We report here the draft genome sequences of two Listeria monocytogenes strains from some of the earliest reported cases of human listeriosis in North America. The strains were isolated in 1933 from ...patients in Massachusetts and Connecticut, USA, and belong to the widely disseminated hypervirulent clonal complex 1 (CC1) and CC2.
frequently exhibits resistance to arsenic. We report here the draft genome sequences of eight genetically diverse arsenic-resistant
strains from human listeriosis and food-associated environments. ...The availability of these genomes will help elucidate the role of heavy-metal resistance in the ecology of
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Herein we present the draft genome sequence and annotation of "Candidatus Rickettsia asemboensis" strain NMRCii. "Ca. Rickettsia asemboensis" is phylogenetically related to but distinct from the ...flea-borne spotted fever pathogen Rickettsia felis. "Ca. Rickettsia asemboensis" was initially identified in and subsequently isolated from Ctenocephalides cat and dog fleas from Kenya.
Abstract
Toxicogenomics is a critical area of inquiry for hazard identification and to identify both mechanisms of action and potential markers of exposure to toxic compounds. However, data generated ...by these experiments are highly dimensional and present challenges to standard statistical approaches, requiring strict correction for multiple comparisons. This stringency often fails to detect meaningful changes to low expression genes and/or eliminate genes with small but consistent changes particularly in tissues where slight changes in expression can have important functional differences, such as brain. Machine learning offers an alternative analytical approach for “omics” data that effectively sidesteps the challenges of analyzing highly dimensional data. Using 3 rat RNA transcriptome sets, we utilized an ensemble machine learning approach to predict developmental exposure to a mixture of organophosphate esters (OPEs) in brain (newborn cortex and day 10 hippocampus) and late gestation placenta of male and female rats, and identified genes that informed predictor performance. OPE exposure had sex specific effects on hippocampal transcriptome, and significantly impacted genes associated with mitochondrial transcriptional regulation and cation transport in females, including voltage-gated potassium and calcium channels and subunits. To establish if this holds for other tissues, RNAseq data from cortex and placenta, both previously published and analyzed via a more traditional pipeline, were reanalyzed with the ensemble machine learning methodology. Significant enrichment for pathways of oxidative phosphorylation and electron transport chain was found, suggesting a transcriptomic signature of OPE exposure impacting mitochondrial metabolism across tissue types and developmental epoch. Here we show how machine learning can complement more traditional analytical approaches to identify vulnerable “signature” pathways disrupted by chemical exposures and biomarkers of exposure.
Temperature dictates the performance of aquatic ectotherms. However, the physiological and biochemical processes that drive thermally-mediated life history patterns (and limits) remain poorly ...understood because they are rarely studied simultaneously. In our previous work, we have established life history outcomes (e.g., survivorship, development time, growth rates, and fitness) in mayflies (Neocloeon triangulifer) reared at static temperatures ranging from 14 to 30°C at 2°C intervals. In this study, we conducted biochemical measurements (RT-qPCR of select genes and targeted, quantitative metabolomic profiling) on N. triangulifer mature larvae reared at temperatures associated with excellent survival and fitness (22–24°C), compromised survival and fitness (28°C), and chronic lethality (30°C—larvae survived for a few weeks but failed to emerge to adulthood). Patterns of gene expression were similar to those observed in acute ramping experiments reported previously: larvae reared at 30°C resulted in significant upregulation in the thermally responsive gene HEAT SHOCK PROTEIN 90 (HSP90) but no significant changes in hypoxia responsive genes EGGLAYING DEFECTIVE9 (EGL-9) and LACTATE DEHYDROGENASE (LDH). Additionally, primers for genes associated with energy: INSULIN RECEPTOR (IR), mechanistic TARGET OF RAPAMYCIN (mTOR), and TREHALOSE 6 PHOSPHATE SYNTHASE (T6PS) were developed for this study. IR and mTOR were significantly upregulated while T6PS showed trend of downregulation in larvae reared at 30°C. Metabolomic profiles revealed general depletion of lipids and acylcarnitines in larvae exposed to chronic thermal stress, suggesting that larvae were energetically challenged despite continuous access to food. For example, concentrations of lysoPhosphatidylcholine (lysoPC) a C20:3 decreased as fitness decreased with increasing temperature (2.3- and 2.4-fold at 28 and 30°C relative to controls). Tissue concentrations of the biogenic amine histamine increased 2.1- and 3.1-fold with increasing temperature, and were strongly and negatively correlated with performance. Thus, both histamine and lysoPC a C20:3 are potential biomarkers of thermal stress. Taken together, our results primarily associate energetic challenge with thermally mediated fitness reduction in N. triangulifer.
Abstract
Background
There are more than 55 million people with dementia worldwide, and it is estimated that currently 6.5 million people are living with Alzheimer’s disease (AD) in the United States. ...AD exhibits racial disparities whereby the prevalence is 2‐fold higher in Non‐Hispanic Blacks (NHB) compared to Non‐Hispanic Whites (NHW). It is hypothesized that epigenetics and aberrant imprinting caused by early life exposure to adverse environmental agents may contribute to AD risk later in life, although to date a comprehensive assessment of the imprinting state of the genome in AD‐affected populations has not been reported.
Methods
To address this hypothesis, we investigated cytosine methylation at candidate imprint control regions (ICRs) in post‐mortem tissues (brain) of nine AD cases (5NHB, 4NHW) and eight controls (4NHB, 4NHW), using whole genome bisulfite sequencing. Furthermore, we performed a limited clinical study in which blood samples from six individuals, three AD patients (2NHB, 1NHW) and three controls (all NHB), were subjected to methyl‐sequencing. These data were analyzed against an expanded set of candidate ICRs previously described by our group (i.e., human imprintome) to identify regions of the genome exhibiting aberrant methylation in AD patients compared to controls.
Results
We found differential methylation in DNA derived from post‐mortem tissues of AD cases compared to controls overlapping with the expanded set of ICRs in the human imprintome (79 in NHBs and 27 in NHWs), including candidate ICR on chromosome 17 near the NLRP1 inflammasome gene (5771207‐5771575; Hg38). When extended to blood from extant controls and patients, our analysis identified a single nucleotide polymorphism (CA → CG; rs12451480) within the candidate ICR on chromosome 17, that distinguishes controls (CA) from AD patients (CG), and in which the cytosine is methylated.
Conclusion
We demonstrate concordance between the methylation state of post‐mortem brain‐ and blood‐derived DNA distinguishing controls from AD patients. Furthermore, the discovery of a SNP differentiating controls from AD patients, within a candidate ICR that alters its methylation state, is consistent with an aberrant imprinting phenomenon. Our results support the hypothesis that aberrant imprinting, as can result from adverse exposures during early development, may contribute to later risk of AD.
Emerging evidence demonstrates the importance of sufficient vitamin D (1α, 25-dihydroxyvitamin D3) levels during early life stage development with deficiencies associated with long-term effects into ...adulthood. While vitamin D has traditionally been associated with mineral ion homeostasis, accumulating evidence suggests non-calcemic roles for vitamin D including metabolic homeostasis. In this study, we examined the hypothesis that vitamin D deficiency (VDD) during early life stage development precedes metabolic disruption. Three dietary cohorts of zebrafish were placed on engineered diets including a standard laboratory control diet, a vitamin D null diet, and a vitamin D enriched diet. Zebrafish grown on a vitamin D null diet between 2-12 months post fertilization (mpf) exhibited diminished somatic growth and enhanced central adiposity associated with accumulation and enlargement of visceral and subcutaneous adipose depots indicative of both adipocyte hypertrophy and hyperplasia. VDD zebrafish exhibited elevated hepatic triglycerides, attenuated plasma free fatty acids and attenuated lipoprotein lipase activity consistent with hallmarks of dyslipidemia. VDD induced dysregulation of gene networks associated with growth hormone and insulin signaling, including induction of suppressor of cytokine signaling. These findings indicate that early developmental VDD impacts metabolic health by disrupting the balance between somatic growth and adipose accumulation.
Burkitt lymphoma is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. Here, we describe the first completely sequenced genome ...from a Burkitt lymphoma tumor and germline DNA from the same affected individual. We further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma (DLBCL) tumors. We identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13, RET, PIK3R1 and the SWI/SNF genes ARID1A and SMARCA4. Our data implicate a number of genes in cancer for the first time, including CCT6B, SALL3, FTCD and PC. ID3 mutations occurred in 34% of Burkitt lymphomas and not in DLBCLs. We show experimentally that ID3 mutations promote cell cycle progression and proliferation. Our work thus elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a new tumor suppressor gene.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
There is a growing need to understand the potential neurotoxicity of organophosphate flame retardants (OPFRs) and plasticizers because use and, consequently, human exposure, is rapidly ...expanding. We have previously shown in rats that developmental exposure to the commercial flame retardant mixture Firemaster 550 (FM 550), which contains OPFRs, results in sex-specific behavioral effects, and identified the placenta as a potential target of toxicity. The placenta is a critical coordinator of fetal growth and neurodevelopment, and a source of neurotransmitters for the developing brain. We have shown in rats and humans that flame retardants accumulate in placental tissue, and induce functional changes, including altered neurotransmitter production. Here, we sought to establish if OPFRs (triphenyl phosphate and a mixture of isopropylated triarylphosphate isomers) alter placental function and fetal forebrain development, with disruption of tryptophan metabolism as a primary pathway of interest. Wistar rat dams were orally exposed to OPFRs (0, 500, 1000, or 2000 μg/day) or a serotonin (5-HT) agonist 5-methoxytryptamine for 14 days during gestation and placenta and fetal forebrain tissues collected for analysis by transcriptomics and metabolomics. Relative abundance of genes responsible for the transport and synthesis of placental 5-HT were disrupted, and multiple neuroactive metabolites in the 5-HT and kynurenine metabolic pathways were upregulated. In addition, 5-HTergic projections were significantly longer in the fetal forebrains of exposed males. These findings suggest that OPFRs have the potential to impact the 5-HTergic system in the fetal forebrain by disrupting placental tryptophan metabolism.
Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma in adults. The disease exhibits a striking heterogeneity in gene expression profiles and clinical outcomes, but its genetic ...causes remain to be fully defined. Through whole genome and exome sequencing, we characterized the genetic diversity of DLBCL. In all, we sequenced 73 DLBCL primary tumors (34 with matched normal DNA). Separately, we sequenced the exomes of 21 DLBCL cell lines. We identified 322 DLBCL cancer genes that were recurrently mutated in primary DLBCLs. We identified recurrent mutations implicating a number of known and not previously identified genes and pathways in DLBCL including those related to chromatin modification (ARID1A and MEF2B), NF-κB (CARD11 and TNFAIP3), PI3 kinase (PIK3CD , PIK3R1 , and MTOR), B-cell lineage (IRF8 , POU2F2 , and GNA13), and WNT signaling (WIF1). We also experimentally validated a mutation in PIK3CD , a gene not previously implicated in lymphomas. The patterns of mutation demonstrated a classic long tail distribution with substantial variation of mutated genes from patient to patient and also between published studies. Thus, our study reveals the tremendous genetic heterogeneity that underlies lymphomas and highlights the need for personalized medicine approaches to treating these patients.
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