Rotaviruses (RVs) are 11-segmented, double-stranded (ds) RNA viruses and important causes of acute gastroenteritis in humans and other animal species. Early RV particle assembly is a multi-step process that includes the assortment, packaging and replication of the 11 genome segments in close connection with capsid morphogenesis. This process occurs inside virally induced, cytosolic, membrane-less organelles called viroplasms. While many viral and cellular proteins play roles during early RV assembly, the octameric nonstructural protein 2 (NSP2) has emerged as a master orchestrator of this key stage of the viral replication cycle. NSP2 is critical for viroplasm biogenesis as well as for the selective RNA–RNA interactions that underpin the assortment of 11 viral genome segments. Moreover, NSP2’s associated enzymatic activities might serve to maintain nucleotide pools for use during viral genome replication, a process that is concurrent with early particle assembly. The goal of this review article is to summarize the available data about the structures, functions and interactions of RV NSP2 while also drawing attention to important unanswered questions in the field.
J.M. Cohn, A.L Kelsey and K.M. Fiels, revised and adapted by SALTER, D., Planning for Integrated Systems and Technologies: a how-to-do-it manual for librarians. 2nd edition, 2002 revision. London: Facet Publishing, 2002. ISBN 1-85604-431-9 (pbk.): £27.50. xxi, 201 p. - Volume 2 Issue 4
JC polyomavirus (JCPyV), a ubiquitous human pathogen, is the etiological agent of the fatal neurodegenerative disease progressive multifocal leukoencephalopathy (PML). Like most viruses, JCPyV infection requires the activation of host-cell signaling pathways in order to promote viral replication processes. Previous works have established the necessity of the extracellular signal-regulated kinase (ERK), the terminal core kinase of the mitogen-activated protein kinase (MAPK) cascade (MAPK-ERK) for facilitating transcription of the JCPyV genome. However, the underlying mechanisms by which the MAPK-ERK pathway becomes activated and induces viral transcription are poorly understood. Treatment of cells with siRNAs specific for Raf and MAP kinase kinase (MEK) targets proteins in the MAPK-ERK cascade, significantly reducing JCPyV infection. MEK, the dual-specificity kinase responsible for the phosphorylation of ERK, is phosphorylated at times congruent with early events in the virus infectious cycle. Moreover, a MAPK-specific signaling array revealed that transcription factors downstream of the MAPK cascade, including cMyc and SMAD4, are upregulated within infected cells. Confocal microscopy analysis demonstrated that cMyc and SMAD4 shuttle to the nucleus during infection, and nuclear localization is reduced when ERK is inhibited. These findings suggest that JCPyV induction of the MAPK-ERK pathway is mediated by Raf and MEK and leads to the activation of downstream transcription factors during infection. This study further defines the role of the MAPK cascade during JCPyV infection and the downstream signaling consequences, illuminating kinases as potential therapeutic targets for viral infection.
A survey was distributed in 8 states to learn about perceived strengths and challenges of service coordination from those working in early intervention (EI) programs under Part C of the Individuals with Disabilities Education Act. Survey responses from 769 service coordinators and other EI personnel in 8 states provide an overview of state systems and the implementation of service coordination activities within these state EI systems. Respondents suggested that service coordinators experience the following needs: (1) balancing the workload by reducing the number of families served per service coordinator and decreasing the amount of paperwork; (2) improved compensation and funding; and (3) better and more frequent training opportunities. Findings from this survey were analyzed and used by representatives from participating states to determine state and national action plans for improving the professional development and identity of service coordinators, with the goal of prioritizing support for this important part of the early childhood intervention workforce.
A survey was distributed to Part C early intervention (EI) service coordination (SC) stakeholders in one state in order to gain a deeper understanding of service coordinator knowledge, skills, and motivators for professional growth and recognition. Survey participants ( N = 107), including dedicated service coordinators, program managers, social emotional consultants, parent liaisons, local interagency council coordinators, and developmental pediatric consultants, identified knowledge and skills required for the role of service coordinators. Key motivators for professional growth within the SC role were also identified, including monetary, award/acknowledgment, and varied levels of responsibility. Data collected were analyzed, reviewed with Part C administrators, system point of entry leadership, and shared with EI stakeholders. Findings are being used to guide systems planning and decision-making to ensure service coordinators have opportunities for professional growth and are well prepared with the knowledge, skills, and supports necessary to partner with families and other professionals in EI. Information gained may also inform other state Part C programs and professional development entities as they (1) create and assess systems to support SC personnel; (2) build service coordinators' capacity to implement evidence-informed practices; (3) recognize service coordinators' critical role and expertise; and (4) foster the retention of well-trained, well-supported service coordinators.
A survey was developed and distributed to service coordination constituents across the nation to determine whether the DRAFT Knowledge and Skills for Service Coordinators (KSSC) were comprehensive and complete. Participants ( N = 933) included service coordinators (SCs), supervisors/administrators, and other early intervention (EI)-related professionals. Overall, respondents agreed that the DRAFT KSSC were comprehensive and complete, reflective of what SCs should know and be able to do, and the statements were clear. Furthermore, no significant differences were found among SCs, supervisors/administrators, and other EI constituents regarding any of these outcomes. Qualitative data were used to inform edits to the KSSC. Findings were used to validate the DRAFT KSSC, which, in turn, will be used to guide systems planning and decision-making to ensure SCs are well-prepared with the knowledge and skills necessary to partner with families and professionals from diverse backgrounds in EI.
The USA Adopted Children's Immigrant Visa Unit announced June 2008 that it had put a stop to new inter-country adoptions with Vietnam. The reason given was that the way the children were put up for adoption was dependent on the financial arrangements between Vietnamese orphanages and American adoption services providers (ASPs). ASP donations served as a strong financial incentive for orphanages to find additional children for adoption, often by offering monetary aid to parents to relinquish all rights to the child.
JC polyomavirus (JCPyV) infects the majority of the population, establishing a lifelong, asymptomatic infection in the kidney of healthy individuals. People that become severely immunocompromised may experience JCPyV reactivation, which can cause progressive multifocal leukoencephalopathy (PML), a neurodegenerative disease. Due to a lack of therapeutic options, PML results in fatality or significant debilitation among affected individuals. Cellular internalization of JCPyV is mediated by serotonin 5-hydroxytryptamine subfamily 2 receptors (5-HT2Rs) via clathrin-mediated endocytosis. The JCPyV entry process requires the clathrin-scaffolding proteins β-arrestin, adaptor protein 2 (AP2), and dynamin. Further, a β-arrestin interacting domain, the Ala-Ser-Lys (ASK) motif, within the C-terminus of 5-HT2AR is important for JCPyV internalization and infection. Interestingly, 5-HT2R subtypes A, B, and C equally support JCPyV entry and infection, and all subtypes contain an ASK motif, suggesting a conserved mechanism for viral entry. However, the role of the 5-HT2R ASK motifs and the activation of β-arrestin-associated proteins during internalization has not been fully elucidated. Through mutagenesis, the ASK motifs within 5-HT2BR and 5-HT2CR were identified as critical for JCPyV internalization and infectivity. Further, utilizing biochemical pulldown techniques, mutagenesis of the ASK motifs in 5-HT2BR and 5-HT2CR resulted in reduced β-arrestin binding. Utilizing small-molecule chemical inhibitors and RNA interference, G-protein receptor kinase 2 (GRK2) was determined to be required for JCPyV internalization and infection by mediating interactions between β-arrestin and the ASK motif of 5-HT2Rs. These findings demonstrate that GRK2 and β-arrestin interactions with 5-HT2Rs are critical for JCPyV entry by clathrin-mediated endocytosis and resultant infection.IMPORTANCE As intracellular parasites, viruses require a host cell to replicate and cause disease. Therefore, virus-host interactions contribute to viral pathogenesis. JC polyomavirus (JCPyV) infects most of the population, establishing a lifelong asymptomatic infection within the kidney. Under conditions of severe immunosuppression JCPyV may spread to the central nervous system, causing the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). Individuals living with HIV or undergoing immunomodulatory therapies are at risk for developing PML. The mechanisms of how JCPyV uses specific receptors on the surface of host cells to initiate internalization and infection is a poorly understood process. We have further identified cellular proteins involved in JCPyV internalization and infection and elucidated their specific interactions that are responsible for activation of receptors. Collectively, these findings illuminate how viruses usurp cellular receptors during infection, contributing to current development efforts for therapeutic options for the treatment or prevention of PML.
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