Thiamine Pyrophosphate Riboswitches Are Targets for the Antimicrobial Compound Pyrithiamine

SummaryThiamine metabolism genes are regulated in numerous bacteria by a riboswitch class that binds the coenzyme thiamine pyrophosphate (TPP). We demonstrate that the antimicrobial action of the thiamine analog pyrithiamine (PT) is mediated by interaction with TPP riboswitches in bacteria and fungi. For example, pyrithiamine pyrophosphate (PTPP) binds the TPP riboswitch controlling the tenA operon in Bacillus subtilis. Expression of a TPP riboswitch-regulated reporter gene is reduced in transgenic B. subtilis or Escherichia coli when grown in the presence of thiamine or PT, while mutant riboswitches in these organisms are unresponsive to these ligands. Bacteria selected for PT resistance bear specific mutations that disrupt ligand binding to TPP riboswitches and derepress certain TPP metabolic genes. Our findings demonstrate that riboswitches can serve as antimicrobial drug targets and expand our understanding of thiamine metabolism in bacteria

Common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases.

Using expression profiles from postmortem prefrontal cortex samples of 624 dementia patients and non-demented controls, we investigated global disruptions in the co-regulation of genes in two neurodegenerative diseases, late-onset Alzheimer's disease (AD) and Huntington's disease (HD). We identified networks of differentially co-expressed (DC) gene pairs that either gained or lost correlation in disease cases relative to the control group, with the former dominant for both AD and HD and both patterns replicating in independent human cohorts of AD and aging. When aligning networks of DC patterns and physical interactions, we identified a 242-gene subnetwork enriched for independent AD/HD signatures. This subnetwork revealed a surprising dichotomy of gained/lost correlations among two inter-connected processes, chromatin organization and neural differentiation, and included DNA methyltransferases, DNMT1 and DNMT3A, of which we predicted the former but not latter as a key regulator. To validate the inter-connection of these two processes and our key regulator prediction, we generated two brain-specific knockout (KO) mice and show that Dnmt1 KO signature significantly overlaps with the subnetwork (P = 3.1 × 10(-12)), while Dnmt3a KO signature does not (P = 0.017)

Validation of serrated polyps (SPs) in Swedish pathology registers

Background Little is known about the natural history of serrated polyps (SPs), partly due to the lack of large-scale epidemiologic data. In this study, we examined the validity of SP identification according to SNOMED (Systematised Nomenclature of Medicine) codes and free text from colorectal histopathology reports. Methods Through the ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) study, we retrieved data on SPs from all pathology departments in Sweden in 2015–2017 by using SNOMED codes and free-text search in colorectal histopathology reports. Randomly selected individuals with a histopathology report of SPs were validated against patient charts using a structured, retrospective review. Results SPs were confirmed in 101/106 individuals with a histopathology report of SPs, yielding a positive predictive value (PPV) of 95% (95%CI = 89–98%). By year of diagnosis, the PPV was 89% (95%CI = 69–97%), 96% (95%CI = 81–99%) and 97% (95%CI = 89–99%) for individuals diagnosed before 2001 (n = 19), between 2001 and 2010 (n = 26) and after 2010 (n = 61), respectively. According to search method, the PPV for individuals identified by SNOMED codes was 100% (95%CI = 93–100%), and 93% (95%CI = 86–97%) using free-text search. Recorded location (colon vs. rectum) was correct in 94% of all SP histopathology reports (95%CI = 84–98%) identified by SNOMED codes. Individuals with SPs were classified into hyperplastic polyps (n = 34; 32%), traditional serrated adenomas (n = 3; 3%), sessile serrated adenomas/polyps (SSA/Ps) (n = 70; 66%), unspecified SPs (n = 3, 3%), and false positive SPs (n = 5, 5%). For individuals identified by SNOMED codes, SSA/Ps were confirmed in 49/52 individuals, resulting in a PPV of 94% (95%CI: 84–98%). In total, 57% had ≥2 polyps (1: n = 44, 2–3: n = 33 and ≥ 4: n = 27). Some 46% of SPs (n = 71) originated from the proximal colon and 24% were ≥ 10 mm in size (n = 37). Heredity for colorectal cancer, intestinal polyposis syndromes, or both was reported in seven individuals (7%). Common comorbidities included diverticulosis (n = 45, 42%), colorectal cancer (n = 19, 18%), and inflammatory bowel disease (n = 10, 9%). Conclusion Colorectal histopathology reports are a reliable data source to identify individuals with SPs

Ocorrência de Tripalea clavaria (Studer, 1878) na plataforma continental do Rio Grande do Sul

The occurrence and distribution of Tripalea clavaria (Studer, 1878) is discussed, in relation to Brazilian and Falklands currents convergence and water mass in the South-western Atlantic

Expression quantitative trait loci are highly sensitive to cellular differentiation state

Blood cell development from multipotent hematopoietic stem cells to specialized blood cells is accompanied by drastic changes in gene expression for which the triggers remain mostly unknown. Genetical genomics is an approach linking natural genetic variation to gene expression variation, thereby allowing the identification of genomic loci containing gene expression modulators (eQTLs). In this paper, we used a genetical genomics approach to analyze gene expression across four developmentally close blood cell types collected from a large number of genetically different but related mouse strains. We found that, while a significant number of eQTLs (365) had a consistent “static” regulatory effect on gene expression, an even larger number were found to be very sensitive to cell stage. As many as 1,283 eQTLs exhibited a “dynamic” behavior across cell types. By looking more closely at these dynamic eQTLs, we show that the sensitivity of eQTLs to cell stage is largely associated with gene expression changes in target genes. These results stress the importance of studying gene expression variation in well-defined cell populations. Only such studies will be able to reveal the important differences in gene regulation between different ce

Coding and regulatory variants are associated with serum protein levels and disease.

Circulating proteins can be used to diagnose and predict disease-related outcomes. A deep serum proteome survey recently revealed close associations between serum protein networks and common disease. In the current study, 54,469 low-frequency and common exome-array variants were compared to 4782 protein measurements in the serum of 5343 individuals from the AGES Reykjavik cohort. This analysis identifies a large number of serum proteins with genetic signatures overlapping those of many diseases. More specifically, using a study-wide significance threshold, we find that 2021 independent exome array variants are associated with serum levels of 1942 proteins. These variants reside in genetic loci shared by hundreds of complex disease traits, highlighting serum proteins' emerging role as biomarkers and potential causative agents of a wide range of diseases

Intra- and inter-individual genetic differences in gene expression

Genetic variation is known to influence the amount of mRNA produced by a gene. Given that the molecular machines control mRNA levels of multiple genes, we expect genetic variation in the components of these machines would influence multiple genes in a similar fashion. In this study we show that this assumption is correct by using correlation of mRNA levels measured independently in the brain, kidney or liver of multiple, genetically typed, mice strains to detect shared genetic influences. These correlating groups of genes (CGG) have collective properties that account for 40-90% of the variability of their constituent genes and in some cases, but not all, contain genes encoding functionally related proteins. Critically, we show that the genetic influences are essentially tissue specific and consequently the same genetic variations in the one animal may up-regulate a CGG in one tissue but down-regulate the same CGG in a second tissue. We further show similarly paradoxical behaviour of CGGs within the same tissues of different individuals. The implication of this study is that this class of genetic variation can result in complex inter- and intra-individual and tissue differences and that this will create substantial challenges to the investigation of phenotypic outcomes, particularly in humans where multiple tissues are not readily available.

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