Measuring cell-type specific differential methylation in human brain tissue

The behavior of epigenetic mechanisms in the brain is obscured by tissue heterogeneity and disease-related histological changes. Not accounting for these confounders leads to biased results. We develop a statistical methodology that estimates and adjusts for celltype composition by decomposing neuronal and non-neuronal differential signal. This method provides a conceptual framework for deconvolving heterogeneous epigenetic data from postmortem brain studies. We apply it to find cell-specific differentially methylated regions between prefrontal cortex and hippocampus. We demonstrate the utility of the method on both Infinium 450k and CHARM data

Evolutionarily unique mechanistic framework of clathrin-mediated endocytosis in plants

In plants, clathrin mediated endocytosis (CME) represents the major route for cargo internalisation from the cell surface. It has been assumed to operate in an evolutionary conserved manner as in yeast and animals. Here we report characterisation of ultrastructure, dynamics and mechanisms of plant CME as allowed by our advancement in electron microscopy and quantitative live imaging techniques. Arabidopsis CME appears to follow the constant curvature model and the bona fide CME population generates vesicles of a predominantly hexagonal-basket type; larger and with faster kinetics than in other models. Contrary to the existing paradigm, actin is dispensable for CME events at the plasma membrane but plays a unique role in collecting endocytic vesicles, sorting of internalised cargos and directional endosome movement that itself actively promote CME events. Internalized vesicles display a strongly delayed and sequential uncoating. These unique features highlight the independent evolution of the plant CME mechanism during the autonomous rise of multicellularity in eukaryotes

Seizures in Fragile X syndrome: Associations and longitudinal analysis of a large clinic-based cohort

Fragile X syndrome (FXS), the most common inherited cause of intellectual disability, learning disability, and autism spectrum disorder, is associated with an increased prevalence of certain medical conditions including seizures. The goal of this study was to better understand seizures in individuals with FXS using the Fragile X Online Registry with Accessible Research Database, a multisite observational study initiated in 2012 involving FXS clinics in the Fragile X Clinic and Research Consortium. Seizure data were available for 1,607 participants, mostly male (77%) and white (74.5%). The overall prevalence of at least one seizure was 12%, with this rate being significantly higher in males than females (13.7 vs. 6.2%

Drosophila TNF modulates tissue tension in the embryo to facilitate macrophage invasive migration

Migrating cells penetrate tissue barriers during development, inflammatory responses, and tumor metastasis. We study if migration in vivo in such three-dimensionally confined environments requires changes in the mechanical properties of the surrounding cells using embryonic Drosophila melanogaster hemocytes, also called macrophages, as a model. We find that macrophage invasion into the germband through transient separation of the apposing ectoderm and mesoderm requires cell deformations and reductions in apical tension in the ectoderm. Interestingly, the genetic pathway governing these mechanical shifts acts downstream of the only known tumor necrosis factor superfamily member in Drosophila, Eiger, and its receptor, Grindelwald. Eiger-Grindelwald signaling reduces levels of active Myosin in the germband ectodermal cortex through the localization of a Crumbs complex component, Patj (Pals-1-associated tight junction protein). We therefore elucidate a distinct molecular pathway that controls tissue tension and demonstrate the importance of such regulation for invasive migration in vivo

Arbaclofen in fragile X syndrome: results of phase 3 trials

Background: Arbaclofen improved multiple abnormal phenotypes in animal models of fragile X syndrome (FXS) and showed promising results in a phase 2 clinical study. The objective of the study is to determine safety and efficacy of arbaclofen for social avoidance in FXS. Methods: Two phase 3 placebo-controlled trials were conducted, a flexible dose trial in subjects age 12-50 (209FX301, adolescent/adult study) and a fixed dose trial in subjects age 5-11 (209FX302, child study). The primary endpoint for both trials was the Social Avoidance subscale of the Aberrant Behavior Checklist-Community Edition, FXS-specific (ABC-C FX ). Secondary outcomes included other ABC-C FX subscale scores, Clinical Global Impression-Improvement (CGI-I), Clinical Global Impression-Severity (CGI-S), and Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) Socialization domain score. Results: A total 119 of 125 randomized subjects completed the adolescent/adult study (n = 57 arbaclofen, 62 placebo) and 159/172 completed the child study (arbaclofen 5 BID n = 38; 10 BID n = 39; 10 TID n = 38; placebo n = 44). There were no serious adverse events (AEs); the most common AEs included somatic (headache, vomiting, nausea), neurobehavioral (irritability/agitation, anxiety, hyperactivity), decreased appetite, and infectious conditions, many of which were also common on placebo. In the combined studies, there were 13 discontinuations (n = 12 arbaclofen, 1 placebo) due to AEs (all neurobehavioral). The adolescent/adult study did not show benefit for arbaclofen over placebo for any measure. In the child study, the highest dose group showed benefit over placebo on the ABC-C FX Irritability subscale (p = 0.03) and Parenting Stress Index (PSI, p = 0.03) and trends toward benefit on the ABC-C FX Social Avoidance and Hyperactivity subscales (both p < 0.1) and CGI-I (p = 0.119). Effect size in the highest dose group was similar to effect sizes for FDA-approved serotonin reuptake inhibitors (SSRIs). Conclusions: Arbaclofen did not meet the primary outcome of improved social avoidance in FXS in either study. Data from secondary measures in the child study suggests younger patients may derive benefit, but additional studies with a larger cohort on higher doses would be required to confirm this finding. The reported studies illustrate the challenges but represent a significant step forward in translating targeted treatments from preclinical models to clinical trials in humans with FXS

Task sharing in an interprofessional medication management program – a survey of general practitioners and community pharmacists

Background Pharmacist-led medication review and medication management programs (MMP) are well-known strategies to improve medication safety and effectiveness. If performed interprofessionally, outcomes might even improve. However, little is known about task sharing in interprofessional MMP, in which general practitioners (GPs) and community pharmacists (CPs) collaboratively perform medication reviews and continuously follow-up on patients with designated medical and pharmaceutical tasks, respectively. In 2016, ARMIN (Arzneimittelinitiative Sachsen-Thüringen) an interprofessional MMP was launched in two German federal states, Saxony and Thuringia. The aim of this study was to understand how GPs and CPs share tasks in MMP when reviewing the patients’ medication. Methods This was a cross-sectional postal survey among GPs and CPs who participated in the MMP. Participants were asked who completed which MMP tasks, e.g., checking drug-drug interactions, dosing, and side effects. In total, 15 MMP tasks were surveyed using a 5-point Likert scale ranging from “I complete this task alone” to “GP/CP completes this task alone”. The study was conducted between 11/2020 and 04/2021. Data was analyzed using descriptive statistics. Results In total, 114/165 (69.1%) GPs and 166/243 (68.3%) CPs returned a questionnaire. The majority of GPs and CPs reported (i) checking clinical parameters and medication overuse and underuse to be completed by GPs, (ii) checking storage conditions of drugs and initial compilation of the patient’s medication including brown bag review being mostly performed by CPs, and (iii) checking side-effects, non-adherence, and continuous updating of the medication list were carried out jointly. The responses differed most for problems with self-medication and adding and removing over-the-counter medicines from the medication list. In addition, the responses revealed that some MMP tasks were not sufficiently performed by either GPs or CPs. Conclusions Both GPs’ and CPs’ expertise are needed to perform MMP as comprehensively as possible. Future studies should explore how GPs and CPs can complement each other in MMP most efficiently

Changing the perspective on early development of Rett syndrome

We delineated the achievement of early speech-language milestones in 15 young children with Rett syndrome (MECP2 positive) in the first two years of life using retrospective video analysis. By contrast to the commonly accepted concept that these children are normal in the pre-regression period, we found markedly atypical development of speech-language capacities, suggesting a paradigm shift in the pathogenesis of Rett syndrome and a possible approach to its early detection

Developmental delay in Rett syndrome: data from the natural history study

Background: Early development appears normal in Rett syndrome (OMIM #312750) and may be more apparent than real. A major purpose of the Rett Syndrome (RTT) Natural History Study (NHS) was to examine achievement of developmental skills or abilities in classic and atypical RTT and assess phenotype-genotype relations in classic RTT. Methods: Developmental skills in four realms, gross and fine motor, and receptive and expressive communication from initial enrollment and longitudinal assessments for up to 7 years, were assessed from 542 females meeting criteria for classic RTT and 96 females with atypical RTT divided into two groups: 50 with better and 46 with poorer functional scores. Data were analyzed for age at acquisition and loss of developmental features and for phenotype-genotype effects. Acquired, lost, and retained skills were compared between classic RTT and atypical RTT with better or poorer functional scores using Fisher's Exact test. To examine if the mean total score from the Motor Behavioral Assessment during follow-up differed for acquiring a skill, we used a generalized estimating equation assuming compound symmetry correlation structure within a subject. A general linear model was used to examine whether the mean age of acquisition or loss of a developmental skill differed by mutation type. P values <0.05 were considered significant and were two-sided without adjustment for multiple testing. Statistical analyses utilized SAS 9.3 (SAS Institute, Cary, NC, USA). Results: Early developmental skills or abilities were often acquired albeit later than normal. More complex motor and communication acquisitions were delayed or absent. Clinical severity was less in those achieving the respective skill. Individuals with R133C, R294X, and R306C point mutations and 3′ truncations tended to have better developmental outcomes. Conclusions: Early developmental skills were acquired by many, but clear differences from normal emerged, particularly in skills expected after age 6 months. When comparing clinical severity, greater acquisition of specific skills was associated with specific mutations, confirming the impression that these mutations confer milder developmental abnormalities. These data may serve for planning and interpretation of early intervention studies in RTT. Trial registration This NHS study, clinicaltrials.gov (NCT00296764), represents the largest group of RTT participants assessed repeatedly by direct examination