Research in the genetics of neurodevelopmental disorders such as autism suggests that several hundred genes are likely risk factors for these disorders. This heterogeneity presents a challenge and an ...opportunity at the same time. Although the exact identity of many of the genes remains to be discovered, genes identified to date encode proteins that play roles in certain conserved pathways: protein synthesis, transcriptional and epigenetic regulation, and synaptic signaling. The next generation of research in neurodevelopmental disorders must address the neural circuitry underlying the behavioral symptoms and comorbidities, the cell types playing critical roles in these circuits, and common intercellular signaling pathways that link diverse genes. Results from clinical trials have been mixed so far. Only when we can leverage the heterogeneity of neurodevelopmental disorders into precision medicine will the mechanism-based therapeutics for these disorders start to unlock success.
DC microgrids often present a hierarchical control architecture, requiring integration of communication layers. This leads to the possibility of malicious attackers disrupting the overall system. ...Motivated by this application, in this article, we present a distributed monitoring scheme to provide attack-detection capabilities for linear large-scale systems. The proposed architecture relies on a Luenberger observer together with a bank of unknown-input observers at each subsystem, providing attack detection capabilities. We describe the architecture and analyze conditions under which attacks are guaranteed to be detected, and, conversely, when they are stealthy . Our analysis shows that some classes of attacks cannot be detected using either module independently; rather, by exploiting both modules simultaneously, we are able to improve the detection properties of the diagnostic tool as a whole. Theoretical results are backed up by simulations, where our method is applied to a realistic model of a low-voltage DC microgrid under attack.
Predicting missing historical or forecasting streamflows for future periods is a challenging task. This paper presents open-source data-driven machine learning models for streamflow prediction. The ...Random Forests algorithm is employed and the results are compared with other machine learning algorithms. The developed models are applied to the Kızılırmak River, Turkey. First model is built with streamflow of a single station (SS), and the second model is built with streamflows of multiple stations (MS). The SS model uses input parameters derived from one streamflow station. The MS model uses streamflow observations of nearby stations. Both models are tested to estimate missing historical and predict future streamflows. Model prediction performances are measured by root mean squared error (RMSE), Nash-Sutcliffe efficiency (NSE), coefficient of determination (R
), and percent bias (PBIAS). The SS model has an RMSE of 8.54, NSE and R
of 0.98, and PBIAS of 0.7% for the historical period. The MS model has an RMSE of 17.65, NSE of 0.91, R
of 0.93, and PBIAS of -13.64% for the future period. The SS model is useful to estimate missing historical streamflows, while the MS model provides better predictions for future periods, with its ability to better catch flow trends.
Abnormal mTOR Activation in Autism Winden, Kellen D; Ebrahimi-Fakhari, Darius; Sahin, Mustafa
Annual review of neuroscience,
07/2018, Letnik:
41, Številka:
1
Journal Article
Recenzirano
The mechanistic target of rapamycin (mTOR) is an important signaling hub that integrates environmental information regarding energy availability and stimulates anabolic molecular processes and cell ...growth. Abnormalities in this pathway have been identified in several syndromes in which autism spectrum disorder (ASD) is highly prevalent. Several studies have investigated mTOR signaling in developmental and neuronal processes that, when dysregulated, could contribute to the development of ASD. Although many potential mechanisms still remain to be fully understood, these associations are of great interest because of the clinical availability of mTOR inhibitors. Clinical trials evaluating the efficacy of mTOR inhibitors to improve neurodevelopmental outcomes have been initiated.
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems due to an inactivating variant in either
TSC1
or
TSC2
, resulting in the hyperactivation of the ...mechanistic target of rapamycin (mTOR) pathway. Dysregulated mTOR signaling results in increased cell growth and proliferation. Clinically, TSC patients exhibit great phenotypic variability, but the neurologic and neuropsychiatric manifestations of the disease have the greatest morbidity and mortality. TSC-associated epilepsy occurs in nearly all patients and is often difficult to treat because it is refractory to multiple antiseizure medications. The advent of mTOR inhibitors offers great promise in the treatment of TSC-associated epilepsy and other neurodevelopmental manifestations of the disease; however, the optimal timing of therapeutic intervention is not yet fully understood.
Background
The purpose of this study was to determine intern physicians’ attitudes and beliefs toward obesity and individuals with obesity and the frequency at which they encounter discriminatory ...language in their work environments.
Methods
This cross-sectional study was performed with intern physicians at the Ondokuz Mayıs University Medical Faculty in Samsun, Türkiye. A questionnaire was employed for data collection (Appendix). Two hundred eighteen (82.2%) interns took part in the study. The questionnaire consisted of 53 questions in five sections, and included the attitudes toward obese persons (ATOP) and beliefs about obese persons (BAOP) scales.
Results
The interns most frequently cited genetic factors (98.1%) and endocrine disorder-metabolic disorders (98.1%) as non-behavioral causes of obesity, and overeating (96.2%) and physical immobility (96.2%) as behavioral causes. Lifestyle changes and exercise were most frequently recommended for treatment. The interns’ attitudes toward individuals with obesity were very slightly negative, but close to neutral. Analysis showed that 46.8% of the interns reported hearing members of academic staff, intern physicians, or health workers make negative or derogatory comments or jokes about obese patients during their education, while 22.0% reported witnessing an obese patient being subjected to discriminatory treatment in the hospital environment.
Conclusion
Medical faculties must develop curricula aimed at comprehensively addressing obesity-related bias. Such a curriculum should allow students to reflect on their biases, be aimed at reducing the effect of those biases on patient communication, and involve strategies directed toward eliminating those effects from physicians’ treatment decisions.
Graphical Abstract
The purpose of the study was to evaluate the relationship between school burnout, sense of school belonging, and academic achievement in medical students. This cross-sectional study was performed ...with students at the Ondokuz Mayıs University Medical Faculty (Samsun, Turkey) between 1 and 31 May 2019. Six hundred one (71.0%) first, second, and third-year students were included in the study. A questionnaire was employed as the data collection method. The questionnaire consisted of two parts. The first part consisted of questions investigating sociodemographic information produced by the authors by scanning the literature. The second part consisted of the School Burnout Inventory and the Psychological Sense of School Membership Scale. The relationship between the sense of school belonging, school burnout, and academic achievement was evaluated using structural equation modeling. The structural equation modeling analysis determined that school burnout played a mediating role in the relationship between the sense of school belonging and academic achievement in preclinical medical students. As the sense of belonging to the school increases in preclinical medical students, academic achievement increases. School burnout in preclinical medical students increases as a sense of school belonging decreases. Academic achievement among preclinical medical students decreases as school burnout levels increase. Increasing the sense of school belonging can be effective in preventing school burnout and increasing academic achievement.
In this work, we present a novel consensus-based secondary control scheme for current sharing and voltage balancing in dc microgrids (DCmGs), composed of distributed generation units (DGUs), dynamic ...RLC lines, and nonlinear ZIE (constant impedance, constant current, and exponential) loads. Situated atop a primary voltage control layer, our secondary controllers have a distributed structure and utilize information exchanged over a communication network to compute necessary control actions. Besides showing that the desired objectives are always attained in steady state, we deduce sufficient conditions for the existence and uniqueness of an equilibrium point for constant power loads-<inline-formula> <tex-math notation="LaTeX">E </tex-math></inline-formula> loads with zero exponent. Our control design hinges only on the local parameters of the generation units, facilitating plug-and-play operations. We provide a voltage stability analysis and illustrate the performance and robustness of our designs via simulations. All results hold for arbitrary, albeit connected, mG and communication network topologies.
Although there is increasing recognition of the role of somatic mutations in genetic disorders, the prevalence of somatic mutations in neurodevelopmental disease and the optimal techniques to detect ...somatic mosaicism have not been systematically evaluated.
Using a customized panel of known and candidate genes associated with brain malformations, we applied targeted high-coverage sequencing (depth, ≥200×) to leukocyte-derived DNA samples from 158 persons with brain malformations, including the double-cortex syndrome (subcortical band heterotopia, 30 persons), polymicrogyria with megalencephaly (20), periventricular nodular heterotopia (61), and pachygyria (47). We validated candidate mutations with the use of Sanger sequencing and, for variants present at unequal read depths, subcloning followed by colony sequencing.
Validated, causal mutations were found in 27 persons (17%; range, 10 to 30% for each phenotype). Mutations were somatic in 8 of the 27 (30%), predominantly in persons with the double-cortex syndrome (in whom we found mutations in DCX and LIS1), persons with periventricular nodular heterotopia (FLNA), and persons with pachygyria (TUBB2B). Of the somatic mutations we detected, 5 (63%) were undetectable with the use of traditional Sanger sequencing but were validated through subcloning and subsequent sequencing of the subcloned DNA. We found potentially causal mutations in the candidate genes DYNC1H1, KIF5C, and other kinesin genes in persons with pachygyria.
Targeted sequencing was found to be useful for detecting somatic mutations in patients with brain malformations. High-coverage sequencing panels provide an important complement to whole-exome and whole-genome sequencing in the evaluation of somatic mutations in neuropsychiatric disease. (Funded by the National Institute of Neurological Disorders and Stroke and others.).
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by epilepsy, intellectual disability, and benign tumors of the brain, heart, skin, and kidney. Animal models have ...contributed to our understanding of normal and abnormal human brain development, but the construction of models that accurately recapitulate a human pathology remains challenging. Recent advances in stem cell biology with the derivation of human-induced pluripotent stem cells (hiPSCs) from somatic cells from patients have opened new avenues to the study of TSC. This approach combined with gene-editing tools such as CRISPR/Cas9 offers the advantage of preserving patient-specific genetic background and the ability to generate isogenic controls by correcting a specific mutation. The patient cell line and the isogenic control can be differentiated into the cell type of interest to model various aspects of TSC. In this review, we discuss the remarkable capacity of these cells to be used as a model for TSC in two- and three-dimensional cultures, the potential variability in iPSC models, and highlight differences between findings reported to date.
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