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opencc-zeroNov 2022View details →

A self-purifying microfluidic system for identifying drugs acting against adult schistosomes

The discovery of novel antihelmintic molecules to combat the development and spread of schistosomiasis, a disease caused by several Schistosoma flatworm species, mobilizes significant research efforts worldwide. With a limited number of biochemical assays for measuring the viability of adult worms, the anti-schistosomicidal activity of molecules is usually evaluated by microscopic observation of worm mobility and/or integrity upon drug exposure. Even if these phenotypical assays enable multiple parameters analysis, they are often conducted during several days and need to be associated with image-based analysis to minimized subjectivity. We describe here a self-purifying microfluidic system enabling the selection of healthy adult worms and the identification of molecules acting instantly on the parasite. The worms are assayed in a dynamic environment that eliminates unhealthy worms that cannot attach firmly to the chip walls prior to being exposed to the drug. The detachment of the worms is also used as a second step readout for identifying active compounds. We have validated this new fluidic screening approach using the two major antihelmintic drugs, Praziquantel and Artemisinin. The reported dynamic system is simple to produce and to parallelize. Importantly, it enables quick and sensitive detection of antischistosomal compounds in no more than one hour.

zenodo40/100

The ER folding sensor UGGT1 acts on TAPBPR-chaperoned peptide-free MHC I

Adaptive immune responses are triggered by antigenic peptides presented on major histocompatibility complex class I (MHC I) at the surface of pathogen-infected or cancerous cells. Formation of stable peptide-MHC I complexes is facilitated by tapasin and TAPBPR, two related MHC I-specific chaperones that catalyze selective loading of suitable peptides onto MHC I in a process called peptide editing or proofreading. On their journey to the cell surface, MHC I complexes must pass a quality control step performed by UGGT1, which senses the folding status of the transiting N-linked glycoproteins in the endoplasmic reticulum (ER). UGGT1 reglucosylates non-native glycoproteins and thereby allows them to revisit the ER folding machinery. Here, we describe a reconstituted in-vitro system of purified human proteins that enabled us to delineate the function of TAPBPR during the UGGT1-catalyzed quality control and reglucosylation of MHC I. By combining glycoengineering with liquid chromatography-mass spectrometry, we show that TAPBPR promotes reglucosylation of peptide-free MHC I by UGGT1. Thus, UGGT1 cooperates with TAPBPR in fulfilling a crucial function in the quality control mechanisms of antigen processing and presentation.

opencc-by-4.0Jan 2023View details →

opencc-zeroMar 2023View details →

Increased water temperature and turbidity act independently to alter social behaviour in guppies (Poecilia reticulata)

Changes in environmental conditions can shift the costs and benefits of aggregation or interfere with the sensory perception of near neighbours. This affects group cohesion with potential impacts on the benefits of collective behaviour such as reduced predation risk. Organisms are rarely exposed to one stressor in isolation, yet there are only a few studies exploring the interactions between multiple stressors and their effects on social behaviour. Here we tested the effects of increased water temperature and turbidity on refuge use and three measures of aggregation in guppies (Poecilia reticulata), increasing temperature and turbidity in isolation or in combination. When stressors were elevated in isolation, the distribution of fish within the arena as measured by the index of dispersion became more aggregated at higher temperatures but less aggregated when turbidity was increased. Another measure of cohesion at the global scale, the mean inter-individual distance, also indicated that fish were less aggregated in turbid water. This is likely due to turbidity acting as a visual constraint, as there was no evidence of a change in risk perception as refuge use was not affected by turbidity. Fish decreased refuge use and were closer to their nearest neighbour at higher temperatures. However, nearest-neighbour distance was not affected by turbidity, suggesting that local-scale interactions can be robust to the moderate increase in turbidity used here (5 NTU) compared to other studies which show a decline in shoal cohesion at higher turbidity (>100 NTU). We did not observe any significant interaction terms between the two stressors, indicating no synergistic or antagonistic effects. Our study suggests that the effects of environmental stressors on social behaviour may be unpredictable and dependent on the metric used to measure cohesion, highlighting the need for mechanistic studies to link behaviour to the physiology and sensory effects of environmental stressors.

opencc-zeroJun 2023View details →

Trans-acting genotypes drive mRNA expression affecting metabolic and thermal tolerance traits

Evolutionary processes driving physiological trait variation depend on the underlying genomic mechanisms. Evolution of these mechanisms depends on whether traits are genetically complex (involving many genes) and how gene expression that impacts the traits is converted to phenotype. Yet, genomic mechanisms that impact physiological traits are diverse and context-dependent (e.g., vary by environment or among tissues), making them difficult to discern. Here we examine the relationships between genotype, mRNA expression, and physiological traits to discern the genetic complexity and whether the gene expression affecting the physiological traits is primarily cis or trans-acting. We use low-coverage whole genome sequencing and tissue-specific mRNA expression among individuals to identify polymorphisms directly associated with physiological traits and expressed quantitative trait loci (eQTL) driving variation in six temperature-specific physiological traits (standard metabolic rate, thermal tolerance, and four substrate-specific cardiac metabolic rates). Not surprisingly, there were few, only five, SNPs directly associated with physiological traits. Yet, by focusing on a select set of mRNAs belonging to co-expression modules that explain up to 82% of temperature specific (12°C or 28°C) metabolism and thermal tolerance, we identified hundreds of significant eQTL for mRNA whose expression affects physiological traits. Surprisingly, most eQTL (97.4% for heart and 96.7% for brain) of eQTL were trans-acting. This could be due to higher effect size or greater importance of trans versus cis-acting eQTLs for mRNAs that are central to co-expression modules. That is, we may have enhanced the identification of trans-acting factors by looking for SNPs associated with mRNAs in co-expression modules that are known to be correlated with the expression of 10s or 100s of other genes, and thus have identified eQTLs with widespread effects on broad gene expression patterns. Overall, these data indicate that the genomic mechanism driving physiological variation across environments is driven by trans-acting tissue-specific mRNA expression.

zenodo40/100

Data and code for 'Pseudogenes act as a neutral reference for detecting selection in prokaryotic pangenomes'

This repository contains the code and files for reproducing the analyses and results reported in 'Pseudogenes act as a neutral reference for detecting selection in prokaryotic pangenomes' by Gavin M. Douglas and B. Jesse Shapiro (<a href="https://doi.org/10.1038/s41559-023-02268-6">https://doi.org/10.1038/s41559-023-02268-6</a>). File organization and descriptions: <ul> <li>code/ - Contains GitHub repository releases of code used in manuscript (the other folders contain datafiles only). This code is provided here as well as on GitHub to ensure long-term access. <ul> <li>handy_pop_gen-1.1.0/ - release v1.1.0 of the convenience repository (used for specific data processing and analysis steps referred to in the manuscript).</li> <li>pangenome_pseudogene_null-1.1.0/ - Main code repository for manuscript.</li> </ul> </li> </ul>   <ul> <li>broad_pangenome_analysis/ <ul> <li>element_info/element_counts.tsv.gz - Counts of (filtered) pseudogenes and intact genes called per genome accession.</li> <li>element_info/gene_sizes.tsv.gz - Gene sizes in base-pairs.</li> <li>element_info/pseudogene_sizes.tsv.gz - Filtered pseudogene sizes in base-pairs.</li> <li>element_info/element_percent_coverage/*tsv.gz - Tables containing the percent genome coverage of genes and pseudogenes, by accession and averaged over accessions per species separately.</li> <li>example_Mycoplasmopsis_bovis_panaroo_output.csv.gz - Panaroo output table for Mycoplasmopsis bovis, which was used for an example. Corresponds to the gene_presence_absence.csv file in the raw Panaroo output.</li> <li>focal_and_non.focal_full_to_short.tsv.gz - Mapfile of full to short (and unique) species ids used in analysis. Primarily to include species ids in cluster names without making them unnecessarily long.</li> <li>genome_info/accessions.tsv.gz - Genome accessions used for broad pangenome analysis (note that not all genome accessions could be downloaded [and were ignored], which is indicated in the "could_download" column).</li> <li>genome_info/genome_sizes.tsv.gz - Sizes of all genomes used for the broad pangenome analysis.</li> <li>metrics_additional_subsamples.tsv.gz - Contains columns also found in the pangenome_and_related_metrics.tsv.gz file below, but based on genome subsamplings of 3 and 20, rather than 9.</li> <li>model_output/pangenome_linear_models.rds - R Data Serialization files containing the output of R linear model objects (generated by lm and provided as an R list object). There are separate elements in the list for the mean number of genes, genomic fluidity, percentage singletons (si), and si/sp.</li> <li>model_output/linear_model_coef.tsv.gz - Coefficient summary table for all linear models.</li> <li>pangenome_and_related_metrics.tsv.gz - Metrics used for broad pangenome analysis across 670 prokaryotic species. Note that this table was filtered down to 668 species after excluding those with < 9 genomes.</li> <li>pangenome_and_related_metrics_filt.tsv.gz - Filtered table, as described above.</li> <li>taxonomy.tsv.gz - Taxonomy for all species used for this analysis, taken from GTDB. Row names are species names.</li> </ul> </li> </ul>   <ul> <li>indepth_10_species_analysis/ <ul> <li>cluster_breakdown_tables/ - Folder containing tables providing breakdown of how clusters are distributed by element type, pangenome partition, and species. Provided for easy plotting.</li> <li>cluster_COG_annot.tsv.gz - Mapping of cluster IDs to COG annotations.</li> <li>cluster_filt_lengths_and_additional.tsv.gz - Metadata on clusters, most pertinently the length of the representative sequence in the cluster (which was used to filter out some clusters, below the cut-off which pseudogenes could not be called).</li> <li>cluster_member_breakdown.tsv.gz - Table providing information on each element (called pseudogenes and intact genes) and provides information such as what cluster they are part of, what species and genome accession they are found in, etc.</li> <li>cluster_types.rds - R Data Serialization file containing R list providing breakdown of all clusters into categories (intact/pseudogene/mixed, where mixed means containing both pseudogene and intact elements).</li> <li>COG_enrichment_results/ultra.cloud-COG-gene-enrichments.tsv.gz - Output file with enrichment test summaries for COG IDs in significant COG categories, which was run for the ultra-cloud pangenome partition model only.</li> <li>element_glmm_input.tsv.gz - Table containing all information used for fitting generalized linear mixed models.</li> <li>focal_species.txt - Names of species used for the in-depth analysis.</li> <li>genome_info/ - Folder containing the genome accessions (and the corresponding genome sizes) for all ten analyzed species.</li> <li>glmm_output/ - Folder containing R Data Serialization files containing output R objects after fitting generalized linear mixed models (only ultra-rare files are present, due to file size constraints).</li> <li>per_genome_element.type_percent_coverages.rds - R Data Serialization file containing R list providing the percent coverage by intact genes vs pseudogenes per accession (nested by species)</li> </ul> </li> </ul>

opencc-by-4.0May 2023View details →

opencc-zeroOct 2023View details →

Within and between population comparisons suggest independently acting selection maintaining parallel clines in Scots pine (Pinus sylvestris)

Parallel clines in traits related to adaptation in a species can be due to independent selection on a pair of traits, or due to selection in one trait resulting in a parallel cline in a correlated trait. To distinguish between the mechanisms giving rise to parallel adaptive population divergence of multiple traits along an environmental gradient we need to study variation, correlations, and selective forces within individual populations along the gradient. In many tree species, budset timing forms a latitudinal cline, and parallel clinal variation is also found in other seedling traits, such as first year height and fall frost injury. In this study, we set up a common garden experiment with open pollinated progeny from natural populations of Scots pine (Pinus sylvestris), with one large sample from single population (500 families) and smaller samples from across a latitudinal gradient. Budset timing, first year height and induced fall frost injury were first measured in a greenhouse. The seedlings were then planted in the field, where survival and height were measured at the age of nine years as fitness proxies. We compared between and within population variation and genetic correlations of these three seedling traits, and estimated selection gradients at the family level in our main population, taking into account the potential effects of seed weight. Between population genetic correlations between seedling traits were high (0.76-0.95). Within population genetic correlations in the main population were lower (0.14-0.35), as in other populations (0.10-0.39). Within population, extensive adaptive variation persists in the seedling traits, in line with rather weak selection gradients, yet maintaining the clines. Although our sampling does not cover the whole cline equally, the results suggest that the individual clines in these traits are maintained by largely independently acting selection, which results in fewer constraints in adaptation under changing climate.

The LATITUDE Study: Long-Acting Therapy to Improve Treatment SUccess in Daily LifE

ClinicalTrials.gov study NCT03635788. IPD Sharing: YES. Countries: 2. Publications: 2.

More Options for Children and Adolescents (MOCHA): Oral and Long-Acting Injectable Cabotegravir and Rilpivirine in HIV-Infected Children and Adolescents

ClinicalTrials.gov study NCT03497676. IPD Sharing: YES. Countries: 5. Publications: 6.

An Evaluation of a Multi-target Stool DNA (Mt-sDNA) Test, Cologuard, for CRC Screening in Individuals Aged 45-49 and at Average Risk for Development of Colorectal Cancer: Act Now

ClinicalTrials.gov study NCT03728348. IPD Sharing: YES. Countries: 1. Publications: 1.

Long-Acting Cabotegravir Plus VRC-HIVMAB075-00-AB (VRC07-523LS) for Viral Suppression in Adults Living With HIV-1

ClinicalTrials.gov study NCT03739996. IPD Sharing: YES. Countries: 2. Publications: 1.