Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders

The Rho-guanine nucleotide exchange factor (RhoGEF) TRIO acts as a key regulator of neuronal migration, axonal outgrowth, axon guidance, and synaptogenesis by activating the GTPase RAC1 and modulating actin cytoskeleton remodeling. Pathogenic variants in TRIO are associated with neurodevelopmental diseases, including intellectual disability (ID) and autism spectrum disorders (ASD). Here, we report the largest international cohort of 24 individuals with confirmed pathogenic missense or nonsense variants in TRIO. The nonsense mutations are spread along the TRIO sequence, and affected individuals show variable neurodevelopmental phenotypes. In contrast, missense variants cluster into two mutational hotspots in the TRIO sequence, one in the seventh spectrin repeat and one in the RAC1-activating GEFD1. Although all individuals in this cohort present with developmental delay and a neuro-behavioral phenotype, individuals with a pathogenic variant in the seventh spectrin repeat have a more severe ID associated with macrocephaly than do most individuals with GEFD1 variants, who display milder ID and microcephaly. Functional studies show that the spectrin and GEFD1 variants cause a TRIO-mediated hyper- or hypo-activation of RAC1, respectively, and we observe a striking correlation between RAC1 activation levels and the head size of the affected individuals. In addition, truncations in TRIO GEFD1 in the vertebrate model X. tropicalis induce defects that are concordant with the human phenotype. This work demonstrates distinct clinical and molecular disorders clustering in the GEFD1 and seventh spectrin repeat domains and highlights the importance of tight control of TRIO-RAC1 signaling in neuronal development.<br/

Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders

The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins, and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Utilizing exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with YnMyr chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), with ages ranging from 1 to 50 years old, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%), and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%), and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%), and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each), as well as hypertrophy of the clava (24%) were common neuroimaging findings. acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism, and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localisation and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-Myristoylation was similarly affected in acbd6-deficient zebrafish and Xenopus tropicalis models, including Fus, Marcks, and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders

Measuring the health-related Sustainable Development Goals in 188 countries : a baseline analysis from the Global Burden of Disease Study 2015

Background In September, 2015, the UN General Assembly established the Sustainable Development Goals (SDGs). The SDGs specify 17 universal goals, 169 targets, and 230 indicators leading up to 2030. We provide an analysis of 33 health-related SDG indicators based on the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015). Methods We applied statistical methods to systematically compiled data to estimate the performance of 33 health-related SDG indicators for 188 countries from 1990 to 2015. We rescaled each indicator on a scale from 0 (worst observed value between 1990 and 2015) to 100 (best observed). Indices representing all 33 health-related SDG indicators (health-related SDG index), health-related SDG indicators included in the Millennium Development Goals (MDG index), and health-related indicators not included in the MDGs (non-MDG index) were computed as the geometric mean of the rescaled indicators by SDG target. We used spline regressions to examine the relations between the Socio-demographic Index (SDI, a summary measure based on average income per person, educational attainment, and total fertility rate) and each of the health-related SDG indicators and indices. Findings In 2015, the median health-related SDG index was 59.3 (95% uncertainty interval 56.8-61.8) and varied widely by country, ranging from 85.5 (84.2-86.5) in Iceland to 20.4 (15.4-24.9) in Central African Republic. SDI was a good predictor of the health-related SDG index (r(2) = 0.88) and the MDG index (r(2) = 0.2), whereas the non-MDG index had a weaker relation with SDI (r(2) = 0.79). Between 2000 and 2015, the health-related SDG index improved by a median of 7.9 (IQR 5.0-10.4), and gains on the MDG index (a median change of 10.0 [6.7-13.1]) exceeded that of the non-MDG index (a median change of 5.5 [2.1-8.9]). Since 2000, pronounced progress occurred for indicators such as met need with modern contraception, under-5 mortality, and neonatal mortality, as well as the indicator for universal health coverage tracer interventions. Moderate improvements were found for indicators such as HIV and tuberculosis incidence, minimal changes for hepatitis B incidence took place, and childhood overweight considerably worsened. Interpretation GBD provides an independent, comparable avenue for monitoring progress towards the health-related SDGs. Our analysis not only highlights the importance of income, education, and fertility as drivers of health improvement but also emphasises that investments in these areas alone will not be sufficient. Although considerable progress on the health-related MDG indicators has been made, these gains will need to be sustained and, in many cases, accelerated to achieve the ambitious SDG targets. The minimal improvement in or worsening of health-related indicators beyond the MDGs highlight the need for additional resources to effectively address the expanded scope of the health-related SDGs.Peer reviewe

Calcaneal ultrasound analysis of Nigerian adults with type 2 diabetes

Objective: Type 2 diabetes is a major chronic disease in northern Nigeria. Although type 2diabetes is usually associated with increased bone mineral density, we were interested in estimating the bone mineral density of patients with type 2 diabetes in a region of the world where the usual calcium intake is well below the recommended dietary recommendations. Research Design and Methods: A total of 50 patients (25M/25F) with type 2 diabetes and 50 healthy controls (20M/30F) were recruited at the Jos University Teaching hospital in Jos, Nigeria. Information regarding age, weight, height, medication use and duration of disease were obtained. Body composition analysis to determine lean body mass and body fat was performed using bioelectrical impedance analysis. Bone quality was assessed using quantitative ultrasound of the calcaneus. Glucose control was monitored using fasting glucose concentrations. Results: Both male and females subjects with type 2 diabetes had superior ultrasound parameters including broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness index (SI) relative to controls. However, there were no significant differences in these parameters between the subjects with diabetes and the controls. No associations between ultrasound parameters and body mass index or body composition were found for either the diabetic subjects or controls. A non-significant trend was observed between glucose control and SI for the female diabetic subjects. A statistically 2 significant correlation was obtained between SI and duration of disease but only for the female diabetic subjects. Conclusions: Calcaneal ultrasound is a relatively inexpensive means for monitoring bone quality in patients with type 2 diabetes. The more favorable bone ultrasound parameters observed for patients with type 2 diabetes may be the result of the bonepromoting effects of hyperinsulinemia. Keywords: type 2 diabetes, bone density, calcaneal ultrasound, stiffness index, hyperglycemia, Nigeria Highland Medical Research Journal Vol. 3(2) 2005: 1-1

Machine learning of large‐scale spatial distributions of wild turkeys with high‐dimensional environmental data

Abstract Species distribution modeling often involves high‐dimensional environmental data. Large amounts of data and multicollinearity among covariates impose challenges to statistical models in variable selection for reliable inferences of the effects of environmental factors on the spatial distribution of species. Few studies have evaluated and compared the performance of multiple machine learning (ML) models in handling multicollinearity. Here, we assessed the effectiveness of removal of correlated covariates and regularization to cope with multicollinearity in ML models for habitat suitability. Three machine learning algorithms maximum entropy (MaxEnt), random forests (RFs), and support vector machines (SVMs) were applied to the original data (OD) of 27 landscape variables, reduced data (RD) with 14 highly correlated covariates being removed, and 15 principal components (PC) of the OD accounting for 90% of the original variability. The performance of the three ML models was measured with the area under the curve and continuous Boyce index. We collected 663 nonduplicated presence locations of Eastern wild turkeys (Meleagris gallopavo silvestris) across the state of Mississippi, United States. Of the total locations, 453 locations separated by a distance of ≥2 km were used to train the three ML algorithms on the OD, RD, and PC data, respectively. The remaining 210 locations were used to validate the trained ML models to measure ML performance. Three ML models had excellent performance on the RD and PC data. MaxEnt and SVMs had good performance on the OD data, indicating the adequacy of regularization of the default setting for multicollinearity. Weak learning of RFs through bagging appeared to alleviate multicollinearity and resulted in excellent performance on the OD data. Regularization of ML algorithms may help exploratory studies of the effects of environmental factors on the spatial distribution and habitat suitability of wildlife

Using Family and Ecological Systems Approaches to Conceptualize Family- and Community-Based Experiences of Transgender and/or Nonbinary Youth From the Trans Teen and Family Narratives Project

The current study used family and ecological systems approaches to understand transgender and/or nonbinary (TNB) youths\u27 experiences of their gender identity within family and community contexts. A sample of 33 TNB youth, ages 13-17 years (M = 15.18, SD = 1.24), were recruited from community-based venues in the New England region of the United States to participate in the Trans Teen and Family Narratives Project, a longitudinal community-based mixed methods study. TNB youth in the sample identified as trans girls (n = 12), trans boys (n = 17), and nonbinary (n = 3 assigned female at birth; n = 1 assigned male at birth). Race/ethnicity of the sample was 73% White and 15% mixed race/ethnicity. All participants completed a one-time, in-person semi-structured qualitative interview at baseline about their family and community-based experiences related to their TNB identity. Interviews were audio-recorded and professionally transcribed. Interview transcripts were coded and analyzed using immersion/crystallization and thematic analysis approaches. Eight themes were developed, which correspond to different levels of the ecological systems model: individual-level (identity processes, emotions/coping), family-level (general family experiences, family support), community-level (general community experiences; community support; lesbian, gay, bisexual, transgender, queer (LGBTQ) community), and societal/institutional-level (external forces). Findings emphasize the importance of using family and ecological systems approaches to understanding the family- and community-based experiences of TNB youth and have implications for improving clinical practice with TNB youth and families

Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly.

BACKGROUND: Coat protein complex 1 (COPI) is integral in the sorting and retrograde trafficking of proteins and lipids from the Golgi apparatus to the endoplasmic reticulum (ER). In recent years, coat proteins have been implicated in human diseases known collectively as "coatopathies". METHODS: Whole exome or genome sequencing of two families with a neuro-developmental syndrome, variable microcephaly and cataracts revealed biallelic variants in COPB1, which encodes the beta-subunit of COPI (?-COP). To investigate Family 1's splice donor site variant, we undertook patient blood RNA studies and CRISPR/Cas9 modelling of this variant in a homologous region of the Xenopus tropicalis genome. To investigate Family 2's missense variant, we studied cellular phenotypes of human retinal epithelium and embryonic kidney cell lines transfected with a COPB1 expression vector into which we had introduced Family 2's mutation. RESULTS: We present a new recessive coatopathy typified by severe developmental delay and cataracts and variable microcephaly. A homozygous splice donor site variant in Family 1 results in two aberrant transcripts, one of which causes skipping of exon 8 in COPB1 pre-mRNA, and a 36 amino acid in-frame deletion, resulting in the loss of a motif at a small interaction interface between ?-COP and ?'-COP. Xenopus tropicalis animals with a homologous mutation, introduced by CRISPR/Cas9 genome editing, recapitulate features of the human syndrome including microcephaly and cataracts. In vitro modelling of the COPB1 c.1651T>G p.Phe551Val variant in Family 2 identifies defective Golgi to ER recycling of this mutant ?-COP, with the mutant protein being retarded in the Golgi. CONCLUSIONS: This adds to the growing body of evidence that COPI subunits are essential in brain development and human health and underlines the utility of exome and genome sequencing coupled with Xenopus tropicalis CRISPR/Cas modelling for the identification and characterisation of novel rare disease genes.The article is available via Open Access. Click on the 'Additional link' above to access the full-text.Published version, accepted versio

Homo narrativus

Quelle définition donner au « topos » ? Au confluent de quelles traditions théoriques et critiques apparaît cette notion ? Quelle peut être sa pertinence comme noyau d'interprétation et de lecture sérielle du roman français, du Moyen-Âge jusqu'à la fin de l'Ancien Régime ? Depuis 1987, la Société d'Analyse de la Topique Romanesque (SATOR) s'efforce de constituer un thésaurus des topoi dans les romans de langue française avant 1800. Dix ans après sa fondation, elle a souhaité dresser un bilan de son activité, prendre la mesure du terrain qu'elle a défriché et de sa contribution à la compréhension des procédés de l'invention romanesque. C'est l'objet de la trentaine de textes réunis dans ce volume par Nathalie Ferrand et Michèle Weil, à la suite du XIe colloque de la SATOR, qui s'est tenu en 1997 à l'Université Paul-Valéry de Montpellier