Macleoddesai9035

Nucleoporins (NUPs) are an essential component of the nuclear-pore complex, which regulates nucleocytoplasmic transport of macromolecules. Pathogenic variants in NUP genes have been linked to several inherited human diseases, including a number with progressive neurological degeneration. We present six affected individuals with bi-allelic truncating variants in NUP188 and strikingly similar phenotypes and clinical courses, representing a recognizable genetic syndrome; the individuals are from four unrelated families. Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation. this website Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies. All affected individuals died as a result of respiratory failure, and five of them died within the first year of life. Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism. CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals. Removal of NUP188 also resulted in aberrant dendrite tiling, suggesting a potential role of NUP188 in dendritic development. Two of the NUP188 pathogenic variants are enriched in the Ashkenazi Jewish population in gnomAD, a finding we confirmed with a separate targeted population screen of an international sampling of 3,225 healthy Ashkenazi Jewish individuals. Taken together, our results implicate bi-allelic loss-of-function NUP188 variants in a recessive syndrome characterized by a distinct neurologic, ophthalmologic, and facial phenotype. Population-scale biobanks that combine genetic data and high-dimensional phenotyping for a large number of participants provide an exciting opportunity to perform genome-wide association studies (GWAS) to identify genetic variants associated with diverse quantitative traits and diseases. A major challenge for GWAS in population biobanks is ascertaining disease cases from heterogeneous data sources such as hospital records, digital questionnaire responses, or interviews. In this study, we use genetic parameters, including genetic correlation, to evaluate whether GWAS performed using cases in the UK Biobank ascertained from hospital records, questionnaire responses, and family history of disease implicate similar disease genetics across a range of effect sizes. We find that hospital record and questionnaire GWAS largely identify similar genetic effects for many complex phenotypes and that combining together both phenotyping methods improves power to detect genetic associations. We also show that family history GWAS using cases ascertained on family history of disease agrees with combined hospital record and questionnaire GWAS and that family history GWAS has better power to detect genetic associations for some phenotypes. Overall, this work demonstrates that digital phenotyping and unstructured phenotype data can be combined with structured data such as hospital records to identify cases for GWAS in biobanks and improve the ability of such studies to identify genetic associations. Learning a new motor task modifies feedforward (i.e., voluntary) motor commands and such learning also changes the sensitivity of feedback responses (i.e., reflexes) to mechanical perturbations [1-9]. For example, after people learn to generate straight reaching movements in the presence of an external force field or learn to reduce shoulder muscle activity when generating pure elbow movements with shoulder fixation, evoked stretch reflex responses to mechanical perturbations reflect the learning expressed during self-initiated reaching. Such a transfer from feedforward motor commands to feedback responses is thought to take place because of shared neural circuits at the level of the spinal cord, brainstem, and cerebral cortex [10-13]. The presence of shared neural resources also predicts the transfer from feedback responses to feedforward motor commands. Little is known about such a transfer presumably because it is relatively hard to elicit learning in reflexes without engaging associated voluntary responses following mechanical perturbations. Here, we demonstrate such transfer by leveraging two approaches to elicit stretch reflexes while minimizing engagement of voluntary motor responses in the learning process applying very short mechanical perturbations [14-19] and instructing participants to not respond to them [20-26]. Taken together, our work shows that transfer between feedforward and feedback control is bidirectional, furthering the notion that these processes share common neural circuits that underlie motor learning and transfer. Working memory (WM) relies on the prioritization of relevant information and suppression of irrelevant information [1, 2]. Prioritizing relevant information has been linked to theta frequency neural oscillations in lateral prefrontal cortex and suppressing irrelevant information has been linked to alpha oscillations in occipito-parietal cortex [3,11]. Here, we used a retrospective-cue WM paradigm to manipulate prioritization and suppression task demands designed to drive theta oscillations in prefrontal cortex and alpha oscillations in parietal cortex, respectively. To causally test the role of these neural oscillations, we applied rhythmic transcranial magnetic stimulation (TMS) in either theta or alpha frequency to prefrontal and parietal regions identified using functional MRI. The effect of rhythmic TMS on WM performance was dependent on whether the TMS frequency matched or mismatched the expected underlying task-driven oscillations of the targeted region. Functional MRI in the targeted regions predicted subsequent TMS effects across subjects supporting a model by which theta oscillations are excitatory to neural activity, and alpha oscillations are inhibitory. Together, these results causally establish dissociable roles for prefrontal theta oscillations and parietal alpha oscillations in the control of internally maintained WM representations. Published by Elsevier Inc.