Timothy D. Arthur's research while affiliated with University of California, San Diego and other places
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Publications (32)
Stem cells exist in vitro in a spectrum of interconvertible pluripotent cell states. Understanding the genetic and epigenetic regulatory processes underlying cell state transitions between these pluripotency states will have broad applications. Here, we applied a machine learning algorithm to analyze RNA-seq and ATAC-seq data derived from hundreds...
The causal variants and genes underlying thousands of cardiac GWAS signals have yet to be identified. Here, we leverage spatiotemporal information on 966 RNA-seq cardiac samples and perform an expression quantitative trait locus (eQTL) analysis detecting eQTLs considering both eGenes and eIsoforms. We identify 2,578 eQTLs associated with a specific...
Reactivation of fetal-specific genes and isoforms occurs during heart failure. However, the underlying molecular mechanisms and the extent to which the fetal program switch occurs remains unclear. Limitations hindering transcriptome-wide analyses of alternative splicing differences (i.e. isoform switching) in cardiovascular system (CVS) tissues bet...
Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association stud...
Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify four genomic loci with suggestive associations for SARS-CoV-2 susceptibility and nineteen for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. GWAS signals in ele...
Pancreatic progenitor cells (PPC) are an early developmental multipotent cell type that give rise to mature endocrine, exocrine, and ductal cells. To investigate the extent to which regulatory variants active in PPC contribute to pancreatic complex traits and disease in the adult, we derived PPC from induced pluripotent stem cells (iPSCs) of nine u...
The causal variants and genes underlying thousands of cardiac GWAS signals have yet to be identified. To address this issue, we leveraged spatiotemporal information on 966 RNA-seq cardiac samples and performed an expression quantitative trait locus (eQTL) analysis detecting ~26,000 eQTL signals associated with more than 11,000 eGenes and 7,000 eIso...
Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we applied colocalization to compare summary statistics for 16 GWASs from the COVID-19 Host Genetics Initiative to investigate similarities and differences in their genetic signals. We identified 9 loci associated with...
Transcriptome-wide expression changes occur during heart failure, including reactivation of fetal-specific isoforms. However, the underlying molecular mechanisms and the extent to which a fetal gene program switch occurs remains unclear. Limitations hindering transcriptome-wide analyses of alternative splicing differences (i.e. isoform switching) i...
Pancreatic progenitor cells (PPCs), which are multipotent cells that have the potential to give rise to endocrine, exocrine and epithelial cells, provide a powerful model system to examine the molecular characteristics of differentiating, fetal-like pancreas cells and to study the genetics of pancreatic disease. We differentiated ten induced plurip...
A mosaic of cross-phylum chemical interactions occurs between all metazoans and their microbiomes. A number of molecular families that are known to be produced by the microbiome have a marked effect on the balance between health and disease1–9. Considering the diversity of the human microbiome (which numbers over 40,000 operational taxonomic units1...
Inflammatory bowel diseases (IBD) are associated with alterations in gut microbial abundances and lumenal metabolite concentrations, but the effects of specific metabolites on the gut microbiota in health and disease remain largely unknown. Here, we analysed the influences of metabolites that are differentially abundant in IBD on the growth and phy...
As metagenomic studies move to increasing numbers of samples, communities like the human gut may benefit more from the assembly of abundant microbes in many samples, rather than the exhaustive assembly of fewer samples. We term this approach leaderboard metagenome sequencing. To explore protocol optimization for leaderboard metagenomics in real sam...
Sphingolipids are structural membrane components and important eukaryotic signaling molecules. Sphingolipids regulate inflammation and immunity and were recently identified as the most differentially abundant metabolite in stool from inflammatory bowel disease (IBD) patients. Commensal bacteria from the Bacteroidetes phylum also produce sphingolipi...
In the version of this Article originally published, in the first sentence of the second paragraph of the Discussion section, the word “operingrationally” should have read “operationally”. This has now been amended in all versions of the Article.
The human gut microbiome matures towards the adult composition during the first years of life and is implicated in early immune development. Here, we investigate the effects of microbial genomic diversity on gut microbiome development using integrated early childhood data sets collected in the DIABIMMUNE study in Finland, Estonia and Russian Kareli...
Switching ON resistance
Clonal bacterial colonies will often grow dissimilar patches, similar to a tortoiseshell pattern. These differing phenotypes arise by reversible mechanisms called phase variation. Jiang et al. developed an algorithm to survey bacterial genomes for invertible promoters that cause phase variation. Inverted repeats signal the p...
Type 1 diabetes (T1D) is an autoimmune disease that targets pancreatic islet beta cells and incorporates genetic and environmental factors¹, including complex genetic elements², patient exposures³ and the gut microbiome⁴. Viral infections⁵ and broader gut dysbioses⁶ have been identified as potential causes or contributing factors; however, human st...
Bacterial community acquisition in the infant gut impacts immune education and disease susceptibility. We compared bacterial strains across and within families in a prospective birth cohort of 44 infants and their mothers, sampled longitudinally in the first months of each child's life. We identified mother-to-child bacterial transmission events an...
Background
Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract that is associated with changes in the gut microbiome. Here, we sought to identify strain-specific functional correlates with IBD outcomes.
Methods
We performed metagenomic sequencing of monthly stool samples from 20 IBD patients and...
Host factors in the intestine help select for bacteria that promote health. Certain commensals can utilize mucins as an energy source, thus promoting their colonization. However, health conditions such as inflammatory bowel disease (IBD) are associated with a reduced mucus layer, potentially leading to dysbiosis associated with this disease. We cha...
According to the hygiene hypothesis, the increasing incidence of autoimmune diseases in western countries may be explained by changes in early microbial exposure, leading to altered immune maturation. We followed gut microbiome development from birth until age three in 222 infants in Northern Europe, where early-onset autoimmune diseases are common...
Citations
... Gene expression has long been known to be regulated in a spatial (organ, tissue, or cell type) and temporal (fetal-like and adult) specific manner [15][16][17][18][19][20][21][22] , indicating that cardiac regulatory variants function, and hence affect, the expression of a gene and its associated cardiac traits and disease, across a range of developmental stages and in different cellular contexts [15][16][17][23][24][25][26] . With the development of cell type deconvolution techniques 27,28 , bulk RNA-seq enables the characterization of cell type-specific gene expression as well as the expression of both genes and associated isoforms 24,29,30 . Furthermore, the GTEx consortium has generated bulk RNA-seq from hundreds of adult cardiac samples from multiple tissue types and whole genome-sequenced the donors 25 . ...
... GTEx and the eQTL catalogue provided us with the unique opportunity to investigate the associations among genotype and gene expression [29]. Through eQTL analysis, we associated these aTRH related SNPs with the genes they could potentially regulate [30]. Three candidate genes: SDC3, LAPTM5, and UGT2B4 were identified that were regulated by SNPs in 1p53 and 4q13.2-21.1 locus. ...
... Schmiedel et al. found several genes whose expression in specific immune cell types and tissues, including resting and activated naive CD4 + cells, influenced and colocalized with genetic determinants of COVID-19 outcomes (Schmiedel et al. 2021). D'Antonio et al. found genes that colocalized with COVID-19 loci in whole blood, including ABO and IFNAR2, and identified the causal variants using fine-mapping (D'Antonio et al. 2021). ...
... Bile acids are eventually resorbed in the intestine and returned to the liver through enterohepatic circulation where they can be re-conjugated or repaired in the hepatocyte [6]. influenced in part by the chemical identity of the amino acid that is conjugated to the sterol core [9,11]. ...
... These commensal bacteria utilize host lipids as an energy source and metabolize some lipids to new isoforms to enhance mucosal barrier function. Conversely, gut bacteria have also been associated with detrimental changes to dietary lipids, as demonstrated by studies of the microbiome associated with irritable bowel syndrome (69,70). These studies begin to shed light on the potential circular relationship between dietary lipids, changes in the local host environment, and selection for bacteria that metabolize those same nutrients and benefit from changes to the environment (71). ...
... The library generation was carried out with a miniaturised version of the Kapa HyperPlus Illuminacompatible library prep kit (Kapa Biosystems) [73]. The DNA extracts were normalized to 5 ng total input per sample using an Echo 550 acoustic liquid-handling robot (Labcyte Inc). ...
... 21,25 Indeed, the participation of microbial components (including bacterial-derived lipids) in maintenance of host's health has been described for several species of the Bacteroidetes and Verrucomicrobia families. 21,[25][26][27][28] Undoubtedly, the involvement of bacterio-lipids in host's gut homeostasis is driving a strong scientific interest. ...
... We note that a locus here could be a nucleotide, gene, or gene set --any contiguous or non-contiguous stretch of DNA in which multiple mutations interact with strong antagonism (e.g. two mutations in the same locus would be just as beneficial as only one of these). We next use equation (7) to obtain a formula for d N /d S that has only three free parameters when a single value for is chosen: µ [43]). Invertible promoters are restricted out of the genome and re-ligated in the opposite direction to turn gene expression on or off. ...
... longum, B. breve, and B. pseudocatenulatum [4,5]. In infant cohort studies, associations between HMO degradation, enrichment of select Bifidobacterium species, higher fecal acetate and lactate, and advantageous health outcomes have been observed [6][7][8][9][10][11]. As such, robust colonization of Bifidobacterium during infancy has been linked with improved markers for type 1 diabetes [12], reduced likelihood of obesity [13,14], robust vaccine responses [15], and lower antimicrobial resistance gene carriage [8,16,17]. ...
... The lack of persistent Lactobacillus after supplementation was consistent with a recent infant probiotic study that showed that following treatment with Bifidobacteriumand Lactobacillus-based probiotics, some Bifidobacterium persisted but no Lactobacillus persisted in the infant gut (Beck et al., 2022). Bifidobacterium was noticeably more abundant than Lactobacillus in the cohort studied here, which is supported by previous studies (Vatanen et al., 2018). ...