Reciprocal copy number variations (CNVs) of 16p11.2 are associated with a wide spectrum of neuropsychiatric and neurodevelopmental disorders. Here, we use human induced pluripotent stem cells ...(iPSCs)-derived dopaminergic (DA) neurons carrying CNVs of 16p11.2 duplication (16pdup) and 16p11.2 deletion (16pdel), engineered using CRISPR-Cas9. We show that 16pdel iPSC-derived DA neurons have increased soma size and synaptic marker expression compared to isogenic control lines, while 16pdup iPSC-derived DA neurons show deficits in neuronal differentiation and reduced synaptic marker expression. The 16pdel iPSC-derived DA neurons have impaired neurophysiological properties. The 16pdel iPSC-derived DA neuronal networks are hyperactive and have increased bursting in culture compared to controls. We also show that the expression of RHOA is increased in the 16pdel iPSC-derived DA neurons and that treatment with a specific RHOA-inhibitor, Rhosin, rescues the network activity of the 16pdel iPSC-derived DA neurons. Our data suggest that 16p11.2 deletion-associated iPSC-derived DA neuron hyperactivation can be rescued by RHOA inhibition.
Mutations of the X-linked gene encoding methyl-CpG-binding protein 2 (
) cause classical forms of Rett syndrome (RTT) in girls. A subset of patients who are recognized to have an overlapping ...neurological phenotype with RTT but are lacking a mutation in a gene that causes classical or atypical RTT can be described as having a 'Rett-syndrome-like phenotype (RTT-L). Here, we report eight patients from our cohort diagnosed as having RTT-L who carry mutations in genes unrelated to RTT. We annotated the list of genes associated with RTT-L from our patient cohort, considered them in the light of peer-reviewed articles on the genetics of RTT-L, and constructed an integrated protein-protein interaction network (PPIN) consisting of 2871 interactions connecting 2192 neighboring proteins among RTT- and RTT-L-associated genes. Functional enrichment analysis of RTT and RTT-L genes identified a number of intuitive biological processes. We also identified transcription factors (TFs) whose binding sites are common across the set of RTT and RTT-L genes and appear as important regulatory motifs for them. Investigation of the most significant over-represented pathway analysis suggests that HDAC1 and CHD4 likely play a central role in the interactome between RTT and RTT-L genes.
Perinatal stroke is a cerebrovascular injury that occur in gestation or up until a child’s first month of life. Impacting cognitive, social, and psychological development in children long after the ...stroke, perinatal stroke is yet to be fully understood. While the exact timing of injury can often not be determined, diagnosis relies on recognition of abnormalities in motor and behavioral development in these affected children, in order to be treated. Although there are long term morbidities specific to perinatal stroke, there are also a multitude of other factors that contribute to child development, and have the potential to alter outcome. These factors include family adjustment, family history, family functioning, and family socioeconomic status, among others. As is relatively well-established, parental mental health and socioeconomic status have an effect on child development in general; this literature review focuses specifically on perinatal stroke and the effect of the above factors on both patients and family’s cognitive and social outcome. In doing so, steps can be outlined that can alleviate the negative impact of these factors may have on the affected children’s psychosocial development.
Tuberous sclerosis complex (TSC) is a neurogenetic disorder that leads to elevated mechanistic targeting of rapamycin complex 1 (mTORC1) activity. Cilia can be affected by mTORC1 signaling, and ...ciliary deficits are associated with neurodevelopmental disorders. Here, we examine whether neuronal cilia are affected in TSC. We show that cortical tubers from TSC patients and mutant mouse brains have fewer cilia. Using high-content image-based assays, we demonstrate that mTORC1 activity inversely correlates with ciliation in TSC1/2-deficient neurons. To investigate the mechanistic relationship between mTORC1 and cilia, we perform a phenotypic screen for mTORC1 inhibitors with TSC1/2-deficient neurons. We identify inhibitors of the heat shock protein 90 (Hsp90) that suppress mTORC1 through regulation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling. Pharmacological inhibition of Hsp90 rescues ciliation through downregulation of Hsp27. Our study uncovers the heat-shock machinery as a druggable signaling node to restore mTORC1 activity and cilia due to loss of TSC1/2, and it provides broadly applicable platforms for studying TSC-related neuronal dysfunction.
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•Tubers from TSC patients have a distinct ciliary gene signature and fewer cilia•High-content assays with TSC-deficient neurons can be used as a drug-screening platform•17-AGG can regulate the mTORC1 signaling cascade at multiple levels•Hsp27 is a druggable target of mTORC1-dependent impaired ciliation
Di Nardo et al. find that cortical tubers from TSC patients and mutant mouse brains have fewer cilia. An image-based screening of mTORC1 activity in TSC1/2-deficient neurons leads to the identification of the heat-shock machinery as a druggable signaling node to restore mTORC1 activity and cilia.
Perinatal stroke is a cerebrovascular injury that occur in gestation or up until a child’s first month of life. Impacting cognitive, social, and psychological development in children long after the ...stroke, perinatal stroke is yet to be fully understood. While the exact timing of injury can often not be determined, diagnosis relies on recognition of abnormalities in motor and behavioral development in these affected children, in order to be treated. Although there are long term morbidities specific to perinatal stroke, there are also a multitude of other factors that contribute to child development, and have the potential to alter outcome. These factors include family adjustment, family history, family functioning, and family socioeconomic status, among others. As is relatively well-established, parental mental health and socioeconomic status have an effect on child development in general; this literature review focuses specifically on perinatal stroke and the effect of the above factors on both patients and family’s cognitive and social outcome. In doing so, steps can be outlined that can alleviate the negative impact of these factors may have on the affected children’s psychosocial development. ;
Non-contrast head CT scan is the current standard for initial imaging of patients with head trauma or stroke symptoms. We aimed to develop and validate a set of deep learning algorithms for automated ...detection of the following key findings from these scans: intracranial haemorrhage and its types (ie, intraparenchymal, intraventricular, subdural, extradural, and subarachnoid); calvarial fractures; midline shift; and mass effect.
We retrospectively collected a dataset containing 313 318 head CT scans together with their clinical reports from around 20 centres in India between Jan 1, 2011, and June 1, 2017. A randomly selected part of this dataset (Qure25k dataset) was used for validation and the rest was used to develop algorithms. An additional validation dataset (CQ500 dataset) was collected in two batches from centres that were different from those used for the development and Qure25k datasets. We excluded postoperative scans and scans of patients younger than 7 years. The original clinical radiology report and consensus of three independent radiologists were considered as gold standard for the Qure25k and CQ500 datasets, respectively. Areas under the receiver operating characteristic curves (AUCs) were primarily used to assess the algorithms.
The Qure25k dataset contained 21 095 scans (mean age 43 years; 9030 43% female patients), and the CQ500 dataset consisted of 214 scans in the first batch (mean age 43 years; 94 44% female patients) and 277 scans in the second batch (mean age 52 years; 84 30% female patients). On the Qure25k dataset, the algorithms achieved an AUC of 0·92 (95% CI 0·91–0·93) for detecting intracranial haemorrhage (0·90 0·89–0·91 for intraparenchymal, 0·96 0·94–0·97 for intraventricular, 0·92 0·90–0·93 for subdural, 0·93 0·91–0·95 for extradural, and 0·90 0·89–0·92 for subarachnoid). On the CQ500 dataset, AUC was 0·94 (0·92–0·97) for intracranial haemorrhage (0·95 0·93–0·98, 0·93 0·87–1·00, 0·95 0·91–0·99, 0·97 0·91–1·00, and 0·96 0·92–0·99, respectively). AUCs on the Qure25k dataset were 0·92 (0·91–0·94) for calvarial fractures, 0·93 (0·91–0·94) for midline shift, and 0·86 (0·85–0·87) for mass effect, while AUCs on the CQ500 dataset were 0·96 (0·92–1·00), 0·97 (0·94–1·00), and 0·92 (0·89–0·95), respectively.
Our results show that deep learning algorithms can accurately identify head CT scan abnormalities requiring urgent attention, opening up the possibility to use these algorithms to automate the triage process.
Qure.ai.
This study is intended to assess and help us understand the role of school resource inadequacy (SRI) on school social engagement (SSE). The authors also utilize this opportunity to analyze the ...influence of school resource inadequacies on principal stress (PS) and the influence of PS on SSE. School administrators would stand to benefit by understanding the direct influences of school resource inadequacies on SSE, the direct influence of school resource inadequacies on PS, the direct influence of PS on SSE, and the interactional effect of school resource inadequacies and PS on SSE. This study utilizes data from the “Teaching and Learning International Survey (TALIS) Principal Questionnaire,” 2018 available for England (United Kingdom). The respondents for this survey are principals of public and private schools in England (United Kingdom). Cronbach alpha values were calculated for the variables to confirm the reliability of variables considered for this study. Also used in this study are the Kaiser‐Meyer‐Olkin (KMO) test and the Andrew F. Hayes model 4 to test the mediating influence and interactional effects. SPSS 23.0 was used for the purpose of data analysis and the output tables are from the results of the tests done using SPSS. The results reiterate the relationship between SRI and PS. This study also establishes the relationship between PS and SSE as being negative, meaning that the lower the PS greater is the SSE. Results also show evidence of the relationship between SRI and SSE, meaning that adequate school resources have a positive influence on SSE. Further, the mediating effect of PS on SSE and SRI was also tested and established. The findings of this study are important for school administrators and regulators in understanding the relationship between school resources, SSE, and the mediating influence of PS. This study establishes the relationship between SRI and PS, SRI and SSE, PS, and SSE. The research is also unique as it establishes the mediating influence of PS.
The development of cracks is a regular phenomenon that causes water and various chemicals to seep into the structure reducing the strength and longevity of the building. The intrusion of external ...materials might affect the reinforcements when exposed to moisture and CO
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exposure, degrading the structure. Regular maintenance and treatments are needed to fix the cracks and maintain the structure. Research is in progress identifying solutions to these issues with active and self-processes in concrete which aids in repairing the cracks by generating calcium carbonate (CaCO
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) particles which could seal the porosity of concrete and micro-cracks. Various bacteria like Bacillus pasteurii, Bacillus subtilis, Bacillus cohnii and Bacillus sphaericus are chosen for the crack sealing treatment as those bacteria could survive in an alkaline medium. Distinct species of bacteria have various growth conditions. Bacterial self-healing treatments were situated in an environment containing various minerals and chemicals at a constant temperature and for a specific amount of time to develop healing properties. This paper investigates the different experimental works studied on self-healing processes in large concrete samples with different sizes and materials. Studies revealed that bacteria enhanced the systemic toughness, flow ability, durability, and flexural modulus of normal concrete. This paper also investigates the different mathematical formulations established to examine the stress-strain behaviour of bacterium, which has been utilized to increase the strength of concrete.
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