. For each Gene, the TSS was defined based on HTA-2.0 annotation, using the start position for transcripts in the + strand, and the end position for transcripts in the - strand. CpGs position was obtained from Illumina 450K array annotation. Only CpGs in autosomal chromosomes (from chromosome 1 to 22) were tested. In the main analysis, we fitted for each CpG-Gene pair a linear regression model between gene expression and methylation levels adjusted for age, sex, cohort, and blood cell type composition. A second model was run without adjusting for blood cellular composition and it is only reported on the online web catalog, but not discussed in this manuscript. Although some of the unique associations of the unadjusted model might be real, others might be confounded by the large methylation and expression changes among blood cell types. To ensure that CpGs paired to a higher number of Genes do not have higher chances of being part of an eQTM, multiple-testing was controlled at the CpG level, following a procedure previously applied in the Genotype-Tissue Expression (GTEx) project (Gamazon et al., 2018). Briefly, our statistic used to test the hypothesis that a pair CpG-Gene is significantly associated is based on considering the lowest p-value observed for a given CpG and all its paired Gene (e.g., those in the 1 Mb window centered at the TSS). As we do not know the distribution of this statistic under the null, we used a permutation test. We generated 100 permuted gene expression datasets and ran our previous linear regression models obtaining 100 permuted p-values for each CpG-Gene pair. Then, for each CpG, we selected among all CpG-Gene pairs the minimum p-value in each permutation and fitted a beta distribution that is the distribution we obtain when dealing with extreme values (e.g. minimum) (Dudbridge and Gusnanto, 2008). Next, for each CpG, we took the minimum p-value observed in the real data and used the beta distribution to compute the probability of observing a lower p-value. We defined this probability as the empirical p-value of the CpG. Then, we considered as significant those CpGs with empirical p-values to be significant at 5% false discovery rate using Benjamini-Hochberg method. Finally, we applied a last step to identify all significant CpG-Gene pairs for all eCpGs. To do so, we defined a genome-wide empirical p-value threshold as the empirical p-value of the eCpG closest to the 5% false discovery rate threshold. We used this empirical p-value to calculate a nominal p-value threshold for each eCpG, based on the beta distribution obtained from the minimum permuted p-values. This nominal p-value threshold was defined as the value for which the inverse cumulative distribution of the beta distribution was equal to the empirical p-value. Then, for each eCpG, we considered as significant all eCpG-Gene variants with a p-value smaller than nominal p-value. For the meQTLs catalogue, we selected 9.9 M cis and trans meQTLs with a p-value <1e-7 in the ARIES dataset consisting of data from children of 7 years old (Gaunt et al., 2016). Then, we tested whether this subset of 9.9 M SNPs were also meQTLs in HELIX by running meQTL analyses using MatrixEQTL R package (Shabalin, 2012), adjusting for cohort, sex, age, blood cellular composition and the first 20 principal components (PCs) calculated from genome-wide genetic data of the GWAS variability. We confirmed 2.8 M meQTLs in HELIX (p-value <1e-7). Trans meQTLs represented <10% of the 2.8 M meQTLs. Enrichment of eCpGs for meQTLs was computed using a Chi-square test, using non eCpGs as background. Finally, we tested whether meQTLs were also eQTLs for the eGenes linked to the eCpGs. To this end, we run eQTL analyses (gene expression being the outcome and 2.8 M SNPs the predictors) with MatrixEQTL adjusting for cohort, sex, age, blood cellular composition and the first 20 GWAS PCs in HELIX. We considered as significant eQTLs the SNP-Gene pairs with p-value <1e-7 and with the direction of the effect consistent with the direction of the meQTL and the eQTM. Background: The identification of expression quantitative trait methylation (eQTMs), defined as associations between DNA methylation levels and gene expression, might help the biological interpretation of epigenome-wide association studies (EWAS). We aimed to identify autosomal cis eQTMs in children’s blood, using data from 832 children of the Human Early Life Exposome (HELIX) project. Methods: Blood DNA methylation and gene expression were measured with the Illumina 450K and the Affymetrix HTA v2 arrays, respectively. The relationship between methylation levels and expression of nearby genes (1 Mb window centered at the transcription start site, TSS) was assessed by fitting 13.6 M linear regressions adjusting for sex, age, cohort, and blood cell composition. Results: We identified 39,749 blood autosomal cis eQTMs, representing 21,966 unique CpGs (eCpGs, 5.7% of total CpGs) and 8,886 unique transcript clusters (eGenes, 15.3% of total transcript clusters, equivalent to genes). In 87.9% of these cis eQTMs, the eCpG was located at <250 kb from eGene’s TSS; and 58.8% of all eQTMs showed an inverse relationship between the methylation and expression levels. Only around half of the autosomal cis-eQTMs eGenes could be captured through annotation of the eCpG to the closest gene. eCpGs had less measurement error and were enriched for active blood regulatory regions and for CpGs reported to be associated with environmental exposures or phenotypic traits. 40.4% of eQTMs had at least one genetic variant associated with methylation and expression levels. The overlap of autosomal cis eQTMs in children’s blood with those described in adults was small (13.8%), and age-shared cis eQTMs tended to be proximal to the TSS and enriched for genetic variants. See HELIX_Blood_eQTM_READMEfile_20210205.xlsx.

Many sensory systems use ribbon-type synapses to transmit their signals to downstream circuits. The properties of this synaptic transfer fundamentally dictate which aspects in the original stimulus will be accentuated or suppressed, thereby partially defining the detection limits of the circuit. Accordingly, sensory neurons have evolved a wide variety of ribbon geometries and vesicle pool properties to best support their diverse functional requirements. However, the need for diverse synaptic functions does not only arise across neuron types, but also within. Here we show that UV-cones, a single type of photoreceptor of the larval zebrafish eye, exhibit striking differences in their synaptic ultrastructure and consequent calcium to glutamate transfer function depending on their location in the eye. We arrive at this conclusion by combining serial section electron microscopy and simultaneous "dual-colour" 2-photon imaging of calcium and glutamate signals from the same synapse in vivo. We further use the functional dataset to fit a cascade-like model of the ribbon synapse with different vesicle pool sizes, transfer rates and other synaptic properties. Exploiting recent developments in simulation-based inference, we obtain full posterior estimates for the parameters and compare these across different retinal regions. The model enables us to extrapolate to new stimuli and to systematically investigate different response behaviours of various ribbon configurations. We also provide an interactive, easy-to-use version of this model as an online tool. Overall, we show that already on the synaptic level of single neuron types there exist highly specialized mechanisms which are advantageous for the encoding of different visual features.

Objective: We employed Mendelian Randomization to explore whether the effects of blood pressure (BP) and BP lowering through different antihypertensive drug classes on stroke risk vary by stroke etiology. Methods: We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drug targets from a GWAS on 757,601 individuals. Applying two-sample Mendelian randomization, we examined associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes (large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and lobar), and the related small vessel disease phenotype of WMH. Results: Genetic predisposition to higher systolic and diastolic BP was associated with higher risk of any stroke, ischemic stroke, and ICH. We found associations between genetically determined BP and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic proxies for calcium channel blockers, but not beta blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for CCBs showed particularly strong associations with small vessel stroke and the related radiological phenotype of WMH. Conclusions: This study supports a causal role of hypertension in all major stroke subtypes except lobar ICH. We find differences in the effects of BP and BP lowering through antihypertensive drug classes between stroke subtypes and identify calcium channel blockade as a promising strategy for preventing manifestations of cerebral small vessel disease. Objective: We employed Mendelian Randomization to explore whether the effects of blood pressure (BP) and BP lowering through different antihypertensive drug classes on stroke risk vary by stroke etiology. Methods: We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drug targets from a GWAS on 757,601 individuals. Applying two-sample Mendelian randomization, we examined associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes (large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and lobar), and the related small vessel disease phenotype of WMH. Results: Genetic predisposition to higher systolic and diastolic BP was associated with higher risk of any stroke, ischemic stroke, and ICH. We found associations between genetically determined BP and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic proxies for calcium channel blockers, but not beta blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for CCBs showed particularly strong associations with small vessel stroke and the related radiological phenotype of WMH. Conclusions: This study supports a causal role of hypertension in all major stroke subtypes except lobar ICH. We find differences in the effects of BP and BP lowering through antihypertensive drug classes between stroke subtypes and identify calcium channel blockade as a promising strategy for preventing manifestations of cerebral small vessel disease. 1

This is the raw data supporting the findings (both main text and supplementary) for our manuscript "Staphylococcus aureus cell wall structure and dynamics during host-pathogen interaction". Each excel file contains the raw data for each figure. Murine work was carried out according to UK law in the Animals (Scientific Procedures) Act 1986, under Project License P3BFD6DB9 (Staphylococcus aureus and other pathogens, pathogenesis to therapy, University of Sheffield Review Board).

Transmission of Plasmodium falciparum malaria parasites occurs when nocturnal Anopheles mosquito vectors feed on human blood. In Africa, where malaria burden is greatest, bednets treated with pyrethroid insecticide were highly effective in preventing mosquito bites and reducing transmission, and essential to achieving unprecedented reductions in malaria until 2015. Since then, progress has stalled and with insecticidal bednets losing efficacy against pyrethroid-resistant Anopheles vectors, methods that restore performance are urgently needed to eliminate any risk of malaria returning to the levels seen prior to their widespread use throughout sub-Saharan Africa. Here we show that the primary malaria vector Anopheles gambiae is targeted and killed by small insecticidal net barriers positioned above a standard bednet, in a spatial region of high mosquito activity but zero contact with sleepers, opening the way for deploying many more insecticides on bednets than currently possible. Tested against wild pyrethroid-resistant Anopheles gambiae in Burkina Faso, pyrethroid bednets with organophosphate barriers achieved significantly higher killing rates than bednets alone. Treated barriers on untreated bednets were equally effective, without significant loss of personal protection. Mathematical modelling of transmission dynamics predicted reductions in clinical malaria incidence with barrier bednets that exceeded those of ‘next-generation’ nets recommended by WHO against resistant vectors. Mathematical models of mosquito-barrier interactions identified alternative barrier designs to increase performance. Barrier bednets that overcome insecticide resistance are feasible using existing insecticides and production technology, and early implementation of affordable vector control tools is a realistic prospect. BB_Hut_Trial_2017_rotation_plan_Dryad_Sept_2019.xlsx Hut trial data from Tengrela village, Cascades region, Burkina Faso, 16/07/2017 - 25/08/2017. Data formatted as simplified version of Kiware et al 2016 ED 2 framework (https://scfbm.biomedcentral.com/articles/10.1186/s13029-016-0050-1). The second sheet details the randomised hut trial full latin-square rotation plan. Any missing values are detailed in the notes section.