Adverse Effects of Trichothiodystrophy DNA Repair and Transcription Gene Abnormalities on Human Fetal Development

The effects of DNA repair and transcription genes in human prenatal life have never been studied. Trichothiodystrophy (TTD) is a rare (affected frequency of 10^-6^) recessive disorder caused by mutations in genes involved in the nucleotide excision repair (NER) pathway and in transcription. Based on our clinical observations, we conducted a genetic epidemiologic study to investigate gestational outcomes associated with TTD. We compared pregnancies resulting in TTD-affected offspring (N=24) with respect to abnormalities in their antenatal and neonatal periods to pregnancies resulting in their unaffected siblings (N=18), accounting for correlation, and to population reference values. Significantly higher incidence of several severe gestational complications was noted in TTD-affected pregnancies. Gestational complications were noted in nearly all pregnancies resulting in TTD-affected offspring with _XPD_ and _TTDN1_, but not _TTD-A_, gene mutations. Abnormal placental development may explain the constellation of observed complications; therefore, we hypothesize that some TTD genes play an important role in normal placental and fetal development. We investigated this hypothesis by analyzing the expression patterns of TTD genes. Expression of _TTDA_ was strongly negatively correlated (r=-0.7,P<0.0001) with gestational age, while _XPD, XPB_ and _TTDN1_ were consistently expressed from 14 to 40 weeks gestation. *Conclusion:* Our results indicate an important role for _XPD, XPB_ and _TTDN1_ gene products during normal human placental and fetal development

Etničke diobe, politika i vahabizam u postsovjetskom Sjevernom Kavkazju

This paper presents new evidence from a 1999 survey among 500 25-26 year olds in Vladikavkaz, capital of North Ossetia, and a survey of forced migrants who were entering North Ossetia from Chechnia in 2000. The paper seeks to explain how and why Islamic fundamentalism is able to contribute to the destabilisation of the present-day North Caucasus despite the fundamentalists being extremely small proportions of the populations in all the region\u27s republics.Članak predstavlja nove činjenice koje se temelje na anketi iz 1999. godine. Anketa je obuhvatila 500 osoba dobi 25-26 godina u Vladikavkazu, glavnome gradu Sjeverne Osetije, te prisilne migrante koji su došli u Sjevernu Osetiju iz Cečenije tijekom 2000. godine. Cilj je članka objasniti kako je i zašto islamski fundamentalizam u stanju doprinijeti destabilizaciji današnjeg Sjevernog Kavkazja usprkos tome što fundamentalisti predstavljaju veoma malen dio populacije u svim zemljama u regiji

Modelling Energy Consumption based on Resource Utilization

Power management is an expensive and important issue for large computational infrastructures such as datacenters, large clusters, and computational grids. However, measuring energy consumption of scalable systems may be impractical due to both cost and complexity for deploying power metering devices on a large number of machines. In this paper, we propose the use of information about resource utilization (e.g. processor, memory, disk operations, and network traffic) as proxies for estimating power consumption. We employ machine learning techniques to estimate power consumption using such information which are provided by common operating systems. Experiments with linear regression, regression tree, and multilayer perceptron on data from different hardware resulted into a model with 99.94\% of accuracy and 6.32 watts of error in the best case.Comment: Submitted to Journal of Supercomputing on 14th June, 201

Predicting Cancer Immunotherapy Response From Gut Microbiomes Using Machine Learning Models

Cancer immunotherapy has significantly improved patient survival. Yet, half of patients do not respond to immunotherapy. Gut microbiomes have been linked to clinical responsiveness of melanoma patients on immunotherapies; however, different taxa have been associated with response status with implicated taxa inconsistent between studies. We used a tumor-agnostic approach to find common gut microbiome features of response among immunotherapy patients with different advanced stage cancers. A combined meta-analysis of 16S rRNA gene sequencing data from our mixed tumor cohort and three published immunotherapy gut microbiome datasets from different melanoma patient cohorts found certain gut bacterial taxa correlated with immunotherapy response status regardless of tumor type. Using multivariate selbal analysis, we identified two separate groups of bacterial genera associated with responders versus non-responders. Statistical models of gut microbiome community features showed robust prediction accuracy of immunotherapy response in amplicon sequencing datasets and in cross-sequencing platform validation with shotgun metagenomic datasets. Results suggest baseline gut microbiome features may be predictive of clinical outcomes in oncology patients on immunotherapies, and some of these features may be generalizable across different tumor types, patient cohorts, and sequencing platforms. Findings demonstrate how machine learning models can reveal microbiome-immunotherapy interactions that may ultimately improve cancer patient outcomes

Early transcriptome changes associated with western diet induced NASH in Ldlr−/− mice points to activation of hepatic macrophages and an acute phase response

BackgroundNonalcoholic fatty liver disease (NAFLD) is a global health problem. Identifying early gene indicators contributing to the onset and progression of NAFLD has the potential to develop novel targets for early therapeutic intervention. We report on the early and late transcriptomic signatures of western diet (WD)-induced nonalcoholic steatohepatitis (NASH) in female and male Ldlr−/− mice, with time-points at 1 week and 40 weeks on the WD. Control Ldlr−/− mice were maintained on a low-fat diet (LFD) for 1 and 40 weeks.MethodsThe approach included quantitation of anthropometric and hepatic histology markers of disease as well as the hepatic transcriptome.ResultsOnly mice fed the WD for 40 weeks revealed evidence of NASH, i.e., hepatic steatosis and fibrosis. RNASeq transcriptome analysis, however, revealed multiple cell-specific changes in gene expression after 1 week that persisted to 40 weeks on the WD. These early markers of disease include induction of acute phase response (Saa1-2, Orm2), fibrosis (Col1A1, Col1A2, TGFβ) and NASH associated macrophage (NAM, i.e., Trem2 high, Mmp12 low). We also noted the induction of transcripts associated with metabolic syndrome, including Mmp12, Trem2, Gpnmb, Lgals3 and Lpl. Finally, 1 week of WD feeding was sufficient to significantly induce TNFα, a cytokine involved in both hepatic and systemic inflammation.ConclusionThis study revealed early onset changes in the hepatic transcriptome that develop well before any anthropometric or histological evidence of NALFD or NASH and pointed to cell-specific targeting for the prevention of disease progression

Interaction between the microbiome and TP53 in human lung cancer.

BACKGROUND: Lung cancer is the leading cancer diagnosis worldwide and the number one cause of cancer deaths. Exposure to cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier integrity and increases susceptibility to infections. Herein, we hypothesize that somatic mutations together with cigarette smoke generate a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from 33 controls and 143 cancer cases, we conduct 16S ribosomal RNA (rRNA) bacterial gene sequencing, with RNA-sequencing data from lung cancer cases in The Cancer Genome Atlas serving as the validation cohort. RESULTS: Overall, we demonstrate a lower alpha diversity in normal lung as compared to non-tumor adjacent or tumor tissue. In squamous cell carcinoma specifically, a separate group of taxa are identified, in which Acidovorax is enriched in smokers. Acidovorax temporans is identified within tumor sections by fluorescent in situ hybridization and confirmed by two separate 16S rRNA strategies. Further, these taxa, including Acidovorax, exhibit higher abundance among the subset of squamous cell carcinoma cases with TP53 mutations, an association not seen in adenocarcinomas. CONCLUSIONS: The results of this comprehensive study show both microbiome-gene and microbiome-exposure interactions in squamous cell carcinoma lung cancer tissue. Specifically, tumors harboring TP53 mutations, which can impair epithelial function, have a unique bacterial consortium that is higher in relative abundance in smoking-associated tumors of this type. Given the significant need for clinical diagnostic tools in lung cancer, this study may provide novel biomarkers for early detection

Lack of IL‐7 and IL‐15 signaling affects interferon‐γ production by, more than survival of, small intestinal intraepithelial memory CD8 + T cells

Survival of antigen‐specific CD8 + T cells in peripheral lymphoid organs during viral infection is known to be dependent predominantly on IL‐7 and IL‐15. However, little is known about a possible influence of tissue environmental factors on this process. To address this question, we studied survival of memory antigen‐specific CD8 + T cells in the small intestine. Here, we show that 2 months after vaccinia virus infection, B8R 20–27 /H2‐K b tetramer + CD8 + T cells in the small intestinal intraepithelial (SI‐IEL) layer are found in mice deficient in IL‐15 expression. Moreover, SI‐IEL and lamina propria lymphocytes do not express the receptor for IL‐7 (IL‐7Rα/CD127). In addition, after in vitro stimulation with B8R 20–27 peptide, SI‐IEL cells do not produce high amounts of IFN‐γ neither at 5 days nor at 2 months postinfection (p.i.). Importantly, the lack of IL‐15 was found to shape the functional activity of antigen‐specific CD8 + T cells, by narrowing the CTL avidity repertoire. Taken together, these results reveal that survival factors, as well as the functional activity, of antigen‐specific CD8 + T cells in the SI‐IEL compartments may markedly differ from their counterparts in peripheral lymphoid tissues.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/88067/1/3513_ftp.pd

CTL Responses of High Functional Avidity and Broad Variant Cross-Reactivity Are Associated with HIV Control

Cytotoxic T lymphocyte (CTL) responses targeting specific HIV proteins, in particular Gag, have been associated with relative control of viral replication in vivo. However, Gag-specific CTL can also be detected in individuals who do not control the virus and it remains thus unclear how Gag-specific CTL may mediate the beneficial effects in some individuals but not in others. Here, we used a 10mer peptide set spanning HIV Gag-p24 to determine immunogen-specific T-cell responses and to assess functional properties including functional avidity and cross-reactivity in 25 HIV-1 controllers and 25 non-controllers without protective HLA class I alleles. Our data challenge the common belief that Gag-specific T cell responses dominate the virus-specific immunity exclusively in HIV-1 controllers as both groups mounted responses of comparable breadths and magnitudes against the p24 sequence. However, responses in controllers reacted to lower antigen concentrations and recognized more epitope variants than responses in non-controllers. These cross-sectional data, largely independent of particular HLA genetics and generated using direct ex-vivo samples thus identify T cell responses of high functional avidity and with broad variant reactivity as potential functional immune correlates of relative HIV control

Identifying Individual T Cell Receptors of Optimal Avidity for Tumor Antigens.

Cytotoxic T cells recognize, via their T cell receptors (TCRs), small antigenic peptides presented by the major histocompatibility complex (pMHC) on the surface of professional antigen-presenting cells and infected or malignant cells. The efficiency of T cell triggering critically depends on TCR binding to cognate pMHC, i.e., the TCR-pMHC structural avidity. The binding and kinetic attributes of this interaction are key parameters for protective T cell-mediated immunity, with stronger TCR-pMHC interactions conferring superior T cell activation and responsiveness than weaker ones. However, high-avidity TCRs are not always available, particularly among self/tumor antigen-specific T cells, most of which are eliminated by central and peripheral deletion mechanisms. Consequently, systematic assessment of T cell avidity can greatly help distinguishing protective from non-protective T cells. Here, we review novel strategies to assess TCR-pMHC interaction kinetics, enabling the identification of the functionally most-relevant T cells. We also discuss the significance of these technologies in determining which cells within a naturally occurring polyclonal tumor-specific T cell response would offer the best clinical benefit for use in adoptive therapies, with or without T cell engineering