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Objective: We investigated whether air in the cisterns or ventricles on postoperative computed tomography (CT) (reflecting the opening of the cerebrospinal fluid spaces during surgery) is a predictor of classical or nodular leptomeningeal disease (LMD) after resection of brain metastases., Methods: We retrospectively analyzed 73 patients who underwent gross total resection of brain metastases between 2012 and 2020. Patients with air in the cisterns or ventricles on postoperative day 1 CT were categorized into the air-positive group, whereas those without air in the cisterns or ventricles on postoperative day 1 CT were categorized into the air-negative group. The primary outcome was the occurrence of classical or nodular LMD (nLMD), which was assessed using survival analysis., Results: There were 15 (21%) patients in the air-positive group and 58 (79%) in the air-negative group. The air-positive group exhibited significantly more cerebellar and ventricular contact lesions than the air-negative group. The 4-year rate of classical or nLMD was significantly higher in the air-positive group than in the air-negative group (67% vs. 33%, P < 0.001). Multivariate analysis identified air in the cisterns or ventricles on postoperative CT as the only significant predictor of classical or nLMD (P < 0.001)., Conclusions: Postoperative air in the cisterns or ventricles can predict early classical or nodular leptomeningeal disease., (Copyright © 2024. Published by Elsevier Inc.)

Advanced computational models and simulations to unravel the complexities of brain function have known a growing interest in recent years in the field of neurosciences, driven by significant technological progress in computing platforms. Multicompartment models, which capture the detailed morphological and functional properties of neural circuits, represent a significant advancement in this area providing more biological coherence than single compartment modeling. These models serve as a cornerstone for exploring the neural basis of sensory processing, learning paradigms, adaptive behaviors, and neurological disorders. Yet, the high complexity of these models presents a challenge for their real-time implementation, which is essential for exploring alternative therapies for neurological disorders such as electroceutics that rely on biohybrid interaction. Here, we present an accessible, user-friendly, and real-time emulator for multicompartment Hodgkin-Huxley neurons on SoC FPGA. Our system enables real-time emulation of multicompartment neurons while emphasizing cost-efficiency, flexibility, and ease of use. We showcase an implementation utilizing a technology that remains underrepresented in the current literature for this specific application. We anticipate that our system will contribute to the enhancement of computation platforms by presenting an alternative architecture for multicompartment computation. Additionally, it constitutes a step toward developing neuromorphic-based neuroprostheses for bioelectrical therapeutics through an embedded real-time platform running at a similar timescale to biological networks., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Beaubois, Cheslet, Ikeuchi, Branchereau and Levi.)

Background and Objectives: Photodynamic therapy (PDT) with talaporfin sodium is an intraoperative local therapy administered after the surgical removal of malignant gliomas. However, its clinical efficacy in a large patient population has not been determined. To analyze the clinical outcomes and prognosis in isocitrate dehydrogenase (IDH)-wildtype glioblastoma patients treated with PDT., Methods: This retrospective study included patients with newly diagnosed IDH-wildtype glioblastoma treated at Kobe University Hospital between January 2013 and December 2022. PDT involves irradiation of the resection cavity with a 664-nm semiconductor laser after an intravenous infusion of talaporfin sodium. The main outcome measures were the recurrence patterns and survival times, which were compared between the PDT and non-PDT groups. Univariate and multivariate analyses were used to determine the prognostic factors. In addition, adverse events and prognostic factors in the PDT group were analyzed., Results: A total of 44 and 56 patients were included in the PDT and non-PDT groups, respectively. The local recurrence rate was significantly lower in the PDT group than in the non-PDT group (51.3% vs 83.9%), whereas the distant recurrence and dissemination rates were significantly higher in the PDT group than in the non-PDT group (48.7% vs 16.1%). Two grade 3 adverse events were observed in the PDT group. The median progression-free survival and overall survival times were significantly longer in the PDT group than in the non-PDT group (progression-free survival: 10.8 vs 9.3 months, respectively, and overall survival: 24.6 vs 17.6 months, respectively). Multivariate analysis of the PDT groups revealed that younger age was an independent prognostic factor., Conclusion: PDT with talaporfin sodium provided effective local control with minimal adverse effects. The survival time of the patients treated with PDT was significantly longer than that of the patients who did not receive PDT. Therefore, a randomized controlled clinical trial on PDT is warranted., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Background/aim: Radiotherapy (RT) for advanced oropharyngeal cancer (OPC) is effective, especially when combined with chemotherapy (CRT). However, its success can vary depending on factors, such as tumor stage, HPV infection (p16 status), and the patient's nutritional and immune status. This study examined the controlling nutritional status (CONUT) score and tumor immunity as predictive factors for treatment outcomes in OPC, aiming to develop a personalized risk score., Patients and Methods: A retrospective analysis was conducted on 84 patients with OPC treated with definitive RT or CRT, and survival outcomes were compared based on various factors, including BMI, CONUT score, CD8 expression, and HLA class II expression., Results: We observed better overall survival (OS) rates in CD8-positive patients and those with higher HLA class II expression. The univariate analysis identified stage, p16 status, BMI, CONUT score, and CD8 expression as significantly associated with OS. In multivariate analysis, stage, BMI, and CONUT score remained significant predictors of OS. A risk scoring system was developed based on stage, p16 status, BMI, CONUT score, and CD8 expression. Patients were categorized into low-risk and high-risk groups, with significantly better survival in the low-risk group., Conclusion: A combined risk score incorporating clinical, nutritional, and immune factors can improve the prediction of treatment outcomes for OPC patients. This risk stratification may enable personalized treatment plans and improve ΟS rates., Competing Interests: The Authors declare that they have no conflicts of interest in relation to this study., (©2024 The Author(s). Published by the International Institute of Anticancer Research.)

Purpose: To investigate the relationship between the tumor microenvironment (TME), tumor-related seizures (TRS), and cerebrospinal fluid (CSF) markers that predict preoperative seizures in patients with glioblastoma., Methods: In total, 47 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma who underwent preoperative CSF examination, 3-T magnetic resonance spectroscopy (MRS), and neurological surgery between January 2017 and December 2023 were included. We measured the concentrations of soluble CD163 (sCD163), a soluble form of the M2 macrophage marker, in the CSF, the metabolite concentration on MRS, and the number of CD163-positive M2 macrophages in the tumor tissue. Factors associated with preoperative seizures were examined., Results: Twelve patients (25.5%) had preoperative seizures. sCD163 levels in the CSF were positively correlated with the number of CD163-positive M2 macrophages in the tumor tissue, and both were significantly lower in the preoperative seizure group than in the non-preoperative seizure group (p = 0.0124 and p < 0.0001, respectively). MRS indicated that only glutathione (GSH) concentrations were higher in the preoperative seizure group than in the non-preoperative seizure group (2.55 mM and 1.87 mM, respectively; p = 0.0171). CD163-positive M2 macrophages were inversely correlated with GSH levels. sCD163 in the CSF had a high predictive accuracy (sensitivity, 91.7%; specificity, 54.3%; and area under the receiver operator curve, 0.745) for preoperative seizures., Conclusions: The CSF level of sCD163 is useful for predicting the TME and preoperative seizures in IDH wild-type glioblastoma., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Objectives: Spinal dural arteriovenous fistulas (SDAVFs) lead to progressive neurological decline with symptoms such as paraparesis, bowel and bladder dysfunction, and sensory disturbances because of impaired spinal cord venous drainage. This study aimed to systematically review the literature on multiple synchronous SDAVFs and present 2 cases from our institution., Methods: A comprehensive search was performed to identify all published cases of multiple synchronous SDAVFs. Overall, 23 patients with multiple synchronous SDAVFs were identified, including 21 from 19 articles and 2 from this study. The clinical presentation, lesion location, radiographic features, surgical treatment, and outcomes were analyzed in each patient., Results: All patients in this study were male, and the duration from symptom onset to diagnosis in many of these patients was longer than that previously reported. Previous studies suggested that multiple SDAVFs typically occurred within 3 or fewer vertebral levels. However, >50% of the examined patients had remote lesions separated by more than 3 vertebral levels. Patients with remote lesions had a significantly worse outcome (1/7 vs 8/11, 95% CI 0.001-0.998; P = .049)., Conclusion: Accurately locating fistulas before spinal angiography is critical for managing multiple remote SDAVFs. Considering the possibility of multiple remote SDAVFs, careful interpretation of imaging findings is essential for an accurate diagnosis and appropriate treatment planning., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Aims/introduction: Imeglimin is a recently approved oral antidiabetic agent that improves insulin resistance, and promotes insulin secretion from pancreatic β-cells. Here, we investigated the effects of imeglimin on glucagon secretion from pancreatic α-cells., Materials and Methods: Experiments were carried out in high-fat, high-sucrose diet-fed mice. The effects of imeglimin were examined using insulin and glucose tolerance tests, glucose clamp studies, and measurements of glucagon secretion from isolated islets. Glucagon was measured using both the standard and the sequential protocol of Mercodia sandwich enzyme-linked immunosorbent assay; the latter eliminates cross-reactivities with other proglucagon-derived peptides., Results: Plasma glucagon, insulin and glucagon-like peptide-1 levels were increased by imeglimin administration in high-fat, high-sucrose diet-fed mice. Glucose clamp experiments showed that the glucagon increase was not caused by reduced blood glucose levels. After both single and long-term administration of imeglimin, glucagon secretions were significantly enhanced during glucose tolerance tests. Milder enhancement was observed when using the sequential protocol. Long-term administration of imeglimin did not alter α-cell mass. Intraperitoneal imeglimin administration did not affect glucagon secretion, despite significantly decreased blood glucose levels. Imeglimin did not enhance glucagon secretion from isolated islets. Imeglimin administration improved fatty liver by suppressing de novo lipogenesis through decreasing sterol regulatory element binding protein-1c and carbohydrate response element binding protein and their target genes, while enhancing fatty acid oxidation through increasing carnitine palmitoyltransferase I., Conclusions: Overall, the present results showed that imeglimin enhances glucagon secretion through an indirect mechanism. Our findings also showed that glucagon secretion promoted by imeglimin could contribute to improvement of fatty liver through suppressing de novo lipogenesis and enhancing fatty acid oxidation., (© 2024 The Author(s). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Ribosome profiling, which is based on deep sequencing of ribosome footprints, has served as a powerful tool for elucidating the regulatory mechanism of protein synthesis. However, the current method has substantial issues: contamination by rRNAs and the lack of appropriate methods to measure ribosome numbers in transcripts. Here, we overcome these hurdles through the development of "Ribo-FilterOut", which is based on the separation of footprints from ribosome subunits by ultrafiltration, and "Ribo-Calibration", which relies on external spike-ins of stoichiometrically defined mRNA-ribosome complexes. A combination of these approaches estimates the number of ribosomes on a transcript, the translation initiation rate, and the overall number of translation events before its decay, all in a genome-wide manner. Moreover, our method reveals the allocation of ribosomes under heat shock stress, during aging, and across cell types. Our strategy of modified ribosome profiling measures kinetic and stoichiometric parameters of cellular translation across the transcriptome., (© 2024. The Author(s).)

Pencil-beam presaturation (BeamSAT) magnetic resonance imaging (MRI) produces selective magnetic resonance angiography (MRA) images of specific arteries, including the unilateral internal carotid artery (ICA-selective MRA) or vertebral artery (VA-selective MRA). We evaluate the influence of flow pattern, visualized using BeamSAT MRI, on preoperative cerebral hemodynamic status and postoperative hyperperfusion syndrome (HPS). Patients undergoing carotid artery stenting or carotid endarterectomy were categorized into two groups to evaluate flow pattern. Patients with neither crossflow on BeamSAT MRI nor mismatch in middle cerebral artery (MCA) signal intensity between ICA-selective and conventional MRA were classified into Group I, comprising 29 patients. Group II included all other patients comprising 19 patients, who were suspected of experiencing changes in intracranial flow patterns. Cerebral blood flow and cerebrovascular reactivity (CVR) were assessed using single-photon emission computed tomography, and potential HPS symptoms were retrospectively assessed by chart review. Preoperative ipsilateral CVR was significantly lower in Group II than in Group I (18.0% ± 20.0% vs. 48.3% ± 19.5%; P < 0.0001). Group II showed significantly impaired CVR (odds ratio 17.7, 95% confidence interval 1.82-171; P = 0.013) in multivariate analysis. The partial areas under the curve of the BeamSAT logistic model (0.843) were significantly larger than those of the conventional logistic model (0.626) over the range of high sensitivity (0.6-1) (P = 0.04). The incidence of postoperative HPS symptoms was significantly higher in Group II than in Group I (8/19 vs. 1/29; P = 0.001). BeamSAT MRI may be a valuable and non-invasive tool for assessing cerebral hemodynamics and predicting postoperative HPS., Competing Interests: Declaration of competing interest The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Characterization and modeling of biological neural networks has emerged as a field driving significant advancements in our understanding of brain function and related pathologies. As of today, pharmacological treatments for neurological disorders remain limited, pushing the exploration of promising alternative approaches such as electroceutics. Recent research in bioelectronics and neuromorphic engineering have fostered the development of the new generation of neuroprostheses for brain repair. However, achieving their full potential necessitates a deeper understanding of biohybrid interaction. In this study, we present a novel real-time, biomimetic, cost-effective and user-friendly neural network capable of real-time emulation for biohybrid experiments. Our system facilitates the investigation and replication of biophysically detailed neural network dynamics while prioritizing cost-efficiency, flexibility and ease of use. We showcase the feasibility of conducting biohybrid experiments using standard biophysical interfaces and a variety of biological cells as well as real-time emulation of diverse network configurations. We envision our system as a crucial step towards the development of neuromorphic-based neuroprostheses for bioelectrical therapeutics, enabling seamless communication with biological networks on a comparable timescale. Its embedded real-time functionality enhances practicality and accessibility, amplifying its potential for real-world applications in biohybrid experiments., (© 2024. The Author(s).)

Mutations in ARID1B, a member of the mSWI/SNF complex, cause severe neurodevelopmental phenotypes with elusive mechanisms in humans. The most common structural abnormality in the brain of ARID1B patients is agenesis of the corpus callosum (ACC), characterized by the absence of an interhemispheric white matter tract that connects distant cortical regions. Here, we find that neurons expressing SATB2, a determinant of callosal projection neuron (CPN) identity, show impaired maturation in ARID1B +/- neural organoids. Molecularly, a reduction in chromatin accessibility of genomic regions targeted by TCF-like, NFI-like, and ARID-like transcription factors drives the differential expression of genes required for corpus callosum (CC) development. Through an in vitro model of the CC tract, we demonstrate that this transcriptional dysregulation impairs the formation of long-range axonal projections, causing structural underconnectivity. Our study uncovers new functions of the mSWI/SNF during human corticogenesis, identifying cell-autonomous axonogenesis defects in SATB2 + neurons as a cause of ACC in ARID1B patients., Competing Interests: Declaration of interests J.A.K. is an inventor on patents describing the cerebral organoid technology (patent numbers: US10407664B2, EP12196954.7A) and co-founder and scientific advisory board member of a:head bio AG., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Muscle fiber type composition (% slow-twitch and % fast-twitch fibers) is associated with metabolism, with increased slow-twitch fibers alleviating metabolic disorders. Previously, we reported that dietary fish oil intake induced a muscle fiber-type transition in a slower direction in rats. The aim of this study was to determine the functionality of eicosapentaenoic acid (EPA), a unique fatty acid in fish oil, to skeletal muscle fiber type and metabolism in rats. Here, we showed that dietary EPA promotes whole-body oxidative metabolism and improves muscle function by increasing proportion of slow-twitch type 1 fibers in rats. Transcriptomic and metabolomic analyses revealed that EPA supplementation activated the peroxisome proliferator-activated receptor δ (PPARδ) and AMP-activated protein kinase (AMPK) pathways in L6 myotube cultures, which potentially increasing slow-twitch fiber share. This highlights the role of EPA as an exercise-mimetic dietary component that improves metabolism and muscle function, with potential benefits for health and athletic performance., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

An inter-regional cortical tract is one of the most fundamental architectural motifs that integrates neural circuits to orchestrate and generate complex functions of the human brain. To understand the mechanistic significance of inter-regional projections on development of neural circuits, we investigated an in vitro neural tissue model for inter-regional connections, in which two cerebral organoids are connected with a bundle of reciprocally extended axons. The connected organoids produced more complex and intense oscillatory activity than conventional or directly fused cerebral organoids, suggesting the inter-organoid axonal connections enhance and support the complex network activity. In addition, optogenetic stimulation of the inter-organoid axon bundles could entrain the activity of the organoids and induce robust short-term plasticity of the macroscopic circuit. These results demonstrated that the projection axons could serve as a structural hub that boosts functionality of the organoid-circuits. This model could contribute to further investigation on development and functions of macroscopic neuronal circuits in vitro., (© 2024. The Author(s).)

Current gene silencing tools based on RNA interference (RNAi) or, more recently, clustered regularly interspaced short palindromic repeats (CRISPR)‒Cas13 systems have critical drawbacks, such as off-target effects (RNAi) or collateral mRNA cleavage (CRISPR‒Cas13). Thus, a more specific method of gene knockdown is needed. Here, we develop CRISPRδ, an approach for translational silencing, harnessing catalytically inactive Cas13 proteins (dCas13). Owing to its tight association with mRNA, dCas13 serves as a physical roadblock for scanning ribosomes during translation initiation and does not affect mRNA stability. Guide RNAs covering the start codon lead to the highest efficacy regardless of the translation initiation mechanism: cap-dependent, internal ribosome entry site (IRES)-dependent, or repeat-associated non-AUG (RAN) translation. Strikingly, genome-wide ribosome profiling reveals the ultrahigh gene silencing specificity of CRISPRδ. Moreover, the fusion of a translational repressor to dCas13 further improves the performance. Our method provides a framework for translational repression-based gene silencing in eukaryotes., (© 2024. The Author(s).)

Background: The treatment of vertebrobasilar junction (VBJ) aneurysms is challenging. Although flow diverters (FDs) are a possible treatment option, geometrical conditions hinder intervention. VBJ aneurysms possess dual inflow vessels from the bilateral vertebral arteries (VAs), one of which is ideally occluded prior to FD treatment. However, it remains unclear which VA should be occluded., Observations: A 75-year-old male with a growing VBJ complex aneurysm exhibiting invagination toward the brainstem and causing perifocal edema required intervention. Preoperative computational fluid dynamics (CFD) analysis demonstrated that left VA occlusion would result in more stagnant flow and less impingement of flow than right VA occlusion. According to the simulated strategy, surgical clipping of the left VA just proximal to the aneurysm was performed, followed by FD placement from the basilar artery trunk to the right VA. The patient demonstrated tolerance of the VA occlusion, and follow-up computed tomography angiography at 18 months after FD treatment confirmed the disappearance of the aneurysm., Lessons: Preoperative flow dynamics simulations using CFD analysis can reveal an optimal treatment strategy involving a hybrid surgery that combines FD placement and direct surgical occlusion for a VBJ complex aneurysm.

Motor nerve organoids could be generated by culturing a spheroid of motor neurons differentiated from human induced pluripotent stem (iPS) cells within a polydimethylsiloxane (PDMS) chip which guides direction and fasciculation of axons extended from the spheroid. To isolate axon bundles from motor nerve organoids, we developed a rapid laser dissection method based on localized photothermal combustion. By illuminating a blue laser on a black mark on the culture device using a dry-erase marker, we induced highly localized heating near the axon bundles. Moving the laser enabled spatial control over the local heating and severing of axon bundles. This laser dissection requires a black mark, as other colors did not produce the same localized heating effect. A CO 2 laser destroyed the tissue and the device and could not be used. With this simple, economical laser dissection technique, we could rapidly collect abundant pure axon samples from motor nerve organoids for biochemical analysis. Extracted axonal proteins and RNA were indistinguishable from manual dissection. This method facilitates efficient axon isolation for further analyses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ikegami, Duenki, Arakaki, Sakai, Osaki, Ashihara, Furushima and Ikeuchi.)