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Abstract Phosphodiesterase 10 A (PDE10A), a pivotal element of the second messenger signaling downstream of the dopamine receptor stimulation, is conceived to be crucially involved in the mood instability of bipolar I disorder (BD-I) as a primary causal factor or in response to dysregulated dopaminergic tone. We aimed to determine whether striatal PDE10A availability is altered in patients with BD-I and assessed its relationship with the clinical characteristics of BD-I. This case-control study used positron emission tomography (PET) with 2-(2-(3-(4-(2-[18F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([18F]MNI-659), a radioligand that binds to PDE10A, to examine the alterations of the striatal PDE10A availability in the living brains of individuals with BD-I and their association with the clinical characteristics of BD-I. [18F]MNI-659 PET data were acquired from 25 patients with BD-I and 27 age- and sex-matched healthy controls. Patients with BD-I had significantly lower PDE10A availability than controls in the executive (F = 8.86; P = 0.005) and sensorimotor (F = 6.13; P = 0.017) subregions of the striatum. Lower PDE10A availability in the executive subregion was significantly associated with a higher frequency of mood episodes in patients with BD-I (r = –0.546; P = 0.007). This study provides the first evidence of altered PDE10A availability in patients with BD-I. Lower PDE10A availability in the executive subregion of the striatum is associated with an increased recurrence risk, suggesting that PDE10A may prevent BD-I relapse. Further studies are required to elucidate the role of PDE10A in BD-I pathophysiology and explore its potential as a treatment target.

Abstract Phosphorus and molybdenum play important roles in the formation of microbial cell structures and specific enzymes crucial for metabolic processes. Nevertheless, questions remain about the preservation of these elements within ancient microfossils. Here, we present shape-accurate ion images capturing phosphorus and molybdenum on Palaeoproterozoic filamentous microfossils by pioneering a methodology using lateral high-resolution secondary ion mass spectrometry. Introducing electrically conductive glass for mounting isolated microfossils facilitated clearer observations with increased secondary ion yields. Phosphorus was detected along the contours of microfossils, providing direct evidence of phospholipid utilization in the cell membrane. Trace amounts of molybdenum were detected within microfossil bodies, suggesting potential remnants of molybdenum-bearing proteins, such as nitrogenase. These findings align with the hypothesized cyanobacterial origin of filamentous gunflint microfossils. Our methodology introduces a groundbreaking tool for obtaining crucial insights into the cellular evolution and metabolic pathways of microorganisms, allowing comparisons of their morphological characteristics.

Introduction: Focal autoimmune pancreatitis (AIP) without elevated serum IgG4 levels presents a diagnostic challenge compared to pancreatic tumors, often leading to surgical intervention. Case Presentation: We report a case of serum IgG4-negative focal AIP type 1 in a 52-year-old male. Despite repeated endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and fine-needle biopsy (FNB), preoperative diagnosis was elusive. Initially, a 30-mm hypoechoic mass in the pancreatic head was detected by ultrasonography, with dynamic computed tomography revealing well-defined borders and homogeneous delayed enhancement. Serum IgG4 levels were within the normal range (115 mg/dL). Two EUS-FNAs and one EUS-FNB failed to provide a definitive diagnosis, leading to suspicion of a solid pseudopapillary neoplasm and subsequent pancreaticoduodenectomy. Postoperative histopathology confirmed focal AIP type 1 with IgG4-positive plasma cells. After 38 months, there is no recurrence, and serum IgG4 levels remain normal. Conclusion: Diagnosis of focal AIP, particularly when serum IgG4 is negative, warrants consideration despite its difficulty. Imaging findings, such as a well-defined mass with homogeneous delayed enhancement, should prompt evaluation for characteristic features like capsule-like rim, pancreatic duct penetration, and biliary tract wall thickening.

Yusuke Suzuki,1 Hitoshi Suzuki,1 Yuko Makita,1 Akiko Takahata,1 Keiko Takahashi,1 Masahiro Muto,1 Yohei Sasaki,1 Atikemu Kelimu,1 Keiichi Matsuzaki,2 Hiroyuki Yanagawa,1 Keiko Okazaki,1 Yasuhiko Tomino1 1Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, 2Kyoto University Health Service, Kyoto, Japan Abstract: Immunoglobulin (Ig) A nephropathy (IgAN) is the most common form of glomerular disease worldwide and is associated with a poor prognosis. Thus, development of a curative treatment and strategies for early diagnosis and treatment are urgently needed. Pathological analysis of renal biopsy is the gold standard for the diagnosis and assessment of disease activity; however, immediate and frequent assessment based on biopsy specimens is difficult. Therefore, a simple and safe alternative is desirable. On the other hand, it is now widely accepted that multi-hit steps, including production of aberrantly glycosylated serum IgA1 (first hit), and IgG or IgA autoantibodies that recognize glycan containing epitopes on glycosylated serum IgA1 (second hit) and their subsequent immune complex formation (third hit) and glomerular deposition (fourth hit), are required for continued progression of IgAN. Although the prognostic and predictive values of several markers have been discussed elsewhere, we recently developed a highly sensitive and specific diagnostic method by measuring serum levels of glycosylated serum IgA1 and related IgA immune complex. In addition, we confirmed a significant correlation between serum levels of these essential effector molecules and disease activity after treatment, suggesting that each can be considered as a practical surrogate marker of therapeutic effects in this slowly progressive disease. Such a noninvasive diagnostic and activity assessment method using these disease-oriented specific biomarkers may be useful in the early diagnosis of and intervention in IgAN, with appropriate indication for treatment, and thus aid in the future development and dissemination of specific and curative treatments. Keywords: galactose-deficient immunoglobulin A1, anti-glycan antibody, immune complex, N-acetylgalactosamine, surrogate marker

Abstract Volatiles such as helium and carbon dioxide provide insights into geological processes spanning from the Earth’s deep interior to its surface. Integration with geophysical data providing enhanced vertical resolution with a wider horizontal range better elucidates the mantle dynamics and its interactions with the crust. Here we present geochemistry of volatiles dissolved in fluid samples from fault-related springs, thermal spa waters, and groundwaters across the Korean Peninsula. These were examined in conjunction with existing geophysical information. Remarkably, there is a strong spatial correlation between helium isotopes and S-wave velocity, suggesting the influence of mantle upwelling on both geochemical and geophysical parameters. Furthermore, the computed helium flux is comparable to that of volcanic regions, implying partial melting induced by mantle upwelling due to edge-driven convection beneath the Korean Peninsula. Therefore, these findings suggest that mantle-derived volatiles can be released diffusely over large areas through faults in the modern Earth’s intraplate environment.

Abstract Primary biliary cholangitis (PBC) is frequently associated with autoimmune disease. Although PBC complicated with CREST syndrome (PBC-CREST) has been reported, the long-term outcomes of the affected patients have not been fully investigated. Herein, the long-term outcomes of PBC-CREST were evaluated. Next, the GLOBE and UK-PBC scores were validated and compared between the PBC alone and PBC-CREST groups. A total of 302 patients who were diagnosed with PBC between December 1990 and August 2021 at Fukushima Medical University Hospital were included. The liver transplantation (LT)-free survival rates were compared between patients with PBC alone (n = 245) and those with PBC-CREST (n = 57). Moreover, 173 patients, excluding those with liver-related death/LT within 1 year after ursodeoxycholic acid administration, were divided into two subgroups (PBC alone (n = 147) and PBC-CREST (n = 26)), and the GLOBE and UK-PBC scores were compared between the subgroups. The survival rates without LT (3/5/10 years) were 92/87/80% for the PBC-alone group and 98/96/96% for the PBC-CREST group, with a significantly better prognosis in the PBC-CREST group (log-rank P = 0.0172). Multivariate analysis revealed that the presence of CREST syndrome is an independent protective factor for the presence of cirrhosis. The predicted 5/10/15-year risks of liver-related death or LT based on the UK-PBC score were significantly lower in the PBC-CREST group (2.4/7.6/13.2%) than in the PBC-alone group (4.8/11.8/18.8%) (P

Abstract DNAX-associated protein 12 kD size (DAP12) is a dominant immunoreceptor tyrosine-based activation motif (ITAM)-signaling adaptor that activates costimulatory signals essential for osteoclastogenesis. Although several DAP12-associated receptors (DARs) have been identified in osteoclasts, including triggering receptor expressed on myeloid cells 2 (TREM-2), C-type lectin member 5 A (CLEC5A), and sialic acid-binding Ig-like lectin (Siglec)-15, their precise role in the development of osteoclasts and bone remodeling remain poorly understood. In this study, mice deficient in Trem-2, Clec5a, Siglec-15 were generated. In addition, mice double deficient in these DAR genes and FcεRI gamma chain (FcR)γ, an alternative ITAM adaptor to DAP12, were generated. Bone mass analysis was conducted on all mice. Notably, Siglec-15 deficient mice and Siglec-15/FcRγ double deficient mice exhibited mild and severe osteopetrosis respectively. In contrast, other DAR deficient mice showed normal bone phenotype. Likewise, osteoclasts from Siglec-15 deficient mice failed to form an actin ring, suggesting that Siglec-15 promotes bone resorption principally by modulating the cytoskeletal organization of osteoclasts. Furthermore, biochemical analysis revealed that Sigelc-15 activates macrophage colony-stimulating factor (M-CSF)-induced Ras-associated protein-1 (RAP1)/Ras-related C3 botulinum toxin substrate 1 (Rac1) pathway through formation of a complex with p130CAS and CrkII, leading to cytoskeletal remodeling of osteoclasts. Our data provide genetic and biochemical evidence that Siglec-15 facilitates M-CSF-induced cytoskeletal remodeling of the osteoclasts.

ObjectiveTo evaluate the feasibility of the Sleep Health through University Student Habits (SHUSH) program, a brief sleep improvement intervention based upon principles of cognitive-behavioral therapy for insomnia (CBT-I) developed for Japanese university students.MethodsPretest-posttest, single-arm pilot study design with 3-month follow up was used to evaluate the feasibility of SHUSH. We developed then offered a 90-min sleep education class based upon the two-process model of sleep regulation, sleep restriction, stimulus control, and sleep hygiene. We recommended individualized sleep prescriptions (e.g., prescribed time to bed and prescribed time out of bed) from 11 days of daily sleep diary data. We then offered 15 min of individualized follow-up meetings each week for three consecutive weeks in person or online in which we supported adherence to sleep prescriptions. Fifteen university students with self-reported sleep disturbance (Insomnia Severity Index; ISI score ≥ 9) completed the SHUSH program. Participants were on average age 19.7 years old; nine were women, and they were students in occupational therapy and physical therapy. We assessed validated Japanese versions of sleep-related (e.g., ISI, Sleep hygiene practice scale; SHPS), mental health-related (e.g., Generalized Anxiety Disorder Screener) patient-reported outcomes (PROs) and daily sleep diary variables (e.g., sleep onset latency and sleep efficiency).ResultsComparing baseline and posttest data, a statistically significant difference was observed in insomnia symptom severity, daytime sleepiness, sleep hygiene practices, eveningness to morningness, anxiety, depression, sleep diary improvements (e.g., sleep onset latency, total time in bed, and sleep efficiency). Comparing posttest and 3-mo follow up data (n = 10), a statistically significant difference wasn't observed for most PRO effects. However, there was a statistically significant difference in ineffective sleep behaviors (i.e., SHPS-J). We did observe a rebound effect for some SHPS-J items.ConclusionSHUSH was developed as a brief cognitive-behavioral intervention for insomnia. SHUSH participants showed improvements on sleep-related and mental health-related PROs after 4 weeks of intervention. At 3 months follow-up sleep quality and mental health gains were maintained. SHUSH was a feasible program. Randomized controlled trials are needed to test treatment efficacy on sleep related and mental health related PROs in the future.

Abstract New standard zircons applicable to in situ analysis of Hf/W ratio by Nanoscale secondary ion mass spectrometer (NanoSIMS) were prepared and applied to Hf-W dating of a differentiated meteorite classified as mesosiderite. The standard zircons were synthesized by high-pressure experiment from starting materials which were mixture of hafnium oxide, tungsten oxide and high-purity zircon powder. The mixed powders were stirred and pulverized by a high-energy ball mill. They were then sintered at 1000 °C and 6 GPa using multi-anvil apparatus. Homogeneity of Hf/W ratios of synthesized zircons was examined by SEM–EDS, EPMA, and Laser Ablation Inductively Coupled Plasma Mass Spectrometer (LA-ICPMS). Hf/W ratios of the same zircons were measured by a NanoSIMS with 2 nA oxygen primary beam and mass resolving power of 10,000. The relative sensitivity factor (RSF) of Hf/W ratio was determined by comparing zircon data measured by LA-ICPMS and NanoSIMS. Observed RSF (Hf/W) of zircon is 0.585 ± 0.180 (hereafter all error 2σ) consistent with 0.855 ± 0.468 of previous work within experimental error margin. The value is higher than observed RSF of glass matrix, 0.301 ± 0.062, and significantly higher than glass data of 0.21–0.22 in references. Based on the RSF, the Hf/W ratios of zircons extracted from mesosiderite “Asuka 882,023” were measured together with W isotopic compositions by NanoSIMS. Observed data in 180Hf/186W–182W/186W diagram are fitted by a straight line, yielding a slope (182Hf/180Hf) of 8.19 ± 3.50 × 10–6. This slope is converted into an absolute zircon Hf-W age of 4536.5+4.6 –7.2 Ma using the age anchor of CV3 chondrite. This age agrees well with a reference value of 4532.0+11.4 –20.8 Ma.

Abstract Previous studies have developed and explored magnetic resonance imaging (MRI)-based machine learning models for predicting Alzheimer’s disease (AD). However, limited research has focused on models incorporating diverse patient populations. This study aimed to build a clinically useful prediction model for amyloid-beta (Aβ) deposition using source-based morphometry, using a data-driven algorithm based on independent component analyses. Additionally, we assessed how the predictive accuracies varied with the feature combinations. Data from 118 participants clinically diagnosed with various conditions such as AD, mild cognitive impairment, frontotemporal lobar degeneration, corticobasal syndrome, progressive supranuclear palsy, and psychiatric disorders, as well as healthy controls were used for the development of the model. We used structural MR images, cognitive test results, and apolipoprotein E status for feature selection. Three-dimensional T1-weighted images were preprocessed into voxel-based gray matter images and then subjected to source-based morphometry. We used a support vector machine as a classifier. We applied SHapley Additive exPlanations, a game-theoretical approach, to ensure model accountability. The final model that was based on MR-images, cognitive test results, and apolipoprotein E status yielded 89.8% accuracy and a receiver operating characteristic curve of 0.888. The model based on MR-images alone showed 84.7% accuracy. Aβ-positivity was correctly detected in non-AD patients. One of the seven independent components derived from source-based morphometry was considered to represent an AD-related gray matter volume pattern and showed the strongest impact on the model output. Aβ-positivity across neurological and psychiatric disorders was predicted with moderate-to-high accuracy and was associated with a probable AD-related gray matter volume pattern. An MRI-based data-driven machine learning approach can be beneficial as a diagnostic aid.

Abstract Cognitive dysfunction, especially memory impairment, is a typical clinical feature of long-term symptoms caused by repetitive mild traumatic brain injury (rmTBI). The current study aims to investigate the relationship between regional brain atrophy and cognitive impairments in retired athletes with a long history of rmTBI. Overall, 27 retired athletes with a history of rmTBI (18 boxers, 3 kickboxers, 2 wrestlers, and 4 others; rmTBI group) and 23 age/sex-matched healthy participants (control group) were enrolled. MPRAGE on 3 T MRI was acquired and segmented. The TBV and TBV–adjusted regional brain volumes were compared between groups, and the relationship between the neuropsychological test scores and the regional brain volumes were evaluated. Total brain volume (TBV) and regional brain volumes of the mammillary bodies (MBs), hippocampi, amygdalae, thalami, caudate nuclei, and corpus callosum (CC) were estimated using the SPM12 and ITK–SNAP tools. In the rmTBI group, the regional brain volume/TBV ratio (rmTBI vs. control group, Mann–Whitney U test, p

Objectives We examined the association of schooling, sibling life situation, and dietary habits with the estimated 24-h urinary salt excretion and the urinary sodium-to-potassium (Na/K) ratio in 3-year-old children.Methods The subjects were 639 children who underwent a health checkup in four cities and towns in Kyoto Prefecture from January to November 2019. The children’s parents answered questionnaires about weekday childcare places, the birth order, and the awareness of reducing the salt intake. The questions on food intake frequency included 10 items. The estimated 24-h salt excretion and Na/K ratio were calculated from the participants’ first voiding urine in the morning.Results Data were available for 294 children. The median (interquartile range (IQR)) of salt excretion (g/day) was 2.6 (1.7–3.4), and urinary Na/K ratio (mmol ratio) was 2.6 (1.6–4.1). Multinomial logistic regression analysis showed that the group with older siblings was significantly associated with high salt (odds ratio 1.89 (95% confidence interval 1.04 to 3.46)). In the urinary Na/K ratio, the nursery group had a significantly lower Na/K (odds ratio 0.32 (0.17 to 0.60)). High processed meat products intake was associated with a higher Na/K (odds ratio 1.96 (1.05–3.66)), whereas high vegetable intake was associated with a lower Na/K (odds ratio 0.45 (0.23–0.87)). Other factors showed no significant associations.Conclusions In Japanese 3-year-old children, the estimated 24-h urinary salt excretion was associated with older siblings, and the urinary Na/K ratios were associated with schooling situation and the intake of processed meat products and vegetables.

ABSTRACT Purpose: Amid rising health awareness, natural products which has milder effects than medical drugs are becoming popular. However, only few systems can quantitatively assess their impact on living organisms. Therefore, we developed a deep-learning system to automate the counting of cells in a gerbil model, aiming to assess a natural product’s effectiveness against ischemia. Methods: The image acquired from paraffin blocks containing gerbil brains was analyzed by a deep-learning model (fine-tuned Detectron2). Results: The counting system achieved a 79%-positive predictive value and 85%-sensitivity when visual judgment by an expert was used as ground truth. Conclusions: Our system evaluated hydrogen water’s potential against ischemia and found it potentially useful, which is consistent with expert assessment. Due to natural product’s milder effects, large data sets are needed for evaluation, making manual measurement labor-intensive. Hence, our system offers a promising new approach for evaluating natural products.

Introduction Reducing neonatal deaths in premature infants in low- and middle-income countries is key to reducing global neonatal mortality. International neonatal networks, along with patient registries of premature infants, have contributed to improving the quality of neonatal care; however, the involvement of low-to-middle-income countries was limited. This project aims to form an international collaboration among neonatal networks in Asia (AsianNeo), including low-, middle- and high-income countries (or regions). Specifically, it aims to determine outcomes in sick newborn infants, especially very low birth weight (VLBW) infants or very preterm infants, with a view to improving the quality of care for such infants.Methods and analysis Currently, AsianNeo comprises nine neonatal networks from Indonesia, Japan, Malaysia, Philippines, Singapore, South Korea, Sri Lanka, Taiwan and Thailand. AsianNeo will undertake the following four studies: (1) institutional questionnaire surveys investigating neonatal intensive care unit resources and the clinical management of sick newborn infants, with a focus on VLBW infants (nine countries/regions); (2) a retrospective cohort study to describe and compare the outcomes of VLBW infants among Asian countries and regions (four countries/regions); (3) a prospective cohort study to develop the AsianNeo registry of VLBW infants (six countries/regions); and (4) implementation and evaluation of educational and quality improvement projects in AsianNeo countries and regions (nine countries/regions).Ethics and dissemination The study protocol was approved by the Research Ethics Board of the National Center for Child Health and Development, Tokyo, Japan (reference number 2020–244, 2022–156). The study findings will be disseminated through educational programmes, quality improvement activities, conference presentations and medical journal publications.

The existence of cortical columns, regarded as computational units underlying both lower and higher-order information processing, has long been associated with highly evolved brains, and previous studies suggested their absence in rodents. However, recent discoveries have unveiled the presence of ocular dominance columns (ODCs) in the primary visual cortex (V1) of Long-Evans rats. These domains exhibit continuity from layer 2 through layer 6, confirming their identity as genuine ODCs. Notably, ODCs are also observed in Brown Norway rats, a strain closely related to wild rats, suggesting the physiological relevance of ODCs in natural survival contexts, although they are lacking in albino rats. This discovery has enabled researchers to explore the development and plasticity of cortical columns using a multidisciplinary approach, leveraging studies involving hundreds of individuals—an endeavor challenging in carnivore and primate species. Notably, developmental trajectories differ depending on the aspect under examination: while the distribution of geniculo-cortical afferent terminals indicates matured ODCs even before eye-opening, consistent with prevailing theories in carnivore/primate studies, examination of cortical neuron spiking activities reveals immature ODCs until postnatal day 35, suggesting delayed maturation of functional synapses which is dependent on visual experience. This developmental gap might be recognized as ‘critical period’ for ocular dominance plasticity in previous studies. In this article, I summarize cross-species differences in ODCs and geniculo-cortical network, followed by a discussion on the development, plasticity, and evolutionary significance of rat ODCs. I discuss classical and recent studies on critical period plasticity in the venue where critical period plasticity might be a component of experience-dependent development. Consequently, this series of studies prompts a paradigm shift in our understanding of species conservation of cortical columns and the nature of plasticity during the classical critical period.

Information regarding follow-up duration after treatment for newly diagnosed diffuse large B-cell lymphoma (DLBCL) is important. However, a clear endpoint has yet to be established. We totally enrolled 2182 patients newly diagnosed with DLBCL between 2008 and 2018. The median age of the patients was 71 years. All patients were treated with rituximab- and anthracycline-based chemotherapies. Each overall survival (OS) was compared with the age- and sex-matched Japanese general population (GP) data. At a median follow-up of 3.4 years, 985 patients experienced an event and 657 patients died. Patients who achieved an event-free survival (EFS) at 36 months (EFS36) had an OS equivalent to that of the matched GP (standard mortality ratio [SMR], 1.17; P=0.1324), whereas those who achieved an EFS24 did not have an OS comparable to that of the matched GP (SMR, 1.26; P=0.0095). Subgroup analysis revealed that relatively old patients (>60 years), male patients, those with limited-stage disease, those with a good performance status, and those with low levels of soluble interleukin 2 receptor already had a comparable life expectancy to the matched GP at an EFS24. In contrast, relatively young patients had a shorter life expectancy than matched GP, even with an EFS36. In conclusion, an EFS36 was shown to be a more suitable endpoint for newly diagnosed DLBCL patients than an EFS24. Of note, younger patients require a longer EFS period than older patients in order to obtain an equivalent life expectancy to the matched GP.

We report a rare case of a primary renal neuroendocrine tumor. The patient was a 64-year-old woman. The patient's chief complaint was gross hematuria. Dynamic contrast-enhanced computed tomography (CT) revealed a hypovascular mass 13 cm in diameter in the right kidney. The border of the mass was clear. A grossly contrast-impaired area and internal granular calcification were observed. A right radical nephrectomy was performed. Macroscopically, the mass was hemorrhaged and necrotic. It was diagnosed as a neuroendocrine tumor (NET) (Grade 2) histologically. Findings, such as hypovascularity, calcification, and necrosis, in our case were similar to those in previous reports. These findings are considered relatively characteristic of primary renal NETs.