Michael J. Austin

Regulation of CXCL-8 (Interleukin-8) Induction by Double-Stranded RNA Signaling Pathways during Hepatitis C Virus Infection

ABSTRACT Hepatitis C virus (HCV) infection induces the α-chemokine interleukin-8 (CXCL-8), which is regulated at the levels of transcription and mRNA stability. In the current study, CXCL-8 regulation by double-stranded (ds)RNA pathways was analyzed in the context of HCV infection. A constitutively active mutant of the retinoic acid-inducible gene I (RIG-I), RIG-N, activated CXCL-8 transcription. Promoter mutagenesis experiments indicated that NF-κB and interferon (IFN)-stimulated response element (ISRE) binding sites were required for the RIG-N induction of CXCL-8 transcription. IFN-β promoter stimulator 1 (IPS-1) expression also activated CXCL-8 transcription, and mutations of the ISRE and NF-κB binding sites reduced and abrogated CXCL-8 transcription, respectively. In the presence of wild-type RIG-I, transfection of JFH-1 RNA or JFH-1 virus infection of Huh7.5.1 cells activated the CXCL-8 promoter. Expression of IFN regulatory factor 3 (IRF-3) stimulated transcription from both full-length and ISRE-driven CXCL-8 promoters. Chromatin immunoprecipitation assays demonstrated that IRF-3 and NF-κB bound directly to the CXCL-8 promoter in response to virus infection and dsRNA transfection. RIG-N stabilized CXCL-8 mRNA via the AU-rich element in the 3′ untranslated region of CXCL-8 mRNA, leading to an increase in its half-life following tumor necrosis factor alpha induction. The data indicate that HCV infection triggers dsRNA signaling pathways that induce CXCL-8 via transcriptional activation and mRNA stabilization and define a regulatory link between innate antiviral and inflammatory cellular responses to virus infection.

Functional Characterization of Core Genes from Patients with Acute Hepatitis C Virus Infection

BACKGROUNDnThe hepatitis C virus (HCV) core protein is implicated in diverse aspects of HCV-induced pathogenesis. There is a paucity of information on core in acute hepatitis C infection.nnnMETHODSnWe analyzed core gene sequences and protein functions from 13 patients acutely infected with HCV genotype 1.nnnRESULTSnAlthough core isolates differed slightly between patients, core quasispecies were relatively homogeneous within each patient. In 2 of 4 patients studied temporally, core quasispecies did not change over time. Comparison with more than 2700 published core isolates indicated that amino acid changes from a prototype reference strain found in acute core isolates were present in chronically infected persons at low frequency (6.4%; range, 0%-32%). Core isolates associated with lipid droplets to similar degrees in Huh7 cells. Core diffusion in cells was not affected by nonconservative changes F130L and G161S in the lipid targeting domain of core. Core isolates inhibited interferon-stimulated response element- and nuclear factor kappaB-dependent transcription and tumor necrosis factor alpha-induced nuclear translocation of nuclear factor kappaB and were also secreted from Huh7 cells.nnnCONCLUSIONSnThe data suggest that upon transmission, core quasispecies undergo genetic homogenization associated with amino acid changes that are rarely found in chronic infection and that, despite genetic variation, acute core isolates retain similar functions in vitro.

Federal Support for Social Work Education: Section 707 of the 1967 Social Security Act Amendments

In this article, we trace the history and brief impact of federal support for social work education through section 707 of the 1967 amendments to the Social Security Act. The key factors that contributed to the passage of section 707 and the first year of federal policy implementation are analyzed using 185 applications from educational institutions that sought funds for initiating or expanding undergraduate and graduate social work education.

Intellectual Origins of Community Organizing, 1920-1939

The roots of contemporary community organization practice can be traced to the settlement house workers and organizers of the councils of social agencies of the early 1900s. However, the education of future organizers should include the practice wisdom found in the writings of the organizers and educators who wrote in the 1920s and 1930s, including Hart, Lindeman, McClenahan, Pettit, and Steiner. Students of community organizing can be guided by the insights found in the first textbooks and thereby gain a perspective similar to the well-documented history of casework practice. The early manuals on community organizing represent an important dimension of the history of social work practice.

Organizing for neighborhood health care: an historical reflection.

The Cincinnati Social Unit began in 1917 and lasted through 1920. It was an early experiment in community organizing for the purpose of improving public health. The data of the time and contemporary evaluations indicate it was highly successful, but its socialist sponsors failed to successfully negate conservative hostility toward the program. It failed to survive because of the politics of post-World War I America.