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A first-in-human investigator-initiated clinical study of a corneal endothelial cell substitute (CLS001) derived from a clinical-grade induced pluripotent stem cell (iPSC) line shows improvement of visual acuity and corneal stromal edema, with no adverse events for up to 1 year after surgery for the treatment of bullous keratopathy. While preclinical tests, including multiple whole-genome analysis and tumorigenicity tests adhering to the Food and Drug Administration (FDA) draft guidelines, are negative, an additional whole-genome analysis conducted on transplanted CLS001 cells reveals a de novo in-frame deletion of exon22 in the EP300 gene. No adverse events related to the mutation are observed. Our study demonstrates the feasibility of using iPSC-derived cells to replace donor transplant for bullous keratopathy, while shedding light on risk management of gene mutation in cell products. Further follow-up is required for long-term analysis of clinical safety and efficacy., Competing Interests: Declaration of interests S.S. and S.H. have a patent on CLS001 differentiation protocol., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

In the last decades, research from cognitive science, clinical psychology, psychiatry, and social neuroscience has provided mounting evidence that several social cognitive abilities are impaired in people with schizophrenia and contribute to functional difficulties and poor clinical outcomes. Social dysfunction is a hallmark of the illness, and yet, social cognition is seldom assessed in clinical practice or targeted for treatment. In this article, 17 international experts, from three different continents and six countries with expertise in social cognition and social neuroscience in schizophrenia, convened several meetings to provide clinicians with a summary of the most recent international research on social cognition evaluation and treatment in schizophrenia, and to lay out primary recommendations and procedures that can be integrated into their practice. Given that many extant measures used to assess social cognition have been developed in North America or Western Europe, this article is also a call for researchers and clinicians to validate instruments internationally and we provide preliminary guidance for the adaptation and use of social cognitive measures in clinical and research evaluations internationally. This effort will assist promoting scientific rigor, enhanced clinical practice, and will help propel international scientific research and collaboration and patient care.

This study introduces a novel method for rapidly and efficiently inducing human spinal lower motor neurons (LMNs) from induced pluripotent stem cells (iPSCs) to eventually elucidate the pathomechanisms of amyotrophic lateral sclerosis (ALS) and facilitate drug screening. Previous methods were limited by low induction efficiency, poor LMN purity, or labor-intensive induction and evaluation processes. Our protocol overcomes these challenges, achieving around 80% induction efficiency within just two weeks by combining a small molecule-based approach with transcription factor transduction. Moreover, to exclude non-LMN cells from the analysis, we utilized time-lapse microscopy and machine learning to analyze the morphology and viability of iPSC-derived LMNs on a single-cell basis, establishing an effective pathophysiological evaluation system. This rapid, efficient, and streamlined protocol, along with our single-cell-based evaluation method, enables large-scale analysis and drug screening using iPSC-derived motor neurons., Competing Interests: Declaration of interests H.O. reports grants and personal fees from K Pharma Inc and SanBio Co. Ltd., outside the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Despite the lack of clinically validated strategies for treating spinal cord injury (SCI), combining therapeutic strategies with rehabilitation is believed to promote recovery of motor function; however, current research findings are inconsistent., Objectives: To explore whether combination therapy involving therapy and rehabilitative training (CIRT) has a synergistic effect on motor function recovery in animal models of SCI., Methods: We conducted a systematic review and meta-analysis of studies identified in a keyword search of 6 databases and extracted open-field motor scores from the Basso Mouse Scale (BMS) and the Basso, Beattie, and Bresnahan Locomotor Rating Scale (BBB) for meta-analysis using a weighted mean difference (WMD) and 95 % CI. We also performed qualitative synthesis and analysis of secondary outcome measures related to histological improvements and adverse effects., Results: Eighty-seven preclinical studies were included. Combination treatment with treadmill training resulted in a significant improvement in motor function (1.40, 95 % CI 0.82 to 1.98, P < 0.01, I 2 = 49 %), especially when initiated 1-2 weeks post-injury (1.77, 95 % CI 1.10 to 2.45, P < 0.01, I 2 = 33 %) in rats. In mice, CIRT lasting <6 weeks may enhance recovery (0.95, 95 % CI 0.49 to 1.40, P < 0.01, I 2 = 33 %). Although there is a trend toward better outcomes in the chronic phase, insufficient sample sizes prevent definitive conclusions from being drawn. Combined therapy also enhances the reorganization of inhibitory synaptic structures and functions, without aggravating allodynia or spasticity., Conclusions: This systematic review and meta-analysis suggest that CIRT can lead to superior motor function recovery compared to single-modality therapy (SMT) in animal models of SCI, with no significant adverse effects on allodynia or spasticity. However, the efficacy of CIRT depends on various factors, and further research is needed to establish optimal treatment strategies and understand the underlying mechanisms of recovery., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

In this study, anion-responsive π-conjugated macrocycles were synthesized to demonstrate anion-binding and ion-pairing properties along with the ordered structures. Ion-pairing charge-by-charge assembly of a [1+2]-type complex of a macrocycle as a pseudo π-electronic anion and a countercation was revealed by single-crystal X-ray analysis. Further, two-dimensional (2D) arrays of the macrocycles bearing alkoxy chains, exhibiting anion-driven disordered structures, were constructed on a highly oriented pyrolytic graphite (HOPG) substrate as observed by scanning tunneling microscopy (STM)., (© 2025 The Author(s). Chemistry - An Asian Journal published by Wiley-VCH GmbH.)

Sjögren-Larsson syndrome (SLS) is an autosomal recessive leukodystrophy characterized by ichthyosis, intellectual disability, and progressive spastic paralysis caused by biallelic pathogenic variants in the ALDH3A2 gene that encodes the fatty aldehyde dehydrogenase, fatty aldehyde dehydrogenase (FALDH); FALDH catalyzes several metabolic reactions involved in fatty aldehyde oxidation. Only a few studies have been performed to determine the lipid profile of patients with SLS. In a previous postmortem study of the brain of a 65-year-old patient with SLS, lipidomic analysis revealed an accumulation of long-chain unsaturated ether lipid species in the white matter and gray matter. In the present study, we established a disease model using patient-derived neuronal and oligodendrocyte lineage cells to analyze the lipid metabolism and gene expression profiles in SLS. To achieve this, we generated induced pluripotent stem cells (iPSCs) from two patients with the SLS phenotype carrying previously known ALDH3A2 pathogenic variants: One was a compound heterozygote (c.1339A>G:p.(Lys447Glu) and c.57&#95;132dup:p.(Ile45Serfs*34)) and the other was a homozygote (c.1339A>G: p.(Lys447Glu)). The FALDH activity was almost zero in the SLS-iPSC lines established from both patients. Phospholipid analysis of neurospheres, and oligospheres (spheres enriched with oligodendrocyte-lineage cells) derived from the iPSCs by liquid chromatography-mass spectrometry showed accumulation of ether phospholipids in the Sjögren-Larsson patient-derived neurospheres and oligospheres. The results are consistent with the previously reported accumulation of ether lipids in the postmortem brain tissue of an SLS patient. Therefore, iPSCs and iPSC-derived neurospheres and oligospheres established from SLS patients can be useful tools for future pathological analysis of the central nervous system pathophysiology in SLS., (© 2024 The Author(s). Congenital Anomalies published by John Wiley & Sons Australia, Ltd on behalf of Japanese Teratology Society.)

Eosinophilic pneumonia is a known side effect of dupilumab; however, diffuse alveolar hemorrhage has not yet been reported in association with dupilumab. We herein report a case of diffuse alveolar hemorrhage caused by dupilumab. A 57-year-old man with severe asthma was unable to discontinue oral steroids and thus was prescribed dupilumab. The patient was admitted to the hospital four weeks after treatment because of suspected eosinophilic pneumonia. Bronchoscopy revealed diffuse alveolar hemorrhage characterized by hemosiderin-phagocytic macrophages in the bronchoalveolar lavage fluid without eosinophils. The steroid dosage improved the respiratory status and resolved the infiltrate shadow. Dupilumab may thus cause diffuse alveolar hemorrhage, which can be differentiated using bronchoscopy.

Chronic complete spinal cord injury (SCI) is difficult to treat because of scar formation and cavitary lesions. While human iPS cell-derived neural stem/progenitor cell (hNS/PC) therapy shows promise, its efficacy is limited without the structural support needed to address cavitary lesions. Our study investigated a combined approach involving surgical scar resection, decellularized extracellular matrix (dECM) hydrogel as a scaffold, and hNS/PC transplantation. To mitigate risks such as prion disease associated with spinal cord-derived dECM, we used kidney-derived dECM hydrogel. This material was chosen for its biocompatibility and angiogenic potential. In vitro studies with dorsal root ganglia (DRG) confirmed its ability to support axonal growth. In a chronic SCI rat model, scar resection enhanced the local microenvironment by increasing neuroprotective microglia and macrophages, while reducing inhibitory factors that prevent axonal regeneration. The combination of scar resection and dECM hydrogel further promoted vascular endothelial cell migration. These changes improved the survival of transplanted hNS/PCs and facilitated host axon regeneration. Overall, the integrated approach of scar resection, dECM hydrogel scaffolding, and hNS/PC transplantation has been proven to be a more effective treatment strategy for chronic SCI. However, despite histological improvements, no functional recovery occurred and further research is needed to enhance functional outcomes., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Introduction: Tau protein plays a pivotal role in the pathogenesis of Alzheimer's disease (AD) and in regulating neuronal excitability. Among tau-coding microtubule associated protein tau ( MAPT ) gene mutations, the A152T mutation is reported to increase the risk of AD and neuronal excitability in mouse models., Methods: To investigate the effects of MAPT gene expression and its mutations on neuronal activity in human neurons, we employed genome editing technology to introduce the A152T or P301S mutations into induced pluripotent stem cells (iPSCs). We then differentiated them into excitatory and inhibitory neurons. As a control, iPSCs in which the MAPT gene was replaced with a fluorescent protein were also created., Results: In excitatory neuronal cultures, the A152T mutation was found to enhance spontaneous neuronal activity and the association of tau and Fyn. However, in inhibitory neuron-enriched cultures, the A152T mutation did not affect neuronal activity. Inhibition of NMDA receptors (NMDAR) and the reduction of tau protein levels decreased neuronal excitability in both A152T/A152T and healthy control (WT/WT) excitatory neurons. In addition, the A152T mutation increased the interaction between tau and Fyn. These findings suggest that the tau-Fyn interaction plays a critical role in regulating neuronal activity under physiological conditions, while the A152T mutation enhances neuronal activity by strengthening this endogenous interaction between tau and Fyn. In addition, transcriptomic analysis revealed structural changes specific to excitatory neurons with the A152T mutation. Common changes observed in both A152T and P301S lines recapitulated a dedifferentiation phenotype, consistent with previous reports., Conclusions: These data demonstrate that the A152T mutation in the MAPT gene increases neuronal excitability through the tau-Fyn-NMDAR pathway in excitatory neurons, shedding light on its role in AD pathogenesis., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:This research project was conducted in collaboration with Keio University and Fujifilm Corporation. H.T., K.S., K.N., and S. E.-Y. are employees of Fujifilm Corporation. H.O. is a founder scientist and a Scientific Advisory Board Member for SanBio Co., Ltd., and K Pharma Inc. H.T., S. E.-Y., S. M., and H.O. are inventors on a patent application (JP 2021-61793, US2022-0326225) for "PLURIPOTENT STEM CELL, NERVE CELL, AND APPLICATION THEREOF". The remaining authors declare no conflicts of interest., (© 2024 The Author(s).)

We present the case of a 54-year-old woman who was diagnosed with intraductal papillary neoplasm of the bile duct (IPNB) in the remnant intrapancreatic bile duct, 37 years after surgery for congenital biliary dilatation. Endoscopic ultrasonography revealed a papillary, low-echoic mass in the intrapancreatic bile duct, and peroral cholangioscopy revealed a papillary mucosa. A pancreaticoduodenectomy was performed, and the patient was pathologically diagnosed with type 1 pancreatobiliary-type IPNB with associated invasive carcinoma. As a similar atypical epithelium was identified in the pancreatic duct, it was suggested that the IPNB extended longitudinally to the pancreatic duct through the common channel.

As the field of neural organoids and assembloids rapidly expands, there is an emergent need for guidance and advice on designing, conducting and reporting experiments to increase the reproducibility and utility of these models. Here, our consortium- representing specialized laboratories from around the world- presents a framework for the experimental process that ranges from ensuring the quality and integrity of human pluripotent stem cells to characterizing and manipulating neural cells in vitro, and from transplantation techniques to considerations for modeling human development, evolution, and disease. As with all scientific endeavors, we advocate for rigorous experimental designs tailored to explicit scientific questions, and transparent methodologies and data sharing, to provide useful knowledge for both current research practices and for developing regulatory standards., (© 2024. Springer Nature Limited.)

Background and study aims Because more than a few patients have intraductal papillary mucinous neoplasms of the pancreas (IPMNs) with mural nodules (MNs) that are benign, clinical plans should be determined by using histocytological specimens especially, for patients with high risk for surgery or with a small MN. Patients and methods This study included 27 patients to evaluate the efficacy of peroral pancreatoscopy using a SpyGlass DS system (POPS-DS) for patients with MN-positive IPMN, mainly focusing on the ability of POPS-DS to detect malignancy. Results Biopsy specimens obtained under POPS-DS guidance could be used for histological evaluation of all patients with MNs in the main pancreatic duct and 67% of the patients with MNs in the branch ducts, whereas fluid specimens collected during POPS-DS could be used for histocytological evaluation for all patients. For the 13 patients who underwent surgery just after POPS-DS, the sensitivity, specificity, and accuracy of POPS-DS to detect malignancy were 89%, 100%, and 92%, respectively. For the 12 patients who underwent surveillance without surgery, the cumulative 3-year progression rates for nine benign IPMNs and three malignant ones determined using POPS-DS were 0% and 100%, respectively. However, the sensitivity of POPS to detect IPMN epithelium in the resection margin was 20%. Only one patient developed procedure-related pancreatitis (mild). Conclusions POPS-DS could be used to accurately detect malignancy in patients with MN-positive IPMN. Therefore, histocytological evaluation using POPS-DS can contribute to selection of patients for whom surgery would be appropriate., Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Objective Surgery is recommended for large pedunculated gallbladder polyps (PGPs), which measure 10 mm or more in size, because they tend to be neoplastic polyps (NPs), such as adenomas and adenocarcinomas. However, after resection, they are often found to be non-neoplastic polyps (non-NPs). This study aimed to evaluate the usefulness of plain computed tomography (CT) in distinguishing NPs from non-NPs. Methods Of the 80 patients who underwent cholecystectomy for PGPs ≥10 mm between January 2008 and February 2021, 46 who underwent plain and contrast-enhanced CT (CE-CT) before resection were included in this study. We retrospectively assessed the polyp detection rate (PDR) using CT and calculated the difference in the CT values between PGPs and the surrounding bile. Results Twenty-one patients had NPs (12 adenomas, 5 carcinomas in adenoma, and 4 adenocarcinomas). The others were non-NPs (24 cholesterol polyps and one hyperplastic polyp). The PDR using plain CT was significantly higher in the NP group than in the non-NP group (38% (8/21) vs. 0% (0/25), p <0.01). The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of NPs were 38%, 100%, 100%, 66%, and 72%, respectively. The difference in the CT values between PGPs and the surrounding bile was significantly larger in the NP group than in the non-NP group (14.12 ± 11.38 HU, 5.04 ± 6.15 HU, p <0.01). Conclusions PGPs detected using plain CT had a high probability of being NPs. Plain CT is therefore considered to be useful for differentiating NPs from non-NPs.

Ex vivo studies of the brain are often employed as experimental systems in neuroscience. In general, brains for ex vivo MRI studies are usually fixed with paraformaldehyde to preserve molecular structure and prevent tissue destruction during long-term storage. As a result, fixing brain tissue causes microstructural changes and a decrease in brain volume. Therefore, the purpose of this study was to investigate the regional effect of brain volume and microstructural changes on the restricted diffusion of water molecules in the common marmoset brain using in vivo and ex vivo brains from the same individual. We used 9.4T magnetic resonance imaging and also compared the T2-weighted images and diffusion-weighted imaging (DWI) data between in vivo and ex vivo brains to investigate changes in brain volume and diffusion of water molecules in 12 common marmosets. We compared fractional anisotropy, mean diffusivity, AD (axial diffusivity), and radial diffusivity values in white matter and gray matter between in vivo and ex vivo brains. We observed that AD showed the strongest correlation with regional volume changes in gray matter. The results showed a strong correlation between AD and changes in brain volume. By comparing the in vivo and ex vivo brains of the same individual, we identified significant correlations between the local effects of perfusion fixation on microstructural and volumetric changes of the brain and alterations in the restricted diffusion of water molecules within the brain. These findings provide valuable insights into the complex relationships between tissue fixation, brain structure, and water diffusion properties in the marmoset brain., (© 2024. The Author(s).)

Estimating the direction of functional connectivity (FC) can help further elucidate complex brain function. However, the estimation of directed FC at the voxel level in fMRI data, and evaluating its performance, has yet to be done. We therefore developed a novel directed seed-based connectivity analysis (SCA) method based on normalized pairwise Granger causality that provides greater detail and accuracy over ROI-based methods. We evaluated its performance against 145 cortical retrograde tracer injections in male and female marmosets that were used as ground truth cellular connectivity on a voxel-by-voxel basis. The receiver operating characteristic (ROC) curve was calculated for each injection, and we achieved area under the ROC curve of 0.95 for undirected and 0.942 for directed SCA in the case of high cell count threshold. This indicates that SCA can reliably estimate the strong cellular connections between voxels in fMRI data. We then used our directed SCA method to analyze the human default mode network (DMN) and found that dlPFC (dorsolateral prefrontal cortex) and temporal lobe were separated from other DMN regions, forming part of the language-network that works together with the core DMN regions. We also found that the cerebellum (Crus I-II) was strongly targeted by the posterior parietal cortices and dlPFC, but reciprocal connections were not observed. Thus, the cerebellum may not be a part of, but instead a target of, the DMN and language-network. Summarily, our novel directed SCA method, visualized with a new functional flat mapping technique, opens a new paradigm for whole-brain functional analysis., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Advanced pathological and genetic approaches have revealed that mutations in fused in sarcoma/translated in liposarcoma (FUS/TLS), which is pivotal for DNA repair, alternative splicing, translation and RNA transport, cause familial amyotrophic lateral sclerosis (ALS). The generation of suitable animal models for ALS is essential for understanding its pathogenesis and developing therapies. Therefore, we used CRISPR-Cas9 to generate FUS-ALS mutation in the non-classical nuclear localization signal (NLS), H517D (mouse position: H509D) and genome-edited mice. Fus WT/H509D mice showed progressive motor impairment (accelerating rotarod and DigiGait system) with age, which was associated with the loss of motor neurons and disruption of the nuclear lamina and nucleoporins and DNA damage in spinal cord motor neurons. We confirmed the validity of our model by showing that nuclear lamina and nucleoporin disruption were observed in lower motor neurons differentiated from patient-derived human induced pluripotent stem cells (hiPSC-LMNs) with FUS-H517D and in the post-mortem spinal cord of patients with ALS. RNA sequence analysis revealed that most nuclear lamina and nucleoporin-linking genes were significantly decreased in FUS-H517D hiPSC-LMNs. This evidence suggests that disruption of the nuclear lamina and nucleoporins is crucial for ALS pathomechanisms. Combined with patient-derived hiPSC-LMNs and autopsy samples, this mouse model might provide a more reliable understanding of ALS pathogenesis and might aid in the development of therapeutic strategies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Abstract: Spinal cord injury (SCI) results in permanent neurological dysfunction and neuropathic pain. To address this pathology, we recently conducted a clinical study in which we transplanted neural precursor cells (NPCs) derived from human induced pluripotent stem cells into patients during the subacute phase of SCI. One of the therapeutic mechanisms of cell transplantation is the formation of synaptic connections with the host's neural tissues, which we demonstrated using a chemogenetic tool. In addition, we have developed innovative strategies to enhance the effectiveness of cell transplantation through gene therapy. Moreover, our current study is focused on developing cell therapy for chronic SCI, a more challenging pathology characterized by the formation of cavities and scar tissue. In such situations, transplanting NPCs with neurogenic properties could effectively penetrate scar tissue and form functional synapses with the host neurons. To improve the outcomes of cell transplantation alone, we have found that incorporating rehabilitation is beneficial. In animal models of SCI, we have established an effective rehabilitative training program in which NPCs were transplanted during the chronic phase. Robotic rehabilitation has demonstrated improvements in gait ability and trunk function in clinical situations. Therefore, regenerative medicine shows promise for chronic SCI, particularly when rehabilitation strategies are incorporated., (Copyright © 2024 International Association for the Study of Pain.)

Intervention for social cognition could be key to improving social functioning in patients with schizophrenia. A first step towards its clinical implementation involves interviewing patients about their subjective difficulties with social cognition as they experience them in the real world. The present study focused on the clinical subtypes classified by the discrepancies between the subjective difficulties in social cognition and actual cognitive impairment. A total of 131 outpatients with schizophrenia and 68 healthy controls were included. Objective measurement of social cognition was performed using a test battery covering four representative domains, and subjective difficulties were determined by a questionnaire covering the same domains. A two-step cluster analysis explored the potential classification of social cognition in patients with schizophrenia. There was little correlation between the objective performance on social cognition tasks and subjective difficulties in social cognition. The analysis yielded three clusters: the low-impact group (low objective impairment and low subjective difficulties), the unaware group (high objective impairment but low subjective difficulties), and the perceptive group (moderate objective impairment and high subjective difficulties). Positive, negative, and general symptoms were more severe in the two groups that showed impaired performance on the social cognition tasks (i.e., the unaware and perceptive groups) than those in the low-impact group. Neurocognition and functional capacity were the lowest in the unaware group, and social functioning was the lowest in the perceptive group. Awareness about the clinical subtypes of social cognition could serve as a guidepost for providing individualized, targeted interventions., (© 2024. The Author(s).)

A 70-year-old man was incidentally diagnosed with a single hepatic mass lesion in his right hepatic lobe during a computed tomography scan. The lesion exhibited consistent enhancement with contrast agents on computed tomography (CT), magnetic resonance imaging (MRI), and hepatic arterial angiography. While a definitive diagnosis could not be made preoperatively, the lesion was surgically resected due to its slight enlargement over two months, suggesting a potential malignancy. Pathological examination revealed the lesion to be a bile duct adenoma (BDA). The BDA was characterized by dense proliferative small gland cavities containing several to dozens of cells. Immunohistochemical staining showed positive CK7 and negative p53. The patient remains alive and free of recurrence five years after hepatectomy. Although BDAs are rare benign hepatic tumors, they carry a risk of harboring or developing malignant tissue, such as cholangiocarcinoma. Therefore, BDAs or lesions suspicious of BDA should be surgically resected or closely monitored., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Okano et al.)

Purpose: The importance of tumor markers is well established; yet little is known about their prognostic value for patients with obstructive colorectal cancer (OCRC). We investigated the clinical significance of carcinoembryonic antigen (CEA) and CA 19-9 levels in patients with non-metastatic OCRC, who underwent insertion of a self-expandable metallic stent and curative surgery., Methods: Clinical data on 91 patients with OCRC were analyzed retrospectively to evaluate the associations of preoperative serum values of tumor makers with short- and long-term outcomes., Results: The 91 patients comprised 53 men and 38 women, with a median age of 71 years. Twelve patients had an elevated preoperative CA 19-9 level. Multivariate analyses revealed that an elevated CA 19-9 level was independently associated with poor disease-free survival (DFS) [hazard ratio (HR) = 4.57, 95% confidence interval (CI) 2.06-10.14, P < 0.001] and overall survival (HR = 4.06, 95% CI 1.46-11.24, P = 0.007). A CEA level > 5 ng/ml had no prognostic value, whereas a CEA level > 10.8 ng/ml was significantly associated with worse DFS (P = 0.032)., Conclusion: Measuring the CA 19-9 level concomitantly with the CEA level for patients with advanced CRC, including OCRC, may provide a valuable means to improve prognostication., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

The common marmoset is an essential model for understanding social cognition and neurodegenerative diseases. This study explored the structural and functional brain connectivity in a marmoset under isoflurane anesthesia, aiming to statistically overcome the effects of high inter-individual variability and noise-related confounds such as physiological noise, ensuring robust and reliable data. Similarities and differences in individual subject data, including assessments of functional and structural brain connectivities derived from resting-state functional MRI and diffusion tensor imaging were meticulously captured. The findings highlighted the high consistency of structural neural connections within the species, indicating a stable neural architecture, while functional connectivity under anesthesia displayed considerable variability. Through independent component and dual regression analyses, several distinct brain connectivities were identified, elucidating their characteristics under anesthesia. Insights into the structural and functional features of the marmoset brain from this study affirm its value as a neuroscience research model, promising advancements in the field through fundamental and translational studies., Competing Interests: Declaration of competing interest None, (Copyright © 2024. Published by Elsevier Inc.)

Purpose: This study explores the application of adipose-derived mesenchymal stromal cells (adMSCs) as a therapy for ocular inflammatory diseases utilizing a chronic GVHD model., Methods: Human adMSCs were administered via subconjunctival injection into mice with chronic ocular GVHD. Clinical scores and changes in T cell populations were analyzed., Results: The study showed significant improvement in corneal integrity, including epithelial damage, opacity, thickness, and structure, after subconjunctival adMSC transplantation. Additionally, adMSC transplantation increased CD45 + and Foxp3 + Tregs while decreasing CD4 + T cells, 1IL17A + Th17 cells, and IFNγ + Th1 cells in local cervical lymph nodes. Moreover, adMSC-conditioned media enhanced wound closure and cell migration toward the wound bed in vitro. The cells disappeared within a week suggesting that trophic factors were involved., Conclusion: The dual benefit of adMSCs in immune-related ocular disorders underscores their potential for clinical application. This study focuses on subconjunctival delivery, effects of adMSCs and migration post-injection, with implications for optimizing cellular therapy application. The observed dual action, combining immunomodulation and tissue repair enhancement, underscores holistic approach of adMSC therapy in regenerative medicine, making it a potent treatment for diseases involving inflammation and tissue damage in the ocular surface., Competing Interests: Disclosure of potential conflicts of interest R. T. and H. N are affiliated with Rohto Pharmaceuticals, a company with a vested interest in the clinical application of the cells utilized in this study. The study was supported by a grant from the Japan Society for the Promotion of Science (JSPS) to S. S. The study was funded in part by Rohto Pharmaceuticals., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Many RNA-binding proteins (RBPs) are linked to the dysregulation of RNA metabolism in motor neuron diseases (MNDs). However, the molecular mechanisms underlying MN vulnerability have yet to be elucidated. Here, we found that such an RBP, Quaking5 (Qki5), contributes to formation of the MN-specific transcriptome profile, termed "MN-ness," through the posttranscriptional network and maintenance of the mature MNs. Immunohistochemical analysis and single-cell RNA sequencing (scRNA-seq) revealed that Qki5 is predominantly expressed in MNs, but not in other neuronal populations of the spinal cord. Furthermore, comprehensive RNA sequencing (RNA-seq) analyses revealed that Qki5-dependent RNA regulation plays a pivotal role in generating the MN-specific transcriptome through pre-messenger ribonucleic acid (mRNA) splicing for the synapse-related molecules and c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) signaling pathways. Indeed, MN-specific ablation of the Qki5 caused neurodegeneration in postnatal mice and loss of Qki5 function resulted in the aberrant activation of stress-responsive JNK/SAPK pathway both in vitro and in vivo. These data suggested that Qki5 plays a crucial biological role in RNA regulation and safeguarding of MNs and might be associated with pathogenesis of MNDs., Competing Interests: Competing interests statement:H.O. is a paid member of the Scientific Advisory Boards of San Bio Co., Ltd., and K Pharma Inc. M. Yano is a paid member of the Scientific Advisory Board of K Pharma Inc.

Disease-related cells differentiated from patient-derived iPSCs are useful for elucidating the pathophysiological mechanisms underlying these diseases. In this study, four iPSC lines were established from independent patients with sensorineural hearing loss and a mutation in EYA4. These iPSCs showed pluripotency, the capacity to differentiate into three germ layers, and normal karyotypes, suggesting that these lines are useful for the pathological study of sensorineural hearing loss and drug screening for ear disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background/aims: Endoscopic biliary drainage using self-expandable metallic stents (SEMSs) for malignant biliary strictures occasionally induces acute cholecystitis (AC). This study evaluated the efficacy of prophylactic gallbladder stents (GBS) during SEMS placement., Methods: Among 158 patients who underwent SEMS placement for malignant biliary strictures between January 2018 and March 2023, 30 patients who attempted to undergo prophylactic GBS placement before SEMS placement were included., Results: Technical success was achieved in 21 cases (70.0%). The mean diameter of the cystic duct was more significant in the successful cases (6.5 mm vs. 3.7 mm, p<0.05). Adverse events occurred for 7 patients (23.3%: acute pancreatitis in 7; non-obstructive cholangitis in 1; perforation of the cystic duct in 1 with an overlap), all of which improved with conservative treatment. No patients developed AC when the GBS placement was successful, whereas 25 of the 128 patients (19.5%) without a prophylactic GBS developed AC during the median follow-up period of 357 days (p=0.043). In the multivariable analysis, GBS placement was a significant factor in preventing AC (hazard ratio, 0.61; 95% confidence interval, 0.37-0.99; p=0.045)., Conclusions: GBS may contribute to the prevention of AC after SEMS placement for malignant biliary strictures.

The field of aging biology, which aims to extend healthy lifespans and prevent age-related diseases, has turned its focus to the Callithrix jacchus (common marmoset) to understand the aging process better. This study utilized magnetic resonance imaging (MRI) to non-invasively analyze the brains of 216 marmosets, investigating age-related changes in brain structure; the relationship between body weight and brain volume; and potential differences between males and females. The key findings revealed that, similar to humans, Callithrix jacchus experiences a reduction in total intracranial volume, cortex, subcortex, thalamus, and cingulate volumes as they age, highlighting site-dependent changes in brain tissue. Notably, the study also uncovered sex differences in cerebellar volume. These insights into the structural connectivity and volumetric changes in the marmoset brain throughout aging contribute to accumulating valuable knowledge in the field, promising to inform future aging research and interventions for enhancing healthspan., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is a major neurodegenerative disease for which there is currently no curative treatment. The blood-brain barrier (BBB), multiple physiological functions formed by mainly specialized brain microvascular endothelial cells (BMECs), serves as a gatekeeper to protect the central nervous system (CNS) from harmful molecules in the blood and aberrant immune cell infiltration. The accumulation of evidence indicating that alterations in the peripheral milieu can contribute to neurodegeneration within the CNS suggests that the BBB may be a previously overlooked factor in the pathogenesis of ALS. Animal models suggest BBB breakdown may precede neurodegeneration and link BBB alteration to the disease progression or even onset. However, the lack of a useful patient-derived model hampers understanding the pathomechanisms of BBB dysfunction and the development of BBB-targeted therapies. In this study, we differentiated BMEC-like cells from human induced pluripotent stem cells (hiPSCs) derived from ALS patients to investigate BMEC functions in ALS patients. TARDBP N345K/+ carrying patient-derived BMEC-like cells exhibited increased permeability to small molecules due to loss of tight junction in the absence of neurodegeneration or neuroinflammation, highlighting that BMEC abnormalities in ALS are not merely secondary consequences of disease progression. Furthermore, they exhibited increased expression of cell surface adhesion molecules like ICAM-1 and VCAM-1, leading to enhanced immune cell adhesion. BMEC-like cells derived from hiPSCs with other types of TARDBP gene mutations ( TARDBP K263E/K263E and TARDBP G295S/G295S ) introduced by genome editing technology did not show such BMEC dysfunction compared to the isogenic control. Interestingly, transactive response DNA-binding protein 43 (TDP-43) was mislocalized to cytoplasm in TARDBP N345K/+ carrying model. Wnt/β-catenin signaling was downregulated in the ALS patient ( TARDBP N345K/+ )-derived BMEC-like cells and its activation rescued the leaky barrier phenotype and settled down VCAM-1 expressions. These results indicate that TARDBP N345K/+ carrying model recapitulated BMEC abnormalities reported in brain samples of ALS patients. This novel patient-derived BMEC-like cell is useful for the further analysis of the involvement of vascular barrier dysfunctions in the pathogenesis of ALS and for promoting therapeutic drug discovery targeting BMEC., Competing Interests: HO reports grants and personal fees from K Pharma, Inc. during the conduct of the study; and personal fees from Sanbio Co. Ltd., outside the submitted work; In addition, HO has a patent on a therapeutic agent for amyotrophic lateral sclerosis and composition for treatment licensed to K Pharma, Inc. The remaining 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 Matsuo, Nagamatsu, Nagata, Umeda, Shiota, Morimoto, Suzuki, Aoki, Okano, Nakamori and Nishihara.)

We report the establishment of a human induced pluripotent stem cell (iPSC) line from a 54-year-old male patient with an A1555G mutation in the mitochondrial 12S ribosomal RNA gene (MTRNR1), associated with sensorineural hearing loss. The established iPSC line expressed stemness markers or undifferentiated state markers. We also demonstrated the capacity of the cells to differentiate into the three germ layers, suggesting its pluripotency and utility in the pathological study of sensorineural hearing loss and drug screening for ear disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Extracellular vesicles (EVs) hold the potential for elucidating the pathogenesis of amyotrophic lateral sclerosis (ALS) and serve as biomarkers. Notably, the comparative and longitudinal alterations in the protein profiles of EVs in serum (sEVs) and cerebrospinal fluid (CSF; cEVs) of sporadic ALS (SALS) patients remain uncharted. Ropinirole hydrochloride (ROPI; dopamine D2 receptor [D2R] agonist), a new anti-ALS drug candidate identified through induced pluripotent stem cell (iPSC)-based drug discovery, has been suggested to inhibit ALS disease progression in the Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis (ROPALS) trial, but its mechanism of action is not well understood. Therefore, we tried to reveal longitudinal changes with disease progression and the effects of ROPI on protein profiles of EVs., Methods: We collected serum and CSF at fixed intervals from ten controls and from 20 SALS patients participating in the ROPALS trial. Comprehensive proteomic analysis of EVs, extracted from these samples, was conducted using liquid chromatography/mass spectrometer (LC/MS). Furthermore, we generated iPSC-derived astrocytes (iPasts) and performed RNA sequencing on astrocytes with or without ROPI treatment., Results: The findings revealed notable disparities yet high congruity in sEVs and cEVs protein profiles concerning disease status, time and ROPI administration. In SALS, both sEVs and cEVs presented elevated levels of inflammation-related proteins but reduced levels associated with unfolded protein response (UPR). These results mirrored the longitudinal changes after disease onset and correlated with the revised ALS Functional Rating Scale (ALSFRS-R) at sampling time, suggesting a link to the onset and progression of SALS. ROPI appeared to counteract these changes, attenuating inflammation-related protein levels and boosting those tied to UPR in SALS, proposing an anti-ALS impact on EV protein profiles. Reverse translational research using iPasts indicated that these changes may partly reflect the DRD2-dependent neuroinflammatory inhibitory effects of ROPI. We have also identified biomarkers that predict diagnosis and disease progression by machine learning-driven biomarker search., Conclusions: Despite the limited sample size, this study pioneers in reporting time-series proteomic alterations in serum and CSF EVs from SALS patients, offering comprehensive insights into SALS pathogenesis, ROPI-induced changes, and potential prognostic and diagnostic biomarkers., (© 2024. The Author(s).)

Introduction: Spinal cord injury (SCI) is a condition in which the spinal cord parenchyma is damaged by various factors. The mammalian central nervous system has been considered unable to regenerate once damaged, but recent progress in basic research has gradually revealed that injured neural cells can indeed regenerate. Drug therapy using novel agents is being actively investigated as a new treatment for SCI. One notable treatment method is regeneration therapy using hepatocyte growth factors (HGF)., Area Covered: HGF has pluripotent neuroregenerative actions, as indicated by its neuroprotective and regenerative effects on the microenvironment and damaged cells, respectively. This review examines these effects in various phases of SCI, from basic research to clinical studies, and the application of this treatment to other diseases., Expert Opinion: In regenerative medicine for SCI, drug therapies have tended to be more likely to be developed compared to cell replacement treatment. Nevertheless, there are still challenges to be addressed for these clinical applications due to a wide variety of pathology and animal experimental models of basic study, but HGF could be an effective treatment for SCI with expanded application.

Purpose: Sarcopenia influences the short- and long-term outcomes of various medical conditions including malignancy. Ishii's screening test estimates the probability of sarcopenia based on a score calculated by three simple variables: age, grip strength, and calf circumference. We investigated the clinical significance of Ishii's score for patients with non-metastatic obstructive colorectal cancer (OCRC) who underwent curative surgery after intraluminal decompression., Methods: Ishii's score was calculated in 79 patients with OCRC. Muscle volume loss and decreased muscle quality were evaluated by computed tomography (CT) images as skeletal muscle index (SMI) and intramuscular adipose tissue content (IMAC), respectively., Results: There were 46 men and 33 women, with a median age of 70 years old. The cutoff value for Ishii's score was 155.1 and 15 patients were in the high-score group. The high-score group was significantly associated with worse time to recurrence (TTR) and overall survival (OS), and a high Ishii's score was an independent negative prognostic factor for TTR (hazard ratio = 2.93, P = 0.015). A high Ishii's score was significantly associated with a low SMI value but not with the IMAC value., Conclusion: A high Ishii's score was independently associated with poorer TTR in patients with non-metastatic OCRC., (© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Genetic variants in the apolipoprotein E ( APOE ) gene affect the onset and progression of Alzheimer's disease (AD). The APOE Christchurch ( APOE Ch) variant has been identified as the most prominent candidate for preventing the onset and progression of AD. In this study, we generated isogenic APOE3 Ch/ 3 Ch human-induced pluripotent stem cells (iPSCs) from APOE3 / 3 healthy control female iPSCs and induced them into astrocytes. RNA expression analysis revealed the inherent resilience of APOE3 Ch/ 3 Ch astrocytes to induce a reactive state in response to inflammatory cytokines. Moreover, cytokine treatment changed astrocytic morphology with more complexity in APOE3 / 3 astrocytes, but not in APOE3 Ch/ 3 Ch astrocytes, indicating resilience of the rare variant to a reactive state. Interestingly, we observed robust morphological alterations containing more intricate processes when cocultured with iPSC-derived cortical neurons, in which APOE3 Ch/ 3 Ch astrocytes reduced complexity compared with APOE3 / 3 astrocytes. To assess the impacts of tau propagation effects, we next developed a sophisticated and sensitive assay utilizing cortical neurons derived from human iPSCs, previously generated from donors of both sexes. We showed that APOE3 Ch/ 3 Ch astrocytes effectively mitigated tau propagation within iPSC-derived neurons. This study provides important experimental evidence of the characteristic functions exhibited by APOE3Ch/3Ch astrocytes, thereby offering valuable insights for the advancement of novel clinical interventions in AD research., Competing Interests: H.O. is a scientific consultant for SanBio and K Pharma. The other authors declare no competing financial interests., (Copyright © 2024 the authors.)

We diagnosed six cases of acute hepatitis C virus (HCV) infection at our hospital between October 2003 and December 2022. During the same period, we diagnosed 402 cases of chronic HCV infection and 636 cases of acute hepatic injury. Acute HCV infection cases accounted for 1.4% of all HCV infections and 0.9% of all acute hepatic injury cases. The acute HCV infection group was younger, had more severe hepatitis, and exhibited higher levels of bilirubinemia compared to the chronic HCV infection group. Two acute HCV infection cases achieved spontaneous viral clearance, while the remaining four cases progressed to chronic infection and were treated with direct-acting antivirals (DAAs). Liver enzyme elevation and liver function deterioration did not differ significantly between the acute HCV and other acute liver injury groups. Notably, DAA treatment was equally effective for acute and chronic HCV cases (75% vs. 90%, p = 0.34). Early DAA treatment in acute cases might contribute to interrupting viral transmission among high-risk populations, such as people who inject drugs or men who have sex with men. While there are currently no specific guidelines for acute HCV infection treatment in Japan, our findings suggest that DAA therapy should be initiated immediately following diagnosis. Further studies with larger patient cohorts are warranted to confirm these observations., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Ethics Committee of Suzuka General Hospital issued approval No. 316. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Okano et al.)

Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson's disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: Patients with schizophrenia can have significant subjective difficulties in social cognition, but few undergo testing or treatment for social cognition. The Social Cognition Psychometric Evaluation (SCOPE) study recommends six social cognitive measures; however, the reliability and validity of these measures in different cultural and linguistic areas has not been adequately examined. We examined the psychometric properties of nine social cognitive measures and the relationship to social function, with the aim of determining the level of recommendation for social cognitive measures in clinical practice in Japan., Methods: For our test battery, an expert panel previously selected nine measures: the Bell Lysaker Emotion Recognition Task (BLERT); Facial Emotion Selection Test (FEST); Hinting Task (Hinting); Metaphor and Sarcasm Scenario Test (MSST); Intentionality Bias Task (IBT); Ambiguous Intentions and Hostility Questionnaire (AIHQ); Social Attribution Task-Multiple Choice (SAT-MC); SAT-MCII; and Biological Motion (BM) task. In total, 121 outpatients with schizophrenia and 70 healthy controls were included in the analysis, and the results were provided to an expert panel to determine the recommendations for each measure. The quantitative psychological indices of each measure were evaluated for practicality, tolerability, test-retest reliability, correlation with social function, and the incremental validity of social function., Results: Hinting and FEST received the highest recommendations for use in screening, severity assessment, and longitudinal assessment, followed by BLERT, MSST AIHQ, SAT-MC, and SAT-MCII, with IBT and BM receiving the lowest recommendations., Conclusion: This study provides a uniform assessment tool that can be used in future international clinical trials for social cognitive impairment., Competing Interests: Declaration of Competing Interest T.U. and T.N. belong to the Department of Psychiatry and Implementation Science, Toho University Faculty of Medicine, which is funded by the Nippon Life Insurance Company. The remaining authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: Emergency resuscitative thoracotomy is a potentially lifesaving procedure for patients with cardiac pulmonary arrest and profound circulatory failure resulting from a severe injury. However, survival rate post-emergency resuscitative thoracotomy shows considerable variation, with many studies constrained by limited sample sizes and ambiguous criteria for inclusion. Herein, we assessed the outcomes of emergency resuscitative thoracotomy and identified predictors of futility using Japan Trauma Data Bank data., Methods: Data of patients aged ≥18 years between 2004 and 2019 were analyzed. The primary outcome measure was survival at discharge. Descriptive statistics were used to compare the survivor and nonsurvivor groups. A multivariable logistic regression analysis was conducted to identify predictors of survival in patients undergoing emergency resuscitative thoracotomy while adjusting for confounding factors., Results: Among patients who underwent emergency resuscitative thoracotomy, 684/5062 (13.5%) survived. Age <65 years (adjusted odds ratio, 1.351; 95% confidence interval, 1.130-1.615; p  < 0.001), absence of cardiac pulmonary arrest on emergency department arrival (adjusted odds ratio, 1.694; 95% confidence interval, 1.280-2.243; p  < 0.01), Injury Severity Score <16 (adjusted odds ratio, 2.195; 95% confidence interval, 1.611-2.992; p  < 0.01), and penetrating injury (adjusted odds ratio, 1.834; 95% confidence interval, 1.384-2.431; p  < 0.01) were identified as factors associated with survival at discharge., Conclusion: The survival rate for emergency resuscitative thoracotomy in Japan stands at approximately 13.5%. Factors contributing to survival include younger age, absence of cardiopulmonary arrest at emergency department arrival, lack of severe trauma, and sustaining penetrating injuries., Competing Interests: Authors declare no Conflict of Interests for this article., (© 2024 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)

Ischemic stroke is a major cerebrovascular disease with high morbidity and mortality rates; however, effective treatments for ischemic stroke-related neurological dysfunction have yet to be developed. In this study, we generated neural progenitor cells from human leukocyte antigen major loci gene-homozygous-induced pluripotent stem cells (hiPSC-NPCs) and evaluated their therapeutic effects against ischemic stroke. hiPSC-NPCs were intracerebrally transplanted into rat ischemic brains produced by transient middle cerebral artery occlusion at either the subacute or acute stage, and their in vivo survival, differentiation, and efficacy for functional improvement in neurological dysfunction were evaluated. hiPSC-NPCs were histologically identified in host brain tissues and showed neuronal differentiation into vGLUT-positive glutamatergic neurons, extended neurites into both the ipsilateral infarct and contralateral healthy hemispheres, and synaptic structures formed 12 weeks after both acute and subacute stage transplantation. They also improved neurological function when transplanted at the subacute stage with γ-secretase inhibitor pretreatment. However, their effects were modest and not significant and showed a possible risk of cells remaining in their undifferentiated and immature status in acute-stage transplantation. These results suggest that hiPSC-NPCs show cell replacement effects in ischemic stroke-damaged neural tissues, but their efficacy is insufficient for neurological functional improvement after acute or subacute transplantation. Further optimization of cell preparation methods and the timing of transplantation is required to balance the efficacy and safety of hiPSC-NPC transplantation.

Animal models of brain function are critical for the study of human diseases and development of effective interventions. Resting-state network (RSN) analysis is a powerful tool for evaluating brain function and performing comparisons across animal species. Several studies have reported RSNs in the common marmoset (Callithrix jacchus; marmoset), a non-human primate. However, it is necessary to identify RSNs and evaluate commonality and inter-individual variance through analyses using a larger amount of data. In this study, we present marmoset RSNs detected using > 100,000 time-course image volumes of resting-state functional magnetic resonance imaging data with careful preprocessing. In addition, we extracted brain regions involved in the composition of these RSNs to understand the differences between humans and marmosets. We detected 16 RSNs in major marmosets, three of which were novel networks that have not been previously reported in marmosets. Since these RSNs possess the potential for use in the functional evaluation of neurodegenerative diseases, the data in this study will significantly contribute to the understanding of the functional effects of neurodegenerative diseases., (© 2024. The Author(s).)

Individual traits and reactions to ambiguity differ and are conceptualized in terms of an individual's attitudes toward ambiguity or ambiguity tolerance. The development of natural language processing technology has made it possible to measure mental states and reactions through open-ended questions, rather than predefined numerical rating scales, which have traditionally been the dominant method in psychological research. This study presented three ambiguity-related situations and responses collected online from 591 participants in an open-ended format. After the analysis with bidirectional encoder representations from transformers, correlations were calculated using scores from the numerical evaluation by conventional questionnaire, and a significant moderate positive correlation was found. Therefore, this study found that attitudes toward ambiguity can be measured using an open-ended response method of reporting everyday life states. It is a novel methodology that can be expanded to other scales in psychology and can potentially be used in educational and clinical situations where participants can be asked to respond with minimal burden., (© 2024. The Author(s).)

Better understanding of the earliest molecular pathologies of all neurodegenerative diseases is expected to improve human therapeutics. We investigated the earliest molecular pathology of spinocerebellar ataxia type 1 (SCA1), a rare familial neurodegenerative disease that primarily induces death and dysfunction of cerebellum Purkinje cells. Extensive prior studies have identified involvement of transcription or RNA-splicing factors in the molecular pathology of SCA1. However, the regulatory network of SCA1 pathology, especially central regulators of the earliest developmental stages and inflammatory events, remains incompletely understood. Here, we elucidated the earliest developmental pathology of SCA1 using originally developed dynamic molecular network analyses of sequentially acquired RNA-seq data during differentiation of SCA1 patient-derived induced pluripotent stem cells (iPSCs) to Purkinje cells. Dynamic molecular network analysis implicated histone genes and cytokine-relevant immune response genes at the earliest stages of development, and revealed relevance of ISG15 to the following degradation and accumulation of mutant ataxin-1 in Purkinje cells of SCA1 model mice and human patients., (© 2024. The Author(s).)

Wound healing after closed-head injury is a significant medical issue. However, conventional models of focal traumatic brain injury, such as fluid percussion injury and controlled cortical impact, employ mechanical impacts on the exposed cerebral cortex after craniotomy. These animal models are inappropriate for studying gliosis, as craniotomy itself induces gliosis. To address this, we developed a closed-head injury model and named "photo injury", which employs intense light illumination through a thinned-skull cranial window. Our prior work demonstrated that the gliosis of focal cerebral lesion after the photo injury does not encompass artificial gliosis and comprises two distinct reactive astrocyte subpopulations. The reactive astrocytes accumulated in the perilesional recovery area actively proliferate and express Nestin, a neural stem cell marker, while those in distal regions do not exhibit these traits. The present study investigated the role of perilesional reactive astrocytes (PRAs) in wound healing using the ablation of reactive astrocytes by the conditional knockout of Stat3. The extensive and non-selective ablation of reactive astrocytes in Nestin-Cre:Stat3 f/f mice resulted in an exacerbation of injury, marked by increased inflammation and BBB disruption. On the other hand, GFAP-CreER T2 :Stat3 f/f mice exhibited the partial and selective ablation of the PRAs, while their exacerbation of injury was at the same extent as in Nestin-Cre:Stat3 f/f mice. The comparison of these two mouse strains indicates that the PRAs are an essential astrocyte component for wound healing after closed-head injury, and their anti-inflammatory and regenerative functions are significantly affected even by incomplete accumulation. In addition, the reporter gene expression in the PRAs by GFAP-CreER T2 indicated a substantial elimination of these cells and an absence of differentiation into other cell types, despite Nestin expression, after wound healing. Thus, the accumulation and subsequent elimination of PRA are proposed as promising diagnostic and therapeutic avenues to bolster wound healing after closed-head injury., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Diffusion MRI is a physical measurement method that quantitatively indicates the displacement of water molecules diffusing in voxels. However, there are insufficient data to characterize the diffusion process physically in a uniform structure such as a phantom. This study investigated the transitional relationship between structure scale, temperature, and diffusion time for simple restricted diffusion using a capillary phantom., Methods: We performed diffusion-weighted pulsed-gradient stimulated-echo acquisition mode (STEAM) MRI with a 9.4 Tesla MRI system (Bruker BioSpin, Ettlingen, Germany) and a quadrature coil with an inner diameter of 86 mm (Bruker BioSpin). We measured the diffusion coefficients (radial diffusivity [RD]) of capillary plates (pore sizes 6, 12, 25, 50, and 100 μm) with uniformly restricted structures at various temperatures (10ºC, 20ºC, 30ºC, and 40ºC) and multiple diffusion times (12-800 ms). We evaluated the characteristics of scale, temperature, and diffusion time for restricted diffusion., Results: The RD decayed and became constant depending on the structural scale. Diffusion coefficient fluctuations with temperature occurred mostly under conditions of a large structural scale and short diffusion time. We obtained data suggesting that temperature-dependent changes in the diffusion coefficients follow physical laws., Conclusion: No water molecules were observed outside the glass tubes in the capillary plates, and the capillary plates only reflected a restricted diffusion process within the structure.We experimentally evaluated the characteristics of simple restricted diffusion to reveal the transitional relationship of the diffusion coefficient with diffusion time, structure scale, and temperature through composite measurement.

Background: Ultrasound-guided central venous catheterization (CVC) has become the standard of care. However, providers use a variety of approaches, encompassing the internal jugular vein (IJV), supraclavicular subclavian vein (SupraSCV), infraclavicular subclavian vein (InfraSCV), proximal axillary vein (ProxiAV), distal axillary vein (DistalAV), and femoral vein., Objective: This review aimed to compare the first-pass success rate and arterial puncture rate for different approaches to ultrasound-guided CVC above the diaphragm., Methods: In May 2023, Embase, MEDLINE, CENTRAL, ClinicalTrials.gov, and World Health Organization International Clinical Trials Platform were searched for randomized controlled trials (RCTs) comparing the 5 CVC approaches. The Confidence in Network Meta-Analysis tool was used to assess confidence. Thirteen RCTs (4418 participants and 13 comparisons) were included in this review., Results: The SupraSCV approach likely increased the proportion of first-attempt successes compared to the other 4 approaches. The SupraSCV first-attempt success demonstrated risk ratios (RRs) > 1.21 with a lower 95% confidence interval (CI) exceeding 1. Compared to the IJV, the SupraSCV approach likely increased the first-attempt success proportion (RR 1.22; 95% confidence interval [CI] 1.06-1.40, moderate confidence), whereas the DistalAV approach reduced it (RR 0.72; 95% CI 0.59-0.87, high confidence). Artery puncture had little to no difference across all approaches (low to high confidence)., Conclusion: Considering first-attempt success and mechanical complications, the SupraSCV may emerge as the preferred approach, while DistalAV might be the least preferable approach. Nevertheless, head-to-head studies comparing the approaches with the greatest first attempt success should be undertaken., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Spinal cord injury is a condition in which the parenchyma of the spinal cord is damaged by trauma or various diseases. While rapid progress has been made in regenerative medicine for spinal cord injury that was previously untreatable, most research in this field has focused on the early phase of incomplete injury. However, the majority of patients have chronic severe injuries; therefore, treatments for these situations are of fundamental importance. The reason why the treatment of complete spinal cord injury has not been studied is that, unlike in the early stage of incomplete spinal cord injury, there are various inhibitors of neural regeneration. Thus, we assumed that it is difficult to address all conditions with a single treatment in chronic complete spinal cord injury and that a combination of several treatments is essential to target severe pathologies. First, we established a combination therapy of cell transplantation and drug-releasing scaffolds, which contributes to functional recovery after chronic complete transection spinal cord injury, but we found that functional recovery was limited and still needs further investigation. Here, for the further development of the treatment of chronic complete spinal cord injury, we review the necessary approaches to the different pathologies based on our findings and the many studies that have been accumulated to date and discuss, with reference to the literature, which combination of treatments is most effective in achieving functional recovery., Competing Interests: None

Postsynaptic proteins play crucial roles in synaptic function and plasticity. During brain development, alterations in synaptic number, shape, and stability occur, known as synapse maturation. However, the postsynaptic protein composition changes during development are not fully understood. Here, we show the trajectory of the postsynaptic proteome in developing male mice and common marmosets. Proteomic analysis of mice at 2, 3, 6, and 12 weeks of age shows that proteins involved in synaptogenesis are differentially expressed during this period. Analysis of published transcriptome datasets shows that the changes in postsynaptic protein composition in the mouse brain after 2 weeks of age correlate with gene expression changes. Proteomic analysis of marmosets at 0, 2, 3, 6, and 24 months of age show that the changes in the marmoset brain can be categorized into two parts: the first 2 months and after that. The changes observed in the first 2 months are similar to those in the mouse brain between 2 and 12 weeks of age. The changes observed in marmoset after 2 months old include differential expression of synaptogenesis-related molecules, which hardly overlap with that in mice. Our results provide a comprehensive proteomic resource that underlies developmental synapse maturation in rodents and primates., (© 2024. The Author(s).)

Inflammatory responses are known to suppress neural regeneration in patients receiving stem cell-based regenerative therapy for spinal cord injury (SCI). Consequently, pathways involved in neurogenesis and immunomodulation, such as the hepatocyte growth factor (HGF)/MET signaling cascade, have garnered significant attention. Notably, various studies, including our own, have highlighted the enhanced recovery of locomotor functions achieved in SCI animal models by combining HGF pretreatment and human induced stem cell-derived neural stem/progenitor cell (hiPSC-NS/PC) transplantation. However, these studies implicitly hypothesized that the functionality of HGF in SCI would be time consistent and did not elucidate its dynamics. In the present article, we investigated the time-course of the effect of HGF on SCI, aiming to uncover a more precise mechanism for HGF administration, which is indispensable for developing crystallizing protocols for combination therapy. To this end, we performed a detailed investigation of the temporal variation of HGF using the RNA-seq data we obtained in our most recent study. Leveraging the time-series design of the data, which we did not fully exploit previously, we identified three components in the effects of HGF that operate at different times: early effects, continuous effects, and delayed effects. Our findings suggested a concept where the three components together contribute to the acceleration of neurogenesis and immunomodulation, which reinforce the legitimacy of empirically fine-tuned protocols for HGF administration and advocate the novel possibility that the time-inconsistent effects of HGF progressively augment the efficacy of combined therapy., (© 2024. The Author(s).)

The transplantation of neural stem/progenitor cells (NS/PCs) derived from human induced pluripotent stem cells (hiPSCs) has shown promise in spinal cord injury (SCI) model animals. Establishing a functional synaptic connection between the transplanted and host neurons is crucial for motor function recovery. To boost therapeutic outcomes, we developed an ex vivo gene therapy aimed at promoting synapse formation by expressing the synthetic excitatory synapse organizer CPTX in hiPSC-NS/PCs. Using an immunocompromised transgenic rat model of SCI, we evaluated the effects of transplanting CPTX-expressing hiPSC-NS/PCs using histological and functional analyses. Our findings revealed a significant increase in excitatory synapse formation at the transplantation site. Retrograde monosynaptic tracing indicated extensive integration of transplanted neurons into the surrounding neuronal tracts facilitated by CPTX. Consequently, locomotion and spinal cord conduction significantly improved. Thus, ex vivo gene therapy targeting synapse formation holds promise for future clinical applications and offers potential benefits to individuals with SCI., Competing Interests: Declaration of interests H.O. and M.N. are compensated scientific consultants from K Pharma, and H.O. is also a compensated scientific consultant from San Bio. No management, preparation, analysis, interpretation, or review of data were performed by the funding sources., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Obesity and aging are major risk factors for several life-threatening diseases. Accumulating evidence from both rodents and humans suggests that the levels of nicotinamide adenine dinucleotide (NAD + ), a regulator of many biological processes, declines in multiple organs and tissues with aging and obesity. Administration of an NAD + intermediate, nicotinamide mononucleotide (NMN), replenishes intracellular NAD + levels and mitigates aging- and obesity-associated derangements in animal models. In this human clinical study, we aimed to investigate the safety and effects of 8-week oral administration of NMN on biochemical, metabolic, ophthalmologic, and sleep quality parameters as well as on chronological alterations in NAD + content in peripheral tissues. An 8-week, single-center, single-arm, open-label clinical trial was conducted. Eleven healthy, middle-aged Japanese men received two 125-mg NMN capsules once daily before breakfast. The 8-week NMN supplementation regimen was well-tolerated; NAD + levels in peripheral blood mononuclear cells increased over the course of NMN administration. In participants with insulin oversecretion after oral glucose loading, NMN modestly attenuated postprandial hyperinsulinemia, a risk factor for coronary artery disease (n = 3). In conclusion, NMN overall safely and effectively boosted NAD + biosynthesis in healthy, middle-aged Japanese men, showing its potential for alleviating postprandial hyperinsulinemia.