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Sophia Chiu - Top 30 Publications

Enteric Glia Regulate Gastrointestinal Motility but are not Required for Maintenance of the Epithelium in Mice.

When the glial fibrillary acidic protein (GFAP) promoter is used to express cellular toxins that eliminate glia in mice, intestinal epithelial permeability and proliferation increase; this led to the concept that glia are required for maintenance of the gastrointestinal epithelium. Many enteric glia, however, particularly in the mucosa, do not express GFAP. In contrast, virtually all enteric glia express proteolipid protein 1 (PLP1). We investigated whether elimination of PLP1-expressing cells compromises epithelial maintenance or gastrointestinal motility.

Working with influenza-like illness: Presenteeism among US health care personnel during the 2014-2015 influenza season.

Health care personnel (HCP) working while experiencing influenza-like illness (ILI) contribute to influenza transmission in health care settings. Studies focused on certain HCP occupations or work settings have demonstrated that some HCP often continue to work while ill.

Inherently variable responses to glucocorticoid stress among endogenous retroviruses isolated from 23 mouse strains.

Active participation of endogenous retroviruses (ERVs) in disease processes has been exemplified by the finding that the HERV (human ERV)-W envelope protein is involved in the pathogenesis of multiple sclerosis, an autoimmune disease. We also demonstrated that injury-elicited stressors alter the expression of murine ERVs (MuERVs), both murine leukemia virus-type and mouse mammary tumor virus (MMTV)-type (MMTV-MuERV). In this study, to evaluate MMTV-MuERVs' responses to stress (e.g., injury, infection)-elicited systemic glucocorticoid (GC) levels, we examined the GC-stress response of 64 MMTV-MuERV promoters isolated from the genomes of 23 mouse strains. All 64 promoters responded to treatment with a synthetic GC, dexamethasone (DEX), at a wide range from a 0.6- to 85.7-fold increase in reporter activity compared to no treatment. An analysis of the 10 lowest and 10 highest DEX responders revealed specific promoter elements exclusively present in either the three lowest or the two highest responders. Each promoter had a unique profile of transcription regulatory elements and the glucocorticoid response element (GRE) was identified in all promoters with the number of GREs ranging from 2 to 7. The three lowest DEX responders were the only promoters with two GREs. The findings from this study suggest that certain MMTV-MuERVs are more responsive to stress-elicited systemic GC elevation compared to the others. The mouse strain-specific genomic MMTV-MuERV profiles and individual MMTV-MuERVs' differential responses to GC-stress might explain, at least in part, the variable inflammatory responses to injury and/or infection, often observed among different mouse strains.

Patterns in Zika Virus Testing and Infection, by Report of Symptoms and Pregnancy Status - United States, January 3-March 5, 2016.

CDC recommends Zika virus testing for potentially exposed persons with signs or symptoms consistent with Zika virus disease, and recommends that health care providers offer testing to asymptomatic pregnant women within 12 weeks of exposure. During January 3-March 5, 2016, Zika virus testing was performed for 4,534 persons who traveled to or moved from areas with active Zika virus transmission; 3,335 (73.6%) were pregnant women. Among persons who received testing, 1,541 (34.0%) reported at least one Zika virus-associated sign or symptom (e.g., fever, rash, arthralgia, or conjunctivitis), 436 (9.6%) reported at least one other clinical sign or symptom only, and 2,557 (56.4%) reported no signs or symptoms. Among 1,541 persons with one or more Zika virus-associated symptoms who received testing, 182 (11.8%) had confirmed Zika virus infection. Among the 2,557 asymptomatic persons who received testing, 2,425 (94.8%) were pregnant women, seven (0.3%) of whom had confirmed Zika virus infection. Although risk for Zika virus infection might vary based on exposure-related factors (e.g., location and duration of travel), in the current setting in U.S. states, where there is no local transmission, most asymptomatic pregnant women who receive testing do not have Zika virus infection.

Travel-Associated Zika Virus Disease Cases Among U.S. Residents--United States, January 2015-February 2016.

Zika virus is an emerging mosquito-borne flavivirus. Recent outbreaks of Zika virus disease in the Pacific Islands and the Region of the Americas have identified new modes of transmission and clinical manifestations, including adverse pregnancy outcomes. However, data on the epidemiology and clinical findings of laboratory-confirmed Zika virus disease remain limited. During January 1, 2015-February 26, 2016, a total of 116 residents of 33 U.S. states and the District of Columbia had laboratory evidence of recent Zika virus infection based on testing performed at CDC. Cases include one congenital infection and 115 persons who reported recent travel to areas with active Zika virus transmission (n = 110) or sexual contact with such a traveler (n = 5). All 115 patients had clinical illness, with the most common signs and symptoms being rash (98%; n = 113), fever (82%; 94), and arthralgia (66%; 76). Health care providers should educate patients, particularly pregnant women, about the risks for, and measures to prevent, infection with Zika virus and other mosquito-borne viruses. Zika virus disease should be considered in patients with acute onset of fever, rash, arthralgia, or conjunctivitis, who traveled to areas with ongoing Zika virus transmission ( or who had unprotected sex with a person who traveled to one of those areas and developed compatible symptoms within 2 weeks of returning.

Genomic landscapes of endogenous retroviruses unveil intricate genetics of conventional and genetically-engineered laboratory mouse strains.

Laboratory strains of mice, both conventional and genetically engineered, have been introduced as critical components of a broad range of studies investigating normal and disease biology. Currently, the genetic identity of laboratory mice is primarily confirmed by surveying polymorphisms in selected sets of "conventional" genes and/or microsatellites in the absence of a single completely sequenced mouse genome. First, we examined variations in the genomic landscapes of transposable repetitive elements, named the TREome, in conventional and genetically engineered mouse strains using murine leukemia virus-type endogenous retroviruses (MLV-ERVs) as a probe. A survey of the genomes from 56 conventional strains revealed strain-specific TREome landscapes, and certain families (e.g., C57BL) of strains were discernible with defined patterns. Interestingly, the TREome landscapes of C3H/HeJ (toll-like receptor-4 [TLR4] mutant) inbred mice were different from its control C3H/HeOuJ (TLR4 wild-type) strain. In addition, a CD14 knock-out strain had a distinct TREome landscape compared to its control/backcross C57BL/6J strain. Second, an examination of superantigen (SAg, a "TREome gene") coding sequences of mouse mammary tumor virus-type ERVs in the genomes of the 46 conventional strains revealed a high diversity, suggesting a potential role of SAgs in strain-specific immune phenotypes. The findings from this study indicate that unexplored and intricate genomic variations exist in laboratory mouse strains, both conventional and genetically engineered. The TREome-based high-resolution genetics surveillance system for laboratory mice would contribute to efficient study design with quality control and accurate data interpretation. This genetics system can be easily adapted to other species ranging from plants to humans.

Where Do Agricultural Producers Get Safety and Health Information?

There is little empirical guidance regarding communication sources and channels used and trusted by agricultural producers. The goal of this study was to characterize frequency of use and levels of trust in agricultural safety and health information sources and channels accessed by agricultural producers. A sample of 195 agricultural producers was surveyed at county fairs in Iowa. Information was collected about the frequency of use and level of trust in 14 information sources and channels. Associations between age, gender, and education level and use and trust of each information source or channel were estimated using logistic regression. The sample consisted of 72% men with a mean age of 50.1 (SD = 15.6) years. Newspaper and magazine articles were the most commonly used agricultural safety and health information source or channel; 77% (n = 140) of respondents reporting using them at least monthly. Among those reporting monthly or more frequent use, 75% reported trusting mostly or completely, compared with 58% using and 49% trusting the Internet. High levels of use and trust of newspaper and magazine articles did not vary significantly by age, gender, or education level. Age in the highest tertile (57-83 years) was marginally associated with lower odds of using, as well as using and trusting, all the information sources and channels studied except for medical clinics (use only: odds ratio [OR], 3.51, 95% confidence interval [CI], 0.79-15.64; use and trust: OR, 5.90, 95% CI, 0.91-38.42). These findings suggest that traditional media may be more effective than digital media for delivering agricultural safety and health information to agricultural producers. Medical clinics may be an untapped venue for communicating with older agricultural producers.

CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms.

Although clinically tested JAK inhibitors reduce splenomegaly and systemic symptoms, molecular responses are not observed in most myeloproliferative neoplasm (MPN) patients. We previously demonstrated that MPN cells become persistent to type I JAK inhibitors that bind the active conformation of JAK2. We investigated whether CHZ868, a type II JAK inhibitor, would demonstrate activity in JAK inhibitor persistent cells, murine MPN models, and MPN patient samples. JAK2 and MPL mutant cell lines were sensitive to CHZ868, including type I JAK inhibitor persistent cells. CHZ868 showed significant activity in murine MPN models and induced reductions in mutant allele burden not observed with type I JAK inhibitors. These data demonstrate that type II JAK inhibition is a viable therapeutic approach for MPN patients.

Infrequent development of resistance in genotype 1-6 hepatitis C virus-infected subjects treated with sofosbuvir in phase 2 and 3 clinical trials.

Sofosbuvir is a chain-terminating nucleotide analogue inhibitor of the hepatitis C virus (HCV) NS5B RNA polymerase that is efficacious in subjects with HCV genotype 1-6 infection. Sofosbuvir resistance is primarily conferred by the S282T substitution in NS5B.

Risk of venous thromboembolism in patients with cancer treated with Cisplatin: a systematic review and meta-analysis.

Several reports suggest that cisplatin is associated with an increased risk of thromboembolism. However, because the excess risk of venous thromboembolic events (VTEs) with cisplatin-based chemotherapy has not been well described, we conducted a systemic review and meta-analysis of randomized controlled trials evaluating the incidence and risk of VTEs associated with cisplatin-based chemotherapy.

Arterial thromboembolism in cancer patients treated with cisplatin: a systematic review and meta-analysis.

Cisplatin has been associated with an increased risk of arterial thromboembolic events (ATEs). However, because this association is mostly based on case reports and retrospective studies, we conducted a systemic review and meta-analysis of randomized controlled trials evaluating the incidence and risk of ATEs associated with cisplatin. Eligible studies included prospective randomized phase II and III trials evaluating cisplatin-based vs non-cisplatin-based chemotherapy in patients with solid tumors, which were identified from PubMed articles published between 1990 and 2010. Incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using a random effects model. A total of 8216 patients from 38 trials were included. Among patients treated with cisplatin-based chemotherapy, the summary incidence of ATEs was 0.67% (95% CI = 0.40% to 0.95%), and the RR of ATEs was 1.36 (95% CI = 0.86 to 2.17; P = .19). No increase in ATEs was detected in any prespecified subgroup.

ERE database: a database of genomic maps and biological properties of endogenous retroviral elements in the C57BL/6J mouse genome.

Endogenous retroviral elements (EREs), a family of transposable elements, constitute a substantial fraction of mammalian genomes. It is expected that profiles of the ERE sequences and their genomic locations are unique for each individual. Comprehensive characterization of the EREs' genomic locations and their biological properties is essential for understanding their roles in the pathophysiology of the host. In this study, we identified and mapped putative EREs (a total of 111 endogenous retroviruses [ERVs] and 488 solo long terminal repeats [sLTRs]) within the C57BL/6J mouse genome. The biological properties of individual ERE isolates (both ERVs and sLTRs) were then characterized in the following aspects: transcription potential, tropism trait, coding potential, recombination event, integration age, and primer binding site for replication. In addition, a suite of database management system programs was developed to organize and update the data acquired from current and future studies and to make the data accessible via internet.

Age-dependent and tissue-specific structural changes in the C57BL/6J mouse genome.

We tested the hypothesis that structural changes in the genome parallel age- and organ-specific phenotypes in conjunction with the differential transposition activities of retroelements. The genomes of the liver from C57BL/6J mice were larger than other organs, coinciding with an increase in genomic copies of certain retroelements. In addition, there were differential increments in the genome size of the liver with increasing age, which peaked at 5 weeks. The findings that the genome structure of an individual is variable depending on age and organ type in association with the transposition of retroelements may have broad implications in understanding biologic phenomena.

Identification of a unique library of complex, but ordered, arrays of repetitive elements in the human genome and implication of their potential involvement in pathobiology.

Approximately 2% of the human genome is reported to be occupied by genes. Various forms of repetitive elements (REs), both characterized and uncharacterized, are presumed to make up the vast majority of the rest of the genomes of human and other species. In conjunction with a comprehensive annotation of genes, information regarding components of genome biology, such as gene polymorphisms, non-coding RNAs, and certain REs, is found in human genome databases. However, the genome-wide profile of unique RE arrangements formed by different groups of REs has not been fully characterized yet. In this study, the entire human genome was subjected to an unbiased RE survey to establish a whole-genome profile of REs and their arrangements. Due to the limitation in query size within the bl2seq alignment program (National Center for Biotechnology Information [NCBI]) utilized for the RE survey, the entire NCBI reference human genome was fragmented into 6206 units of 0.5M nucleotides. A number of RE arrangements with varying complexities and patterns were identified throughout the genome. Each chromosome had unique profiles of RE arrangements and density, and high levels of RE density were measured near the centromere regions. Subsequently, 175 complex RE arrangements, which were selected throughout the genome, were subjected to a comparison analysis using five different human genome sequences. Interestingly, three of the five human genome databases shared the exactly same arrangement patterns and sequences for all 175 RE arrangement regions (a total of 12,765,625 nucleotides). The findings from this study demonstrate that a substantial fraction of REs in the human genome are clustered into various forms of ordered structures. Further investigations are needed to examine whether some of these ordered RE arrangements contribute to the human pathobiology as a functional genome unit.

Prevalent de novo somatic mutations in superantigen genes of mouse mammary tumor viruses in the genome of C57BL/6J mice and its potential implication in the immune system.

Superantigens (SAgs) of mouse mammary tumor viruses (MMTVs) play a crucial role in T cell selection in the thymus in a T cell receptor (TCR) Vβ-specific manner and SAgs presented by B cells activate T cells in the periphery. The peripheral T cell repertoire is dynamically shaped by the steady induction of T cell tolerance against self antigens throughout the lifespan. We hypothesize that de novo somatic mutation of endogenous MMTV SAgs contributes to the modulation of the peripheral T cell repertoire.

Post-injury stress signals alter epigenetic profile of cytosine methylation in the proviral genome of endogenous retroviruses.

The majority of epigenetic methylation events at cytosine residues of the genome are reported to occur in transposable elements, as a result, it contributes to genome stability by repressing their transposition activity. Our recent studies demonstrated that the expression of certain murine endogenous retroviruses (MuERVs), a family of retrotransposons, is modulated in the liver after burn injury and sepsis. In this study, we investigated whether burn-elicited stress signals alter epigenetic methylation profile of cytosine residues of the MuERV proviral genome. Female C57BL/6J mice were subjected to ~18% total body surface area burn. The genomic DNAs from the livers, which were collected at 3 and 24 h after burn, were treated with bisulfite to convert unmethylated cytosines (C) to thymines (T). From four experimental groups (no burn-3h, burn-3h, no burn-24h, and burn-24h), 91, 98, 94, and 86 unique U3 sequences (from sense or antisense strand) were cloned, respectively and a total of 16 different U3 sizes were identified among them. The survey of C to T conversions in these U3 sequences revealed that the epigenetic profiles of cytosine methylation are differentially affected (increase or decrease in demethylated cytosine residues) by stress signals from burn and/or anesthesia-resuscitation in a position of cytosine residue and/or size of U3 sequence-specific manner. In addition, the methylation characteristics of the majority of cytosine residues of the different U3 sequences within each size group were conserved. The findings from this study suggest that burn-elicited stress signals contribute to a transient or permanent alteration in cytosine methylation characteristics of certain MuERV loci in the genome, potentially modulating transcription activity of their own as well as neighboring genes.

Experimental polymicrobial peritonitis-associated transcriptional regulation of murine endogenous retroviruses.

Despite advancements in understanding the pathophysiology of sepsis, clinical outcomes are variable, and the mortality rate remains high among patients. We investigated whether expression of murine endogenous retroviruses (MuERVs), constituting approximately 10% of the mouse genome, is differentially regulated in response to sepsis-elicited stress signals. ICR mice were subjected to cecal ligation and puncture, and MuERV expression was examined. There was evident regulation (induced or repressed) of MuERV expression in the liver and lung after cecal ligation and puncture. In particular, expression of several variant transcripts was increased, primarily in the liver, at 12 and/or 48 h: nine splicing variants and one 5.06-kb nonspliced transcript. Four novel splicing signals were also identified. Six variant transcripts were presumed to be splicing products of the 5.06-kb transcript, whereas the other three were envelope variants transcribed from at least five MuERV loci. These findings demonstrate that expression of certain MuERVs, including their envelope subgenomic transcripts, are altered during the course of sepsis pathogenesis.