Topological analysis of protein co-abundance networks identifies novel host targets important for HCV infection and pathogenesis

<p>Abstract</p> <p>Background</p> <p>High-throughput methods for obtaining global measurements of transcript and protein levels in biological samples has provided a large amount of data for identification of 'target' genes and proteins of interest. These targets may be mediators of functional processes involved in disease and therefore represent key points of control for viruses and bacterial pathogens. Genes and proteins that are the most highly differentially regulated are generally considered to be the most important. We present topological analysis of co-abundance networks as an alternative to differential regulation for confident identification of target proteins from two related global proteomics studies of hepatitis C virus (HCV) infection.</p> <p>Results</p> <p>We analyzed global proteomics data sets from a cell culture study of HCV infection and from a clinical study of liver biopsies from HCV-positive patients. Using lists of proteins known to be interaction partners with pathogen proteins we show that the most differentially regulated proteins in both data sets are indeed enriched in pathogen interactors. We then use these data sets to generate co-abundance networks that link proteins based on similar abundance patterns in time or across patients. Analysis of these co-abundance networks using a variety of network topology measures revealed that both degree and betweenness could be used to identify pathogen interactors with better accuracy than differential regulation alone, though betweenness provides the best discrimination. We found that though overall differential regulation was not correlated between the cell culture and liver biopsy data, network topology was conserved to an extent. Finally, we identified a set of proteins that has high betweenness topology in both networks including a protein that we have recently shown to be essential for HCV replication in cell culture.</p> <p>Conclusions</p> <p>The results presented show that the network topology of protein co-abundance networks can be used to identify proteins important for viral replication. These proteins represent targets for further experimental investigation that will provide biological insight and potentially could be exploited for novel therapeutic approaches to combat HCV infection.</p

Dermal and muscle fibroblasts and skeletal myofibers survive chikungunya virus infection and harbor persistent RNA

Chikungunya virus (CHIKV) is an arthritogenic alphavirus that acutely causes fever as well as severe joint and muscle pain. Chronic musculoskeletal pain persists in a substantial fraction of patients for months to years after the initial infection, yet we still have a poor understanding of what promotes chronic disease. While replicating virus has not been detected in joint-associated tissues of patients with persistent arthritis nor in various animal models at convalescent time points, viral RNA is detected months after acute infection. To identify the cells that might contribute to pathogenesis during this chronic phase, we developed a recombinant CHIKV that expresses Cre recombinase (CHIKV-3'-Cre). CHIKV-3'-Cre replicated in myoblasts and fibroblasts, and it induced arthritis during the acute phase in mice. Importantly, it also induced chronic disease, including persistent viral RNA and chronic myositis and synovitis similar to wild-type virus. CHIKV-3'-Cre infection of tdTomato reporter mice resulted in a population of tdTomato+ cells that persisted for at least 112 days. Immunofluorescence and flow cytometric profiling revealed that these tdTomato+ cells predominantly were myofibers and dermal and muscle fibroblasts. Treatment with an antibody against Mxra8, a recently defined host receptor for CHIKV, reduced the number of tdTomato+ cells in the chronic phase and diminished the levels of chronic viral RNA, implicating these tdTomato+ cells as the reservoir of chronic viral RNA. Finally, isolation and flow cytometry-based sorting of the tdTomato+ fibroblasts from the skin and ankle and analysis for viral RNA revealed that the tdTomato+ cells harbor most of the persistent CHIKV RNA at chronic time points. Therefore, this CHIKV-3'-Cre and tdTomato reporter mouse system identifies the cells that survive CHIKV infection in vivo and are enriched for persistent CHIKV RNA. This model represents a useful tool for studying CHIKV pathogenesis in the acute and chronic stages of disease

Distinct roles of interferon alpha and beta in controlling chikungunya virus replication and modulating neutrophil-mediated inflammation

Type I interferons (IFNs) are key mediators of the innate immune response. Although members of this family of cytokines signal through a single shared receptor, biochemical and functional variation exists in response to different IFN subtypes. While previous work has demonstrated that type I IFNs are essential to control infection by chikungunya virus (CHIKV), a globally emerging alphavirus, the contributions of individual IFN subtypes remain undefined. To address this question, we evaluated CHIKV pathogenesis in mice lacking IFN-β (IFN-β knockout [IFN-β-KO] mice or mice treated with an IFN-β-blocking antibody) or IFN-α (IFN regulatory factor 7 knockout [IRF7-KO] mice or mice treated with a pan-IFN-α-blocking antibody). Mice lacking either IFN-α or IFN-β developed severe clinical disease following infection with CHIKV, with a marked increase in foot swelling compared to wild-type mice. Virological analysis revealed that mice lacking IFN-α sustained elevated infection in the infected ankle and in distant tissues. In contrast, IFN-β-KO mice displayed minimal differences in viral burdens within the ankle or at distal sites and instead had an altered cellular immune response. Mice lacking IFN-β had increased neutrophil infiltration into musculoskeletal tissues, and depletion of neutrophils in IFN-β-KO but not IRF7-KO mice mitigated musculoskeletal disease caused by CHIKV. Our findings suggest disparate roles for the IFN subtypes during CHIKV infection, with IFN-α limiting early viral replication and dissemination and IFN-β modulating neutrophil-mediated inflammation

A cluster-randomized controlled trial of automated internet weight-loss programs in primary care: Role of automated provider feedback

OBJECTIVE: Despite the high prevalence of obesity and associated health risks in the United States adult population, few primary care providers (PCPs) have time and training to provide weight-management counseling to their patients. This study aims to compare the effect of referral to a comprehensive automated digital weight-loss program, with or without provider email feedback, with usual care on weight loss in patients with overweight or obesity. METHODS: A total of 550 adults (mean [SD], 51.4 [11.2] years, BMI = 35.1 [5.5] kg/m RESULTS: Weight changes (mean [SE]) at 12 months were -0.92 (0.46), -3.68 (0.46), and -3.58 (0.48) kg in the EUC, IWL, and IWL + PCP groups, respectively. Outcomes were significantly different in EUC versus IWL and EUC versus IWL + PCP (p \u3c 0.001), but not in IWL versus IWL + PCP. CONCLUSIONS: Referral by PCPs to an automated weight-loss program holds promise for patients with obesity. Future research should explore ways to further promote accountability and adherence

Serologic features of cohorts with variable genetic risk for systemic lupus erythematosus

Abstract Background Systemic lupus erythematosus (SLE) is an autoimmune disease with genetic, hormonal, and environmental influences. In Western Europe and North America, individuals of West African descent have a 3–4 fold greater incidence of SLE than Caucasians. Paradoxically, West Africans in sub-Saharan Africa appear to have a low incidence of SLE, and some studies suggest a milder disease with less nephritis. In this study, we analyzed sera from African American female SLE patients and four other cohorts, one with SLE and others with varying degrees of risk for SLE in order to identify serologic factors that might correlate with risk of or protection against SLE. Methods Our cohorts included West African women with previous malaria infection assumed to be protected from development of SLE, clinically unaffected sisters of SLE patients with high risk of developing SLE, healthy African American women with intermediate risk, healthy Caucasian women with low risk of developing SLE, and women with a diagnosis of SLE. We developed a lupus risk index (LRI) based on titers of IgM and IgG anti-double stranded DNA antibodies and levels of C1q. Results The risk index was highest in SLE patients; second highest in unaffected sisters of SLE patients; third highest in healthy African-American women and lowest in healthy Caucasian women and malaria-exposed West African women. Conclusion This risk index may be useful in early interventions to prevent SLE. In addition, it suggests new therapeutic approaches for the treatment of SLE.https://deepblue.lib.umich.edu/bitstream/2027.42/143866/1/10020_2018_Article_19.pd

Pretest probability assessment derived from attribute matching

BACKGROUND: Pretest probability (PTP) assessment plays a central role in diagnosis. This report compares a novel attribute-matching method to generate a PTP for acute coronary syndrome (ACS). We compare the new method with a validated logistic regression equation (LRE). METHODS: Eight clinical variables (attributes) were chosen by classification and regression tree analysis of a prospectively collected reference database of 14,796 emergency department (ED) patients evaluated for possible ACS. For attribute matching, a computer program identifies patients within the database who have the exact profile defined by clinician input of the eight attributes. The novel method was compared with the LRE for ability to produce PTP estimation <2% in a validation set of 8,120 patients evaluated for possible ACS and did not have ST segment elevation on ECG. 1,061 patients were excluded prior to validation analysis because of ST-segment elevation (713), missing data (77) or being lost to follow-up (271). RESULTS: In the validation set, attribute matching produced 267 unique PTP estimates [median PTP value 6%, 1(st)–3(rd )quartile 1–10%] compared with the LRE, which produced 96 unique PTP estimates [median 24%, 1(st)–3(rd )quartile 10–30%]. The areas under the receiver operating characteristic curves were 0.74 (95% CI 0.65 to 0.82) for the attribute matching curve and 0.68 (95% CI 0.62 to 0.77) for LRE. The attribute matching system categorized 1,670 (24%, 95% CI = 23–25%) patients as having a PTP < 2.0%; 28 developed ACS (1.7% 95% CI = 1.1–2.4%). The LRE categorized 244 (4%, 95% CI = 3–4%) with PTP < 2.0%; four developed ACS (1.6%, 95% CI = 0.4–4.1%). CONCLUSION: Attribute matching estimated a very low PTP for ACS in a significantly larger proportion of ED patients compared with a validated LRE

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Search for supersymmetry in events with b-quark jets and missing transverse energy in pp collisions at 7 TeV

Results are presented from a search for physics beyond the standard model based on events with large missing transverse energy, at least three jets, and at least one, two, or three b-quark jets. The study is performed using a sample of proton-proton collision data collected at sqrt(s) = 7 TeV with the CMS detector at the LHC in 2011. The integrated luminosity of the sample is 4.98 inverse femtobarns. The observed number of events is found to be consistent with the standard model expectation, which is evaluated using control samples in the data. The results are used to constrain cross sections for the production of supersymmetric particles decaying to b-quark-enriched final states in the context of simplified model spectra.Comment: Submitted to Physical Review

Sensitization in Transplantation: Assessment of Risk (STAR) 2017 Working Group Meeting Report

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144684/1/ajt14752_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144684/2/ajt14752.pd