Brain Development Disorders Research Articles

Brain organoids: A revolutionary tool for modeling neurological disorders and development of therapeutics.

Brain organoids are self-organized, three-dimensional (3D) aggregates derived from pluripotent stem cells that have cell types and cellular architectures resembling those of the developing human brain. The current understanding of human brain developmental processes and neurological disorders has advanced significantly with the introduction of this in vitro model. Brain organoids serve as a translational link between two-dimensional (2D) cultures and in vivo models which imitate the neural tube formation at the early and late stages and the differentiation of neuroepithelium with whole-brain regionalization. In addition, the generation of region-specific brain organoids made it possible to investigate the pathogenic and etiological aspects of acquired and inherited brain disease along with drug discovery and drug toxicity testing. In this review article, we first summarize an overview of the existing methods and platforms used for generating brain organoids and their limitations and then discuss the recent advancement in brain organoid technology. In addition, we discuss how brain organoids have been used to model aspects of neurodevelopmental and neurodegenerative diseases, including autism spectrum disorder (ASD), Rett syndrome, Zika virus-related microcephaly, Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD).

Blood-cerebrospinal fluid barrier permeability of metals/metalloids and its determinants in pediatric patients

Concerns regarding adverse effects of metal/metalloids exposure on brain development and neurological disorders among children are increasing. However, the transport patterns of metals/metalloids across the blood-cerebrospinal fluid barrier (BCSFB) need to be clarified in children. A total of 99 Chinese pediatric patients were enrolled from February 2020 to August 2021, with a median age of 6.76 months. We detected 16 metal/metalloid levels in matched serum and cerebrospinal fluid (CSF) samples using inductively coupled plasma mass spectrometry. The BCSFB permeability of metals/metalloids were estimated and the potential effects of biomedical parameters were explored. Most metals/metalloids were detectable among > 80.0% of CSF samples. Significant correlations were observed between strontium (Sr, r = 0.46), molybdenum (Mo, r = 0.50), and cadmium (Cd, r = 0.24) concentrations in serum and CSF (P < 0.05). Ratios of metal/metalloid levels in CSF to serum (Rmetal) ranged from 0.02 to 0.74, and hazardous metals/metalloids including arsenic (As), Cd, lead (Pb), thallium (Tl), and manganese (Mn) showed high transfer efficiencies across the BCSFB (Rmetals > 0.5). With the adjustment of age and sex, albumin, β2-microglobulin, and total protein levels in CSF were positively associated with copper (Cu) permeability (FDR-adjusted P < 0.05), while glucose in CSF was negatively correlated with calcium (Ca), Cu, Sr, and Mo BCSFB permeability (FDR-adjusted P < 0.05). Q-Alb promoted Cu permeability across the BCSFB (FDR-adjusted P < 0.001), while C-reactive protein levels in serum were positively associated with selenium (Se) permeability (FDR-adjusted P = 0.046). For the first time, our findings provided data for the BCSFB permeability of 16 metals/metalloids in children, and indicated that some biomedical parameters could influence the transformation of metals/metalloids from serum to CSF. Metals/metalloids with strong BCSFB permeability warrant attention for their potential neurotoxicity.

Glial Cell Adhesion Molecule (GlialCAM) Determines Proliferative versus Invasive Cell States in Glioblastoma.

The malignant brain cancer glioblastoma (GBM) contains groups of highly invasive cells that drive tumor progression as well as recurrence after surgery and chemotherapy. The molecular mechanisms that enable these GBM cells to exit the primary mass and disperse throughout the brain remain largely unknown. Here we report using human tumor specimens and primary spheroids from male and female patients that glial cell adhesion molecule (GlialCAM), which has normal roles in brain astrocytes and is mutated in the developmental brain disorder megalencephalic leukoencephalopathy with subcortical cysts (MLC), is differentially expressed in subpopulations of GBM cells. High levels of GlialCAM promote cell-cell adhesion and a proliferative GBM cell state in the tumor core. In contrast, GBM cells with low levels of GlialCAM display diminished proliferation and enhanced invasion into the surrounding brain parenchyma. RNAi-mediated inhibition of GlialCAM expression leads to activation of proinvasive extracellular matrix adhesion and signaling pathways. Profiling GlialCAM-regulated genes combined with cross-referencing to single-cell transcriptomic datasets validates functional links among GlialCAM, Mlc1, and aquaporin-4 in the invasive cell state. Collectively, these results reveal an important adhesion and signaling axis comprised of GlialCAM and associated proteins including Mlc1 and aquaporin-4 that is critical for control of GBM cell proliferation and invasion status in the brain cancer microenvironment.SIGNIFICANCE STATEMENT Glioblastoma (GBM) contains heterogeneous populations of cells that coordinately drive proliferation and invasion. We have discovered that glial cell adhesion molecule (GlialCAM)/hepatocyte cell adhesion molecule (HepaCAM) is highly expressed in proliferative GBM cells within the tumor core. In contrast, GBM cells with low levels of GlialCAM robustly invade into surrounding brain tissue along blood vessels and white matter. Quantitative RNA sequencing identifies various GlialCAM-regulated genes with functions in cell-cell adhesion and signaling. These data reveal that GlialCAM and associated signaling partners, including Mlc1 and aquaporin-4, are key factors that determine proliferative and invasive cell states in GBM.

Advanced Techniques Using In Vivo Electroporation to Study the Molecular Mechanisms of Cerebral Development Disorders.

The mammalian cerebral cortex undergoes a strictly regulated developmental process. Detailed in situ visualizations, imaging of these dynamic processes, and in vivo functional gene studies significantly enhance our understanding of brain development and related disorders. This review introduces basic techniques and recent advancements in in vivo electroporation for investigating the molecular mechanisms underlying cerebral diseases. In utero electroporation (IUE) is extensively used to visualize and modify these processes, including the forced expression of pathological mutants in human diseases; thus, this method can be used to establish animal disease models. The advent of advanced techniques, such as genome editing, including de novo knockout, knock-in, epigenetic editing, and spatiotemporal gene regulation, has further expanded our list of investigative tools. These tools include the iON expression switch for the precise control of timing and copy numbers of exogenous genes and TEMPO for investigating the temporal effects of genes. We also introduce the iGONAD method, an improved genome editing via oviductal nucleic acid delivery approach, as a novel genome-editing technique that has accelerated brain development exploration. These advanced in vivo electroporation methods are expected to provide valuable insights into pathological conditions associated with human brain disorders.

Pathogenic variants of human GABRA1 gene associated with epilepsy: A computational approach

Critical for brain development, neurodevelopmental and network disorders, the GABRA1 gene encodes for the α1 subunit, an abundantly and developmentally expressed subunit of heteropentameric gamma-aminobutyric acid A receptors (GABAARs) mediating primary inhibition in the brain. Mutations of the GABAAR subunit genes including GABRA1 gene are associated with epilepsy, a group of syndromes, characterized by unprovoked seizures and diagnosed by integrative approach, that involves genetic testing. Despite the diagnostic use of genetic testing, a large fraction of the GABAAR subunit gene variants including the variants of GABRA1 gene is not known in terms of their molecular consequence, a challenge for precision and personalized medicine. Addressing this, one hundred thirty-seven GABRA1 gene variants of unknown clinical significance have been extracted from the ClinVar database and computationally analyzed for pathogenicity. Eight variants (L49H, P59L, W97R, D99G, G152S, V270G, T294R, P305L) are predicted as pathogenic and mapped to the α1 subunit's extracellular domain (ECD), transmembrane domains (TMDs) and extracellular linker. This is followed by the integration with relevant data for cellular pathology and severity of the epilepsy syndromes retrieved from the literature. Our results suggest that the pathogenic variants in the ECD of GABRA1 (L49H, P59L, W97R, D99G, G152S) will probably manifest decreased surface expression and reduced current with mild epilepsy phenotypes while V270G, T294R in the TMDs and P305L in the linker between the second and the third TMDs will likely cause reduced cell current with severe epilepsy phenotypes. The results presented in this study provides insights for clinical genetics and wet lab experimentation.

The Effect of Neoalgae Spirulina Supplements Intakes on Increasing Body Height and Weight of Stunting Children in Mranggen, Sukoharjo, Central Java

Background: Children who are stunted have a higher risk of experiencing health and brain development disorders, and have a lower likelihood of achievement and a bright future. Spirulina is one of the food sources enriched with nutrients that affect the nutritional status of children. The study aims to discover the effect of the administration of Spirulina Neoalgae supplements on increasing the height and weight of stunting toddlers in Mranggen village. Subjects dan Method: The study used a quasi-experimental design conducted in Mranggen Village, Sukoharjo, Central Java. A total of 100 toddlers selected using total sampling were included in this study. The independent variable in this study was the intervention of Spirulina Neoalgae supplements and the dependent variables in this study were body weight and height. Toddlers were given supplement interventions for 4 weeks. The collected data were subsequently analyzed using the Paired-Test. Results: Before the intervention the average height was (Mean= 82.92; SD = 8.77) and body weight was (Mean= 9.97; SD= 2.09). After the supplement intervention for 2 weeks, the average height was (Mean= 83.56; SD = 8.61) and body weight was (Mean= 10.11; SD= 2.07). Average height (Mean= 84.56; SD= 8.57) and body weight (Mean= 11.04; SD = 2.10) in week four increased and the result was statistically significant (p &gt;0.001). Conclusion: The administration of neoalgae supplements affects increasing height and weight in stunted children in Mranggen Village, Sukoharjo, Central Java. Keywords: Supplements, Neoalgae, Nutritional Status, Height, Weight, Stunting

KEJADIAN STUNTING DENGAN KEMAMPUAN KOGNITIF ANAK USIA SEKOLAH

compared to children their age. Stunting can cause children to experience brain development disorders. Studies have found that stuntesd children have lower cognitive abilities and poorer school performance. The impact of child stunting is often associated with lowerintelligence at school age. Cognitive can be defined as the ability to learn new skills and concepts, the ability to understand what is happening in the environment, and the skills to use memory and solve simple problems. The purpose of this study was to determine the relationship between the incidence of stunting and the cognitive abilities of school-age children in Percut Sei Tuan Village. This type of research is cross sectional. The population in this research sample of 107 school-age children was taken using random sampling so that the total sample was 51 school-age children. Data collection through measurement of height, weight and questionnaires. Analysis using chi-square. The results showed that the frequency of stunting was the majority experienced stuntingas much as 82.4% and the frequency of cognitive abilities of the majority experienced moderate cognitive impairment was 68.6% and there was a relationship between the incidence of stunting and the cognitive abilities of school-age children with p-value0.031. Based on the results of this study,it is suggested that the role of the mother plays a very important role in the nutrition and development of children.

Performansi Algoritma Clustering K-Means untuk Penentuan Status Malnutrisi pada Balita

Malnutrition has always been a global problem and is the main cause of child mortality in developing countries. Nutritional status is a measure of success in meeting the nutritional needs of toddlers which can be seen from the achievement of toddler's weight. The short-term effects of malnutrition on toddlers are physical growth disorders in children, metabolic disorders, brain development disorders, and intelligence disorders. In the long term, malnutrition will cause a decrease in learning outcomes and cognitive abilities, decreased immunity, the risk of developing diabetes, heart and blood vessel disease, obesity, stroke, cancer, and disability in old age. To find out about the growth and development of early childhood, especially in relation to the development of early childhood nutritional values, regular measurements of the height and weight of toddlers from an early age are carried out through Posyandu activities. Toddler height and weight data will be grouped according to the nutritional characteristics of each toddler. In this study, infants will be clustered based on their nutritional characteristics using the K-Means algorithm clustering method. Based on the evaluation results, the number of clusters 3 is more optimal than the number of clusters 5 in the toddler dataset used in the study. It is hoped that the research results obtained can serve as a basis or recommendation material for posyandu throughout Indonesia to determine the nutritional status of the under-five age group, so that the handling is more appropriate and can help prevent malnutrition in under-fives.

The structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification

Cells remodel glycerophospholipid acyl chains via the Lands cycle to adjust membrane properties. Membrane-bound O-acyltransferase (MBOAT) 7 acylates lyso-phosphatidylinositol (lyso-PI) with arachidonyl-CoA. MBOAT7 mutations cause brain developmental disorders, and reduced expression is linked to fatty liver disease. In contrast, increased MBOAT7 expression is linked to hepatocellular and renal cancers. The mechanistic basis of MBOAT7 catalysis and substrate selectivity are unknown. Here, we report the structure and a model for the catalytic mechanism of human MBOAT7. Arachidonyl-CoA and lyso-PI access the catalytic center through a twisted tunnel from the cytosol and lumenal sides, respectively. N-terminal residues on the ER lumenal side determine phospholipid headgroup selectivity: swapping them between MBOATs 1, 5, and 7 converts enzyme specificity for different lyso-phospholipids. Finally, the MBOAT7 structure and virtual screening enabled identification of small-molecule inhibitors that may serve as lead compounds for pharmacologic development.

Association of age of adverse childhood experiences with thalamic volumes and post-traumatic stress disorder in adulthood.

Adverse childhood experiences (ACEs) have been linked to brain development and mental disorders, however, the impact of the age of occurrence of ACEs on thalamic volume and post-traumatic stress disorder (PTSD) after adult trauma remains unclear. This study assessed associations between ACEs at different ages to thalamic volumes and PTSD development following acute adult trauma. Seventy-nine adult trauma survivors were recruited immediately after trauma. Within 2 weeks of the traumatic event, participants completed the PTSD Checklist (PCL) to assess PTSD symptoms, the Childhood Trauma Questionnaire (CTQ) and Childhood Age Range Stress Scale (CARSS) to evaluate ACEs and perceived stress level at preschool (<6 years old) and school (6-13 years old) ages, and structural magnetic resonance imaging (sMRI) to measure thalamic volumes. Participants were divided into three groups: those who experienced no childhood trauma or stress (non-ACEs), those who experienced childhood trauma and stress onset at preschool ages (Presch-ACEs), and those who experienced childhood trauma and stress onset at school ages (Sch-ACEs). At 3 months, participants underwent PTSD symptom evaluation using the Clinician Administered PTSD Scale (CAPS). Adult trauma survivors in the Presch-ACEs group had higher CTQ and CAPS scores. In addition, survivors in the Presch-ACEs group had smaller thalamic volume compared to survivors in the non-ACEs and Sch-ACEs groups. Furthermore, smaller thalamic volume moderated a positive association between post-trauma 2-week PCL and subsequent 3-month CAPS scores. Earlier occurrence of ACEs was associated with smaller thalamic volume, which appears to moderate a positive association between early posttraumatic stress symptom severity and PTSD development after adult trauma. This raises the possibility that early occurrence of ACEs may impact thalamic structure, specifically a reduction in thalamic volume, and that smaller thalamic volume may contribute to susceptibility to PTSD development after adult trauma.

Brain and Stunting: Integrative Clinical and Community Stunting Prevention Perspectives in Disorders of Brain Development

Stunting is a health problem that is very urgent to be addressed. This is associated with increased morbidity, mortality, development of cognitive impairment and an increased risk of various chronic diseases in the future. The research method uses a qualitative approach. With the literature review method, which includes activities related to library data collection methods, reading and recording, and managing research materials. The results of the study show that the treatment of stunting can be divided into 2 methods. First, specific interventions that contribute 30% to the success of treatment, are aimed at children within the First 1,000 Days of Life (HPK), are generally carried out by the health sector and are short-term in nature. This can be done through the target group of adolescents and women of childbearing age, pregnant women, nursing mothers and children 0-23 months, children 24-59 months through priority, important and conditional interventions. The two sensitive interventions, which contribute 70%, are aimed at various development activities outside the health sector targeting the general public. The types of interventions that can be carried out are increasing the supply of drinking water and sanitation, increasing access to and quality of nutrition and health services, increasing awareness, commitment, parenting practices, maternal and child nutrition, increasing access to nutritious food.

A SURVEY ON PREDICTION OF AUTISM SPECTRUM DISORDER USING DATA SCIENCE TECHNIQUES

Autism Spectrum Disorder is a lifelong brain developmental disorder. Diagnosing the level of Autism and predicting the severity of the same are too complex, and it requires a depth analysis of the historical data on the autism patient. Nowadays, Data science techniques play a vital role in diagnosing autism. Decision Tree, Random Forest, Logistic Regression, Adaboost, Naïve Bayse, K-Nearest Neighbour, Support Vector Machine and etc., are the few techniques labeled under the roof of data science are used to predict such disorders. The paper aims to present a survey on the various models proposed by various researchers to predict the severity of autism using data science techniques.

Bacterial TLR2/6 Ligands Block Ciliogenesis, Derepress Hedgehog Signaling, and Expand the Neocortex.

Microbial components have a range of direct effects on the fetal brain. However, little is known about the cellular targets and molecular mechanisms that mediate these effects. Neural progenitor cells (NPCs) control the size and architecture of the brain and understanding the mechanisms regulating NPCs is crucial to understanding brain developmental disorders. We identify ventricular radial glia (vRG), the primary NPC, as the target of bacterial cell wall (BCW) generated during the antibiotic treatment of maternal pneumonia. BCW enhanced proliferative potential of vRGs by shortening the cell cycle and increasing self-renewal. Expanded vRGs propagated to increase neuronal output in all cortical layers. Remarkably, Toll-like receptor 2 (TLR2), which recognizes BCW, localized at the base of primary cilia in vRGs and the BCW-TLR2 interaction suppressed ciliogenesis leading to derepression of Hedgehog (HH) signaling and expansion of vRGs. We also show that TLR6 is an essential partner of TLR2 in this process. Surprisingly, TLR6 alone was required to set the number of cortical neurons under healthy conditions. These findings suggest that an endogenous signal from TLRs suppresses cortical expansion during normal development of the neocortex and that BCW antagonizes that signal through the TLR2/cilia/HH signaling axis changing brain structure and function. IMPORTANCE Fetal brain development in early gestation can be impacted by transplacental infection, altered metabolites from the maternal microbiome, or maternal immune activation. It is less well understood how maternal microbial subcomponents that cross the placenta, such as bacterial cell wall (BCW), directly interact with fetal neural progenitors and neurons and affect development. This scenario plays out in the clinic when BCW debris released during antibiotic therapy of maternal infection traffics to the fetal brain. This study identifies the direct interaction of BCW with TLR2/6 present on the primary cilium, the signaling hub on fetal neural progenitor cells (NPCs). NPCs control the size and architecture of the brain and understanding the mechanisms regulating NPCs is crucial to understanding brain developmental disorders. Within a window of vulnerability before the appearance of fetal immune cells, the BCW-TLR2/6 interaction results in the inhibition of ciliogenesis, derepression of Sonic Hedgehog signaling, excess proliferation of neural progenitors, and abnormal cortical architecture. In the first example of TLR signaling linked to Sonic Hedgehog, BCW/TLR2/6 appears to act during fetal brain morphogenesis to play a role in setting the total cell number in the neocortex.

Hearing and Visual Impairment in Children with Cerebral Palsy, A Study in Tertiary Level Hospital in Bangladesh

Background: Cerebral palsy (CP) is a diagnostic term used to describe a group of motor syndromes resulting from disorders of early brain development. CP remains unexplained in most cases and is typically diagnosed outside the neonatal period. Visual impairment decreases the quality of life and hearing impairment hampers linguistic development. This study aimed to observe the visual and hearing impairment of children with cerebral palsy associated with developmental disabilities. Material Methods: This is a cross-sectional observational descriptive study carried out in the department of Paediatric Neurology CMH Dhaka from March 2018 to February 2022. The participants (N=120) were from birth to 12 years of age. Detailed information was obtained in each case according to protocol. The pediatric neurologist based on the study definition crosschecked the diagnosis. The hearing assessment was done with the help of an Otolaryngologist in the department of Otolaryngology and the ophthalmological evaluation was done with the help of an ophthalmologist of the department of ophthalmology of CMH Dhaka. Hearing impairment, Ophthalmological motor disturbance, and developmental disabilities were correlated. A convenience sampling technique was used in this study. Relevant data were collected from hospital records. All the information was recorded in the fixed protocol. Collected data were classified, edited, coded, and entered into the computer for statistical analysis by using SPSS 2021. Results: In this study, among the 120 children with CP, the mean age of the study was 5.57(SD±3.89) age range of 2-12 years Males were 82(68%) and females were 38(32%), male-female ratio (sex M: F 2.15: 1). Spastic quadriplegia constitutes the predominant group 59(49%), followed by Spastic diplegia 21(18%), Spastic hemiplegia 20(17.5%), dyskinetic CP 09(8%), 7(6%) were mixed CP and 4(3%) were hypotonic CP. Hearing impairment was found in 87 (72%) cases and visual impairment was detected in 92(76%). Among them, the child with Spastic Quadriplegic (83%) and diplegic CP (62%) children had a hearing impairment. Regarding vision, no fix and follow were observed in 69(57%) cases. Among the studied CP child (n=120) 16 children (13.33%) had normal eye finding and 104 (86%) had abnormal eye findings. Refractive error (32.5%) and Squint (19%) were the most common ocular defect among studied patients. Other ocular defect were nystagmus(10%), optic atrophy(12.5%), microphthalmia(10%), corneal opacity(3%), optic hypoplasia(4.1%), cataract(2.5%), pigmentary retinopathy(5%), retro-lental fibroplasias(3.3%) and ptosis(2.5%). In children with hypotonic (athetoid) and mixed CP, almost all (11 of 11) children had visual impairment. Spastic quadriplegic CP children (80%) and Spastic diplegic CP children (90%) had one or more domains of visual impairment. Conclusion: Cerebral Palsy is a non-progressive various form of neurological disorder in children. Early visual screening and hearing assessment can help CP children to minimize mental retardation, learning difficulties, and speech delay.

Myelination dictates axonal viscoelasticity.

During development, dramatic changes in myelination, growth of neural networks and changes in grey-to-white matter ratio build up the astonishingly plastic brain of a child. The progressive increase in myelination insulates the nervous system, which, in turn, modifies the mechanical microenvironment of the brain spatiotemporally. A growing body of evidence demonstrates the role of mechanical forces in growth, differentiation, maturation and electrical properties of neurons. However, due to limitations in imaging resolution, the exact relationship between myelination, axonal organization and the mechanical properties of nerves at the cellular level is still unknown. Here, we propose a novel approach to study the direct relationship between axonal viscoelasticity with changing fibre anisotropy and myelination during development. With the use of atomic force microscopy (AFM) with in situ fluorescent imaging of the primary neuron-oligodendrocyte co-cultures, we found that as axons are progressively myelinated in vitro, their stiffness increases. Direct quantification of myelin along axons using immunofluorescence also demonstrated a positive correlation between increased myelination over time and increased axonal stiffness (p = .001). Notably, AFM measurements along a single axon showed that the Young's modulus measured across myelinated regions were significantly higher than those of adjacent unmyelinated segments at all time points (p < .0001). Force-relaxation analysis also demonstrated that myelin sheath dominates the regulation of viscoelasticity of axons temporally. Collectively, our findings indicate a direct link between myelination, axonal orientation and viscoelasticity, providing important insights about the mechanical environment in the paediatric brain, with direct implications for our understanding of developmental brain disorders and paediatric brain injury.

Laminar heterotopia: A rare cause of epilepsy and mental retardation

Neuronal migration disorders are a category of developmental brain disorders leading to cortical dysplasia. Laminar heterotopia is a form of diffuse gray matter heterotopia, which can result from a failure of proliferation, migration, or organization of neuronal and glial cells in the developing cortex leading to cortical dysplasia. The etiopathogenesis of this malformation remains a subject of discussion. Band heterotopia or double cortex are frequently shown if not always of genetic origin (mutation of genes coding for neuronal migration). We report the case of a young patient who presented episodes of complex seizures since childhood and mild mental retardation.

Role of Nesprin-2 and RanBP2 in BICD2-associated brain developmental disorders.

Bicaudal D2 (BICD2) is responsible for recruiting cytoplasmic dynein to diverse forms of subcellular cargo for their intracellular transport. Mutations in the human BICD2 gene have been found to cause an autosomal dominant form of spinal muscular atrophy (SMA-LED2), and brain developmental defects. Whether and how the latter mutations are related to roles we and others have identified for BICD2 in brain development remains little understood. BICD2 interacts with the nucleoporin RanBP2 to recruit dynein to the nuclear envelope (NE) of Radial Glial Progenitor cells (RGPs) to mediate their well-known but mysterious cell-cycle-regulated interkinetic nuclear migration (INM) behavior, and their subsequent differentiation to form cortical neurons. We more recently found that BICD2 also mediates NE dynein recruitment in migrating post-mitotic neurons, though via a different interactor, Nesprin-2. Here, we report that Nesprin-2 and RanBP2 compete for BICD2-binding in vitro. To test the physiological implications of this behavior, we examined the effects of known BICD2 mutations using in vitro biochemical and in vivo electroporation-mediated brain developmental assays. We find a clear relationship between the ability of BICD2 to bind RanBP2 vs. Nesprin-2 in controlling of nuclear migration and neuronal migration behavior. We propose that mutually exclusive RanBP2-BICD2 vs. Nesprin-2-BICD2 interactions at the NE play successive, critical roles in INM behavior in RGPs and in post-mitotic neuronal migration and errors in these processes contribute to specific human brain malformations.

Fetal cardiac and neonatal cerebral hemodynamics and oxygen metabolism in transposition of the great arteries.

Hemodynamic abnormalities and brain development disorders have been reported previously in fetuses and infants with transposition of the great arteries and intact ventricular septum (TGA-IVS). A ventricular septal defect (VSD) is thought to be an additional risk factor for adverse neurodevelopment, but literature describing this population is sparse. The objectives of this study were to assess fetal cardiac hemodynamics throughout pregnancy, to monitor cerebral hemodynamics and oxygen metabolism in neonates, and to compare these data between patients with TGA-IVS, those with TGA-VSD and age-matched controls. Cardiac hemodynamics were assessed in TGA-IVS and TGA-VSD fetuses and compared with healthy controls matched for gestational age (GA) during three periods: ≤ 22 + 5 weeks (GA1), 27 + 0 to 32 + 5 weeks (GA2) and ≥ 34 + 5 weeks (GA3). Left (LVO), right (RVO) and combined (CVO) ventricular outputs, ductus arteriosus flow (DAF, sum of ante- and retrograde flow in systole and diastole), diastolic DAF, transpulmonary flow (TPF) and foramen ovale diameter were measured. Aortic (AoF) and main pulmonary artery (MPAF) flows were derived as a percentage of CVO. Fetal middle cerebral artery and umbilical artery (UA) pulsatility indices (PI) were measured and the cerebroplacental ratio (CPR) was derived. Bedside optical brain monitoring was used to measure cerebral hemoglobin oxygen saturation (SO2 ) and an index of microvascular cerebral blood flow (CBFi ), along with peripheral arterial oxygen saturation (SpO2 ), in TGA-IVS and TGA-VSD neonates. Using hemoglobin (Hb) concentration measurements, these parameters were used to derive cerebral oxygen delivery and extraction fraction (OEF), as well as an index of cerebral oxygen metabolism (CMRO2i ). These data were acquired in the early preoperative period (within 3 days after birth and following balloon atrial septostomy) and compared with those of age-matched healthy controls, and repeat measurements were collected before discharge when vital signs were stable. LVO was increased in both TGA groups compared with controls throughout pregnancy. Compared with controls, TPF was increased and diastolic DAF was decreased in TGA-IVS fetuses throughout pregnancy, but only during GA1 and GA2 in TGA-VSD fetuses. Compared with controls, DAF was decreased in TGA-IVS fetuses throughout pregnancy and in TGA-VSD fetuses at GA2 and GA3. At GA2, AoF was higher in TGA-IVS and TGA-VSD fetuses than in controls, while MPAF was lower. At GA3, RVO and CVO were higher in the TGA-IVS group than in the TGA-VSD group. In addition, UA-PI was lower at GA2 and CPR higher at GA3 in TGA-VSD fetuses compared with TGA-IVS fetuses. Within 3 days after birth, SpO2 and SO2 were lower in both TGA groups than in controls, while Hb, cerebral OEF and CMRO2i were higher. Preoperative SpO2 was also lower in TGA-VSD neonates than in those with TGA-IVS. From preoperative to predischarge periods, SpO2 and OEF increased in both TGA groups, but CBFi and CMRO2i increased only in the TGA-VSD group. During the predischarge period, SO2 was higher in TGA-IVS than in TGA-VSD neonates, while CBFi was lower. Fetal cardiac and neonatal cerebral hemodynamic/metabolic differences were observed in both TGA groups compared with controls. Compared to those with TGA-IVS, fetuses with TGA-VSD had lower RVO and CVO in late gestation. A higher level of preoperative hypoxemia was observed in the TGA-VSD group. Postsurgical cerebral adaptive mechanisms probably differ between TGA groups. Patients with TGA-VSD have a specific physiology that warrants further study to improve neonatal care and neurodevelopmental outcome. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Optimization Fuzzy Geographically Weighted Clustering with Gravitational Search Algorithm for Factors Analysis Associated with Stunting

Stunting is a significant threat to the quality of human resources in Indonesia because stunting does not only involve physical growth disorders but can also cause children to be vulnerable to disease and experience disorders of brain development and intelligence. Many factors cause stunting, not only malnutrition in pregnant women and toddlers. Grouping can be done to make it easier to see the characteristics of the factors causing stunting in Indonesia. The grouping is done based on the similarity of the characteristics of the factors causing stunting in each province. This study used Fuzzy Geographically Weighted Clustering (FGWC) with Gravitational Search Algorithm (GSA) to group and assess the best cluster using the Partition Coefficient validity index, Classification Entropy, Separation Index, Xie &amp; Beni's Index, and IFV Index. Furthermore, a difference test was conducted to determine the dominant factor causing stunting in the formed cluster. The results showed that the FGWC-GSA gave the best clustering results on the fuzziness value of 2 with the number of clusters 2. Cluster 1 consisted of 16 provinces, and cluster 2 consisted of 18 provinces. Based on the T-test, the variables of infants who received exclusive breastfeeding had significant differences between clusters. Therefore, cluster 2 is a cluster that has dominant problems related to exclusive breastfeeding.

DYRK1A Inhibitors and Perspectives for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease and the most common form of dementia, especially in the elderly. Due to the increase in life expectancy, in recent years, there has been an excessive growth in the number of people affected by this disease, causing serious problems for health systems. In recent years, research has been intensified to find new therapeutic approaches that prevent the progression of the disease. In this sense, recent studies indicate that the dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) gene, which is located on chromosome 21q22.2 and overexpressed in Down syndrome (DS), may play a significant role in developmental brain disorders and early onset neurodegeneration, neuronal loss and dementia in DS and AD. Inhibiting DYRK1A may serve to stop the phenotypic effects of its overexpression and, therefore, is a potential treatment strategy for the prevention of ageassociated neurodegeneration, including Alzheimer-type pathology. In this review, we investigate the contribution of DYRK1A inhibitors as potential anti-AD agents. A search in the literature to compile an in vitro dataset including IC50 values involving DYRK1A was performed from 2014 to the present day. In addition, we carried out structure-activity relationship studies based on in vitro and in silico data. molecular modeling and enzyme kinetics studies indicate that DYRK1A may contribute to AD pathology through its proteolytic process, reducing its kinase specificity. further evaluation of DYRK1A inhibitors may contribute to new therapeutic approaches for AD.