Spontaneous Activity of Cochlear Hair Cells Triggered by Fluid Secretion Mechanism in Adjacent Support Cells.

Spontaneous electrical activity of neurons in developing sensory systems promotes their maturation and proper connectivity. In the auditory system, spontaneous activity of cochlear inner hair cells (IHCs) is initiated by the release of ATP from glia-like inner supporting cells (ISCs), facilitating maturation of central pathways before hearing onset. Here, we find that ATP stimulates purinergic autoreceptors in ISCs, triggering Cl(-) efflux and osmotic cell shrinkage by opening TMEM16A Ca(2+)-activated Cl(-) channels. Release of Cl(-) from ISCs also forces K(+) efflux, causing transient depolarization of IHCs near ATP release sites. Genetic deletion of TMEM16A markedly reduces the spontaneous activity of IHCs and spiral ganglion neurons in the developing cochlea and prevents ATP-dependent shrinkage of supporting cells. These results indicate that supporting cells in the developing cochlea have adapted a pathway used for fluid secretion in other organs to induce periodic excitation of hair cells.

Layer Hall effect in a 2D topological axion antiferromagnet.

Whereas ferromagnets have been known and used for millennia, antiferromagnets were only discovered in the 1930s1. At large scale, because of the absence of global magnetization, antiferromagnets may seem to behave like any non-magnetic material. At the microscopic level, however, the opposite alignment of spins forms a rich internal structure. In topological antiferromagnets, this internal structure leads to the possibility that the property known as the Berry phase can acquire distinct spatial textures2,3. Here we study this possibility in an antiferromagnetic axion insulator-even-layered, two-dimensional MnBi2Te4-in which spatial degrees of freedom correspond to different layers. We observe a type of Hall effect-the layer Hall effect-in which electrons from the top and bottom layers spontaneously deflect in opposite directions. Specifically, under zero electric field, even-layered MnBi2Te4 shows no anomalous Hall effect. However, applying an electric field leads to the emergence of a large, layer-polarized anomalous Hall effect of about 0.5e2/h (where e is the electron charge and h is Planck's constant). This layer Hall effect uncovers an unusual layer-locked Berry curvature, which serves to characterize the axion insulator state. Moreover, we find that the layer-locked Berry curvature can be manipulated by the axion field formed from the dot product of the electric and magnetic field vectors. Our results offer new pathways to detect and manipulate the internal spatial structure of fully compensated topological antiferromagnets4-9. The layer-locked Berry curvature represents a first step towards spatial engineering of the Berry phase through effects such as layer-specific moiré potential.

The location of the t(4;14) translocation breakpoint within the NSD2 gene identifies a subset of patients with high-risk NDMM.

Although translocation events between chromosome 4 (NSD2 gene) and chromosome 14 (immunoglobulin heavy chain [IgH] locus) (t(4;14)) is considered high risk in newly diagnosed multiple myeloma (NDMM), only ∼30% to 40% of t(4;14) patients are clinically high risk. We generated and compared a large whole genome sequencing (WGS) and transcriptome (RNA sequencing) from 258 t(4;14) (n = 153 discovery, n = 105 replication) and 183 non-t(4;14) NDMM patients with associated clinical data. A landmark survival analysis indicated only ∼25% of t(4;14) patients had an overall survival (OS) <24 months, and a comparative analysis of the patient subgroups identified biomarkers associated with this poor outcome, including translocation breakpoints located in the NSD2 gene and expression of IgH-NSD2 fusion transcripts. Three breakpoints were identified and are designated as: "no-disruption" (upstream of NSD2), "early-disruption" (in the 5' UTR), and "late-disruption" (within the NSD2 gene). Our results show a significant difference in OS based on the location of DNA breakpoints (median OS 28.6 "late-disruption" vs 59.2 "early disruption" vs 75.1 months "no disruption"). These findings have been replicated in an independent replication dataset. Also, univariate and multivariate analysis suggest high-risk markers such as del17p, 1p independently contribute to poor outcome in t(4;14) MM patients.

Making sense of astrocytic calcium signals - from acquisition to interpretation.

Astrocytes functionally interact with neurons and with other brain cells. Although not electrically excitable, astrocytes display a complex repertoire of intracellular Ca2+ signalling that evolves in space and time within single astrocytes and across astrocytic networks. Decoding the physiological meaning of these dynamic changes in astrocytic Ca2+ activity has remained a major challenge. This Review describes experimental preparations and methods for recording and studying Ca2+ activity in astrocytes, focusing on the analysis of Ca2+ signalling events in single astrocytes and in astrocytic networks. The limitations of existing experimental approaches and ongoing technical and conceptual challenges in the interpretation of astrocytic Ca2+ events and their spatio-temporal patterns are also discussed.

Electrical and synaptic integration of glioma into neural circuits.

High-grade gliomas are lethal brain cancers whose progression is robustly regulated by neuronal activity. Activity-regulated release of growth factors promotes glioma growth, but this alone is insufficient to explain the effect that neuronal activity exerts on glioma progression. Here we show that neuron and glioma interactions include electrochemical communication through bona fide AMPA receptor-dependent neuron-glioma synapses. Neuronal activity also evokes non-synaptic activity-dependent potassium currents that are amplified by gap junction-mediated tumour interconnections, forming an electrically coupled network. Depolarization of glioma membranes assessed by in vivo optogenetics promotes proliferation, whereas pharmacologically or genetically blocking electrochemical signalling inhibits the growth of glioma xenografts and extends mouse survival. Emphasizing the positive feedback mechanisms by which gliomas increase neuronal excitability and thus activity-regulated glioma growth, human intraoperative electrocorticography demonstrates increased cortical excitability in the glioma-infiltrated brain. Together, these findings indicate that synaptic and electrical integration into neural circuits promotes glioma progression.

Glutamatergic synaptic input to glioma cells drives brain tumour progression.

A network of communicating tumour cells that is connected by tumour microtubes mediates the progression of incurable gliomas. Moreover, neuronal activity can foster malignant behaviour of glioma cells by non-synaptic paracrine and autocrine mechanisms. Here we report a direct communication channel between neurons and glioma cells in different disease models and human tumours: functional bona fide chemical synapses between presynaptic neurons and postsynaptic glioma cells. These neurogliomal synapses show a typical synaptic ultrastructure, are located on tumour microtubes, and produce postsynaptic currents that are mediated by glutamate receptors of the AMPA subtype. Neuronal activity including epileptic conditions generates synchronised calcium transients in tumour-microtube-connected glioma networks. Glioma-cell-specific genetic perturbation of AMPA receptors reduces calcium-related invasiveness of tumour-microtube-positive tumour cells and glioma growth. Invasion and growth are also reduced by anaesthesia and the AMPA receptor antagonist perampanel, respectively. These findings reveal a biologically relevant direct synaptic communication between neurons and glioma cells with potential clinical implications.

Mitochondrial dysfunction and oxidative stress contribute to cognitive and motor impairment in FOXP1 syndrome.

FOXP1 syndrome caused by haploinsufficiency of the forkhead box protein P1 (FOXP1) gene is a neurodevelopmental disorder that manifests motor dysfunction, intellectual disability, autism, and language impairment. In this study, we used a Foxp1+/- mouse model to address whether cognitive and motor deficits in FOXP1 syndrome are associated with mitochondrial dysfunction and oxidative stress. Here, we show that genes with a role in mitochondrial biogenesis and dynamics (e.g., Foxo1, Pgc-1α, Tfam, Opa1, and Drp1) were dysregulated in the striatum of Foxp1+/- mice at different postnatal stages. Furthermore, these animals exhibit a reduced mitochondrial membrane potential and complex I activity, as well as decreased expression of the antioxidants superoxide dismutase 2 (Sod2) and glutathione (GSH), resulting in increased oxidative stress and lipid peroxidation. These features can explain the reduced neurite branching, learning and memory, endurance, and motor coordination that we observed in these animals. Taken together, we provide strong evidence of mitochondrial dysfunction in Foxp1+/- mice, suggesting that insufficient energy supply and excessive oxidative stress underlie the cognitive and motor impairment in FOXP1 deficiency.

High-resolution structural and functional deep brain imaging using adaptive optics three-photon microscopy.

Multiphoton microscopy has become a powerful tool with which to visualize the morphology and function of neural cells and circuits in the intact mammalian brain. However, tissue scattering, optical aberrations and motion artifacts degrade the imaging performance at depth. Here we describe a minimally invasive intravital imaging methodology based on three-photon excitation, indirect adaptive optics (AO) and active electrocardiogram gating to advance deep-tissue imaging. Our modal-based, sensorless AO approach is robust to low signal-to-noise ratios as commonly encountered in deep scattering tissues such as the mouse brain, and permits AO correction over large axial fields of view. We demonstrate near-diffraction-limited imaging of deep cortical spines and (sub)cortical dendrites up to a depth of 1.4 mm (the edge of the mouse CA1 hippocampus). In addition, we show applications to deep-layer calcium imaging of astrocytes, including fibrous astrocytes that reside in the highly scattering corpus callosum.

Nonlinear Valley Hall Effect.

The valley Hall effect arises from valley-contrasting Berry curvature and requires inversion symmetry breaking. Here, we propose a nonlinear mechanism to generate a valley Hall current in systems with both inversion and time-reversal symmetry, where the linear and second-order charge Hall currents vanish along with the linear valley Hall current. We show that a second-order valley Hall signal emerges from the electric field correction to the Berry curvature, provided a valley-contrasting anisotropic dispersion is engineered. We demonstrate the nonlinear valley Hall effect in tilted massless Dirac fermions in strained graphene and organic semiconductors. Our Letter opens up the possibility of controlling the valley degree of freedom in inversion symmetric systems via nonlinear valleytronics.

Multimodality Imaging in Metabolic Syndrome: State-of-the-Art Review.

Metabolic syndrome comprises a set of risk factors that include abdominal obesity, impaired glucose tolerance, hypertriglyceridemia, low high-density lipoprotein levels, and high blood pressure, at least three of which must be fulfilled for diagnosis. Metabolic syndrome has been linked to an increased risk of cardiovascular disease and type 2 diabetes mellitus. Multimodality imaging plays an important role in metabolic syndrome, including diagnosis, risk stratification, and assessment of complications. CT and MRI are the primary tools for quantification of excess fat, including subcutaneous and visceral adipose tissue, as well as fat around organs, which are associated with increased cardiovascular risk. PET has been shown to detect signs of insulin resistance and may detect ectopic sites of brown fat. Cardiovascular disease is an important complication of metabolic syndrome, resulting in subclinical or symptomatic coronary artery disease, alterations in cardiac structure and function with potential progression to heart failure, and systemic vascular disease. CT angiography provides comprehensive evaluation of the coronary and systemic arteries, while cardiac MRI assesses cardiac structure, function, myocardial ischemia, and infarction. Liver damage results from a spectrum of nonalcoholic fatty liver disease ranging from steatosis to fibrosis and possible cirrhosis. US, CT, and MRI are useful in assessing steatosis and can be performed to detect and grade hepatic fibrosis, particularly using elastography techniques. Metabolic syndrome also has deleterious effects on the pancreas, kidney, gastrointestinal tract, and ovaries, including increased risk for several malignancies. Metabolic syndrome is associated with cerebral infarcts, best evaluated with MRI, and has been linked with cognitive decline. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material. See the invited commentary by Pickhardt in this issue.

Clinico-pathologic profile and outcomes of pediatric endocrine patients managed by endocrine surgeons: Experience over three decades in a tertiary center in India.

BACKGROUND: Pediatric endocrine disorders requiring surgical intervention are rare and so are experienced surgeons dealing with these. The aim of the current study was to investigate disease profile and perioperative outcome of pediatric patients with surgical endocrine disorders in an endocrine surgery unit. METHODS: This retrospective study (Sep 1989-Aug 2019) consisted of pediatric endocrine surgery patients (<18 years) who were managed by a team of pediatric endocrinologists and endocrine surgeons at our center. Patients were divided into three cohorts consisting of a decade each. Clinico-pathologic variables, perioperative events operative and follow-up details were recorded. RESULTS: A total of 332 children were included and their mean age was 14.6 ± 3.9 years (M:F = 1:1.6). Thyroid disorders were most prevalent (59.8%), followed by adrenal (28.2%), parathyroid (10.4%), and pancreas (1.5%). Incidence of benign, malignant, and congenital/developmental disorders were 65.4, 28.1 and 8.3, respectively. Familial association was observed in 8.9% children, which is highest among pheochromocytoma patients. Overall, 201 thyroidectomies + associated procedures, 35 parathyroidectomies, 96 adrenal and paraganglioma resections, and 5 pancreatic procedures were performed. Median hospital stay was 5.6 ± 4.1 days. The number of cases increased significantly over 3 decades. Clinical profile and outcome did not vary except for significant decrease in incidence of malignant pathology (p = 0.04) and increase in VHL cases (p = 0.04) in the last decade though overall increase in familial cases was nonsignificant (p = 0.11). No perioperative mortality was observed except for 3% after adrenalectomy. CONCLUSION: A team of dedicated endocrine surgeons and pediatric endocrinologists is effective in management of pediatric endocrine surgery.

Observation of the Time-Reversal Symmetric Hall Effect in Graphene-WSe2 Heterostructures at Room Temperature.

In this Letter, we provide experimental evidence of the time-reversal symmetric Hall effect in a mesoscopic system, namely, high-mobility graphene-WSe2 heterostructures. This linear, dissipative Hall effect, whose sign depends on the sign of the charge carriers, persists up to room temperature. The magnitude and the sign of the Hall signal can be tuned using an external perpendicular electric field. Our joint experimental and theoretical study establishes that the strain induced by lattice mismatch, or alignment angle inhomogeneity, produces anisotropic bands in graphene while simultaneously breaking the inversion symmetry. The band anisotropy and reduced spatial symmetry lead to the appearance of a time-reversal symmetric Hall effect. Our study establishes graphene-transition metal dichalcogenide-based heterostructures as an excellent platform for studying the effects of broken symmetry on the physical properties of band-engineered two-dimensional systems.

Discovery of a Magnetic Dirac System with a Large Intrinsic Nonlinear Hall Effect.

Magnetic materials exhibiting topological Dirac fermions are attracting significant attention for their promising technological potential in spintronics. In these systems, the combined effect of the spin-orbit coupling and magnetic order enables the realization of novel topological phases with exotic transport properties, including the anomalous Hall effect and magneto-chiral phenomena. Herein, we report experimental signature of topological Dirac antiferromagnetism in TaCoTe2 via angle-resolved photoelectron spectroscopy and first-principles density functional theory calculations. In particular, we find the existence of spin-orbit coupling-induced gaps at the Fermi level, consistent with the manifestation of a large intrinsic nonlinear Hall conductivity. Remarkably, we find that the latter is extremely sensitive to the orientation of the Néel vector, suggesting TaCoTe2 as a suitable candidate for the realization of non-volatile spintronic devices with an unprecedented level of intrinsic tunability.

Fear of Coronavirus Disease 2019 among People with Epilepsy.

BACKGROUND: Epileptic patients are worried about getting coronavirus disease 2019 (COVID-19) infection and have recurrent thoughts of becoming infected with this virus. MATERIALS AND METHODS: This study involved 205 patients diagnosed with epilepsy. The questionnaire included questions about sociodemographic information to analyze the demographic composition. The evaluation of the fear of COVID-19 infection was conducted utilizing the Fear of COVID-19 Scale (FCV-19S). RESULTS: The study enrolled 113 participants (55.10% male and 44.90% female) with an average age of 27.34 years. The mean fear score (FCV-19S) was 14.25, and fear of COVID-19 infection was present in 41 (20%) participants with a mean [standard deviation (SD)] FCV-19S score of 23.19 (3.33). Participants who were >45 years of age, married, graduated, and had low family income were significantly more likely to be fearful of COVID-19. Using logistic regression, education, marital status, and family income were identified as risk factors for having significant fear of coronavirus infection. CONCLUSION: Given the notable prevalence of COVID-19-related fear within the epilepsy community, it is advisable to develop a well-thought-out strategy for promptly identifying vulnerable patients who may be at an increased risk of experiencing fear and anxiety.

Cold snare versus cold forceps polypectomy for endoscopic resection of diminutive polyps: meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: The practices for resection of diminutive colon polyps vary among endoscopists, and U.S. Multi-Society Task force guidelines recommend use of cold snare polypectomy (CSP) for this purpose. In this meta-analysis, we compared CSP and cold forceps polypectomy (CFP) for resection of diminutive polyps. METHODS: Several databases were reviewed to identify randomized controlled trials that compared CSP and CFP for resection of diminutive polyps. The study outcomes of interest were complete resection of all diminutive polyps, complete resection of polyps ≤3 mm in size, failure of tissue retrieval, and polypectomy time. For categorical variables, pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated; for continuous variables, mean differences (MDs) with 95% CIs were calculated. Data were analyzed by using a random-effects model, and heterogeneity was assessed by using the I2 statistic. RESULTS: We included 9 studies with 1037 patients. Rate of complete resection of all diminutive polyps was significantly higher in the CSP group (OR, 1.68; 95% CI, 1.09-2.58). Subgroup analysis, including jumbo or large-capacity forceps, found no significant difference in complete resection between groups (OR, 1.43; 95% CI, .80-2.56). We found no significant between-groups in the rates of complete resection of polyps ≤3 mm in size (OR, .83; 95% CI, .30-2.31). Rate of failure of tissue retrieval was significantly higher in the CSP group (OR, 10.13; 95% CI, 2.29-44.74). No significant between-group difference was noted in polypectomy time. CONCLUSIONS: CFP using large-capacity or jumbo biopsy forceps is noninferior to CSP for complete resection of diminutive polyps.

Amyloid-related Imaging Abnormalities in Alzheimer Disease Treated with Anti-Amyloid-ß Therapy.

Alzheimer disease (AD) is the most common form of dementia worldwide. Treatment of AD has mainly been focused on symptomatic treatment until recently with the advent and approval of monoclonal antibody (MAB) immunotherapy. U.S. Food and Drug Administration-approved drugs such as aducanumab, as well as upcoming newer-generation drugs, have provided an exciting new therapy focused on reducing the amyloid plaque burden in AD. Although this new frontier has shown benefits for patients, it is not without complications, which are mainly neurologic. Increased use of MABs led to the discovery of amyloid-related imaging abnormalities (ARIA). ARIA has been further classified into two categories, ARIA-E and ARIA-H, representing edema and/or effusion and hemorrhage, respectively. ARIA is thought to be caused by increased vascular permeability following an inflammatory response, leading to the extravasation of blood products and proteinaceous fluid. Patients with ARIA may present with headaches, but they are usually asymptomatic and ARIA is only diagnosable at MRI; it is essential for the radiologist to recognize and monitor ARIA. Increased incidence and investigation into this concern have led to the creation of grading scales and monitoring guidelines to diagnose and guide treatment using MABs. Cerebral amyloid angiopathy has an identical pathogenesis to that of ARIA and is its closest differential diagnosis, with imaging findings being the same for both entities and only a history of MAB administration allowing differentiation. The authors discuss the use of MABs for treating AD, expand on ARIA and its consequences, and describe how to identify and grade ARIA to guide treatment properly. ©RSNA, 2023 Quiz questions for this article are available through the Online Learning Center See the invited commentary by Yu in this issue.

Cardiac Changes and Their Reversal Following Curative Surgery in Pheochromocytoma: PheoCard Prospective Cohort Study.

BACKGROUND: Pheochromocytoma and paraganglioma (PPGL) are catecholamine producing tumors of chromaffin cell origin, known to cause varied cardiovascular manifestations from hypertension to myocardial infarction. This study sought to objectively evaluate the cardiac changes in PPGL patients and their reversal following curative surgery. METHODS: The PheoCard study was registered in ClinicalTrials.gov (NCT05082311) and involved 35 consecutive PPGL patients managed as per standard protocol involving alpha blockade followed by curative surgery. They underwent detailed cardiac evaluation using 2D-echocardiography and speckle tracking echocardiography at the time of diagnosis, 7-10 days after alpha blockade, and at 7 days, 3 months, and 6 months after surgical removal. Age- and gender-matched essential hypertensives and healthy individuals (10 in each group) served as two control groups. RESULTS: Patients with PPGLs had significantly higher mean blood pressure, left ventricle end-diastolic dimension and volume (LVEDD, LVEDV), left ventricle end-systolic volume (LVESV), septal wall thickness, LV hypertrophy, lower mean LV ejection fraction (LVEF), early diastolic mitral annular velocity (E/A), decreased amplitude of LV longitudinal strain, and increased circumferential strain (p < 0.001) when compared with the control groups at baseline. After alpha blockade, there was marked reduction in the mean LVEDD, LVEDV, LVESV, and normalization of E/A ratio (p < 0.001) in the PPGL patients. Following curative surgery (normalization of fractionated urinary metanephrines at 7-10 days post-operatively), there was early improvement in all echocardiographic parameters and it continued to improve even at 6 months after surgery. There was marked improvement in the global longitudinal strain as seen on serial speckle tracking echocardiography with recovery of most of the segments of LV depicting the reversal of subclinical endocardial dysfunction (p < 0.001). CONCLUSION: PPGL patients despite normal systolic function have subclinical LV diastolic dysfunction which is reversed after curative surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT05082311.

Clinical and Magnetic Resonance Imaging Radiomics-Based Survival Prediction in Glioblastoma Using Multiparametric Magnetic Resonance Imaging.

INTRODUCTION: Survival prediction in glioblastoma remains challenging, and identification of robust imaging markers could help with this relevant clinical problem. We evaluated multiparametric magnetic resonance imaging-derived radiomics to assess prediction of overall survival (OS) and progression-free survival (PFS). METHODOLOGY: A retrospective, institutional review board-approved study was performed. There were 93 eligible patients, of which 55 underwent gross tumor resection and chemoradiation (GTR-CR). Overall survival and PFS were assessed in the entire cohort and the GTR-CR cohort using multiple machine learning pipelines. A model based on multiple clinical variables was also developed. Survival prediction was assessed using the radiomics-only, clinical-only, and the radiomics and clinical combined models. RESULTS: For all patients combined, the clinical feature-derived model outperformed the best radiomics model for both OS (C-index, 0.706 vs 0.597; P < 0.0001) and PFS prediction (C-index, 0.675 vs 0.588; P < 0.001). Within the GTR-CR cohort, the radiomics model showed nonstatistically improved performance over the clinical model for predicting OS (C-index, 0.638 vs 0.588; P = 0.4). However, the radiomics model outperformed the clinical feature model for predicting PFS in GTR-CR cohort (C-index, 0.641 vs 0.550; P = 0.004). Combined clinical and radiomics model did not yield superior prediction when compared with the best model in each case. CONCLUSIONS: When considering all patients, regardless of therapy, the radiomics-derived prediction of OS and PFS is inferior to that from a model derived from clinical features alone. However, in patients with GTR-CR, radiomics-only model outperforms clinical feature-derived model for predicting PFS.

Peripheral Tubercular Neuritis.

Peripheral neuropathy can affect sensory, motor, or autonomic nerves and manifest with a variety of symptoms. Tuberculosis as a major infectious disease that often affects many organs of the body. However, primary involvement of peripheral nerves is unusual. Peripheral neuropathy in patients with tuberculosis often is associated with other comorbidities, such as immunocompromised states, diabetes mellitus, malnutrition, and some antitubercular medications. This report describes the rare finding of peripheral tubercular neuritis with caseating abscesses of right median and radial nerve in a healthy 24-year man.

Primary diffuse leptomeningeal oligodendrogliomatosis with an isolated 1p deletion.

We report a case of primary diffuse leptomeningeal oligodendrogliomatosis with an isolated 1p deletion confirmed by fluorescent in situ hybridization (FISH) analysis in 52 year-old man. The MRI scan in a patient presenting with progressive headache, nausea and diplopia revealed diffuse leptomeningeal thickening and enhancement without definitive evidence of an intraparenchymal lesion. Biopsy of thickened, enhancing meninges within the left sylvian fissure revealed subarachnoid proliferation of oligodendroglial cells with varying degrees of de-differentiation and sparing of the underlying cortex. An isolated 1p deletion was confirmed by FISH analysis. This is the first reported adult case of a 1p deletion in primary diffuse leptomeningeal oligodendrogliomatosis.