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Isolated c. elegans germ nuclei exhibit distinct genomic profiles of histone modification and gene expression

BMc GENOMIcS 2019年第1期20卷 1-15页

作者： Han, Mei Wei, Guifeng McManus, catherine E. Hillier, LaDeana W. Reinke, Valerie Yale Univ Dept Genet New Haven CT 06520 USA Univ Oxford Dept Biochem Dev Epigenet Oxford OX1 3QU England Univ Washington Sch Med Dept Genome Sci Seattle WA 98195 USA

BackgroundThe wide variety of specialized permissive and repressive mechanisms by which germ cells regulate developmental gene expression are not well understood genome-wide. Isolation of germ cells with high integrity and purity from living animals is necessary to address these open questions, but no straightforward methods are currently *** we present an experimental paradigm that permits the isolation of nuclei from c. elegans germ cells at quantities sufficient for genomic analyses. We demonstrate that these nuclei represent a very pure population and are suitable for both transcriptome analysis (RNA-seq) and chromatin immunoprecipitation (chIP-seq) of histone modifications. From these data, we find unexpected germline- and soma-specific patterns of gene *** new capacity removes a major barrier in the field to dissect gene expression mechanisms in the germ line of c. elegans. consequent discoveries using this technology will be relevant to conserved regulatory mechanisms across species.

关键词： c elegans Germ cells Gene expression Genomics Method development

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Economic evaluation of the hepatitis c elimination strategy in Greece in the era of affordable direct-acting antivirals

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World Journal of Gastroenterology 2019年第11期25卷 1327-1340页

作者： Ilias Gountas Vana Sypsa George Papatheodoridis Kyriakos Souliotis Kostas Athanasakis Homie Razavi Angelos Hatzakis Department of Hygiene Epidemiology and Medical StatisticsMedical SchoolNational and Kapodistrian University of Athens Hellenic Scientific Society for the Study of AIDS and Sexually Transmitted Diseases Department of Gastroenterology Medical SchoolNational and Kapodistrian University of AthensLaiko General Hospital Faculty of Social and Political Sciences University of Peloponnese Department of Health Economics National School of Public Health Center for Disease Analysis

BAcKGROUND Hepatitis c virus(HcV) is a leading cause of worldwide liver-related morbidity and mortality. The World Health Organization released an integrated strategy targeting HcV-elimination by 2030. This study aims to estimate the required interventions to achieve elimination using updated information for direct-acting antiviral(DAA) treatment coverage, to compute the total costs(including indirect/societal costs) of the strategy and to identify whether the elimination strategy is cost-effective/cost-saving in *** To estimate the required interventions and subsequent costs to achieve HcV elimination in *** A previously validated mathematical model was adapted to the Greek HcVinfected population to compare the outcomes of DAA treatment without the additional implementation of awareness or screening campaigns versus an HcV elimination strategy, which includes a sufficient number of treated patients. We estimated the total costs(direct and indirect costs), the disability-adjusted life years and the incremental cost-effectiveness ratio using two different price *** Without the implementation of awareness or screening campaigns,approximately 20000 patients would be diagnosed and treated with DAAs by2030. This strategy would result in a 19.6% increase in HcV-related mortality in2030 compared to 2015. To achieve the elimination goal, 90000 patients need to be treated by 2030. Under the elimination scenario, viremic cases would decrease by78.8% in 2030 compared to 2015. The cumulative direct costs to eliminate the disease would range from 2.1-2.3 billion euros(€) by 2030, while the indirect costs would be €1.1 billion. The total elimination cost in Greece would range from €3.2-3.4 billion by 2030. The cost per averted disability-adjusted life year is estimated between €10100 and €13380, indicating that the elimination strategy is very costeffective. Furthermore, HcV elimination strategy would save €560-895 million *** Without

关键词： Hepatitis c elimination cost effectiveness cost of elimination Indirect costs Projections Mathematical modelling Awareness and screening programs World Health Organization targets

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Exploring c Semantics and Pointer Provenance

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PROcEEDINGS OF THE AcM ON PROGRAMMING LANGUAGES-PAcMPL 2019年第POPL期3卷 1-32页

作者： Memarian, Kayvan Gomes, Victor B. F. Davis, Brooks Kell, Stephen Richardson, Alexander Watson, Robert N. M. Sewell, Peter Univ Cambridge Cambridge England SRI Int 333 Ravenswood Ave Menlo Pk CA 94025 USA

The semantics of pointers and memory objects in c has been a vexed question for many years. c values cannot be treated as either purely abstract or purely concrete entities: the language exposes their representations, but compiler optimisations rely on analyses that reason about provenance and initialisation status, not just runtime representations. The ISO WG14 standard leaves much of this unclear, and in some respects differs with de facto standard usage D which itself is difficult to investigate. In this paper we explore the possible source-language semantics for memory objects and pointers, in ISO c and in c as it is used and implemented in practice, focussing especially on pointer provenance. We aim to, as far as possible, reconcile the ISO c standard, mainstream compiler behaviour, and the semantics relied on by the corpus of existing c code. We present two coherent proposals, tracking provenance via integers and not;both address many design questions. We highlight some pros and cons and open questions, and illustrate the discussion with a library of test cases. We make our semantics executable as a test oracle, integrating it with the cerberus semantics for much of the rest of c, which we have made substantially more complete and robust, and equipped with a web-interface GUI. This allows us to experimentally assess our proposals on those test cases. To assess their viability with respect to larger bodies of c code, we analyse the changes required and the resulting behaviour for a port of FreeBSD to cHERI, a research architecture supporting hardware capabilities, which (roughly speaking) traps on the memory safety violations which our proposals deem undefined behaviour. We also develop a new runtime instrumentation tool to detect possible provenance violations in normal c code, and apply it to some of the SPEc benchmarks. We compare our proposal with a source-language variant of the twin-allocation LLVM semantics proposal of Lee et al. Finally, we describe ong

关键词： c

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MicroRNA transcriptome analysis of poly I:c-stimulated and PRRSV-infected porcine alveolar macrophages

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JOURNAL OF APPLIED GENETIcS 2019年第3-4期60卷 375-383页

作者： Wu, Junjing Ji, Ziyun Qiao, Mu Peng, Xianwen Wu, Huayu Song, Zhongxu Zhao, Haizhong Liu, Guisheng Li, Fenge Mei, Shuqi Hubei Prov Acad Agr Sci Inst Anim Husb & Vet Hubei Key Lab Anim Embryo & Mol Breeding Wuhan Hubei Peoples R China Huazhong Agr Univ Key Lab Pig Genet & Breeding Minist Agr Wuhan Hubei Peoples R China Huazhong Agr Univ Key Lab Agr Anim Genet Breeding & Reprod Minist Educ Wuhan Hubei Peoples R China

Porcine reproductive and respiratory syndrome virus (PRRSV) causes severe reproductive failure in sows, respiratory diseases, and high mortality in piglets, which results in serious economic losses to the swine industry worldwide. Previous studies have described that PRRSV could suppress the host immune system and had antiapoptotic activity in its initial phase of infection. Polyinosinic-polycytidylic acid (poly I:c), a synthesized analogue of viral double-strand RNA, activates innate immunity responses and induces apoptosis in cells. Therefore, we performed miRNA transcriptome analysis of poly I:c-stimulated and PRRSV-infected porcine alveolar macrophages (PAMs) using deep sequencing technology, to compare the different miRNA profiles between the statuses of innate immune activation and inactivation. After sequencing, 267 known mature miRNAs and 64 novel miRNAs were observed in PAMs, and a total of 197 miRNAs were significantly differently expressed in poly I:c-stimulated PAMs, compared with mock control cells. Thirty-three of them were also significantly alerted in PRRSV-infected PAMs. This indicated that PRRSV only slightly alerted the miRNA expression profile of host cells compared with poly I:c-stimulated PAMs, which confirmed that PRRSV could suppress host innate immune responses during the early stages of infection. Among the differentially expressed miRNAs, we found that ssc-miR-27b-3p could significantly inhibit PRRSV RNA and protein replication in MARc-145 cells and PAMs. Its antiviral mechanism needs further research in the future.

关键词： PRRSV Poly I c Innate immune Apoptosis miR-27b

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Ombitasvir/paritaprevir/ritonavir + dasabuvir +/-ribavirin in real world hepatitis c patients

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World Journal of Gastroenterology 2019年第18期25卷 2229-2239页

作者： Nicole Loo Eric Lawitz Naim Alkhouri Jennifer Wells carmen Landaverde Angie coste Rossalynn Salcido Michael Scott Fred Poordad Academic and Clinical Affairs Texas Liver Institute

BAcKGROUND The hepatitis c virus(HcV) NS5A inhibitor ABT-267(ombitasvir, OBV), the HcV NS4/4A protease inhibitor ABT-450(paritaprevir, PTV), the cYP3A inhibitor ritonavir(r) and the non-nucleoside NS5B polymerase inhibitor ABT-333(dasabuvir, DSV)(OBV/PTV/r + DSV) with or without ribavirin(RBV) is a direct-acting antiviral regimen approved in the United States and other major countries for the treatment of HcV in genotype 1(GT1) infected patients. Patients with HcV who are considered "hard-to-cure" have generally been excluded from registration trials due to rigorous study inclusion criteria, presence of comorbidities and previous treatment *** To investigate the efficacy of this regimen in HcV G1-infected patients historically excluded from clinical *** Patients were ≥ 18 years old and chronically infected with HcV GT1(GT1a, GT1b or GT1a/1b). Patients were treatment-na?ve or previously failed a regimen including pegylated interferon/RBV +/-telaprevir, boceprevir, or *** hundred patients were treated with the study drug regimen, which was administered for 12 or 24 wk +/-RBV according to GT1 subtype and presence/absence of cirrhosis. Patients were evaluated every 4 wk from treatment day 1 and at 4 and 12 wk after *** Many of the patients studied had comorbidities(44.2% hypertensive, 33.7%obese, 20.2% cirrhotic) and 16% previously failed HcV treatment. Ninety-six patients completed study follow-up and 99% achieved 12-wk sustained virologic response. The majority(88.4%) of patients had undetectable HcV RNA by week 4. The most common adverse events were fatigue(12%), headache(10%),insomnia(9%) and diarrhea(8%); none led to treatment discontinuation. Physical and mental patient reported outcomes scores significantly improved after treatment. Almost all(98%) patients were treatment *** In an all-comers HcV GT1 population, 12 or 24-wk of OBV/PTV/r + DSV +/-RBV is highly effective and tolerable and results

关键词： Hepatitis c Ombitasvir Paritaprevir Ritonavir Dasabuvir Genotype 1

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Fistuloates A-c: New antioxidative aromatic compounds isolated from cassia fistula

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JOURNAL OF cHEMIcAL RESEARcH 2019年第11-12期43卷 516-521页

作者： Aftab, Zahida Afzal, Masood Bushra Khan, Hidayatullah Badshah, Syed Khan, Dilfaraz Ullah, Hamid Khan, Shafiullah Gomal Univ Inst Chem Sci Dera Ismail Khan 29220 Khyber Pakhtunk Pakistan Univ Sci & Technol Bannu Dept Chem Bannu Pakistan BUITEMS FABS Dept Chem Quetta Pakistan

Three new aromatic compounds named fistuloates: A (3-butyl-6-ethylnonyl-3-(1-phenylethyl) benzoate), B (3-(6-tert-butyl-1-ethoxy-5-ethyl-4-methylnonyl)-5-ethylbenzoic acid isobutyl ester) and c (4,5-diethoxy-2-propylbenzoic acid 7-(6-pentyltetrahydropyran-2-yl)-heptyl ester) were isolated from the ethyl acetate soluble fraction of cassia fistula Linn. The structural formulae of the isolated compounds A-c were established through interpretation of their spectral data. compounds A-c exhibited significant antioxidant properties in 2,2-diphenyl-1-picrylhydrazyl, 2,2 '-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) and superoxide anion radical scavenging assays that signifies that c. fistula carries potential anti-oxidant constituents and may assist to cure diseases associated with oxidative stress and others.

关键词： antioxidant activity c fistula characterization ethyl acetate fraction fistuloates A-c

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Association of the human aryl hydrocarbon receptor repressor (AhRR)-c.565c>G transversion with male infertility: A case-control study from Iran

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JOURNAL OF cELLULAR BIOcHEMISTRY 2019年第6期120卷 8999-9005页

作者： Mohammad-Hasani, Azadeh colagar, Abasalt Hosseinzadeh Fallah, Ali Univ Mazandaran Fac Basic Sci Dept Mol & Cell Biol Babol Sar *** Iran

Dioxins (eg, 2,3,7,8-tetrachlorodibenzo-p-dioxin/TcDD), as environmental endocrine disruptors and toxic carcinogens, can affectmale reproductive health. The influence of dioxins is mediated via the aryl hydrocarbon receptor (AhR) pathway and its repressor (AhRR). In this study, we investigated the association of AhRR-c.565c>G transversion polymorphism with male infertility. In a hospital-based case-control study, 221 semen samples (111 infertile and 110 healthy controls) based onWorld Health Organization guidelines were collected from in vitro fertilization centers of Babol, Iran. The AhRR-c.565c>G (rs2292596) polymorphism was genotyped using a polymerase chain reaction-restriction fragment length polymorphism analysis. The difference in the allele frequency of AhRR-c.565c>G transversion polymorphism did not reach a significant level. The genotype frequency was statistically significantly different between fertile and infertile men. We found that polymorphism rs2292596 (Pro185Ala) was statistically significantly associated with the risk of male infertility. In addition, the statistical difference became more significant when the frequency was compared between the Pro/Pro genotype and the Pro/Ala plus Ala/Ala genotype. The 185 Pro wild-type alleles of AhRR may be associated with the risk of male infertility. The proallele also may diminish inhibition of AhR-mediated signaling of exposure to environmental pollutants.

关键词： AhRR c 565c > G dioxin male infertility reproductive health toxic carcinogen

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Hepatocellular carcinoma in the post-hepatitis c virus era: Should we change the paradigm?

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World Journal of Gastroenterology 2019年第29期25卷 3929-3940页

作者： Hadar Meringer Oren Shibolet Liat Deutsch Department of Gastroenterology and Hepatology Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine Tel Aviv University

Hepatocellular carcinoma (Hcc) is a common and deadly malignancy. The disease usually develops on a background of chronic liver disease. Until recently, the most common etiology was infection with the hepatitis c virus (HcV). The advent of direct-acting antiviral (DAA) therapies has been a major breakthrough in HcV treatment. Sustained virologic response can now be achieved in almost all treated patients, even in patients with a high risk for the development of Hcc, such as the elderly or those with significant fibrosis. Early reports raised concerns of a high risk for Hcc occurrence after DAA therapy both in patients with previous resection of tumors and those without previous tumors. As the World Health Organization’s goals for eradication of HcV are being endorsed worldwide, the elimination of HcV seems feasible. Simultaneous to the decrease in the burden of cirrhosis from HcV, non-alcoholic fatty liver disease (NAFLD) incidence has been increasing dramatically including significant increased incidence of cirrhosis and Hcc in these patients. Surprisingly, a substantial proportion of patients with NAFLD were shown to develop Hcc even in the absence of cirrhosis. Furthermore, Hcc treatment and potential complications are known to be influenced by liver steatosis. These changes in etiology and epidemiology of Hcc suggest the beginning of a new era: The post–HcV era. changes may eventually undermine current practices of early detection, surveillance and management of Hcc. We focused on the risk of Hcc occurrence and recurrence in the post–HcV era, the surveillance needed after DAA therapy and current studies in Hcc patients with NAFLD.

关键词： Hepatocellular carcinoma Hepatitis c virus Direct-acting antivirals Nonalcoholic fatty liver disease Non-alcoholic steatohepatitis

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Using c-elegans notch mutants in an undergraduate cancer biology laboratory course to demonstrate oncogenic effects on cell proliferation

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JOURNAL OF BIOLOGIcAL EDUcATION 2019年第3期53卷 265-273页

作者： Groth, Amy c. Eastern Connecticut State Univ Dept Biol Willimantic CT 06226 USA

Undergraduate laboratory exercises addressing aspects of cancer biology such as increased cell proliferation, gain-of-function signaling mutations and tumour formation often rely on tissue culture or even small mammal models. Many departments have limited or no access to these tools, and even well-equipped departments face logistical problems when incorporating these models into laboratory classes. I have developed a laboratory exercise using the microscopic worm, c. elegans, to demonstrate the effects of Notch receptor mutations on cell proliferation. Notch, which is activated by juxtacrine signaling, is mutated in many human cancers. In this exercise, students compare the germline phenotypes of worms that have a loss-of-function Notch mutation (no cells in the germline) or a gain-of-function Notch mutation (over-proliferation resulting in a germline tumour). Students also genotype the worms and perform sequence analysis to determine the effects of the mutations on the protein sequence. This laboratory exercise demonstrates oncogenic proliferation, correlates genotype to phenotype, exposes students to model organisms and introduces sequence databases and analysis. In addition to cancer biology courses, this exercise could be incorporated in courses with a focus on genetics, cell biology or developmental biology.

关键词： Mutation cancer c elegans laboratory exercise development

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Addendum to: “The Friedrichs angle and alternating projections in Hilbert c ⁎ -modules” [J. Math. Anal. Appl. 516 (2022) 126474]

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Journal of Mathematical Analysis and Applications 2023年第1期522卷

作者： Koen van den Dungen Bram Mesland Adam Rennie Mathematical Institute of the University of Bonn Germany Mathematisch Instituut Universiteit Leiden Netherlands School of Mathematics and Applied Statistics University of Wollongong Wollongong Australia

We show by (counter)example that the intersection of complemented submodules in a Hilbert c ⁎ -module is not necessarily complemented, answering the last open question from [1] .

关键词： Two projections Von Neumann's alternating projection theorem Friedrichs angle Hilbert c ⁎ -module Local-global principle

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