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Thomas, H. E.

Publications and source records attributed to Thomas, H. E..

4 recordsLinked to original sources

Deciphering the evolutionary history of ectoine catabolism, a compatible solute utilized by Vibrio diabolicus as an osmoprotectant and a nutrient source

Bacterial adaptation to fluctuations in salinity includes the intracellular accumulation of organic compounds called compatible solutes (CS) such as the amino acid derivatives ectoine and 5-hydroxyectoine. These compounds also play a less appreciated role as readily available nutrients, scavenged from dissolved organic matter in both marine and terrestrial environments. Vibrio diabolicus is a marine bacterium originally isolated from deep-sea hydrothermal vents and later shown to have worldwide distribution. In this work, we demonstrated the biosynthesis and uptake of CS ectoine and glycine betaine under high osmotic stress conditions, but not in unstressed V. diabolicus cells. A region on chromosome 1 of V. diabolicus strain 3098 encoded homologues of genes for ectoine and 5-hydroxyectoine catabolism (eutDE, ssd_atf_eutBCA), regulation (asnC, enuR), and transport (ectoine TRAP-type uehP, uehQM). Our data showed that ectoine was used as a high energy yielding sole carbon source and the eutD gene was essential for ectoine consumption. Phylogenetics based on EutD (DoeA) and gene neighborhood analyses showed that a catabolism cluster was present in Proteobacteria, Thermosulfobacteriota, Bacillota, Actinomycetota, and Archaea. The cluster had a limited phylogenetic distribution in Gammaproteobacteria and Betaproteobacteria and was widespread in Alphaproteobacteria. Phylogenetic reconstruction was consistent with vertical inheritance with gene loss with repeated horizontal acquisitions of the pathway across lineages. The ectoine catabolism pathway was vertically inherited in Halomonadaceae and Vibrionaceae, with patterns of gene and pathway loss. Betaproteobacteria Burkholderia, Caballeronia, and Paraburkholderia EutD proteins clustered together and EutD from most Pseudomonas species shared a most recent common with this group. EutD from Alphaproteobacteria branched in eight divergent clusters with long branch lengths but showed a remarkable conservation of synteny. Catabolism and transporter genes in this group were contiguous and contained either a TRAP-type UehPQM or an ABC-type EhuABCD ectoine transporter. Gram-positive bacteria and Archaea were not previously shown to consume ectoines, however, we identified putative ectoine catabolism clusters among Bacilli, Clostridia, Actinomycetes, and Halobacteria. IMPORTANCEEctoine is a well-established CS used to overcome osmotic stress, produced by a wide range of bacteria. The demonstration of ectoine biosynthesis and catabolism in V. diabolicus showed that it is conditionally utilized as an osmoprotectant or a nutrient source depending on environmental cues. The conservation of large syntenic blocks of ectoine catabolism, transport, and regulatory genes suggested strong selective pressure to maintain this trait. EutD (DoeA) phylogeny patterns largely followed taxonomy with evidence of horizontal transfer in specific clades, and showed ectoine consumption has a broad taxonomic spread and is lineage enriched. In our dataset, Alphaproteobacteria contained the largest diversity of EutD lineages; Gammaproteobacteria from marine environments formed a strong secondary group; and EutD from Betaproteobacteria were the least diverse. Many species that contained EutD are associated with saline, marine, and plant-associated niches, where ectoine can be scavenged as a nutrient source. The identification of a putative ectoine catabolism pathway in Gram-positive bacteria and Archaea needs to be experimentally confirmed and suggests undiscovered diversity to be revealed by future genome sequencing.

microbiology↗

Dual roles of glycine betaine (GB), dimethylglycine, and sarcosine as osmoprotectants and nutrient sources for Vibrio natriegens

Bacteria respond to osmotic stress by intracellularly accumulating low molecular weight compounds called compatible solutes (CS), also known as osmolytes. Glycine betaine (N,N,N-trimethylglycine, GB) is a highly effective and widely available osmolyte used by bacteria, algae, and plants for abiotic stress protection. Here, we highlight the dual roles of GB, dimethyl glycine (DMG), and sarcosine for both osmoprotection and a less known role as sole carbon sources. First, we showed that the marine halophile Vibrio natriegens can grow in 1% to 7% NaCl and biosynthesize GB, ectoine, and glutamate, and imported GB, DMG, and sarcosine in response to osmotic stress. Betaine-carnitine-choline transporters (BCCTs) for the uptake of GB and DMG, but not sarcosine, were identified. Bioinformatics analyses uncovered homologs of GB, DMG, and sarcosine catabolism genes (dgcAB_fixAB, gbcA, gbcB, purU, soxBDAG, glyA, glxA) clustered in the V. natriegens genome and these genes had a limited distribution among vibrios. We showed V. natriegens ATCC 14048 grew on GB, DMG, and sarcosine as sole carbon sources and gbcA and dgcA were required for growth. A contiguous catabolism cluster was present in a subset of V. fluvialis strains, and we demonstrated growth of V. fluvialis 2013V-1197 in DMG and sarcosine as sole carbon sources. Phylogenetic analysis revealed the catabolism cluster did not share a common ancestor among members of the family Vibrionaceae. IMPORTANCECompatible solutes are frequently the most concentrated organic components in marine organisms allowing them to adapt to high saline environments as well as affording protection to other abiotic stresses. These organic compounds are significant energy stores that have been overlooked for their potential as abundant nutrient sources for bacteria. Our study characterized GB, DMG, and sarcosine catabolism genes and showed their efficient use as carbon and energy sources by marine halophilic vibrios.

microbiology↗

Identifying human islet microRNAs associated with donor sex, age and body mass index

ObjectivesHuman islets are widely researched to understand pathophysiological mechanisms leading to diabetes. Sex, age, and body mass index (BMI) are key donor traits influencing insulin secretion. Islet function is also regulated by an intricate network of microRNAs. MethodsHere, we profiled 754 microRNAs and 58,190 potential targets in up to 131 different human islet donor preparations (without diabetes) and assessed their association with donor traits. We further performed mechanistical studies to observe the causal role of the age-associated key microRNAs on relative telomere length in human islets. ResultsMicroRNA discovery analyses identified miR-199a-5p and miR-214-3p associated with sex, age and BMI; miR-147b with sex and age; miR-378a-5p with sex and BMI; miR-542-3p, miR-34a-3p, miR-34a-5p, miR-497-5p and miR-99a-5p with age and BMI. There were 959 mRNA transcripts associated with sex (excluding those from sex-chromosomes), 940 with age and 418 with BMI. MicroRNA-199a-5p and miR-214-3p levels inversely associate with transcripts critical in islet function, metabolic regulation, and senescence. Our functional studies verified that inhibition of these two microRNAs (miR-199a-5p/-214-3p) slowed down telomere length shortening in human islet cells maintained in vitro and demonstrating cellular senescence. ConclusionsOur analyses identify human islet cell microRNAs influenced by donor traits. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/512222v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1666c2org.highwire.dtl.DTLVardef@b4695forg.highwire.dtl.DTLVardef@720e99org.highwire.dtl.DTLVardef@1c78ae_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

A pro-endocrine pancreatic transcriptional program established during development is retained in human gallbladder epithelial cells

ObjectivePancreatic islet {beta}-cells are factories for insulin production; however ectopic expression of insulin is also well recognized. The gallbladder is a next-door neighbour to the developing pancreas. Here, we wanted to understand if gallbladders contain functional insulin-producing cells. DesignWe compared developing and adult mouse as well as human gallbladder epithelial cells and islets using immunohistochemistry, flow cytometry, ELISAs, RNA-sequencing, real-time PCR, chromatin immunoprecipitation and functional studies. ResultsWe demonstrate that the epithelial lining of developing, as well as adult mouse and human gallbladders naturally contain interspersed cells that retain the capacity to actively transcribe, translate, package, and release insulin. We show for the first time that human gallbladders also contain functional insulin-secreting cells with the potential to naturally respond to glucose in vitro and in situ. Notably, in a NOD mouse model of type 1 diabetes, we observed that insulin-producing cells in the gallbladder are not targeted by autoimmune cells. Conclusion: In summary, our biochemical, transcriptomic, and functional data in human gallbladder epithelial cells collectively demonstrate their potential for insulin-production under pathophysiological conditions, and open newer areas for type 1 diabetes research and therapy. Significance of the study What is already known about this subject?O_LIDeveloping pancreas and gallbladder are next-door neighbours and share similar developmental pathways. C_LIO_LIHuman Gallbladder-derived progenitor cells were shown to differentiate into insulin-producing cells. C_LI What are the new findings?O_LIGallbladder epithelium contains interspersed cells that can transcribe, translate, package and secrete insulin. C_LIO_LIInsulin-producing cells in the gallbladder are not destroyed by immune cells in an animal model of type 1 diabetes (T1D). C_LIO_LIOur studies demonstrating the absence of insulin splice variants in human gallbladder cells, and higher splice forms in human islets, suggest a potential mechanism (via defective ribosomal products) in escaping islet autoimmunity. C_LI How might it impact clinical practice?O_LIDeciphering mechanisms of protection of insulin-producing cells from immune cells in the gallbladder could help in developing strategies to prevent islet autoimmunity in T1D. C_LI

developmental biology↗