Gut inflammation provides a respiratory electron acceptor for Salmonella.

Salmonella enterica serotype Typhimurium (S. Typhimurium) causes acute gut inflammation by using its virulence factors to invade the intestinal epithelium and survive in mucosal macrophages. The inflammatory response enhances the transmission success of S. Typhimurium by promoting its outgrowth in the gut lumen through unknown mechanisms. Here we show that reactive oxygen species generated during inflammation react with endogenous, luminal sulphur compounds (thiosulphate) to form a new respiratory electron acceptor, tetrathionate. The genes conferring the ability to use tetrathionate as an electron acceptor produce a growth advantage for S. Typhimurium over the competing microbiota in the lumen of the inflamed gut. We conclude that S. Typhimurium virulence factors induce host-driven production of a new electron acceptor that allows the pathogen to use respiration to compete with fermenting gut microbes. Thus the ability to trigger intestinal inflammation is crucial for the biology of this diarrhoeal pathogen

Community Memories: A Glimpse of African American Life in Frankfort, Kentucky

Community Memories is a fascinating look into life recalled by African Americans who consider Frankfort their home. Featuring unique oral history recollections and over two hundred candid personal photographs collected from community residents, the book provides an enlightening expression of the black experience in Kentucky’s capital. The memories focus on the elusive concept of community—that which binds together individuals in the living of everyday life. A satisfying blend of public history and local accounts, Community Memories explores the neighborhood, familial, religious, occupational, social, and educational components of the daily community experience of twentieth-century African Americans in Frankfort. Published by the Kentucky Historical Society and distributed by the University Press of Kentucky Senior Editor Winona L. Fletcher is professor emerita of theater and drama at Indiana University. Associate Editor Sheila Mason Burton is assistant director for research coordination at the Kentucky Legislative Research Commission. Associate Editor James E. Wallace is assistant director of the Kentucky Historical Society. Photographs Editor Mary E. Winter is special collections branch manager and photographs archivist at the Kentucky Historical Society. Oral History Editor Douglas A. Boyd is oral history and folklife archivist at the Kentucky Historical Society.https://uknowledge.uky.edu/upk_african_american_studies/1024/thumbnail.jp

The pre-main sequence binary HK Ori : Spectro-astrometry and EXPORT data

In this paper we present multi-epoch observations of the pre-main sequence binary HK Ori. These data have been drawn from the EXPORT database and are complemented by high quality spectro-astrometric data of the system. The spectroscopic data appear to be very well represented by a combination of an A dwarf star spectrum superposed on a (sub-)giant G-type spectrum. The radial velocity of the system is consistent with previous determinations, and does not reveal binary motion, as expected for a wide binary. The spectral, photometric and polarimetric properties and variability of the system indicate that the active object in the system is a T Tauri star with UX Ori characteristics. The spectro-astrometry of HK Ori is sensitive down to milli-arcsecond scales and confirms the speckle interferometric results from Leinert et al. The spectro-astrometry allows with fair certainty the identification of the active star within the binary, which we suggest to be a G-type T Tauri star based on its spectral characteristics.Comment: MNRAS in press 8 pages 7 figure

How common is truly benign MS in a UK population?

Objectives The prevalence and definition of benign multiple sclerosis (BMS) remain controversial. Most definitions are based on the Expanded Disability Status Scale (EDSS), not encompassing the wider impact of disease. The explanation for favourable outcomes remains unclear. We aim to provide a detailed characterisation of patients with low EDSS scores at long disease durations. Methods We screened a population-based registry containing 3062 people with MS to identify individuals with unlimited walking ability at disease durations >15 years. A representative cohort underwent detailed clinical assessment and classified as having BMS according to EDSS score <3, no significant fatigue, mood disturbance, cognitive impairment or disrupted employment, and had not received a disease-modifying therapy. We determined patient-reported perceptions of MS status and made comparisons with EDSS-based definitions. Results Of 1049 patients with disease duration of >15 years, 200 (19.1%) had most recent EDSS score <4.0. Detailed contemporary clinical assessment of a representative sample of 60 of these patients revealed 48 (80%) had an EDSS score of <4.0, 35 (58%) <3.0 and 16 (27%) <2.0. Only nine (15%) fulfilled our criteria for BMS; impaired cognition (57%) and effects on employment (52%) the most common causes for exclusion. Meanwhile, 33/60 (69%) patients considered their disease benign. Population frequency for BMS was estimated at 2.9% (95% CI 2.0 to 4.1). Conclusions Comprehensive assessment reveals a small minority of people with MS who appear genuinely benign after 15 years. Study of such individuals may uncover insights about disease pathogenesis. However, discrepancy between patient perception and clinician perception of BMS undermines use of the term ‘benign’ in clinical settings

Evolutionary conservation and selection of human disease gene orthologs in the rat and mouse genomes

BACKGROUND: Model organisms have contributed substantially to our understanding of the etiology of human disease as well as having assisted with the development of new treatment modalities. The availability of the human, mouse and, most recently, the rat genome sequences now permit the comprehensive investigation of the rodent orthologs of genes associated with human disease. Here, we investigate whether human disease genes differ significantly from their rodent orthologs with respect to their overall levels of conservation and their rates of evolutionary change. RESULTS: Human disease genes are unevenly distributed among human chromosomes and are highly represented (99.5%) among human-rodent ortholog sets. Differences are revealed in evolutionary conservation and selection between different categories of human disease genes. Although selection appears not to have greatly discriminated between disease and non-disease genes, synonymous substitution rates are significantly higher for disease genes. In neurological and malformation syndrome disease systems, associated genes have evolved slowly whereas genes of the immune, hematological and pulmonary disease systems have changed more rapidly. Amino-acid substitutions associated with human inherited disease occur at sites that are more highly conserved than the average; nevertheless, 15 substituting amino acids associated with human disease were identified as wild-type amino acids in the rat. Rodent orthologs of human trinucleotide repeat-expansion disease genes were found to contain substantially fewer of such repeats. Six human genes that share the same characteristics as triplet repeat-expansion disease-associated genes were identified; although four of these genes are expressed in the brain, none is currently known to be associated with disease. CONCLUSIONS: Most human disease genes have been retained in rodent genomes. Synonymous nucleotide substitutions occur at a higher rate in disease genes, a finding that may reflect increased mutation rates in the chromosomal regions in which disease genes are found. Rodent orthologs associated with neurological function exhibit the greatest evolutionary conservation; this suggests that rodent models of human neurological disease are likely to most faithfully represent human disease processes. However, with regard to neurological triplet repeat expansion-associated human disease genes, the contraction, relative to human, of rodent trinucleotide repeats suggests that rodent loci may not achieve a 'critical repeat threshold' necessary to undergo spontaneous pathological repeat expansions. The identification of six genes in this study that have multiple characteristics associated with repeat expansion-disease genes raises the possibility that not all human loci capable of facilitating neurological disease by repeat expansion have as yet been identified

Rats bred for low and high running capacity display alterations in peripheral tissues and nerves relevant to neuropathy and pain

IntroductionDiet and activity are recognized as modulators of nervous system disease, including pain. Studies of exercise consistently reveal a benefit on pain. This study focused on female rats to understand differences related to metabolic status and peripheral nerve function in females.MethodsHere, we investigated parameters of peripheral nerve function relevant to pain in rats selectively bred for high (high‐capacity runners; HCR) or low endurance exercise capacity (low‐capacity runners; LCR) resulting in divergent intrinsic aerobic capacities and susceptibility for metabolic conditions.ResultsLCR female rats have reduced mechanical sensitivity, higher intraepidermal nerve fiber density and TrkA‐positive epidermal axons, increased numbers of Langerhans and mast cells in cutaneous tissues, and a higher fat content despite similar overall body weights compared to female HCR rats. Sensory and motor nerve conduction velocities, thermal sensitivity, and mRNA expression of selected genes relevant to peripheral sensation were not different.ConclusionsThese results suggest that aerobic capacity and metabolic status influence sensory sensitivity and aspects of inflammation in peripheral tissues that could lead to poor responses to tissue damage and painful stimuli. The LCR and HCR rats should prove useful as models to assess how the metabolic status impacts pain.These results suggest that aerobic capacity and metabolic status influence sensory sensitivity and aspects of inflammation in peripheral tissues that could lead to poor responses to tissue damage and painful stimuli. The LCR and HCR rats should prove useful as models to assess how the metabolic status impacts pain.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139060/1/brb3780.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139060/2/brb3780_am.pd

Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome

International audienc

Transcriptional Profiles in Olfactory Pathway-Associated Brain Regions of African Green Monkeys: Associations With Age and Alzheimer’s Disease Neuropathology

Introduction: Olfactory impairment in older individuals is associated with an increased risk of Alzheimer\u27s disease (AD). Characterization of age versus neuropathology-associated changes in the brain olfactory pathway may elucidate processes underlying early AD pathogenesis. Here, we report age versus AD neuropathology-associated differential transcription in four brain regions in the olfactory pathway of 10 female African green monkeys (vervet, Chlorocebus aethiops sabaeus), a well-described model of early AD-like neuropathology. Methods: Transcriptional profiles were determined by microarray in the olfactory bulb (OB), piriform cortex (PC), temporal lobe white matter (WM), and inferior temporal cortex (ITC). Amyloid beta (Aβ) plaque load in parietal and temporal cortex was determined by immunohistochemistry, and concentrations of Aβ42, Aβ40, and norepinephrine in ITC were determined by enzyme-linked immuosorbent assay (ELISA). Transcriptional profiles were compared between middle-aged and old animals, and associations with AD-relevant neuropathological measures were determined. Results: Transcriptional profiles varied by brain region and age group. Expression levels of TRO and RNU4-1 were significantly lower in all four regions in the older group. An additional 29 genes were differentially expressed by age in three of four regions. Analyses of a combined expression data set of all four regions identified 77 differentially expressed genes (DEGs) by age group. Among these DEGs, older subjects had elevated levels of CTSB , EBAG9, LAMTOR3, and MRPL17, and lower levels of COMMD10 and TYW1B. A subset of these DEGs was associated with neuropathology biomarkers. Notably, CTSB was positively correlated with Aβ plaque counts, Aβ42:Aβ40 ratios, and norepinephrine levels in all brain regions. Discussion: These data demonstrate age differences in gene expression in olfaction-associated brain regions. Biological processes exhibiting age-related enrichment included the regulation of cell death, vascular function, mitochondrial function, and proteostasis. A subset of DEGs was specifically associated with AD phenotypes. These may represent promising targets for future mechanistic investigations and perhaps therapeutic intervention

Spatially Resolved Single-Cell Assessment of Pancreatic Cancer Expression Subtypes Reveals Co-expressor Phenotypes and Extensive Intratumoral Heterogeneity

Pancreatic ductal adenocarcinoma (PDAC) has been classified into classical and basal-like transcriptional subtypes by bulk RNA measurements. However, recent work has uncovered greater complexity to transcriptional subtypes than was initially appreciated using bulk RNA expression profiling. To provide a deeper understanding of PDAC subtypes, we developed a multiplex immunofluorescence (mIF) pipeline that quantifies protein expression of six PDAC subtype markers (CLDN18.2, TFF1, GATA6, KRT17, KRT5, and S100A2) and permits spatially resolved, single-cell interrogation of pancreatic tumors from resection specimens and core needle biopsies. Both primary and metastatic tumors displayed striking intratumoral subtype heterogeneity that was associated with patient outcomes, existed at the scale of individual glands, and was significantly reduced in patient-derived organoid cultures. Tumor cells co-expressing classical and basal markers were present in \u3e 90% of tumors, existed on a basal-classical polarization continuum, and were enriched in tumors containing a greater admixture of basal and classical cell populations. Cell-cell neighbor analyses within tumor glands further suggested that co-expressor cells may represent an intermediate state between expression subtype poles. The extensive intratumoral heterogeneity identified through this clinically applicable mIF pipeline may inform prognosis and treatment selection for patients with PDAC

A family of dual-activity glycosyltransferasesphosphorylases mediates mannogen turnover and virulence in Leishmania parasites

Parasitic protists belonging to the genus Leishmania synthesize the non-canonical carbohydrate reserve, mannogen, which is composed of β-1,2-mannan oligosaccharides. Here, we identify a class of dual-activity mannosyltransferase/phosphorylases (MTPs) that catalyze both the sugar nucleotide-dependent biosynthesis and phosphorolytic turnover of mannogen. Structural and phylogenic analysis shows that while the MTPs are structurally related to bacterial mannan phosphorylases, they constitute a distinct family of glycosyltransferases (GT108) that have likely been acquired by horizontal gene transfer from gram-positive bacteria. The seven MTPs catalyze the constitutive synthesis and turnover of mannogen. This metabolic rheostat protects obligate intracellular parasite stages from nutrient excess, and is essential for thermotolerance and parasite infectivity in the mammalian host. Our results suggest that the acquisition and expansion of the MTP family in Leishmania increased the metabolic flexibility of these protists and contributed to their capacity to colonize new host niches