Missense mutations to the **TSC1** gene cause tuberous sclerosis complex

Effective data management and data sharing are crucial components of the research lifecycle, yet evidence suggests that many social science graduate programs are not providing training in these areas. The current exploratory study assesses how U.S. masters and doctoral programs in the social sciences include formal, non-formal, and informal training in data management and sharing. We conducted a survey of 150 graduate programs across six social science disciplines, and used a mix of closed and open-ended questions focused on the extent to which programs provide such training and exposure. Results from our survey suggested a deficit of formal training in both data management and data sharing, limited non-formal training, and cursory informal exposure to these topics. Utilizing the results of our survey, we conducted a syllabus analysis to further explore the formal and non-formal content of graduate programs beyond self-report. Our syllabus analysis drew from an expanded seven social science disciplines for a total of 140 programs. The syllabus analysis supported our prior findings that formal and non-formal inclusion of data management and data sharing training is not common practice. Overall, in both the survey and syllabi study we found a lack of both formal and non-formal training on data management and data sharing. Our findings have implications for data repository staff and data service professionals as they consider their methods for encouraging data sharing and prepare for the needs of data depositors. These results can also inform the development and structuring of graduate education in the social sciences, so that researchers are trained early in data management and sharing skills and are able to benefit from making their data available as early in their careers as possible

siRNA-based identification of IBD-related targets in human monocyte-derived dendritic cells

Inflammatory bowel disease (IBD) is thought to be caused by an aberrant host response to the commensal enteric flora in genetically susceptible individuals. Dendritic cells (DCs) play a key role in the regulation of this response as they sample gut commensals. In healthy individuals DCs actively contribute to tolerance upon recognition of these resident bacteria, whereas in individuals with IBD, DCs will initiate an inflammatory response. To mimic the disease response in vitro, human monocyte-derived DCs were matured with E. coli causing the cells to produce high levels of the pro-inflammatory cytokine IL-12/IL-23p40 (p40) and low levels of the anti-inflammatory cytokine IL-10. A siRNA-based screening assay was developed and screened to identify potential therapeutic targets that shift this balance towards an immunosuppressive state with lower levels of p40 and higher levels of IL-10. The screening assay was optimized and quality controlled using non-targeting controls and positive control siRNAs targeting IL12B and TLR4 transcripts. In the primary screen, smartpool siRNAs were screened for reduction in p40 expression, induction of IL-10 levels, or increase in IL-10:p40 ratios without affecting cell viability. All potential targets were taken forward into a confirmation screen in a different DC donor in which four individual siRNAs per target were screened. At least two siRNAs per target should have an effect to be considered a valid target. This screen resulted in a concise list of ten genes, of which their role in DC maturation is currently being investigated

Missense mutations to the TSC1 gene cause tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterised by the development of hamartomas in a variety of organs and tissues. The disease is caused by mutations in either the TSC1 gene on chromosome 9q34 or the TSC2 gene on chromosome 16p13.3. The TSC1 and TSC2 gene products, TSC1 and TSC2, interact to form a protein complex that inhibits signal transduction to the downstream effectors of the mammalian target of rapamycin (mTOR). Here we investigate the effects of putative TSC1 missense mutations identified in individuals with signs and/or symptoms of TSC on TSC1–TSC2 complex formation and mTOR signalling. We show that specific amino-acid substitutions close to the N-terminal of TSC1 reduce steady-state levels of TSC1, resulting in the activation of mTOR signalling and leading to the symptoms of TSC