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Abstract Hydrocephalus (HC) is a heterogenous disease characterized by alterations in cerebrospinal fluid (CSF) dynamics that may cause increased intracranial pressure. HC is a component of a wide array of genetic syndromes as well as a secondary consequence of brain injury (intraventricular hemorrhage (IVH), infection, etc.) that can present across the age spectrum, highlighting the phenotypic heterogeneity of the disease. Surgical treatments include ventricular shunting and endoscopic third ventriculostomy with or without choroid plexus cauterization, both of which are prone to failure, and no effective pharmacologic treatments for HC have been developed. Thus, there is an urgent need to understand the genetic architecture and molecular pathogenesis of HC. Without this knowledge, the development of preventive, diagnostic, and therapeutic measures is impeded. However, the genetics of HC is extraordinarily complex, based on studies of varying size, scope, and rigor. This review serves to provide a comprehensive overview of genes, pathways, mechanisms, and global impact of genetics contributing to all etiologies of HC in humans.

Abstract To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and most severe of congenital brain arteriovenous malformations, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (2042.5-fold, p = 4.79 x 10−7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (17.5-fold, p = 1.22 x 10−5), which cooperates with p120 RasGAP to regulate vascular development. Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomic analysis defined developing endothelial cells as a likely spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis and impaired hierarchical development of arterial-capillary-venous networks, but only in the presence of a “second-hit” allele. These results illuminate human arterio-venous development and VOGM pathobiology and have implications for patients and their families.

Enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles (cerebral ventriculomegaly), the cardinal feature of congenital hydrocephalus (CH), is increasingly recognized among patients with autism spectrum disorders (ASD). KATNAL2, a member of Katanin family microtubule-severing ATPases, is a known ASD risk gene, but its roles in human brain development remain unclear. Here, we show that nonsense truncation of Katnal2 (Katnal2Δ17) in mice results in classic ciliopathy phenotypes, including impaired spermatogenesis and cerebral ventriculomegaly. In both humans and mice, KATNAL2 is highly expressed in ciliated radial glia of the fetal ventricular-subventricular zone as well as in their postnatal ependymal and neuronal progeny. The ventriculomegaly observed in Katnal2Δ17 mice is associated with disrupted primary cilia and ependymal planar cell polarity that results in impaired cilia-generated CSF flow. Further, prefrontal pyramidal neurons in ventriculomegalic Katnal2Δ17 mice exhibit decreased excitatory drive and reduced high-frequency firing. Consistent with these findings in mice, we identified rare, damaging heterozygous germline variants in KATNAL2 in five unrelated patients with neurosurgically treated CH and comorbid ASD or other neurodevelopmental disorders. Mice engineered with the orthologous ASD-associated KATNAL2 F244L missense variant recapitulated the ventriculomegaly found in human patients. Together, these data suggest KATNAL2 pathogenic variants alter intraventricular CSF homeostasis and parenchymal neuronal connectivity by disrupting microtubule dynamics in fetal radial glia and their postnatal ependymal and neuronal descendants. The results identify a molecular mechanism underlying the development of ventriculomegaly in a genetic subset of patients with ASD and may explain persistence of neurodevelopmental phenotypes in some patients with CH despite neurosurgical CSF shunting. [ABSTRACT FROM AUTHOR]

Dysfunction of motile cilia in ependymal cells has been proposed to be a pathogenic cause of cerebrospinal fluid (CSF) overaccumulation leading to ventricular expansion in hydrocephalus, primarily based on observations of enlarged ventricles in mouse models of primary ciliary dyskinesia. Here, we review human and animal evidence that warrants a rethinking of the cilia hypothesis in hydrocephalus. First, we discuss neuroembryology and physiology data that do not support a role for ependymal cilia as the primary propeller of CSF movement across the ventricles in the human brain, particularly during in utero development prior to the functional maturation of ependymal cilia. Second, we highlight that in contrast to mouse models, motile ciliopathies infrequently cause hydrocephalus in humans. Instead, gene mutations affecting motile cilia function impact not only ependymal cilia but also motile cilia found in other organ systems outside of the brain, causing a clinical syndrome of recurrent respiratory infections and situs inversus, symptoms that do not typically accompany most cases of human hydrocephalus. Finally, we postulate that certain cases of hydrocephalus associated with ciliary gene mutations may arise not necessarily just from loss of cilia-generated CSF flow but also from altered neurodevelopment, given the potential functions of ciliary genes in signaling and neural stem cell fate beyond generating fluid flow. Further investigations are needed to clarify the link between motile cilia, CSF physiology, and brain development, the understanding of which has implications for the care of patients with hydrocephalus and other related neurodevelopmental disorders.

A stroke volume of arterial blood that arrives to the brain housed in the rigid cranium must be matched over the cardiac cycle by an equivalent volume of ejected venous blood. We hypothesize that the brain maintains this equilibrium by organizing coherent arterial and venous pulse waves. To test this hypothesis, we applied wavelet computational methods to diagnostic cerebral angiograms in four human patients, permitting the capture and analysis of cardiac frequency phenomena from fluoroscopic images acquired at faster than cardiac rate. We found that the cardiac frequency reciprocal phase of a small region of interest (ROI) in a named artery predicts venous anatomy pixel-wise and that the predicted pixels reconstitute venous bolus passage timing. Likewise, a small ROI in a named vein predicts arterial anatomy and arterial bolus passage timing. The predicted arterial and venous pixel groups maintain phase complementarity across the bolus travel. We thus establish a novel computational method to analyze vascular pulse waves from minimally invasive cerebral angiograms and provide the first direct evidence of arteriovenous coupling in the intact human brain. This phenomenon of arteriovenous coupling may be a physiologic mechanism for how the brain precisely maintains mechanical equilibrium against volume displacement and kinetic energy transfer resulting from cyclical deformations with each heartbeat. The study also paves the way to study deranged arteriovenous coupling as an underappreciated pathophysiologic disturbance in a myriad of neurological pathologies linked by mechanical disequilibrium.

Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery in children. Recent studies have implicated SMARCC1 , a component of the BRG1-associated factor (BAF) chromatin remodelling complex, as a candidate congenital hydrocephalus gene. However, SMARCC1 variants have not been systematically examined in a large patient cohort or conclusively linked with a human syndrome. Moreover, congenital hydrocephalus-associated SMARCC1 variants have not been functionally validated or mechanistically studied in vivo. Here, we aimed to assess the prevalence of SMARCC1 variants in an expanded patient cohort, describe associated clinical and radiographic phenotypes, and assess the impact of Smarcc1 depletion in a novel Xenopus tropicalis model of congenital hydrocephalus. To do this, we performed a genetic association study using whole-exome sequencing from a cohort consisting of 2697 total ventriculomegalic trios, including patients with neurosurgically-treated congenital hydrocephalus, that total 8091 exomes collected over 7 years (2016–23). A comparison control cohort consisted of 1798 exomes from unaffected siblings of patients with autism spectrum disorder and their unaffected parents were sourced from the Simons Simplex Collection. Enrichment and impact on protein structure were assessed in identified variants. Effects on the human fetal brain transcriptome were examined with RNA-sequencing and Smarcc1 knockdowns were generated in Xenopus and studied using optical coherence tomography imaging, in situ hybridization and immunofluorescence. SMARCC1 surpassed genome-wide significance thresholds, yielding six rare, protein-altering de novo variants localized to highly conserved residues in key functional domains. Patients exhibited hydrocephalus with aqueductal stenosis; corpus callosum abnormalities, developmental delay, and cardiac defects were also common. Xenopus knockdowns recapitulated both aqueductal stenosis and cardiac defects and were rescued by wild-type but not patient-specific variant SMARCC1. Hydrocephalic SMARCC1-variant human fetal brain and Smarcc1-variant Xenopus brain exhibited a similarly altered expression of key genes linked to midgestational neurogenesis, including the transcription factors NEUROD2 and MAB21L2. These results suggest de novo variants in SMARCC1 cause a novel human BAFopathy we term 'SMARCC1-associated developmental dysgenesis syndrome', characterized by variable presence of cerebral ventriculomegaly, aqueductal stenosis, developmental delay and a variety of structural brain or cardiac defects. These data underscore the importance of SMARCC1 and the BAF chromatin remodelling complex for human brain morphogenesis and provide evidence for a 'neural stem cell' paradigm of congenital hydrocephalus pathogenesis. These results highlight utility of trio-based whole-exome sequencing for identifying pathogenic variants in sporadic congenital structural brain disorders and suggest whole-exome sequencing may be a valuable adjunct in clinical management of congenital hydrocephalus patients. [ABSTRACT FROM AUTHOR]

Daily changes in light and food availability are major time cues that influence circadian timing.sup.1. However, little is known about the circuits that integrate these time cues to drive a coherent circadian output.sup.1-3. Here we investigate whether retinal inputs modulate entrainment to nonphotic cues such as time-restricted feeding. Photic information is relayed to the suprachiasmatic nucleus (SCN)--the central circadian pacemaker--and the intergeniculate leaflet (IGL) through intrinsically photosensitive retinal ganglion cells (ipRGCs).sup.4. We show that adult mice that lack ipRGCs from the early postnatal stages have impaired entrainment to time-restricted feeding, whereas ablation of ipRGCs at later stages had no effect. Innervation of ipRGCs at early postnatal stages influences IGL neurons that express neuropeptide Y (NPY) (hereafter, IGL.sup.NPY neurons), guiding the assembly of a functional IGL.sup.NPY-SCN circuit. Moreover, silencing IGL.sup.NPY neurons in adult mice mimicked the deficits that were induced by ablation of ipRGCs in the early postnatal stages, and acute inhibition of IGL.sup.NPY terminals in the SCN decreased food-anticipatory activity. Thus, innervation of ipRGCs in the early postnatal period tunes the IGL.sup.NPY-SCN circuit to allow entrainment to time-restricted feeding. Ablating retinal input at early postnatal stages--but not later time points--impaired entrainment to time-restricted feeding in adult mice, as did silencing intergeniculate-leaflet neurons that express neuropeptide Y and project to the central pacemaker, Author(s): Diego Carlos Fernandez [sup.1] , Ruchi Komal [sup.1] , Jennifer Langel [sup.1] , Jun Ma [sup.1] , Phan Q. Duy [sup.1] [sup.3] , Mario A. Penzo [sup.1] , Haiqing [...]

To describe and assess the educational value of a functional neurosurgery clinical shadowing and research tutorial for pre-medical trainees.

Objective Multiple clinical trials fail to identify clinically measurable health benefits of daily multivitamin and multimineral (MVM) consumption in the general adult population. Understanding the determinants of widespread use of MVMs may guide efforts to better educate the public about effective nutritional practices. The objective of this study was to compare self-reported and clinically measurable health outcomes among MVM users and non-users in a large, nationally representative adult civilian non-institutionalised population in the USA surveyed on the use of complementary health practices.Design Cross-sectional analysis of the effect of MVM consumption on self-reported overall health and clinically measurable health outcomes.Participants Adult MVM users and non-users from the 2012 National Health Interview Survey (n=21 603).Primary and secondary outcome measures Five psychological, physical, and functional health outcomes: (1) self-rated health status, (2) needing help with routine needs, (3) history of 10 chronic diseases, (4) presence of 19 health conditions in the past 12 months, and (5) Kessler 6-Item (K6) Psychological Distress Scale to measure non-specific psychological distress in the past month.Results Among 4933 adult MVM users and 16 670 adult non-users, MVM users self-reported 30% better overall health than non-users (adjusted OR 1.31; 95% CI 1.17 to 1.46; false discovery rate adjusted p

Summary: Trigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play a role in disease pathogenesis. However, no unbiased, large-scale genomic study of TN has been performed to date. Analysis of 290 whole exome-sequenced TN probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment of rare, damaging variants in GABA receptor-binding genes in cases. Mice engineered with a TN-associated de novo mutation (p.Cys188Trp) in the GABAA receptor Cl− channel γ-1 subunit (GABRG1) exhibited trigeminal mechanical allodynia and face pain behavior. Other TN probands harbored rare damaging variants in Na+ and Ca+ channels, including a significant variant burden in the α-1H subunit of the voltage-gated Ca2+ channel Cav3.2 (CACNA1H). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis.

Epilepsy is a common neurological disorder characterized by recurrent and unprovoked seizures thought to arise from impaired balance between neuronal excitation and inhibition. Our understanding of the neurophysiological mechanisms that render the brain epileptogenic remains incomplete, reflected by the lack of satisfactory treatments that can effectively prevent epileptic seizures without significant drug-related adverse effects. Type 2 K+-Cl− cotransporter (KCC2), encoded by SLC12A5, is important for chloride homeostasis and neuronal excitability. KCC2 dysfunction attenuates Cl− extrusion and impairs GABAergic inhibition, and can lead to neuronal hyperexcitability. Converging lines of evidence from human genetics have secured the link between KCC2 dysfunction and the development of epilepsy. Here, we review KCC2 mutations in human epilepsy and discuss potential therapeutic strategies based on the functional impact of these mutations. We suggest that a strategy of augmenting KCC2 activity by antagonizing its critical inhibitory phosphorylation sites may be a particularly efficacious method of facilitating Cl− extrusion and restoring GABA inhibition to treat medication-refractory epilepsy and other seizure disorders.

The genetic diversity of foot-and-mouth disease virus (FMDV) poses a challenge to the successful control of the disease, and it is important to identify the emergence of different strains in endemic settings. The objective of this study was to evaluate the sampling of clinically healthy livestock at slaughterhouses as a strategy for genomic FMDV surveillance. Serum samples (n = 11,875) and oropharyngeal fluid (OPF) samples (n = 5045) were collected from clinically healthy cattle and buffalo on farms in eight provinces in southern and northern Vietnam (2015–2019) to characterize viral diversity. Outbreak sequences were collected between 2009 and 2019. In two slaughterhouses in southern Vietnam, 1200 serum and OPF samples were collected from clinically healthy cattle and buffalo (2017 to 2019) as a pilot study on the use of slaughterhouses as sentinel points in surveillance. FMDV VP1 sequences were analyzed using discriminant principal component analysis and time-scaled phylodynamic trees. Six of seven serotype-O and -A clusters circulating in southern Vietnam between 2017–2019 were detected at least once in slaughterhouses, sometimes pre-dating outbreak sequences associated with the same cluster by 4–6 months. Routine sampling at slaughterhouses may provide a timely and efficient strategy for genomic surveillance to identify circulating and emerging FMDV strains.

The thermodynamic and mechanical properties of the zinc-blende indium pnictides InP, InAs and InSb compounds have been investigated thanks to the statistical moment method in statistical mechanics. We have derived the analytical expressions of thermal induced atomic displacement, lattice constant, elastic moduli (Young's modulus, bulk modulus and shear modulus) and elastic constants of the zinc-blende compounds. The difference of temperature effects on mechanical properties of InSb comparing to InP and InAs compounds has been pointed out. We show that InSb is less affected by temperature while InP changes its mechanical properties from hardness to softness quickly when the temperature increases. The advancement of this method is that it has included the anharmonic effects of thermal lattice vibrations by taking into account the higher-order atomic displacement terms. [ABSTRACT FROM AUTHOR]

Abstract Foot-and-mouth disease virus (FMDV) is endemic in Vietnam, a country that plays an important role in livestock trade within Southeast Asia. The large populations of FMDV-susceptible species in Vietnam are important components of food production and of the national livelihood. In this study, we investigated the phylogeny of FMDV O/PanAsia in Vietnam, reconstructing the virus’ ancestral host species (pig, cattle or buffalo), clinical stage (subclinical carrier or clinically affected) and geographical location. Phylogenetic divergence time estimation and character state reconstruction analyses suggest that movement of viruses between species differ. While inferred transmissions from cattle to buffalo and pigs and from pigs to cattle are well supported, transmission from buffalo to other species, and from pigs to buffalo may be less frequent. Geographical movements of FMDV O/PanAsia virus appears to occur in all directions within the country, with the South Central Coast and the Northeast regions playing a more important role in FMDV O/PanAsia spread. Genetic selection of variants with changes at specific sites within FMDV VP1 coding region was different depending on host groups analyzed. The overall ratio of non-synonymous to synonymous nucleotide changes was greater in pigs compared to cattle and buffalo, whereas a higher number of individual amino acid sites under positive selection were detected in persistently infected, subclinical animals compared to viruses collected from clinically diseased animals. These results provide novel insights to understand FMDV evolution and its association with viral spread within endemic countries. These findings may support animal health organizations in their endeavor to design animal disease control strategies in response to outbreaks.