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The seamless transition through stages of pluripotency relies on a balance between transcription factor networks and epigenetic mechanisms. Here, we reveal the crucial role of the transgene activation suppressor (TASOR), a component of the human silencing hub (HUSH) complex, in maintaining cell viability during the transition from naive to primed pluripotency. TASOR loss in naive pluripotent stem cells (PSCs) triggers replication stress, disrupts H3K9me3 heterochromatin, and impairs silencing of LINE-1 (L1) transposable elements, with more severe effects in primed PSCs. Notably, the survival of Tasor knockout PSCs during this transition can be restored by inhibiting caspase or deleting the mitochondrial antiviral signaling protein (MAVS). This suggests that unscheduled L1 expression activates an innate immune response, leading to cell death specifically in cells exiting naive pluripotency. Our findings highlight the importance of epigenetic programs established in naive pluripotency for normal development., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The mechanism of ulnar collateral ligament (UCL) injury during pitching is excessive elbow varus torque (EVT). The EVT-ball velocity (T-V) relationship allows concurrent assessment of player performance and UCL injury risk. Modifiable physical capacities may underlie individual variation seen in the T-V relationship., Purpose: To identify physical performance characteristics that impact the T-V relationship during pitching., Study Design: Descriptive laboratory study., Methods: A total of 87 National Collegiate Athletic Association Division I pitchers participated. Pitching collection involved measurement of EVT and ball velocity during 5 maximal effort fastballs thrown to a catcher. Physical measures collected were the following: shoulder and hip passive range of motion (ROM) and strength, shoulder rate of torque development (RTD), grip strength, and lumbopelvic stability. Physical measures were entered into univariate linear mixed models with ball velocity as a covariate to predict EVT. Variable reduction for multivariate models involved selection of physical measures based on random forest-derived variable importance and univariate relationship significance, rendering a 27-variable pool. Multivariate linear mixed models predicting EVT, adjusting for physical measures and other physical characteristics, were then created using backward elimination., Results: In univariate analysis, for every 1 m/s (2.2 mph) increase in ball velocity, the mean EVT increased by 1.51 Nċm (95% CI, 0.66-2.37 Nċm; P = .001). In univariate analysis, hip abduction strength symmetry and bilateral lumbopelvic stability significantly increased EVT, while dominant-shoulder ROM, scaption RTD symmetry, and hip ROM significantly decreased EVT. Variables that increased EVT while controlling for ball velocity in the final model include grip strength symmetry, lead-leg lumbopelvic stability, and bodyweight. Increased dominant-shoulder internal rotation (IR) strength, dominant-shoulder flexion ROM, and scaption strength asymmetry decreased EVT as ball velocity increased., Conclusion: Several modifiable physical measures affected EVT in the univariate analysis. In our final model, when controlling for ball velocity, EVT increased with increased grip strength symmetry, lead-leg lumbopelvic stability, and bodyweight and decreased with increased dominant-shoulder IR strength, dominant-shoulder flexion ROM, and scaption strength asymmetry., Clinical Relevance: Defining the individual and multivariate effects of these physical capacities on EVT contextualizes their role in the T-V relationship and helps identify access points through which coaches and clinicians can optimize a pitcher's T-V relationship., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This work was supported by the PAC-12 Student-Athlete Health and Well-Being grant, and grant UL1TR001855 from the National Center for Advancing Translational Science (NCATS) of the US National Institutes of Health. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2024.)

Membrane proteins (MPs) play important roles in various cellular processes and are major targets for drugs. Solubilization of MPs is often needed for structural and biophysical studies. For high-resolution nuclear magnetic resonance measurements, there is a size limit of the sample (<100 kDa), and a high thermal stability at an increased temperature is required. Furthermore, lipid bilayer-like environments are desirable to preserve the native states of MPs. However, existing solubilization techniques do not fulfill these requirements at the same time. In this study, we combined two phospholipid analogues as a solubilizer and stabilizer to isolate MPs. This method maintained bacteriorhodopsin (bR) extracted from purple membranes in its native state for 7 d at 40 °C. The solubility was comparable to that of conventional detergents for MPs, and the thermal stability of the solubilizate was the best among them. The increase in the molecular size caused by the solubilization of bR was only 20 kDa, indicating that 20 phospholipid analogue molecules were sufficient to solubilize one bR molecule. 15 N- 1 H heteronuclear single quantum coherence spectra of solubilized 2 H- and 15 N-labeled bR gave ∼80% of the expected peaks. In addition, the lysate of human neuropeptide Y 2 receptor-expressing mammalian cells exhibited ligand recognition for 7 d at 37 °C, suggesting that this technique can be used for ligand screening. Moreover, the structure of the single membrane-spanning M2 protein of the influenza A virus expressed in Escherichia coli was stably maintained for 7 d at 40 °C. Thus, our method is promising for various MP studies.

Background: Although a preference for solitude (PS) may mitigate the negative effects of social isolation (SI) owing to the enjoyment of time alone, its impact on mental health and its underlying factors remain unclear., Methods: An Internet survey was conducted with 9000 individuals aged 20-79 years in September 2023 and the analyses were performed across three generations. SI was defined as contact with non-cohabitating family members or relatives and friends/neighbors less than once a week. The PS scale, which was used to assess whether a person preferred spending time alone, stratified respondents into three PS-level groups. Mental health status was evaluated using the K6 (distress symptoms), the WHO-5 (well-being), and the UCLA Loneliness Score (severity of loneliness) as the main outcomes. The mediation analyses assessed whether troublesomeness in socializing, a potential negative aspect of PS, could explain the association between PS and mental health status., Results: A mixed-design two-way analysis of covariance showed that both SI and PS had significant main effects on all outcomes without interactions across generations, indicating that SI and higher PS were associated with poor mental health status. The association between higher PS and poor mental status was mediated by socializing troublesomeness across generations., Limitations: The cross-sectional design prevented making causal inferences from the results. Additionally, sampling bias from Internet surveys may limit the generalizability of the results., Conclusions: The results confirmed that there is no protective effect of PS on social isolation-related poor mental health. The hassle of socializing may partly explain why people with a higher PS experience poor mental status, including greater loneliness., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest with respect to the research., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: This study aims to assess the safety of coronary artery bypass grafting (CABG) with percutaneous ventricular assist device (PVAD) in patients with acute myocardial infarction complicated by cardiogenic shock (AMI-CS)., Methods: A retrospective analysis was conducted on 1198 patients with AMI-CS from the J-PVAD registry, who underwent PVAD support using Impella® (Abiomed Inc., Danvers, MA) and subsequent revascularization between February 2020 and December 2021. Patients were divided into two groups based on the method of coronary revascularization: percutaneous coronary intervention (PCI, n = 1084) and CABG (n = 114). The study assessed short-term all-cause and cardiac-related mortality., Results and Conclusion: The CABG group exhibited significantly lower short-term all-cause mortality compared with the PCI group (30-day: 26.2% vs. 39.9%, 90-day: 45.5% vs. 58.4%, log-rank p = 0.004). Short-term cardiac-related mortality was similar toward low in the CABG group compared with the PCI group (30-day: 18.7% vs. 25.6%, 90-day: 29.4% vs. 35.5%, log-rank p = 0.084). Multivariable analysis using the Cox proportional hazard model did not identify revascularization strategy as a risk factor for both all-cause mortality (Hazard ratio (HR): 0.743, 95% confidence intervals (CI): 0.457-1.208, p = 0.231) and cardiac-related mortality (HR: 0.762, 95% CI: 0.390-1.490, p = 0.427). These results were not attenuated even in subgroup analyses separately comparing CABG alone and hybrid therapy with PCI after propensity score matching. Thus, CABG can be a treatment option with feasible short-term outcomes in patients with AMI-CS under PVAD support., (© 2024 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Background: This study was aimed to compare the efficacy of two combination tablets of dipeptidyl peptidase-4 (DPP-4) inhibitors and metformin with different dosages, alogliptin/metformin (AM) and vildagliptin/metformin (VM), on glycemic control in patients with type 2 diabetes (T2D). Methods: This was a prospective, multicenter, open-label, randomized, parallel group, comparative trial. After a run-in period of treatment with metformin alone, a total of 59 Japanese outpatients with T2D, aged 20-79 years with glycated hemoglobin (HbA1c) levels of 6.5%-10% were randomly assigned to 12-week AM treatment, alogliptin 25 mg/metformin 500 mg combination tablet orally once a day, or VM treatment, vildagliptin 50 mg/metformin 250 mg combination tablet orally twice a day. The primary endpoints were the changes in HbA1c and fasting plasma glucose (FPG) levels from baseline to week 12 between the two groups. Blinded intermittently scanned continuous glucose monitoring (isCGM) was performed between weeks 10 and 12. The incidence of adverse events during the study was also evaluated. Results: In all, 52 participants were analyzed. Significant decreases in HbA1c and FPG levels from baseline to week 12 were observed in both treatment groups. However, there were no significant differences between the AM and VM groups in the change in HbA1c level (-0.3% and -0.4%, P = 0.309) or the FPG level (-9.0 and -15.0 mg/dL, P = 0.789). The isCGM revealed that both treatments achieved the recommended glycemic target range. No adverse events, such as severe hypoglycemia, were observed in either group. Conclusions: We concluded that there were no significant differences in the efficacy of two combination tablets of DPP-4 inhibitors and metformin with different dosages on glycemic control in patients with T2D.

Bi-functional enzyme FicD regulates the endoplasmic reticulum chaperone BiP using AMPylation and deAMPylation during ER homeostasis and stress, respectively. Human FicD with an arginine-to-serine mutation disrupts FicD deAMPylation activity resulting in severe neonatal diabetes. We generated the FicD R371S mutation in mice to create a pre-clinical murine model for neonatal diabetes. We observed elevated BiP AMPylation levels across multiple tissues and signature markers for diabetes including glucose intolerance and reduced serum insulin levels. While the pancreas of FicD R371S mice appeared normal at birth, adult FicD R371S mice displayed disturbed pancreatic islet organization that progressed with age. FicD R371S mice provide a preclinical mouse model for the study of UPR associated diabetes and demonstrate the essentiality of FicD for tissue resilience.

Allergic dermatitis (AD) is a skin disease characterized by a chronic inflammation caused by immune dysregulation. In the histopathology of patients with AD, there are several features, such as accumulation of eosinophils and mast cells, hyperkeratosis, and dermal fibrosis which are related to the exacerbation of AD. Mast cells and eosinophils are thought to be involved in fibrosis, but the details are unknown. Yama mouse is an inbred mouse showing genetically eosinophilia. If eosinophils have significant effect on fibrosis, it may be possible to establish a new AD model with severe fibrosis. In this study, AD was induced by applying dinitrofluorobenzene to mice auricle. Yama mice showed AD lesion with more severe dermal fibrosis with severe eosinophil infiltration than Balb/c and Nc/nga mice. The expression of transforming growth factor-β (TGF-β), a cytokine important for fibrosis, was not significantly different among Yama, Balb/c, and Nc/nga mice, while the expression of interleukin-4 (IL-4), which is also mediator of tissue fibrosis, was increased only in Yama mice. The results of this study showed that AD with more severe fibrosis could be induced in Yama mice than in Balb/c and Nc/nga mice. In Yama mice, it can be concluded that the severe fibrosis is TGF-β independent, and IL-4 would be the main mediator of severe fibrosis. This mouse model may be useful for elucidating the mechanism of fibrosis in chronic AD, and for conducting research leading to the development of new therapies.

ATP-grasp superfamily enzymes contain a hand-like ATP-binding fold and catalyze a variety of reactions using a similar catalytic mechanism. More than 30 protein families are categorized in this superfamily, and they are involved in a plethora of cellular processes and human diseases. Here, we identify C12orf29 (RLIG1) as an atypical ATP-grasp enzyme that ligates RNA. Human RLIG1 and its homologs autoadenylate on an active site Lys residue as part of a reaction intermediate that specifically ligates RNA halves containing a 5'-phosphate and a 3'-hydroxyl. RLIG1 binds tRNA in cells and can ligate tRNA within the anticodon loop in vitro. Transcriptomic analyses of Rlig1 knockout mice revealed significant alterations in global tRNA levels in the brains of female mice, but not in those of male mice. Furthermore, crystal structures of a RLIG1 homolog from Yasminevirus bound to nucleotides revealed a minimal and atypical RNA ligase fold with a conserved active site architecture that participates in catalysis. Collectively, our results identify RLIG1 as an RNA ligase and suggest its involvement in tRNA biology., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Ovarian cancer remains a formidable challenge in oncology, necessitating innovative therapeutic approaches. Claudin-6 (CLDN6), a member of the tight junction molecule CLDN family, exhibits negligible expression in healthy tissues but displays aberrant upregulation in various malignancies, including ovarian cancer. Although several therapeutic modalities targeting CLDN6 are currently under investigation, there is still a need for more potent therapeutic options. While T-cell engagers (TCEs) hold substantial promise as potent immunotherapeutic agents, their current efficacy and safety in terms of target antigen selection and T-cell exhaustion due to only CD3 stimulation without co-stimulation must be improved, particularly against solid tumors. To provide an efficacious treatment option for ovarian cancer, we generated SAIL66, a tri-specific antibody against CLDN6/CD3/CD137., Methods: Using our proprietary next-generation TCE technology (Dual-Ig), SAIL66 was designed to bind to CLDN6 with one Fab and CD3/CD137 with the other, thereby activating T cells through CD3 activation and CD137 co-stimulation. The preclinical characterization of SAIL66 was performed in a series of in vitro and in vivo studies which included comparisons to a conventional TCE targeting CLDN6 and CD3., Results: Despite the high similarity between CLDN6 and other CLDN family members, SAIL66 demonstrated high specificity for CLDN6, reducing the risk of off-target toxicity. In an in vitro co-culture assay with CLDN6-positive cancer cells, we confirmed that SAIL66 strongly activated the CD137 signal in the Jurkat reporter system, and preferentially induced activation of both CD4 + and CD8 + T cells isolated from human peripheral blood mononuclear cells compared to conventional TCEs. In vivo studies demonstrated that SAIL66 led to a more pronounced increase in intratumor T-cell infiltration and a decrease in exhausted T cells compared with conventional CLDN6 TCE by contribution of CD137 co-stimulation, resulting in better antitumor efficacy in tumor-bearing mouse models., Conclusion: Our data demonstrate that SAIL66, designed to engage CLDN6, CD3, and CD137, has the potential to enhance antitumor activity and provide a potent therapeutic option for patients with ovarian and other solid tumors expressing CLDN6. Clinical trials are currently underway to evaluate the safety and efficacy of SAIL66., Competing Interests: Competing interests: All authors except for HA are current employees of Chugai Pharmaceutical and Chugai Pharmabody Research. HA received a collaborative research grant from Chugai Pharmaceutical. SI, NK and TKa are inventors on the patent application (WO2021200939), TKa, SI, NK, and TKo are inventors on the patent application (WO2023053282 and WO2023054421) submitted by Chugai Pharmaceutical, which covers SAIL66., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The transcription factor E2F1 serves as a regulator of the cell cycle and promotes cell proliferation. It is highly expressed in cancer tissues and contributes to their malignant transformation. Degradation by the ubiquitin-proteasome system may help to prevent such overexpression of E2F1 and thereby to suppress carcinogenesis. A detailed understanding of the mechanisms underlying E2F1 degradation may therefore inform the development of new cancer treatments. We here identified SCF FBXW7 as a ubiquitin ligase for E2F1 by comprehensive analysis. We found that phosphorylation of E2F1 at serine-403 promotes its binding to FBXW7 (F-box/WD repeat-containing protein 7) followed by its ubiquitination and degradation. Furthermore, calcineurin, a Ca 2+ /calmodulin-dependent serine-threonine phosphatase, was shown to stabilize E2F1 by mediating its dephosphorylation at serine-403 and thereby preventing FBXW7 binding. Treatment of cells with Ca 2+ channel blockers resulted in downregulation of both E2F1 protein and the expression of E2F1 target genes, whereas treatment with the Ca 2+ ionophore ionomycin induced upregulation of E2F1. Finally, the calcineurin inhibitor FK506 attenuated xenograft tumor growth in mice in association with downregulation of E2F1 in the tumor tissue. Impairment of the balance between the opposing actions of FBXW7 and calcineurin in the regulation of E2F1 abundance may therefore play an important role in carcinogenesis., Competing Interests: Competing interests statement:The authors declare no competing interest.

Cutaneous warts are caused by human papillomavirus (HPV) infection. Distinguishing plantar warts from clavus and tylosis can be difficult. A less-invasive method of examining these lesions is necessary. Previously, we collected data on 90 patients with warts and related diseases to explore differentiation methods using HPV typing of tissue from the wart surface. In that study, 21 patients were diagnosed as cases with plantar warts, however, 10 of those 21 cases showed HPV-negative by polymerase chain reaction analysis, causing some ambiguity, thus their outcomes should be confirmed. To assess the role of HPV typing in clinical practice, we followed up these 21 cases (11 HPV-positive and 10 HPV-negative) and analyzed their outcomes. The HPV-positive group included HPV1a (one case), HPV27 (four cases), HPV57 (three cases), and HPV65 (three cases). The median age of the 21 patients was 43 years, that of the 11 HPV-positive cases was 37 years, and that of the 10 HPV-negative cases was 44 years. The sex ratios (male:female) of the HPV-positive and HPV-negative groups were 6:5 and 2:8, respectively. All 21 patients were treated with liquid nitrogen after surface keratin removal, concomitant with salicylic acid topical plaster or oral administration of Yokuinin. The longest follow-up period was 548 days. Kaplan-Meier analysis was performed to assess the healing rate according to HPV-positivity. The healing rate in HPV-positive cases was significantly higher than in HPV-negative cases (P = 0.001). Although the sample size was small, the results suggest HPV typing using non-invasive surface materials facilitates accurate diagnosis and prevents prolonged treatment of plantar warts., (© 2024 Japanese Dermatological Association.)

Interspecies blastocyst complementation holds great potential to address the global shortage of transplantable organs by growing human organs in animals. However, a major challenge in this approach is the limited chimerism of human cells in evolutionarily distant animal hosts due to various xenogeneic barriers. Here, we reveal that human pluripotent stem cells (PSCs) struggle to adhere to animal PSCs. To overcome this barrier, we developed a synthetic biology strategy that leverages nanobody-antigen interactions to enhance interspecies cell adhesion. We engineered cells to express nanobodies and their corresponding antigens on their outer membranes, significantly improving adhesion between different species' PSCs during in vitro assays and increasing the chimerism of human PSCs in mouse embryos. Studying and manipulating interspecies pluripotent cell adhesion will provide valuable insights into cell interaction dynamics during chimera formation and early embryogenesis., Competing Interests: Declaration of interests E.B., J.H., and J.W. are inventors on provisional patent application 63/488,889 entitled “A synthetic nanobody-mediated cell adhesion system to improve chimerism” arising from this work. J.W. is a member of the Cell Stem Cell advisory board., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Anti-IL-4 receptor α antibody (dupilumab) has demonstrated favorable sinonasal outcomes for chronic rhinosinusitis with nasal polyps (CRSwNP), which is mainly caused by type 2 inflammation. Although increased blood eosinophil levels and injection site symptoms are frequently observed as acute adverse events (AEs) of dupilumab, limited knowledge is available regarding the late AEs of dupilumab for CRSwNP., Objectives: We investigated the late AEs following the initiation of dupilumab treatment for CRSwNP., Material and Methods: Fifty-one patients with CRSwNP treated with dupilumab for > 3 months were enrolled, and their clinical data were collected from their medical records., Results: Six (11.8%) patients experienced late AEs. One case of eczema with pruritus, one case of psoriasis-like dermatitis, two cases of severe rash, one case of malignant lymphoma, and one case of alopecia areata were observed. Skin disorders were the most common late AEs in this study. It is a Th1-inflammatory disease, and its mechanism is thought to be due to the immune imbalance caused by dupilumab. We could not confirm whether malignant lymphoma in our case was caused by dupilumab use., Conclusions and Significance: Skin disorders are often late AEs associated with dupilumab; therefore, careful monitoring after dupilumab initiation should be considered.

Bats are important natural hosts of various zoonotic viruses, including Ebola virus, Lyssa virus, and severe acute respiratory syndrome coronavirus (SARS-CoV). Although investigation of bats is valuable for predicting emerging infectious diseases from these animals, few surveys of bat-derived viruses have been conducted in Japan. In the present study, samples were collected from a total of 132 bats of 4 different species from 4 different locations within Yamaguchi Prefecture; these sample were employed for comprehensive detection of bat-derived viruses by polymerase chain reaction (PCR) and reverse transcription (RT)-PCR using primers universal for each of 4 different viral classes. As a result of PCR and RT-PCR, various herpesviruses, astroviruses, coronaviruses, and adenoviruses were identified from a total of 80 bats. The detected herpesviruses belong to the Betaherpesvirinae or Gammaherpesvirinae subfamily, the detected adenoviruses to the genus Mastadenovirus, the detected astroviruses to the genus Mamastrovirus; and the detected coronaviruses belong to the genus Alphacoronavirus. The detected sequences of 12 strains of 4 families showed 100 % amino acid identity with viruses previously detected either in China or South Korea. These findings expand our understanding of viruses carried by bats, and provide insights into the nature of bat-derived viruses in Japan., 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 Masson SAS.. All rights reserved.)

Supernumerary B chromosomes contribute to intraspecific karyotypic variation. B chromosomes have been detected in more than 2000 organisms; they possess unique and diverse features, including non-Mendelian inheritance. Here, we report one or more B chromosomes in the gynodioecious plant Atractylodes lancea. Among 54 A. lancea lines, 0-2 B chromosomes were detected in both hermaphroditic and female plants, with the B chromosomes appearing as DAPI-bright regions within the nuclei. Genomic in situ hybridization revealed that the B chromosomes had no conserved A chromosome DNA sequences, confirmed by fluorescence in situ hybridization probed with independently dissected B chromosomes. In male meiosis, the B chromosome did not pair with an A chromosome and was therefore eliminated; accordingly, only 20.1% and 18.6% of these univalent B chromosomes remained at the end of meiosis for the 1B lines of KY17-148 and KY17-118, respectively. However, we also found that B chromosomes were transmitted from male parents in 40.8%-44.2% and 47.2% of the next generation; although these transmission rates from male parents were not essentially different from Mendelian inheritance (0.5), the transmission of gametes carrying B chromosomes increased through fertilization or seed development. B chromosomes were transmitted from three of four 1B female parents to 64.3%-92.6% of the next generation, suggesting B chromosome accumulation. We propose that the B chromosome of A. lancea has a specific sequence and persists via non-Mendelian inheritance from female parents. Overall, A. lancea, with its unique characteristics, is a promising model for understanding the structure, evolution, and mechanism of non-Mendelian inheritance of B chromosomes., Competing Interests: S.K., K.S., S.I. received research funding from Tsumura & Co., Japan. T.T. and M.S. are the employee of Tsumura & Co., this does not alter our adherence to PLOS ONE policies on sharing data and materials. 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 Hara et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This study aimed to investigate the effects of rolipram, a phosphodiesterase inhibitor, on brain tissue regeneration. Trimethyltin-injected mice, an animal model of hippocampal tissue regeneration, was created by a single injection of trimethyltin chloride (2.2 mg/kg, intraperitoneally). Daily rolipram administration (10 mg/kg, intraperitoneally) was performed from the day after trimethyltin injection until the day before sampling. In Experiment 1, brain samples were collected on day 7 postinjection of trimethyltin following the forced swim test. In Experiment 2, bromodeoxyuridine (150 mg/kg, intraperitoneally/day) was administered on days 3-5 and sampling was on day 21 postinjection of trimethyltin. Samples were routinely embedded in paraffin and sections were obtained for histopathological investigation. In Experiment 1, rolipram-treated mice showed shortened immobility times in the forced swim test. Histopathology revealed that rolipram treatment had improved the replenishment of neuronal nuclei-positive neurons in the dentate gyrus, which was accompanied by an increase in the percentage of phosphorylated cyclic AMP response element-binding protein-positive cells. In addition, rolipram had decreased the percentage of ionized calcium-binding adapter protein 1-positive microglia with activated morphology and the number of tumor necrosis factor-alpha-expressing cells. In Experiment 2, double immunofluorescence for bromodeoxyuridine/neuronal nuclei revealed an increase of double-positive cells in rolipram-treated mice. These results demonstrate that rolipram effectively promotes brain tissue regeneration by enhancing the survival of newborn neurons and inhibiting neuroinflammation., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Canine tumours including urothelial carcinoma, lung adenocarcinoma, mammary gland tumour, squamous cell carcinoma, and melanoma have been identified as causes of death, but effective therapies are limited due to insufficient knowledge of the molecular mechanisms involved. Within the tumour microenvironment, hypoxia activates hypoxia-inducible factor 1α (HIF1α) in tumour cells. High HIF1α expression correlates with enhanced glycolysis and poorer outcomes in human cancers. However, the molecular mechanisms underlying hypoxic tumour cells remain elusive in dogs. In our study, we investigated upregulated genes in a canine malignant melanoma cell line during hypoxia using RNA-sequencing analysis. Glycolysis and HIF1 signalling pathways were upregulated in hypoxic melanoma cells. HIF1α knockout melanoma cells revealed that the glycolysis marker MCT4 is regulated by HIF1α activation. Hypoxia induces high lactate secretion due to enhanced glycolysis in canine melanoma cells. Furthermore, we examined monocarboxylate transporter 4 (MCT4) expression in malignant melanoma and eight other types of canine tumour tissues using immunohistochemistry (IHC). Membrane-localized MCT4 protein was mostly detected in urothelial carcinoma and lung adenocarcinoma rather than malignant melanoma. We conclude that canine MCT4 protein plays a role in lactic acid efflux from glycolytic cells and may serve as a marker for hypoxia and glycolysis in canine tumours. These findings could inform future therapeutic strategies targeting MCT4., (© 2024 John Wiley & Sons Ltd.)

We investigated whether food shape and its variety within a group affect visual appeal using a four-shaped fast-food chicken product known as Chicken McNuggets®. In Experiment 1, participants rated the visual appeal of each nugget shape both individually and when presented in groups of variously shaped nuggets. The results revealed that the rounder nugget was less visually appealing than those of other shapes. Additionally, assortments featuring various shapes were rated as more appealing than those of a single shape. In Experiment 2, the visual appeal of individual nuggets presented in groups and alone was assessed using a visual analog scale. The visual appeal of one specific nugget (target nugget) was higher when presented in a group than alone. Furthermore, a target nugget presented in a group with various shapes was more visually appealing than when presented in a group with the same shape, regardless of the shape of the target nugget. These results suggest that a food product with low visual appeal can be perceived as more appealing when it is presented alongside various food shapes. Indeed, the variety of food shapes presented in a group affected the perceived appeal both of the group and of the individual food item. These findings offer novel insights into the impact of food's visual variation on its appeal., Competing Interests: Declaration of competing interest One of the authors, Yui Tanaka, is an employee at McDonald's (Japan). McDonald's Japan provided the experimental stimuli., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important therapeutic option for patients with hematologic malignancies. However, the development of graft-versus-host disease (GVHD) after allo-HSCT remains a challenge. Although systemic steroid therapy is the established first-line therapy for acute GVHD (aGVHD) and chronic GVHD (cGVHD), many patients are unresponsive or resistant to corticosteroid therapy, and the response is insufficient. This study aimed to evaluate the clinical characteristics of patients who developed aGVHD and cGVHD after allo-HSCT. This noninterventional, retrospective study used large national registry data from the Transplant Registry Unified Management Program. The study included 29,690 patients with a hematologic disease who underwent their first allo-HSCT between January 2010 and December 2019. The primary study endpoints were the cumulative incidence of aGVHD and cGVHD. The secondary endpoints were overall survival (OS) and nonrelapse mortality (NRM) of patients with aGVHD and cGVHD and OS and NRM of patients who received second-line therapy for aGVHD. Of 29,690 patients who underwent allo-HSCT, the graft source was related bone marrow (RBM) in 2807, related peripheral blood (RPB) in 6167, unrelated bone marrow in 10,556, unrelated peripheral blood (UPB) in 774, and unrelated cord blood in 9339. The cumulative incidence of grade II-IV aGVHD at 100 days was high after the related and unrelated mismatched transplantation. The response rates for first- and second-line therapy for aGVHD were low in the RBM/RPB-mismatched (59.6%/61.6%) and UPB-mismatched subgroups (45.5%), respectively. The 3-year NRM in patients with aGVHD was high in the RPB and UPB mismatched subgroups (37.9% and 31.2%, respectively). Developing a novel treatment for steroid-refractory aGVHD is necessary to improve transplantation outcomes, particularly for patients undergoing HLA-mismatched allo-HSCT., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The impact of absolute neutrophil count (ANC) before allogenic hematopoietic stem cell transplantation (HSCT) on the outcomes for patients with aplastic anemia (AA) remains unclear. We retrospectively evaluated the relationship between ANC before transplantation and patient outcomes, involving 883 adult Japanese patients with AA who underwent allogeneic HSCT as their first transplantation between 2008 and 2020. Patients were divided into three groups based on ANC: 0/µL (n = 116); 1-199 (n = 210); and ≥ 200 (n = 557). In the low ANC groups (ANC < 200), patient age was higher, previous anti-thymocyte globulin (ATG) treatments were infrequent, duration from diagnosis to transplantation was shorter, hematopoietic cell transplantation-comorbidity index (HCT-CI) was higher, ATG-based conditioning was used infrequently, and peripheral blood stem cell from related donor and cord blood were used frequently. In multivariate analysis, patient age, previous ATG treatment, HCT-CI, stem cell source, and ANC before transplantation were significantly associated with 5-year overall survival (OS) ("ANC ≥ 200": 80.3% vs. "ANC 1-199": 71.7% vs. "ANC 0": 64.4%). The cumulative incidence of bacterial infection, invasive fungal disease, and early death before engraftment were significantly higher in the low ANC groups. Among patients with ANC of zero before transplantation, younger patient age, shorter duration from diagnosis to transplantation, HCT-CI of 0, and bone marrow from related donor as stem cell source were significantly associated with better OS. Consequently, ANC before allogeneic HSCT was found to be a significant prognostic factor in adult patients with AA. Physicians should pay attention to ANC before transplantation., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: A relationship between endoscopic submucosal dissection (ESD) and deep vein thrombosis has been recognized. We previously reported that a high corrected midazolam dose (total midazolam dose/initial dose of midazolam used to induce sedation) is related to elevated D-dimer levels after ESD. In this study, the effect of compression stockings (CSs) in preventing thrombosis following ESD under sedation was evaluated by measuring D-dimer levels before and after ESD., Methods: The participants were patients who underwent ESD for upper gastrointestinal tumors during the period between April 2018 and October 2022. Patients with pre-ESD D-dimer levels ≥1.6 µg/m and patients with corrected midazolam doses ≤3.0 were excluded. A retrospective investigation of the relationship between CS use and high post-ESD D-dimer levels (difference in D-dimer levels ≥1.0 µg/mL between before and after ESD) was conducted., Results: There were 27 patients in the non-CS group (NCS) and 33 patients in the CS group. The number of patients with high post-ESD D-dimer levels was 13 (48.2%) in the non-CS group and six (18.2%) in the CS group; the number in the CS group was significantly lower ( p = 0.024). On logistic regression analysis, a relationship was seen between the wearing of CSs and a lower number of patients with high post-ESD D-dimer levels (odds ratio 0.24, 95% confidence interval 0.08-0.79, p = 0.019)., Conclusion: Wearing CSs was related to a lower risk of high post-ESD D-dimer levels. This result suggests that thrombus formation is a cause of elevated D-dimer levels after ESD., Competing Interests: None., (© 2024 The Author(s). DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Understanding the physiological changes associated with aging and the associated disease risks is essential to establish biomarkers as indicators of biological aging. This study used the NMR-measured plasma metabolome to calculate age-specific metabolite indices. In doing so, the scope of the study was deliberately simplified to capture general trends and insights into age-related changes in metabolic patterns. In addition, changes in metabolite concentrations with age were examined in detail, with the period from 55-59 to 60-64 years being a period of significant metabolic change, particularly in men, and from 45-49 to 50-54 years in females. These results illustrate the different variations in metabolite concentrations by sex and provide new insights into the relationship between age and metabolic diseases., (© 2024. The Author(s).)

Abstract: Sakurai, M, Qiao, M, Szymanski, DJ, and Crotin, RL. Countermovement jump and momentum generation associations to fastball velocity performance among Division I collegiate pitchers. J Strength Cond Res 38(7): 1288-1294, 2024-The current study explored the relationships between countermovement jump (CMJ) profiles and baseball pitching performance. Nineteen Division I collegiate pitchers performed in-laboratory pitching and bilateral CMJs. Whole-body kinematics and ground reaction force were collected during both pitching and CMJ evaluations. Statistically significant correlations of concentric impulse and peak power in the CMJ test with fastball velocity were observed (r = 0.71 and 0.68). Concentric impulse in CMJ also showed a statistically significant correlation with linear momentum in the anterior-posterior direction during pitching (r = 0.68). Lean body mass and body mass showed statistically significant correlations with both of the 2 linear momentums during pitching (r = 0.71∼0.83), and concentric impulse in CMJ (r = 0.71 and 0.81). Pelvis and trunk pitching mechanics did not correlate with any of the CMJ variables at the statistically significant level, whereas the direction of the correlations varied (|r| < 0.45). Assessment of a baseball pitcher's CMJ should focus on concentric impulse and peak power because only these showed meaningful relationships with fastball velocity or momentum generation during pitching. An increase in lean body mass is also suggested to be able to generate more impulse and momentum. Baseball coaches, strength coaches, and clinicians are encouraged to include lower-body explosive training to enhance the force and power output capacity of baseball pitchers., (Copyright © 2024 National Strength and Conditioning Association.)

Background/aim: The activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway has been implicated in canine soft tissue sarcoma (STS) and may serve as a prognostic marker. This study investigated the correlation between PI3K/Akt activation in tumor cells and tumor-infiltrating lymphocytes (TILs)., Materials and Methods: A total of 59 STS samples were labeled via immunohistochemistry to calculate the density of TILs, including CD3+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ regulatory T cells., Results: Forty-eight samples (81.3%) had intra-tumoral TILs with a high density of CD3+ T cells (mean: 283.3 cells/mm 2 ) and CD8+ T cells (mean: 134.8 cells/mm 2 ). Conversely, CD20+ B cells (mean: 73.6 cells/mm 2 ) and FOXP3+ regulatory T cells (mean: 9.2 cells/mm 2 ) were scarce. The abundance of CD3+/CD8+, CD3+/CD20+, and CD8+/CD20+ TILs were highly correlated in multivariate analyses (r=0.895, 0.946, and 0.856, respectively). Nonetheless, TIL density was unrelated to clinicopathological parameters (sex, age, tumor location, breed) and tumor grade. The abundance of CD8+ T cells was positively correlated with the activation of PI3K/Akt, indicating that samples with high levels of phospho-Akt and phospho-S6 tend to have a higher CD8+ T cell density (p=0.0032 and 0.0218, respectively). Furthermore, TIL density was correlated with the Ki-67 index, a tumor proliferation and growth marker. Samples with a high Ki-67 index had a significantly higher abundance of CD3+ T cells, CD8+ T cells, and CD20+ B cells (p=0.0392, 0.0254, 0.0380, respectively)., Conclusion: PI3K/Akt pathway activation may influence the infiltration of CD8+ T cells within the tumor microenvironment in canine STS. Prospective studies involving a higher number of cases are warranted to confirm these findings., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Community infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have increased rapidly since the emergence of the Omicron strain. During the eighth and ninth pandemic waves-when movement restrictions in the community were eased-the all-case registration system was changed, and the actual status of infection became uncertain., Methods: We conducted regular rapid antigen tests (R-RATs) once or twice a week as self-testing to examine the actual state of coronavirus disease (COVID-19) diagnosis among healthcare employees., Results: Overall, 320 (1.42/day) and 299 (1.76/day) employees were infected in the eighth and ninth pandemic waves. During both periods, 59/263 doctors (22.4%), 335/806 nurses (41.6%), 92/194 administrative employees (47.4%), and 129/218 clinical laboratory technicians (59.2%) were infected. In the eighth wave, 56 of 195 employees were infected through close contact; in the ninth wave, 26 of 62 employees were infected. No significant difference was observed in the number of vaccinations between infected and non-infected employees. The positivity rate of R-RATs was 0.41% and 0.45% in the eighth and ninth waves. R-RATs detected infection in 212 and 229 employees during the eighth and ninth waves, respectively; the ratio of R-RAT-detected positive employees to those who reported infection was significantly higher during the ninth wave (odds ratio: 1.67, 95% confidence interval: 1.17-2.37, p < 0.001)., Conclusions: The number of infected healthcare employees remained high during the eighth and ninth pandemic waves in Japan. The R-RAT is considered effective for detecting mild or asymptomatic COVID-19 at an early stage and at a high rate in healthcare employees.

Small-cell lung cancer (SCLC) is an aggressive cancer for which immune checkpoint inhibitors (ICI) have had only limited success. Bispecific T-cell engagers are promising therapeutic alternatives for ICI-resistant tumors, but not all patients with SCLC are responsive. Herein, to integrate CD137 costimulatory function into a T-cell engager format and thereby augment therapeutic efficacy, we generated a CD3/CD137 dual-specific Fab and engineered a DLL3-targeted trispecific antibody (DLL3 trispecific). The CD3/CD137 dual-specific Fab was generated to competitively bind to CD3 and CD137 to prevent DLL3-independent cross-linking of CD3 and CD137, which could lead to systemic T-cell activation. We demonstrated that DLL3 trispecific induced better tumor growth control and a marked increase in the number of intratumoral T cells compared with a conventional DLL3-targeted bispecific T-cell engager. These findings suggest that DLL3 trispecific can exert potent efficacy by inducing concurrent CD137 costimulation and provide a promising therapeutic option for SCLC., (©2024 American Association for Cancer Research.)

In the animal kingdom, evolutionarily conserved mechanisms known as cell competition eliminate unfit cells during development. Interestingly, cell competition also leads to apoptosis of donor cells upon direct contact with host cells from a different species during interspecies chimera formation. The mechanisms underlying how host animal cells recognize and transmit cell death signals to adjacent xenogeneic human cells remain incompletely understood. In this study, we developed an interspecies cell contact reporter system to dissect the mechanisms underlying competitive interactions between mouse and human pluripotent stem cells (PSCs). Through single-cell RNA-seq analyses, we discovered that Ephrin A ligands in mouse cells play a crucial role in signaling cell death to adjacent human cells that express EPHA receptors during interspecies PSC co-culture. We also demonstrated that blocking the Ephrin A-EPHA receptor interaction pharmacologically, and inhibiting Ephrin forward signaling genetically in the mouse cells, enhances the survival of human PSCs and promotes chimera formation both in vitro and in vivo . Our findings elucidate key mechanisms of interspecies PSC competition during early embryogenesis and open new avenues for generating humanized tissues or organs in animals, potentially revolutionizing regenerative medicine.

Chronic myelomonocytic leukaemia (CMML) is a haematological malignancy with a poor prognosis. Allogeneic haematopoietic stem cell transplantation remains the only curative approach. Without human leucocyte antigen-matched related sibling donors, the optimal alternative donor has yet to be established. Although unrelated bone marrow transplantation (UBMT) has been extensively studied, cord blood transplantation (CBT) for CMML remains largely unexplored. This nationwide retrospective study compared the outcomes of UBMT and single-unit umbilical CBT in patients with CMML. This study included 118 patients who underwent their first allo-HSCT during 2013-2021. Of these, 50 received BMT (UBMT group), while 68 underwent CBT (CBT group). The primary endpoint was the 3-year overall survival (OS). There were comparable 3-year OS rates between the UBMT (51.0%, 95% confidence interval [CI]: 34.1-65.5%) and CBT (46.2%, 95% CI: 33.2-58.1%; P = 0.60) groups. In the inverse probability of treatment weighting analysis, CBT did not show significantly improved outcomes compared with UBMT regarding the 3-year OS rate (hazard ratio 0.97 [95% CI: 0.57-1.66], P = 0.91). Thus, CBT may serve as an alternative to UBMT for patients with CMML. Further research is necessary to optimise transplantation strategies and enhance outcomes in patients with CMML undergoing CBT., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Previous reports have described hiccups during general anesthesia that were possibly induced by drugs, including benzodiazepines. However, there are few reports of hiccups caused by remimazolam. Case presentation A 75-year-old woman underwent corneal transplantation under general anesthesia with remimazolam. She presented with hiccups once the effects of muscle relaxants used during induction wore off, which persisted even after various treatments, such as the administration of antipsychotic drugs. However, when remimazolam administration was terminated after surgery to awaken the patient, the hiccups stopped and did not recur after extubation. Evaluation of predicted blood levels of remimazolam suggests that higher levels of remimazolam might cause hiccups., Conclusion: Remimazolam might induce hiccups during general anesthesia. Anesthesiologists should consider administering muscle relaxants or changing the anesthetic in cases of refractory hiccups under general anesthesia., (© 2024. The Author(s).)

A direct focused He + beam direct machining is presented to fabricate solid-state nano-disk at the surface of a graphene multilayer micro-flake deposited on an Au/Ti/sapphire surface. At irradiation doses larger than 5.0 × 10 17 ions cm -2 and with a beam size well below 1 nm, graphene disks down to 20 nm in diameter have been machined with for nano-disk down to 50 nm in diameter, a central hole for preparing the positioning of a rotation axle. The local heat generated by this irradiation is inducing a partial graphene amorphization and deformation, leading to a complete graphene nano-disk vaporization at doses larger than 5 × 10 18 ions cm -2 . A dry transfer printing technique followed by a graphene surface cleaning was used to transfer the nano-disks from its initial surface to a fresh and clean surface. Tapping mode atomic force micrograph have been recorded to follow the vaporization as a function of the He + dose to confirm the graphene solid-state nano-disk fabrication limit to about 20 nm with this process., (© 2024 IOP Publishing Ltd.)

Objective: The present study aimed to report on the activity of a medical relief team from Juntendo Shizuoka Hospital that was dispatched to the Noto Peninsula Earthquake in Reiwa 6., Design: Narrative report., Results: The activities conducted on-site in the Noto Peninsula involved multiple deployments of the Juntendo University Shizuoka Hospital Disaster Medical Assistance Team (JS-DMAT). The first deployment from January 2nd to January 6th faced challenges due to damaged infrastructure, particularly roads, affecting mobility. The team focused on hospital medical support, patient transportation, and DMAT headquarters assistance. The second deployment, from January 8th to January 12th, encountered persistently damaged roads, leading to incidents but no significant vehicle damage. The team engaged in screening, zoning, medical examinations, and DMAT headquarters support in evacuation shelters. The third team's planned activities in early February were canceled by Shizuoka Prefecture.Additionally, on January 7, 2024, personnel from Juntendo Shizuoka Hospital participated in the Shizuoka Prefectural DMAT Coordination Headquarters activity, documenting DMAT activities and assessing team members' health. The Ministry of Health, Labour and Welfare's request for the fourth Shizuoka Prefecture DMAT dispatch led to the selection of the second JS-DMAT for deployment., Conclusion: The activities related to the Noto Peninsula earthquake by JS-DMAT were reported. Lessons from this disaster are being sought to guide future disaster response preparations., Competing Interests: The authors declare that there are no conflicts of interest., (© 2024 The Juntendo Medical Society.)

Soft tissue sarcoma (STS) is a relatively common tumor in dogs. However, very few canine STS cell lines are available. This study aimed to establish a new cell line, STS-YU1, derived from a recurrence of myxosarcoma in an 11-year-old mixed-breed dog. We examined STS-YU1 for in vitro cell proliferation, migration, anticancer drug sensitivity, transcriptome analysis using next-generation sequencing (RNA-seq), and in vivo tumorigenicity in mice and compared it with previously established STS cell lines, MUMA-G and A72. The cell proliferation and migration of STS-YU1 were higher than MUMA-G although MUMA-G only exhibited tumorigenicity in mice. STS-YU1 showed dose-dependent cytotoxicity to anticancer drugs, but with weak effects. RNA-seq analysis revealed the molecular phenotype of STS-YU1 was different from that of a previously reported cell line, A72. Hence, the use of STS-YU1 would help in efficient drug screening against canine STS in vitro., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The aim was to evaluate the consistency of the results between the UF-1500 and UF-5000, fully automated urine particle analyzers., Methods: A total of 554 randomly selected inpatient and outpatient urine samples were collected for analysis using the UF-1500, the UF-5000, and by manual microscopic examination. The coincidence rate, intraday repeatability, and interday reproducibility were evaluated on the UF-1500 and UF-5000. To analyze the review flags from the UF-1500, the UF-1500 results were compared to manual microscopy as the gold standard., Results: The repeatability of red blood cells (RBCs), white blood cells (WBCs), epithelial cells (ECs), casts, and bacteria using the UF-1500 and UF-5000 is expressed as the relative standard deviations of the intraday and inter-day measurements. For the UF-1500, the relative standard deviation values ranged from 5.9% to 12.6% and 4.9% to 17.2% for the low and 1.6% to 9.3% and 2.3% to 16.9% for the high samples, respectively. The correlation co-efficient for RBCs, WBCs, ECs, SECs, casts, crystals, and bacteria for the UF-1500 were 0.981, 0.993, 0.968, 0.963, 0.821, 0.783, and 0.992, respectively. Review samples from the UF-1500 were confirmed by microscopic examination. Review flags for all 554 samples included 3 samples with "DEBRIS High" and 23 samples with "RBCs/YLC Abnormal classification"., Conclusions: The identification of various urine components by both instruments meets laboratory requirements. These two instruments with different performances have specific characteristics and should be used based upon the needs of each laboratory.

Cadmium (Cd) pollution is a public environmental problem worthy of attention. Long-term exposure to Cd may have adverse effects on human health. Our previous study showed that urinary concentration of Cd (U-Cd) in the residents decreased when Cd-polluted paddy soil was removed. However, from 2008 to 2014, the concentration of U-Cd increased. At the same time, the concentration of urinary β 2 -microglobulin (β 2 -MG), which is considered to be an early sign of cadmium-induced renal dysfunction, increased continuously. To find the cause of elevated urinary cadmium (U-Cd) in residents of cadmium-contaminated areas, we measured the concentration of cadmium in the blood (B-Cd) of 29 elderly residents (15 female and 14 male) and edible rice (R-Cd), and correlations between R-Cd, B-Cd, and U-Cd were analyzed in the formerly cadmium-polluted areas (the Kakehashi River basin). In 2016, we collected blood, urine, and rice samples from each participant. The analysis showed a significant correlation between age and B-Cd, U-Cd, and β 2 -MG. However, there was no significant correlation between R-Cd and U-Cd, B-Cd, or β 2 -MG concentrations. Although we found a slightly higher level of Cd in rice and urine than reported in 2008, we cannot be sure that it indicates an increased Cd contamination in the Kakehashi River basin because larger studies are required for such a conclusion. The increased urinary Cd concentrations in this area may be because Cd in tissues and organs returns to blood and urine as participants age, which leads to an increasing trend., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Recent developments in sequencing and bioinformatics have advanced our understanding of adenosine-to-inosine (A-to-I) RNA editing. Surprisingly, recent analyses have revealed the capability of adenosine deaminase acting on RNA (ADAR) to edit DNA:RNA hybrid strands. However, edited inosines in DNA remain largely unexplored. A precise biochemical method could help uncover these potentially rare DNA editing sites. We explore maleimide as a scaffold for inosine labeling. With fluorophore-conjugated maleimide, we were able to label inosine in RNA or DNA. Moreover, with biotin-conjugated maleimide, we purified RNA and DNA containing inosine. Our novel technique of inosine chemical labeling and affinity molecular purification offers substantial advantages and provides a versatile platform for further discovery of A-to-I editing sites in RNA and DNA., (© 2024 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

A central question for regenerative neuroscience is whether synthetic neural circuits, such as those built from two species, can function in an intact brain. Here, we apply blastocyst complementation to selectively build and test interspecies neural circuits. Despite approximately 10-20 million years of evolution, and prominent species differences in brain size, rat pluripotent stem cells injected into mouse blastocysts develop and persist throughout the mouse brain. Unexpectedly, the mouse niche reprograms the birth dates of rat neurons in the cortex and hippocampus, supporting rat-mouse synaptic activity. When mouse olfactory neurons are genetically silenced or killed, rat neurons restore information flow to odor processing circuits. Moreover, they rescue the primal behavior of food seeking, although less well than mouse neurons. By revealing that a mouse can sense the world using neurons from another species, we establish neural blastocyst complementation as a powerful tool to identify conserved mechanisms of brain development, plasticity, and repair., Competing Interests: Declaration of interests K.K.B. is on the SAB of Gameto Therapeutics. B.T.T. is a current employee of Janssen Research and Development. P.O. is a founder of Theracast. J.C.I.B is a founding scientist and director of the San Diego Institute of Science, Altos Labs., (Copyright © 2024. Published by Elsevier Inc.)

It remains unclear how the various environmental factors are combined in practice to influence vegetable preferences in school-aged children. This study aimed to clarify the environmental factors during infancy and their association with vegetable preference in school-aged children. To find clusters of early childhood environmental factors, we conducted a factor analysis on 58 items related to early childhood environmental factors and a k-means cluster analysis using the factors obtained. The association of the extracted factors and clusters with vegetable preferences was assessed by multiple regression analysis. Twelve factors relating to vegetable eating, cooking and harvesting experience, and parental attitudes were extracted by factor analysis. Three clusters, "low awareness of experiences", "high awareness" and "low positive encouragement", were then extracted. In the multiple regression analysis, all 12 factors were found to be associated with vegetable preferences. Furthermore, it was found that the "high awareness" group had a significantly higher score for vegetable preference than the "low awareness of experiences" group (β = 0.56, 95% CI: 0.37-0.74). Thus, the study found that environmental factors during infancy, in isolation and combination, influenced vegetable preferences in school-aged children. Assessing the combination of various environmental factors during infancy may contribute to a better understanding of future vegetable preferences.

[Purpose] This study was aimed at evaluating the clinical indicators for predicting ambulation at 3 months after putaminal hemorrhage. [Participants and Methods] The participants were 84 inpatients with putaminal hemorrhage. The patients' background characteristics and computed tomography findings at the time of the onset of putaminal hemorrhage were obtained from their medical records. Impaired consciousness, severity of hemiplegia, higher brain dysfunction, sensory impairment, activities of daily living, and ambulatory ability were evaluated. Logistic regression analysis was performed to identify factors associated with ambulation at 3 months, and receiver operating characteristic curve analysis was conducted to determine the predictive value of the identified factors and the optimal cut-off values. [Results] Ventricular rupture, severity of hemiplegia (determined using the 12-grade hemiplegia function test), and Functional Independence Measure cognitive score were found to be independent predictors of prognosis. Severity of hemiplegia was the strongest predictor of ambulation, with a sensitivity of 80.4% and specificity of 100% when the cut-off was set at grade 6 (the ability for coordinated movement of the extensor and flexor muscles of the hip joint). [Conclusion] The severity of hemiplegia, Functional Independence Measure cognitive score, and ventricular rupture were independently associated with ambulation in patients with putaminal hemorrhage. The ability of the hip joint movement is one of the most important factors in ambulation prognosis., Competing Interests: The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript., (2024©by the Society of Physical Therapy Science. Published by IPEC Inc.)

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disorder characterized by systemic hyperinflammation. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potentially curative treatment for primary and relapsed/refractory HLH, the optimal strategy has not been established. We retrospectively analyzed 56 adult patients (≥18 years) with primary and secondary HLH (mainly consisting of Epstein-Barr virus-associated HLH) who underwent allo-HSCT using the registry database of the Japanese Society for Transplantation and Cellular Therapy, including 26 patients who underwent cord blood transplantation (CBT). One-fourth of patients received myeloablative conditioning (MAC), mainly consisting of total body irradiation-based regimens. The 3-year overall survival (OS) was 40.6%, while the 3-year cumulative incidences of relapse and non-relapse mortality (NRM) were 19.8% and 39.6%, respectively. In univariable analysis, age at allo-HSCT (the 3-year OS: 27.5% for ≥ 25 years old vs 58.0% for < 25 years old, P = .025), conditioning intensity (7.1% for MAC vs 51.8% for reduced-intensity conditioning (RIC), P = .002), and donor source (26.0% for CBT vs 52.9% for bone marrow or peripheral blood stem cell transplantation (BMT/PBSCT), P = .030) were associated with significantly inferior OS. In multivariable analysis, older age at allo-HSCT (≥ 25 years old) (Hazard ratio [HR], 2.37; 95% CI, 1.01 to 5.58; P = .048), MAC (HR, 2.45; 95% CI, 1.09 to 5.53; P = .031), and CBT (HR, 2.21; 95% CI, 1.04 to 4.71; P = .040) were independently associated with worse OS. In addition, only conditioning intensity predicted higher NRM (the 3-year NRM: 78.6% for MAC vs 26.6% for RIC), while no factors were associated with the relapse rate. This study includes the largest number of adult HLH patients undergoing CBT. Although the use of CBT is acceptable, BMT/PBSCT are more favorable strategies in allo-HSCT in adult HLH. Regarding conditioning intensity, RIC regimens are more beneficial in this setting., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Aim: This study aimed to examine the feasibility and potential benefits of an optical see-through head-mounted display (OST-HMD) during real-time ultrasound-guided thoracentesis simulations., Material and Methods: Six physicians performed a thoracentesis simulation using an OST-HMD and a wireless image transmission system. The time required, puncture needle visibility, pleural fluid collection success rate, and head movement during the procedure using a smart glass equipped with an inertial measurement unit were all recorded and compared with and without the HMD., Results: Study participants successfully extracted effusions in all procedures. The use of OST-HMD did not significantly affect the time of the procedure, but notably decreased the horizontal and vertical head movements during the procedure., Conclusions: The study demonstrated the feasibility of using an OST-HMD in a simulated real-time ultrasound-guided thoracentesis procedure and showed the potential of HMD in thoracentesis to improve ergonomics and accuracy. Further research is necessary to confirm these findings., (© 2024 Shotaro Okachi et al., published by Sciendo.)

Abstract: Clinically significant cytomegalovirus infection (csCMVi) is frequently observed after allogeneic hematopoietic stem cell transplantation (HSCT) and prophylaxis with letermovir is commonly adopted. However, the clinical benefit of letermovir prophylaxis according to graft sources has not been sufficiently elucidated. We retrospectively analyzed 2194 recipients of HSCT who were CMV-seropositive (236 with letermovir prophylaxis and 1958 without prophylaxis against CMV). csCMVi was significantly less frequent in patients with letermovir prophylaxis than in those without (23.7% vs 58.7% at 100 days after HSCT, P < .001) and the same trend was seen when recipients of bone marrow (BM), peripheral blood stem cell (PBSC), or cord blood (CB) transplantation were separately analyzed. In recipients of BM, nonrelapse mortality (NRM) was significantly lower in the letermovir group at 6 months after HSCT (5.0% vs 14.9%, P = .018), and the same trend was observed in recipients of PBSCs (14.7% vs 24.8%, P = .062); however, there was no statistical significance at 1 year (BM, 21.1% vs 30.4%, P = .67; PBSCs, 21.2% vs 30.4%, P = .096). In contrast, NRM was comparable between recipients of CB with and without letermovir prophylaxis throughout the clinical course (6 months, 23.6% vs 24.3%, P =.92; 1 year, 29.3% vs 31.0%, P = .77), which was confirmed by multivariate analyses. In conclusion, the impact of letermovir prophylaxis on NRM and csCMVi should be separately considered according to graft sources., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Leucine-rich repeat kinase 2 (LRRK2), a Rab kinase associated with Parkinson's disease and several inflammatory diseases, has been shown to localize to stressed lysosomes and get activated to regulate lysosomal homeostasis. However, the mechanisms of LRRK2 recruitment and activation have not been well understood. Here, we found that the ATG8 conjugation system regulates the recruitment of LRRK2 as well as LC3 onto single membranes of stressed lysosomes/phagosomes. This recruitment did not require FIP200-containing autophagy initiation complex, nor did it occur on double-membrane autophagosomes, suggesting independence from canonical autophagy. Consistently, LRRK2 recruitment was regulated by the V-ATPase-ATG16L1 axis, which requires the WD40 domain of ATG16L1 and specifically mediates ATG8 lipidation on single membranes. This mechanism was also responsible for the lysosomal stress-induced activation of LRRK2 and the resultant regulation of lysosomal secretion and enlargement. These results indicate that the V-ATPase-ATG16L1 axis serves a novel non-autophagic role in the maintenance of lysosomal homeostasis by recruiting LRRK2., (© 2024 Eguchi et al.)

The Integrated Testing Strategy version 2 (ITSv2) Defined Approach, which is a reliable skin sensitization hazard and multi-step risk assessment method, does not support quantitative risk assessment such as local lymph node assay EC3 values. In this study, we developed a high-performance in silico evaluation system that quantitatively predicts the EC3 values of chemical substances by combining the ITSv2 Defined Approach for hazard identification (ITSv2 HI) with machine learning models. This system uses in chemico/in vitro test data, molecular descriptors, and distance information based on read-across concepts as explanatory variables. The system achieves an R 2 value of 0.617 on external-validation data. Substances misclassified in ITSv2 HI are considered to have properties that do not match the correspondence between tests expressing the adverse outcome pathway assumed in the ITSv2 Defined Approach and skin sensitization. Therefore, ITSv2 HI is assumed to be correct within the applicability domains of this system. When using only substances within the applicability domains to reconstruct CatBoost models, the R 2 value reached 0.824 on the external-validation data, representing an improvement in system performance. The results demonstrate the utility of explanatory variables that reflect the read-across concept and the advantages of integrating multiple prediction methods., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: As the Japanese population may have less genetic diversity than other ethnic groups, treatment outcomes may be affected when allogeneic hematopoietic cell transplantation is performed in other races. However, evidence explaining the effect of racial differences is limited., Methods: We used the Japanese National Database to examine the outcomes of first allogeneic bone marrow transplantations (BMTs) performed between Japanese and non-Japanese patients from 1996 to 2021. We performed propensity score matching using sex, age group, underlying disease group, HLA mismatch, conditioning regimen intensity, and BMT implementation age to select Japanese-to-Japanese BMT patients as the controls., Results: The numbers of non-Japanese-to-Japanese and Japanese-to-non-Japanese BMT cases included in the analysis were 48 and 75, respectively, and the following outcomes were compared: overall survival, non-relapse mortality, acute graft-vs-host disease (GVHD) ≥ grade II, chronic GVHD, and engraftment of neutrophils and platelets. Most parameters did not differ when comparing BMTs according to ethnicity; only platelet engraftment was delayed in Japanese-to-non-Japanese BMT but not in non-Japanese-to-Japanese BMT., Conclusions: The results of this study suggested that BMT performed in Japanese and non-Japanese patients has little effect on treatment outcomes. The results of this study may be useful for donor selection in Japan, where internationalization has progressed in recent years., Competing Interests: Declaration of competing interest All the authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hematopoietic stem cells (HSCs) are a rare population of cells found in the bone marrow that play a critical role in lifelong hematopoiesis and the reconstitution of the hematopoietic system after hematopoietic stem cell transplantation. Hematopoietic stem cell transplantation remains the only curative treatment for patients with refractory hematologic disorders, and umbilical cord blood (CB) serves as an alternative stem cell source due to its several advantageous characteristics, including human leukocyte antigen flexibility and reduced donor burden. However, CB also has the disadvantage of containing a small number of cells, resulting in limited donor selection and a longer time for engraftment. Therefore, the development of techniques to expand HSCs ex vivo, particularly umbilical CB, is a goal in hematology. While various combinations of cytokines were once the mainstream approach, these protocols had limited expansion rates and did not lead to clinical application. However, in recent years, the development of a technique in which small molecules are added to cytokines has enabled the stable, long-term ex vivo expansion of human HSCs. Clinical trials of expanded umbilical CB using these techniques have been undertaken and have confirmed their efficacy and safety. In addition, we have successfully developed a recombinant-cytokine-free and albumin-free culture system for the long-term expansion of human HSCs. This approach could offer the potential for more selective expansion of human HSCs compared to previous protocols. This review discusses ex vivo culture protocols for expanding human HSCs and presents the results of clinical trials using these techniques, along with future perspectives., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)