Vocational training programs, transition programs and work experience placements for employment of young adults with intellectual disability: A systematic review & a description of employment patterns and day occupations of young adults with intellectual disability residing in Queensland

OBJECTIVE: To review the research examining the effectiveness of vocational training programs, transition programs and work experience placements and describe their impact on work and employment attainment and maintenance for young adults with intellectual disability. METHOD: Electronic searches of six data bases and manual searches of references lists locating all available evidence of programs and interventions to assist young adults with intellectual disability to find paid employment. Interventions described as vocational training, work placements and experience and transition programs aimed at securing employment were included. Two reviewers undertook data extraction and quality assessment and a systematic review was possible. RESULTS: Nine articles met the inclusion criteria reporting on young adults with intellectual disability with a collective total of 325 participants. Authors described the supports and interventions as job skills training, preparation for post-school, transition programs, transition to adult services, and vocational/training programs. CONCLUSIONS: The effectiveness of transition programs aimed at employment, job skills training and work experience placements and their positive impact on the employment outcomes of young adults with intellectual disability is supported by the evidence. Small samples sizes and the qualitative nature of research meant only a systematic review was possible, and no generalisations to the wider population could be made. Further studies with larger sample sizes and longitudinal follow-up is needed to further understand the effectiveness of these programs

Unique and Overlapping Actions of Type I and III IFNs in Influenza A Virus Infection and Implications for Therapy

Influenza A virus (IAV) poses a significant public health burden. Severe disease is characterised by infected lung airway epithelial cells (AECs), inflammation and tissue damage. However, disease severity differs between individuals and this cannot be entirely explained by inter-individual differences in pre-existing immunity or comorbidities. Host-specific, genetically determined factors must contribute to susceptibility. Type I interferon (IFNαβ) is known to have antiviral function in vitro, but its role in restricting IAV infection in vivo is controversial. We demonstrate that responsiveness to IFNαβ signalling is a host-specific determinant with protective or pathogenic potential which determines the severity of IAV-induced disease. IAV infected 129, CBA/J and DBA mouse strains showed dramatically increased mortality and lung damage, yet higher levels of pulmonary IFNαβ, compared to C57BL/6 or BALB/C mice. Ablation of IFNαβR signalling in 129 mice markedly reduced mortality, levels of proinflammatory cytokines, inflammatory cell recruitment and AEC apoptosis. Susceptibility to IAV-induced disease is influenced by the number of functional alleles for the IFNαβR subunit, IFNAR1, within the genome. IFNAR1+/-(129) mice were less susceptible than wild type 129s yet more so than IFNαβR-/-(129) mice. Conversely, triplication of a section of murine chromosome 16 that includes IFNAR1 in C57BL/6 mice enhanced IFNα response to IAV infection and downstream immunopathology. Finally, IFNα therapy of infected B6. A2G-Mxl mice reduced IAV titers, yet increased secretion of proinflammatory cytokines, innate cell recruitment and AEC apoptosis in the lung, due to the potent immunostimulatory capability to IFNα. In contrast, treatment with IFNλ, whose receptor is largely restricted to AECs, promoted IAV control without exacerbating IAV-induced inflammation. Thus, by manipulating the IFNαβ signal in various ways, we demonstrate that excessive IFNαβ in IAV infection can increase AEC death and enhance proinflammatory responses that ultimately increase disease severity. Our findings have important implications for prediction and treatment of severe influenza

“Experience First”: Investigating Co-creation Experience in Social Product Development Networks

Social product development (SPD) is a network-based innovation model in which firms or platforms use social mechanisms and social technologies to mobilize organizationally independent individuals––co-creators––to co-create new products. SPD networks require the maintenance of external participation across the innovation cycle to survive competition and thrive in the innovation sector. While prior research suggests that the viability, survivability, and productivity of social networks generally depend on user experience, we have limited evidence on the particular role of user experience in the context of SPD networks. Responding to this need, we introduce a conceptual model to theorize and operationalize co-creation experience in SPD networks. Through validating the proposed model, we demonstrate why co-creation experience is critical for predicting co-creators’ behavioral intentions and maintaining their actual contribution. Finally, we explore the theoretical and practical implications of the results. Future studies can leverage the findings to better capture co-creation experience and contribute to designing successful SPD networks

Taking Open Innovation to the Next Level: A Conceptual Model of Social Product Development (SPD)

The initial success of open business models is encouraging many organizations to implement their own co-innovation networks. Social product development, or SPD, represents a new business model enabled by social technology platforms. It extends collaboration beyond customer-involvement models to socially-engaged individual actors in the ideation and development of new products. The increasing adoption necessitates developing a framework to help researchers clearly understand and practitioners effectively design the SPD platforms. This paper develops a conceptual model for SPD and illustrates the validity of the model via a case study on a particular SPD platform, focusing on its business model, network governance, and key processes and design features. The proposed model is sufficiently general yet grounded in the phenomenon to guide future research on socially-enabled innovation and SPD networks in particular

Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism.National Institutes of Health (U.S.) (NIH grant R01 GM56203)National Institutes of Health (U.S.) (grant NIH 5P01CA120964)Dana-Farber/Harvard Cancer Center (NIH 5P30CA006516)National Institutes of Health (U.S.) (NIH grant R03MH085679)National Human Genome Research Institute (U.S.) (Intramural Research Program)National Institutes of Health (U.S.) (Molecular Libraries Initiative of the NIH Roadmap for Medical Research

A necroptosis-independent function of RIPK3 promotes immune dysfunction and prevents control of chronic LCMV infection

Necroptosis is a lytic and inflammatory form of cell death that is highly constrained to mitigate detrimental collateral tissue damageand impaired immunity. These constraints make it difficult to define the relevance of necroptosis in diseases such as chronic andpersistent viral infections and within individual organ systems. The role of necroptotic signalling is further complicated becauseproteins essential to this pathway, such as receptor interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like(MLKL), have been implicated in roles outside of necroptotic signalling. We sought to address this issue by individually defining therole of RIPK3 and MLKL in chronic lymphocytic choriomeningitis virus (LCMV) infection. We investigated if necroptosis contributesto the death of LCMV-specific CD8+ T cells or virally infected target cells during infection. We provide evidence showing thatnecroptosis was redundant in the pathogenesis of acute forms of LCMV (Armstrong strain) and the early stages of chronic (Docilestrain) LCMV infection in vivo. The number of immune cells, their specificity and reactivity towards viral antigens and viral loads arenot altered in the absence of either MLKL or RIPK3 during acute and during the early stages of chronic LCMV infection. However, weidentified that RIPK3 promotes immune dysfunction and prevents control of infection at later stages of chronic LCMV disease. Thiswas not phenocopied by the loss of MLKL indicating that the phenotype was driven by a necroptosis-independent function ofRIPK3. We provide evidence that RIPK3 signaling evoked a dysregulated type 1 interferone response which we linked to animpaired antiviral immune response and abrogated clearance of chronic LCMV infectio

Variable levels of drift in tunicate cardiopharyngeal gene regulatory elements.

Background: Mutations in gene regulatory networks often lead to genetic divergence without impacting gene expression or developmental patterning. The rules governing this process of developmental systems drift, including the variable impact of selective constraints on different nodes in a gene regulatory network, remain poorly delineated. Results: Here we examine developmental systems drift within the cardiopharyngeal gene regulatory networks of two tunicate species, Corella inflata and Ciona robusta. Cross-species analysis of regulatory elements suggests that trans-regulatory architecture is largely conserved between these highly divergent species. In contrast, cis-regulatory elements within this network exhibit distinct levels of conservation. In particular, while most of the regulatory elements we analyzed showed extensive rearrangements of functional binding sites, the enhancer for the cardiopharyngeal transcription factor FoxF is remarkably well-conserved. Even minor alterations in spacing between binding sites lead to loss of FoxF enhancer function, suggesting that bound trans-factors form position-dependent complexes. Conclusions: Our findings reveal heterogeneous levels of divergence across cardiopharyngeal cis-regulatory elements. These distinct levels of divergence presumably reflect constraints that are not clearly associated with gene function or position within the regulatory network. Thus, levels of cis-regulatory divergence or drift appear to be governed by distinct structural constraints that will be difficult to predict based on network architectur

Consensus coding sequence (CCDS) database: a standardized set of human and mouse protein-coding regions supported by expert curation.

The Consensus Coding Sequence (CCDS) project provides a dataset of protein-coding regions that are identically annotated on the human and mouse reference genome assembly in genome annotations produced independently by NCBI and the Ensembl group at EMBL-EBI. This dataset is the product of an international collaboration that includes NCBI, Ensembl, HUGO Gene Nomenclature Committee, Mouse Genome Informatics and University of California, Santa Cruz. Identically annotated coding regions, which are generated using an automated pipeline and pass multiple quality assurance checks, are assigned a stable and tracked identifier (CCDS ID). Additionally, coordinated manual review by expert curators from the CCDS collaboration helps in maintaining the integrity and high quality of the dataset. The CCDS data are available through an interactive web page (https://www.ncbi.nlm.nih.gov/CCDS/CcdsBrowse.cgi) and an FTP site (ftp://ftp.ncbi.nlm.nih.gov/pub/CCDS/). In this paper, we outline the ongoing work, growth and stability of the CCDS dataset and provide updates on new collaboration members and new features added to the CCDS user interface. We also present expert curation scenarios, with specific examples highlighting the importance of an accurate reference genome assembly and the crucial role played by input from the research community. Nucleic Acids Res 2018 Jan 4; 46(D1):D221-D228