Schizophrenia (SZ) is a heterogeneous and debilitating psychiatric disorder with a strong genetic component. To elucidate functional networks perturbed in schizophrenia, we analysed a large dataset ...of whole-genome studies that identified SNVs, CNVs, and a multi-stage schizophrenia genome-wide association study. Our analysis identified three subclusters that are interrelated and with small overlaps: GO:0007017~Microtubule-Based Process, GO:00015629~Actin Cytoskeleton, and GO:0007268~SynapticTransmission. We next analysed three distinct trio cohorts of 75 SZ Algerian, 45 SZ French, and 61 SZ Japanese patients. We performed Illumina HiSeq whole-exome sequencing and identified de novo mutations using a Bayesian approach. We validated 88 de novo mutations by Sanger sequencing: 35 in French, 21 in Algerian, and 32 in Japanese SZ patients. These 88 de novo mutations exhibited an enrichment in genes encoding proteins related to GO:0051015~actin filament binding (
= 0.0011) using David, and enrichments in GO: 0003774~transport (
= 0.019) and GO:0003729~mRNA binding (
= 0.010) using Amigo. One of these de novo variant was found in
coding sequence. We studied Coro1c haploinsufficiency in a
mouse and found defects in the corpus callosum. These results could motivate future studies of the mechanisms surrounding genes encoding proteins involved in transport and the cytoskeleton, with the goal of developing therapeutic intervention strategies for a subset of SZ cases.
Autism is a neurodevelopmental disorder with a strong genetic component, probably involving several genes. Genome screens have provided evidence of linkage to chromosome 2q31-q33, which includes the ...SLC25A12 gene. Association between autism and single-nucleotide polymorphisms in SLC25A12 has been reported in various studies. SLC25A12 encodes the mitochondrial aspartate/glutamate carrier functionally important in neurons with high-metabolic activity. Neuropathological findings and functional abnormalities in autism have been reported for Brodmann's area (BA) 46 and the cerebellum. We found that SLC25A12 was expressed more strongly in the post-mortem brain tissues of autistic subjects than in those of controls, in the BA46 prefrontal cortex but not in cerebellar granule cells. SLC25A12 expression was not modified in brain subregions of bipolar and schizophrenic patients. SLC25A12 was expressed in developing human neuronal tissues, including neocortical regions containing excitatory neurons and neocortical progenitors and the ganglionic eminences that generate neocortical inhibitory interneurons. At mid-gestation, when gyri and sulci start to develop, SLC25A12 molecular gradients were identified in the lateral prefrontal and ventral temporal cortex. These fetal structures generate regions with abnormal activity in autism, including the dorsolateral prefrontal cortex (BA46), the pars opercularis of the inferior frontal cortex and the fusiform gyrus. SLC25A12 overexpression or silencing in mouse embryonic cortical neurons also modified dendrite length and the mobility of dendritic mitochondria. Our findings suggest that SLC25A12 overexpression may be involved in the pathophysiology of autism, modifying neuronal networks in specific subregions, such as the dorsolateral prefrontal cortex and fusiform gyrus, at both pre- and postnatal stages.
The molecular mechanisms that lead to the cognitive defects characteristic of Down syndrome (DS), the most frequent cause of mental retardation, have remained elusive. Here we use a transgenic DS ...mouse model (152F7 line) to show that DYRK1A gene dosage imbalance deregulates chromosomal clusters of genes located near neuron-restrictive silencer factor (REST/NRSF) binding sites. We found that Dyrk1a binds the SWI/SNF complex known to interact with REST/NRSF. The mutation of a REST/NRSF binding site in the promoter of the REST/NRSF target gene L1cam modifies the transcriptional effect of Dyrk1a-dosage imbalance on L1cam. Dyrk1a dosage imbalance perturbs Rest/Nrsf levels with decreased Rest/Nrsf expression in embryonic neurons and increased expression in adult neurons. Using transcriptome analysis of embryonic brain subregions of transgenic 152F7 mouse line, we identified a coordinated deregulation of multiple genes that are responsible for dendritic growth impairment present in DS. Similarly, Dyrk1a overexpression in primary mouse cortical neurons induced severe reduction of the dendritic growth and dendritic complexity. We propose that DYRK1A overexpression-related neuronal gene deregulation via disturbance of REST/NRSF levels, and the REST/NRSF–SWI/SNF chromatin remodelling complex, significantly contributes to the neural phenotypic changes that characterize DS.
To study the effect of a new investigational oral gonadotropin-releasing hormone antagonist, linzagolix, on endometriosis-associated pain (EAP).
A multinational, parallel group, randomized, ...placebo-controlled, double-blind, dose-ranging trial.
Clinical centers.
Women aged 18–45 years with surgically confirmed endometriosis and moderate-to-severe EAP.
The interventions were 50, 75, 100, or 200 mg linzagolix (or matching placebo) administered once daily for 24 weeks.
The primary endpoint was the number of responders (≥30% reduction in overall pelvic pain) after 12 weeks. Other endpoints included dysmenorrhea, non-menstrual pelvic pain, serum estradiol, amenorrhea, quality of life (QoL) measures, and bone mineral density (BMD).
Compared with placebo, doses ≥ 75 mg resulted in a significantly greater proportion of responders for overall pelvic pain at 12 weeks (34.5%, 61.5%, 56.4%, and 56.3% for placebo, 75, 100, and 200 mg, respectively). A similar pattern was seen for dysmenorrhea and non-menstrual pelvic pain. The effects were maintained or increased at 24 weeks. Serum estradiol was suppressed, QoL improved, and the rate of amenorrhea increased in a dose-dependent fashion. Mean BMD loss (spine) at 24 weeks was <1% at doses of 50 and 75 mg and increased in a dose-dependent fashion up to 2.6% for 200 mg. BMD of femoral neck and total hip showed a similar pattern.
Linzagolix significantly reduced EAP and improved QoL at doses of 75–200 mg and decreased BMD dose-dependently.
NCT02778399
Tratamiento del dolor asociado a la endometriosis con linzagolix, un antagonista de la hormona liberadora de gonadotropina (GnRH) oral: un ensayo clínico aleatorizado
estudiar el efecto de un nuevo antagonista oral de la hormona liberadora de gonadotropina en investigación, linzagolix, en el dolor asociado a la endometriosis (EAP).
un ensayo multinacional, de grupos paralelos, aleatorizado, controlado con placebo, doble ciego y de rango de dosis.
centros clínicos.
Mujeres de 18 a 45 años con endometriosis confirmada quirúrgicamente y EAP moderado a severa.
las intervenciones fueron 50, 75, 100 o 200 mg de linzagolix (o placebo equivalente) administrado una vez al día durante 24 semanas.
El objetivo primario final fue el número de respondedores (reducción de >30% en el dolor pélvico general) después de 12 semanas. Otros objetivos incluyeron dismenorrea, dolor pélvico no menstrual, estradiol sérico, amenorrea, calidad de vida (QoL) medidas y densidad mineral ósea (DMO).
en comparación con placebo, las dosis de ≥75 mg dieron como resultado una proporción significativamente mayor de respondedores para el dolor pélvico general en 12 semanas (34.5%, 61.5%, 56.4% y 56.3% para placebo, 75, 100 y 200 mg, respectivamente). Se observó un patrón similar para la dismenorrea y el dolor pélvico no menstrual. Los efectos se mantuvieron o aumentaron a las 24 semanas. El estradiol sérico se suprimió, la calidad de vida mejoró, y la tasa de amenorrea aumentó de forma dependiente de la dosis. La pérdida media de DMO (columna vertebral) a las 24 semanas fue <1% a dosis de 50 y 75 mg y aumentó de forma dependiente de la dosis hasta 2.6% por 200 mg. La DMO del cuello femoral y la cadera total mostró un patrón similar.
Linzagolix redujo significativamente la EAP y mejoró la calidad de vida a dosis de 75–200 mg y disminuyó la DMO de forma dosis-dependiente.
In this study, our aim was to evaluate the subsequent fertility status of women treated with different methods for ectopic pregnancy. Patients diagnosed with ectopic pregnancy between January 2012 ...and July 2020 were included in the study. FertiUty outcomes of the patients treated with medical or surgical options were questioned. In the study, 659 patients who met the eUgibility criteria were included. A single dose of MTX was administered in 37 patients (32.2%) and two doses of MTX were appUed in 14 patients (12.2%) and surgery was preferred in 64 patients (55.7%) in the infertile group. In 213 patients (39.2%) in the fertile group, MTX was administered as a single dose while two doses of MTX and surgery was preferred in 49 patients (9.0%) and 282 patients (51.8%), respectively. No statistically significant difference was detected between the groups according to treatment approaches. There was no significant difference regarding fertiUty outcomes following different types of treatments for ectopic pregnancy. For this reason, the methods to be chosen for the treatment of ectopic pregnancy should be evaluated according to the individual factors of the patient.
•Performed systematic spray submodels evaluation to achieve accurate simulation of liquid spray behavior in DISI engines.•The analysis focused on injected parcel distribution, droplet collision, ...spray breakup, and evaporation models.•Coupling uniform distribution for parcel initialization with proper collision model leads to improved spray morphology.•Highlighted importance of KH-RT breakup and droplet heat transfer models to match measured spray penetration and widths.
Gasoline direct-injection spark-ignition (DISI) engines generate a large portion of their unburned hydrocarbon (UHC) and soot emissions during the cold-start phase. A predictive computational fluid dynamics (CFD) modeling framework can be used to understand the physical processes that characterize fuel spray evolution and fuel-film formation at cold start conditions, which can help to reduce engine-out particulate emissions. This study systematically evaluated spray submodels and developed a set of simulation best practices for physical-numerical submodels with the goal of enabling accurate simulations of liquid spray behavior in a DISI engine. Three comprehensive experimental datasets containing free-spray projected liquid volume (PLV), liquid volume fraction (LVF), and near-field X-ray radiography data were used to validate the simulation results and evaluate the spray submodels. Systematic analysis delved into injected parcel distribution, droplet collision, spray breakup, and evaporation via a detailed assessment of the relevant spray submodels. Moreover, the effects of turbulence models and the initial turbulent flow properties on the liquid spray evolution were examined. Based on extensive calibration efforts, a set of simulation best practices for the free spray was developed and validated against the PLV/LVF data. Simulation results indicated that the uniform distribution for parcel initialization, coupled with appropriate droplet collision submodels, provides an improved spray morphology compared to the cluster distribution. The findings also underscored the importance of calibrating the Kelvin-Helmholtz Rayleigh-Taylor (KH-RT) breakup model constants and droplet heat transfer coefficient scaling factor to achieve favorable agreement regarding measured liquid penetration and spray widths. This study marks a substantial stride towards accurately predicting fuel film evolution and soot formation within DISI engine performance.
Autism spectrum disorders (ASDs) are common, heritable, but genetically heterogeneous neurodevelopmental conditions. We recently defined a susceptibility locus for ASDs on chromosome 1q41–q42. ...High-resolution single-nucleotide polymorphisms (126 SNPs) genotyping across the chromosome 1q41–q42 region, followed by a MARK1 (microtubule affinity-regulating kinase 1)-tagged-SNP association study in 276 families with autism from the Autism Genetic Research Exchange, showed that several SNPs within the MARK1 gene were significantly associated with ASDs by transmission disequilibrium tests. Haplotype rs12740310*C-rs3737296*G-rs12410279*A was overtransmitted (Pcorrected= 0.0016), with a relative risk for autism of 1.8 in homozygous carriers. Furthermore, ASD-associated SNP rs12410279 modulates the level of transcription of MARK1. We found that MARK1 was overexpressed in the prefrontal cortex (BA46) but not in cerebellar granule cells, on postmortem brain tissues from patients. MARK1 displayed an accelerated evolution along the lineage leading to humans, suggesting possible involvement of this gene in cognition. MARK1 encodes a kinase-regulating microtubule-dependent transport in axons and dendrites. Both overexpression and silencing of MARK1 resulted in significantly shorter dendrite length in mouse neocortical neurons and modified dendritic transport speed. As expected for a gene encoding a key polarity determinant Par-1 protein kinase, MARK1 is involved in axon–dendrite specification. Thus, MARK1 overexpression in humans may be responsible for subtle changes in dendritic functioning.
Engineering industrial microorganisms for ambitious applications, for example, the production of second-generation biofuels such as butanol, is impeded by a lack of knowledge of primary metabolism ...and its regulation. A quantitative system-scale analysis was applied to the biofuel-producing bacterium Clostridium acetobutylicum, a microorganism used for the industrial production of solvent. An improved genome-scale model, iCac967, was first developed based on thorough biochemical characterizations of 15 key metabolic enzymes and on extensive literature analysis to acquire accurate fluxomic data. In parallel, quantitative transcriptomic and proteomic analyses were performed to assess the number of mRNA molecules per cell for all genes under acidogenic, solventogenic, and alcohologenic steady-state conditions as well as the number of cytosolic protein molecules per cell for approximately 700 genes under at least one of the three steady-state conditions. A complete fluxomic, transcriptomic, and proteomic analysis applied to different metabolic states allowed us to better understand the regulation of primary metabolism. Moreover, this analysis enabled the functional characterization of numerous enzymes involved in primary metabolism, including (i) the enzymes involved in the two different butanol pathways and their cofactor specificities, (ii) the primary hydrogenase and its redox partner, (iii) the major butyryl coenzyme A (butyryl-CoA) dehydrogenase, and (iv) the major glyceraldehyde-3-phosphate dehydrogenase. This study provides important information for further metabolic engineering of C. acetobutylicum to develop a commercial process for the production of n-butanol.
Currently, there is a resurgence of interest in Clostridium acetobutylicum, the biocatalyst of the historical Weizmann process, to produce n-butanol for use both as a bulk chemical and as a renewable alternative transportation fuel. To develop a commercial process for the production of n-butanol via a metabolic engineering approach, it is necessary to better characterize both the primary metabolism of C. acetobutylicum and its regulation. Here, we apply a quantitative system-scale analysis to acidogenic, solventogenic, and alcohologenic steady-state C. acetobutylicum cells and report for the first time quantitative transcriptomic, proteomic, and fluxomic data. This approach allows for a better understanding of the regulation of primary metabolism and for the functional characterization of numerous enzymes involved in primary metabolism.
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