Metabolic processes can influence disease risk and provide therapeutic targets. By conducting genome-wide association studies of 1,091 blood metabolites and 309 metabolite ratios, we identified ...associations with 690 metabolites at 248 loci and associations with 143 metabolite ratios at 69 loci. Integrating metabolite-gene and gene expression information identified 94 effector genes for 109 metabolites and 48 metabolite ratios. Using Mendelian randomization (MR), we identified 22 metabolites and 20 metabolite ratios having estimated causal effect on 12 traits and diseases, including orotate for estimated bone mineral density, α-hydroxyisovalerate for body mass index and ergothioneine for inflammatory bowel disease and asthma. We further measured the orotate level in a separate cohort and demonstrated that, consistent with MR, orotate levels were positively associated with incident hip fractures. This study provides a valuable resource describing the genetic architecture of metabolites and delivers insights into their roles in common diseases, thereby offering opportunities for therapeutic targets.
Abstract
MarkerDB is a freely available electronic database that attempts to consolidate information on all known clinical and a selected set of pre-clinical molecular biomarkers into a single ...resource. The database includes four major types of molecular biomarkers (chemical, protein, DNA genetic and karyotypic) and four biomarker categories (diagnostic, predictive, prognostic and exposure). MarkerDB provides information such as: biomarker names and synonyms, associated conditions or pathologies, detailed disease descriptions, detailed biomarker descriptions, biomarker specificity, sensitivity and ROC curves, standard reference values (for protein and chemical markers), variants (for SNP or genetic markers), sequence information (for genetic and protein markers), molecular structures (for protein and chemical markers), tissue or biofluid sources (for protein and chemical markers), chromosomal location and structure (for genetic and karyotype markers), clinical approval status and relevant literature references. Users can browse the data by conditions, condition categories, biomarker types, biomarker categories or search by sequence similarity through the advanced search function. Currently, the database contains 142 protein biomarkers, 1089 chemical biomarkers, 154 karyotype biomarkers and 26 374 genetic markers. These are categorized into 25 560 diagnostic biomarkers, 102 prognostic biomarkers, 265 exposure biomarkers and 6746 predictive biomarkers or biomarker panels. Collectively, these markers can be used to detect, monitor or predict 670 specific human conditions which are grouped into 27 broad condition categories. MarkerDB is available at https://markerdb.ca.
Most efforts to understand the biology of Vibrio cholerae have focused on a single group, the pandemic-generating lineage harboring the strains responsible for all known cholera pandemics. ...Consequently, little is known about the diversity of this species in its native aquatic environment. To understand the differences in the V. cholerae populations inhabiting regions with a history of cholera cases and those lacking such a history, a comparative analysis of population composition was performed. Little overlap was found in lineage compositions between those in Dhaka, Bangladesh (where cholera is endemic), located in the Ganges Delta, and those in Falmouth, MA (no known history of cholera), a small coastal town on the United States east coast. The most striking difference was the presence of a group of related lineages at high abundance in Dhaka, which was completely absent from Falmouth. Phylogenomic analysis revealed that these lineages form a cluster at the base of the phylogeny for the V. cholerae species and were sufficiently differentiated genetically and phenotypically to form a novel species. A retrospective search revealed that strains from this species have been anecdotally found from around the world and were isolated as early as 1916 from a British soldier in Egypt suffering from choleraic diarrhea. In 1935, Gardner and Venkatraman unofficially referred to a member of this group as Vibrio paracholerae. In recognition of this earlier designation, we propose the name
sp. nov. for this bacterium. Genomic analysis suggests a link with human populations for this novel species and substantial interaction with its better-known sister species.
Cholera continues to remain a major public health threat around the globe. Understanding the ecology, evolution, and environmental adaptation of the causative agent (Vibrio cholerae) and tracking the emergence of novel lineages with pathogenic potential are essential to combat the problem. In this study, we investigated the population dynamics of Vibrio cholerae in an inland locality, which is known as endemic for cholera, and compared them with those of a cholera-free coastal location. We found the consistent presence of the pandemic-generating lineage of V. cholerae in Dhaka, where cholera is endemic, and an exclusive presence of a lineage phylogenetically distinct from other V. cholerae lineages. Our study suggests that this lineage represents a novel species that has pathogenic potential and a human link to its environmental abundance. The possible association with human populations and coexistence and interaction with toxigenic V. cholerae in the natural environment make this potential human pathogen an important subject for future studies.
GWAS has identified thousands of loci associated with disease, yet the causal genes within these loci remain largely unknown. Identifying these causal genes would enable deeper understanding of the ...disease and assist in genetics-based drug development. Exome-wide association studies (ExWAS) are more expensive but can pinpoint causal genes offering high-yield drug targets, yet suffer from a high false-negative rate. Several algorithms have been developed to prioritize genes at GWAS loci, such as the Effector Index (Ei), Locus-2-Gene (L2G), Polygenic Prioritization score (PoPs), and Activity-by-Contact score (ABC) and it is not known if these algorithms can predict ExWAS findings from GWAS data. However, if this were the case, thousands of associated GWAS loci could potentially be resolved to causal genes. Here, we quantified the performance of these algorithms by evaluating their ability to identify ExWAS significant genes for nine traits. We found that Ei, L2G, and PoPs can identify ExWAS significant genes with high areas under the precision recall curve (Ei: 0.52, L2G: 0.37, PoPs: 0.18, ABC: 0.14). Furthermore, we found that for every unit increase in the normalized scores, there was an associated 1.3–4.6-fold increase in the odds of a gene reaching exome-wide significance (Ei: 4.6, L2G: 2.5, PoPs: 2.1, ABC: 1.3). Overall, we found that Ei, L2G, and PoPs can anticipate ExWAS findings from widely available GWAS results. These techniques are therefore promising when well-powered ExWAS data are not readily available and can be used to anticipate ExWAS findings, allowing for prioritization of genes at GWAS loci.
Abstract
The Human Metabolome Database or HMDB (www.hmdb.ca) is a web-enabled metabolomic database containing comprehensive information about human metabolites along with their biological roles, ...physiological concentrations, disease associations, chemical reactions, metabolic pathways, and reference spectra. First described in 2007, the HMDB is now considered the standard metabolomic resource for human metabolic studies. Over the past decade the HMDB has continued to grow and evolve in response to emerging needs for metabolomics researchers and continuing changes in web standards. This year's update, HMDB 4.0, represents the most significant upgrade to the database in its history. For instance, the number of fully annotated metabolites has increased by nearly threefold, the number of experimental spectra has grown by almost fourfold and the number of illustrated metabolic pathways has grown by a factor of almost 60. Significant improvements have also been made to the HMDB's chemical taxonomy, chemical ontology, spectral viewing, and spectral/text searching tools. A great deal of brand new data has also been added to HMDB 4.0. This includes large quantities of predicted MS/MS and GC-MS reference spectral data as well as predicted (physiologically feasible) metabolite structures to facilitate novel metabolite identification. Additional information on metabolite-SNP interactions and the influence of drugs on metabolite levels (pharmacometabolomics) has also been added. Many other important improvements in the content, the interface, and the performance of the HMDB website have been made and these should greatly enhance its ease of use and its potential applications in nutrition, biochemistry, clinical chemistry, clinical genetics, medicine, and metabolomics science.
The family
Rhodobacteraceae
consists of alphaproteobacteria that are metabolically, phenotypically, and ecologically diverse. It includes the roseobacter clade, an informal designation, representing ...one of the most abundant groups of marine bacteria. The rapid pace of discovery of novel roseobacters in the last three decades meant that the best practice for taxonomic classification, a polyphasic approach utilizing phenotypic, genotypic, and phylogenetic characteristics, was not always followed. Early efforts for classification relied heavily on 16S rRNA gene sequence similarity and resulted in numerous taxonomic inconsistencies, with several poly- and paraphyletic genera within this family. Next-generation sequencing technologies have allowed whole-genome sequences to be obtained for most type strains, making a revision of their taxonomy possible. In this study, we performed whole-genome phylogenetic and genotypic analyses combined with a meta-analysis of phenotypic data to review taxonomic classifications of 331 type strains (under 119 genera) within the
Rhodobacteraceae
family. Representatives of the roseobacter clade not only have different environmental adaptions from other
Rhodobacteraceae
isolates but were also found to be distinct based on genomic, phylogenetic, and
in silico
-predicted phenotypic data. As such, we propose to move this group of bacteria into a new family,
Roseobacteraceae
fam. nov. In total, reclassifications resulted to 327 species and 128 genera, suggesting that misidentification is more problematic at the genus than species level. By resolving taxonomic inconsistencies of type strains within this family, we have established a set of coherent criteria based on whole-genome-based analyses that will help guide future taxonomic efforts and prevent the propagation of errors.
We study the challenging incremental few-shot object de-tection (iFSD) setting. Recently, hypernetwork-based approaches have been studied in the context of continuous and finetune-free iFSD with ...limited success. We take a closer look at important design choices of such methods, leading to several key improvements and resulting in a more accurate and flexible framework, which we call Sylph. In particular, we demonstrate the effectiveness of decou-pling object classification from localization by leveraging a base detector that is pretrained for class-agnostic local-ization on large-scale dataset. Contrary to what previous results have suggested, we show that with a carefully de-signed class-conditional hypernetwork, finetune-free iFSD can be highly effective, especially when a large number of base categories with abundant data are available for meta-training, almost approaching alternatives that undergo test-time-training. This result is even more significant considering its many practical advantages: (1) incrementally learning new classes in sequence without additional training, (2) detecting both novel and seen classes in a single pass, and (3) no forgetting of previously seen classes. We benchmark our model on both COCO and LVIS, reporting as high as 17% AP on the long-tail rare classes on LVIS, indicating the promise of hypernetwork-based iFSD.
Cholera has been endemic to the Ganges Delta for centuries. Although the causative agent,
Vibrio cholerae
, is autochthonous to coastal and brackish water, cholera occurs continually in Dhaka, the ...inland capital city of Bangladesh which is surrounded by fresh water. Despite the persistence of this problem, little is known about the environmental abundance and distribution of lineages of
V. cholerae
, the most important being the pandemic generating (PG) lineage consisting mostly of serogroup O1 strains. To understand spatial and temporal dynamics of PG lineage and other lineages belonging to the
V. cholerae
species in surface water in and around Dhaka City, we used qPCR and high-throughput amplicon sequencing. Seven different freshwater sites across Dhaka were investigated for six consecutive months, and physiochemical parameters were measured in situ. Total abundance of
V. cholerae
was found to be relatively stable throughout the 6-month sampling period, with 2 × 10
5
to 4 × 10
5
genome copies/L at six sites and around 5 × 10
5
genome copies/L at the site located in the most densely populated part of Dhaka City. PG O1
V. cholerae
was present in high abundance during the entire sampling period and composed between 24 and 92% of the total
V. cholerae
population, only showing occasional but sudden reductions in abundance. In instances where PG O1 lost its dominance, other lineages underwent a rapid expansion while the size of the total
V. cholerae
population remained almost unchanged. Intraspecies richness of
V. cholerae
was positively correlated with salinity, conductivity, and total dissolved solids (TDS), while it was negatively correlated with dissolved oxygen (DO) concentration in water. Interestingly, negative correlation was observed specifically between PG O1 and salinity, even though the changes in this variable were minor (0–0.8 ppt). Observations in this study suggest that at the subspecies level, population composition of naturally occurring
V. cholerae
can be influenced by fluctuations in environmental factors, which can lead to altered competition dynamics among the lineages.
Protecting rural Canadians from extreme heat Liang, Kevin E; Kosatsky, Tom
CMAJ. Canadian Medical Association journal,
2020-Jun-15, 2020-06-15, 20200615, Volume:
192, Issue:
24
Journal Article
Peer reviewed
Open access
Liang and Kosatsky discuss the importance in protecting rural Canadians from extreme heat. The frequency, intensity and duration of extreme heat events are increasing across Canada. However, as ...reflected in recent reports by the Environment and Climate Change Canada and the Council of Canadian Academies, extreme heat events are regarded as primarily an urban issue. While several Canadian cities have established emergency response plans for extreme heat, few smaller centres or rural districts have done so. Here, the factors that make rural Canadians particularly vulnerable to the effects of extreme heat are examined.
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