A clustering of heterozygous missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder

WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare de novo germline missense variants in WDR5; one identical variant was found in five individuals, and another variant in two individuals. All individuals had neurodevelopmental disorders including speech/language delays (N=11), intellectual disability (N=9), epilepsy (N=7) and autism spectrum disorder (N=4). Additional phenotypic features included abnormal growth parameters (N=7), heart anomalies (N=2) and hearing loss (N=2). Three-dimensional protein structures indicate that all the residues affected by these variants are located at the surface of one side of the WDR5 protein. It is predicted that five out of the six amino acid substitutions disrupt interactions of WDR5 with RbBP5 and/or KMT2A/C, as part of the COMPASS (complex proteins associated with Set1) family complexes. Our experimental approaches in Drosophila melanogaster and human cell lines show normal protein expression, localization and protein-protein interactions for all tested variants. These results, together with the clustering of variants in a specific region of WDR5 and the absence of truncating variants so far, suggest that dominant-negative or gain-of-function mechanisms might be at play. All in all, we define a neurodevelopmental disorder associated with missense variants in WDR5 and a broad range of features. This finding highlights the important role of genes encoding COMPASS family proteins in neurodevelopmental disorders

Effects of angiotensin type 1 receptor blockade on arginine and ADMA synthesis and metabolic pathways in fawn-hooded hypertensive rats

Background. The fawn-hooded hypertensive (FHH) rat develops spontaneous glomerulosclerosis that is ameliorated by inhibition of the angiotensin II type 1 receptor (AT-1). Since kidney damage is associated with nitric oxide (NO) deficiency, we investigated how AT-1 antagonism influenced nitric oxide synthase (NOS), as well as NOS substrate [l-arginine (L-Arg)] and inhibitor [asymmetric dimethylarginine (ADMA)]. L-Arg is synthesized by renal argininosuccinate synthase/argininosuccinate lyase (ASS/ASL) and then either consumed within the kidney by arginase II or NOS or released into the circulation. L-Arg is then taken up from plasma into cells where it can be utilized by NOS and other pathways. The competitive inhibitor of NOS, ADMA, is degraded by dimethylarginine dimethylaminohydrolase (DDAH)

PD-L1, Galectin-9 and CD8(+) tumor-infiltrating lymphocytes are associated with survival in hepatocellular carcinoma

Novel systemic treatments for hepatocellular carcinoma (HCC) are strongly needed. Immunotherapy is a promising strategy that can induce specific antitumor immune responses. Understanding the mechanisms of immune resistance by HCC is crucial for development of suitable immunotherapeutics. We used immunohistochemistry on tissue-microarrays to examine the co-expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM and IDO, as well as tumor CD8(+) lymphocyte infiltration in HCC, in two independent cohorts of patients. We found that at least some expression in tumor cells was seen in 97% of cases for HVEM, 83% for PD-L1, 79% for Gal-9 and 66% for IDO. In the discovery cohort (n = 94), we found that lack of, or low, tumor expression of PD-L1 (p <0.001), Galectin-9 (p <0.001) and HVEM (p <0.001), and low CD8(+)TIL count (p = 0.016), were associated with poor HCC-specific survival. PD-L1, Galectin-9 and CD8CTIL count were predictive of HCC-specific survival independent of baseline clinicopathologic characteristics and the combination of these markers was a powerful predictor of HCCspecific survival (HR 0.29; p P <0.001). These results were confirmed in the validation cohort (n D 60). We show that low expression levels of PD-L1 and Gal-9 in combination with low CD8CTIL count predict extremely poor HCC-specific survival and it requires a change in two of these parameters to significantly improve prognosis. In conclusion, intra-tumoral expression of these immune inhibiting molecules was observed in the majority of HCC patients. Low expression of PD-L1 and Galectin-9 and low CD8(+)TIL count are associated with poor HCC-specific survival. Combining immune biomarkers leads to superior predictors of HCC mortalit

Exploring teacher roles and pupil outcomes in technology-rich early literacy learning

The present study focused on the involvement of Dutch kindergarten teachers in curriculum (design and) implementation of PictoPal activities in three different roles: executor-only, re-designer, and co-designer. PictoPal refers to ICT-rich on- and off-computer activities for early literacy. In the executor-only role, teachers were not involved in design; they implemented ready-made PictoPal activities in their classes. The re-designer and co-designer roles involved teams of teachers in a purposeful act of adjusting, respectively designing and implementing PictoPal. The aim of this study was to understand how teacher roles influence implementation of PictoPal and pupil learning outcomes. Case studies were used to examine each teacher role, and a cross-case analysis was undertaken to compare teacher roles with each other on a common set of measures: teacher perceptions about their role, curriculum practicality, and co-ownership; integration of on- and off-computer activities; and pupil learning. The data was gathered using interviews, checklists, and pre- and post-tests. The findings of this study showed that each teacher role (executor-only, re-designer, and co-designer) contributes significantly to the effectiveness of ICT-rich early literacy learning activities. Significant differences in integration of the on- and off-computer activities were found between the three teacher roles. Teachers as co-designers showed highest extent of integration. Across teacher roles, pupil learning outcomes were not straightforwardly related to the extent of integration. However, teachers as co-designers felt a sense of co-ownership towards PictoPal, which yielded high degrees of integration and willingness to extend implementation of PictoPal beyond the research context. Based on this study, it can be recommended that schools wishing to support early literacy development in kindergarten could responsibly choose to do so by engaging their teachers in collaborative design of ICT-rich activitie