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Short-chain esters, particularly isobutyl acetate and isoamyl acetate, hold significant industrial value due to their wide-ranging applications in flavors, fragrances, solvents, and biofuels. In this study, we demonstrated the biosynthesis of acetate esters using Yarrowia lipolytica as a host by feeding alcohols to the yeast culture. Initially, we screened for optimal alcohol acyltransferases for ester biosynthesis in Y. lipolytica. Strains of Y. lipolytica expressing atf1 from Saccharomyces cerevisiae, produced 251 or 613 mg/L of isobutyl acetate or of isoamyl acetate, respectively. We found that introducing additional copies of ATF1 enhanced ester production. Furthermore, by increasing the supply of acetyl-CoA and refining the culture conditions, we achieved high production of isoamyl acetate, reaching titers of 3404 mg/L. We expanded our study to include the synthesis of a range of acetate esters, facilitated by enriching the culture medium with various alcohols. This study underscores the versatility and potential of Y. lipolytica in the industrial production of acetate esters., (© 2024 American Institute of Chemical Engineers.)

Transcribed enhancer maps can reveal nuclear interactions underpinning each cell type and connect specific cell types to diseases. Using a 5' single-cell RNA sequencing approach, we defined transcription start sites of enhancer RNAs and other classes of coding and noncoding RNAs in human CD4 + T cells, revealing cellular heterogeneity and differentiation trajectories. Integration of these datasets with single-cell chromatin profiles showed that active enhancers with bidirectional RNA transcription are highly cell type-specific and that disease heritability is strongly enriched in these enhancers. The resulting cell type-resolved multimodal atlas of bidirectionally transcribed enhancers, which we linked with promoters using fine-scale chromatin contact maps, enabled us to systematically interpret genetic variants associated with a range of immune-mediated diseases.

Idiopathic inflammatory myopathies (IIMs) are divided into polymyositis and dermatomyositis (DM) with specific cutaneous manifestation. Several myositis-specific autoantibodies (MSAs) have been identified in IIMs and were found to be associated with distinct clinical features, including anti-synthetase syndrome (ASyS) and immune-mediated necrotizing myopathy (IMNM). Moreover, MSA-related clinical features have been identified even within DM. Although MSAs are valuable for the diagnosis of IIMs, the pathogenic roles of these antibodies remain unknown. To investigate the pathogenesis of IIMs, classical murine models of autoimmune myositis, experimental autoimmune myositis, and C protein-induced myositis have been established by immunization with muscle-specific antigens, myosin, and myosin-binding skeletal C protein, respectively. To according to MSA-related autoimmunity, a murine model of ASyS was generated by immunization with a murine recombinant histidyl-transfer RNA (tRNA) synthetase, Jo-1, in which muscle and lung inflammation are induced depending on acquired immunity. Furthermore, it was found that the transfer of human Immunoglobulin G (IgGs) from patients with IMNM, comprising anti-signal recognition particles and anti-3-hydroxy-3-methylglutaryl coenzyme A reductase antibodies, induced complement-mediated myositis in recipient mice. We found that CD8 + T cell-mediated myositis can be established depending on autoimmunity against transcriptional intermediary factor 1γ (TIF1γ), an autoantigen for MSAs induced by recombinant human TIF1γ immunization. These new murine models reflecting MSA-associated IIMs will reveal the immunological mechanisms underlying IIMs., (© 2024 Japanese Dermatological Association.)

Objective: Scapular dyskinesis is one of the causes of shoulder disorders and involves muscle weakness in the serratus anterior. This study investigated whether motor unit (MU) recruitment and firing property, which are important for muscle exertion, have altered in serratus anterior of the individuals with scapular dyskinesis., Methods: Asymptomatic adults with (SD) and without (control) scapular dyskinesis were analyzed. Surface electromyography (sEMG) waveforms were collected at submaximal voluntary contraction of the serratus anterior. The sEMG waveform was decomposed into MU action potential amplitude (MUAP AMP ), mean firing rate (MFR), and recruitment threshold. MUs were divided into low, moderate, and high thresholds, and MU recruitment and firing properties of the groups were compared., Results: High-threshold MUAP AMP was significantly smaller in the SD group than in the control group. The control group also exhibited recruitment properties that reflected the size principle, however, the SD group did not. Furthermore, the SD group had a lower MFR than the control group., Conclusions: Individuals with scapular dyskinesis exhibit altered MU recruitment properties and lower firing rates of the serratus anterior; this may be detrimental to muscle performance. Thus, it may be necessary to improve the neural drive of the serratus anterior when correcting scapular dyskinesis., Competing Interests: The authors have no conflict of interest.

Anti-nuclear matrix protein 2 (NXP2) antibody-positive dermatomyositis (DM) is characterized by extensive and severe myositis. In this study, we evaluated which cytokines/chemokines involved with the activity of the myositis. We performed quantitative immunoassays using the MILLIPLEX ® Multiplex Assays Using Luminex to evaluate serum levels of interferon-γ, interleukin (IL)-1β, IL-6, IL-8, IL-12p40, and tumor necrosis factor-α in samples collected over time from a 9-year-old female with anti-NXP2 antibody-positive DM. In our case, the serum level of IL-8 was elevated when the myositis worsened, and decreased in accordance with the improvement of myositis, suggesting that the serum IL-8 levels were correlated with the myositis activity. Serum levels of IL-8 in samples from five patients with anti-NXP2 antibody-positive DM and five patients with anti-transcriptional intermediary factor 1γ (TIF1γ) antibody-positive DM without both interstitial lung disease (ILD) and malignancy before starting treatments, along with five healthy controls, were also evaluate by an enzyme-linked immunosorbent assay. Serum IL-8 levels were significantly elevated in anti-NXP2 or anti-TIF1γ antibody-positive DM patients with myositis but not ILD, than healthy controls. It was suggested that serum levels of IL-8 correlate with the activity of myositis in DM including anti-NXP2 antibody-positive DM.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (DM) is characterized by amyopathic DM with interstitial lung disease (ILD). Patients with anti-MDA5 antibody-associated ILD frequently develop rapidly progression and present high mortality rate in the acute phase. Here, we established a murine model of ILD mediated by autoimmunity against MDA5. Mice immunized with recombinant murine MDA5 whole protein, accompanied with complete Freund's adjuvant once a week for four times, developed MDA5-reactive T cells and anti-MDA5 antibodies. After acute lung injury induced by intranasal administration of polyinosinic-polycytidylic acid [poly (I:C)] mimicking viral infection, the MDA5-immunized mice developed fibrotic ILD representing prolonged respiratory inflammation accompanied by fibrotic changes 2 wk after poly (I:C)-administration, while the control mice had quickly and completely recovered from the respiratory inflammation. Treatment with anti-CD4 depleting antibody, but not anti-CD8 depleting antibody, suppressed the severity of MDA5-induced fibrotic ILD. Upregulation of interleukin (IL)-6 mRNA, which was temporarily observed in poly (I:C)-treated mice, was prolonged in MDA5-immunized mice. Treatment with anti-IL-6 receptor antibody ameliorated the MDA5-induced fibrotic ILD. These results suggested that autoimmunity against MDA5 exacerbates toll-like receptor 3-mediated acute lung injury, and prolongs inflammation resulting in the development of fibrotic ILD. IL-6 may play a key role initiating ILD in this model., Competing Interests: Competing interests statement:The authors declare no competing interest.

L-theanine, an amino acid component of the tea leaves of Camellia sinensis, is sold in Japan as a supplement for good sleep. Although several studies in humans and mice have reported the effects of L-theanine on brain function, only a few reports have comprehensively clarified the disposition of theanine administered to mice and its effects on concentrations of other blood amino acids. In this study, we aimed to determine the changes in the blood levels of L-theanine administered to mice and amino acid composition of the serum. L-theanine were administered to four-week-old Std-ddY male mice orally or via tail vein injection. L-theanine and other amino acids in serum prepared from blood collected at different time points post-dose were labeled with phenylisothiocyanate and quantified. The serum concentration of orally administered L-theanine peaked 15 min after administration. The area under the curve for tail vein injection revealed the bioavailability of L- theanine to be approximately 70%. L-theanine administration did not affect any amino acid levels in the serum, but a significant increase in the peak area overlapping the Glycine (Gly) peak was observed 30 min after administration. L-theanine administered to mice was rapidly absorbed and eliminated, suggesting that taking L-theanine as a supplement is safe without affecting its own levels or serum levels of other amino acids. However, considering that Gly, similar to L-theanine, is used as a dietary supplement for its anxiolytic effects and to improve sleep, determining the effects of L-theanine administration on Gly is important and needs further research., (© 2024. The Author(s).)

Dermatomyositis constitutes a heterogeneous group of autoimmune inflammatory conditions with a wide variety of clinical outcomes. The symptomatic heterogeneity carries skin, muscle, and joint manifestations; pulmonary and cardiac involvements; and concomitant malignancy. Any of these symptoms often appear at different combinations and time courses, thus posing difficulty in early diagnosis and appropriate treatment choice. Recent progress in laboratory investigations explored the identification of several myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies, allowing precise characterization for a clinical perspective of the disease. MSAs can be detectable in approximately 80% of patients with whole dermatomyositis, some of which closely reflect unique clinical features in the particular disease subset(s), including the distribution and severity of organ involvement, treatment response, and prognosis. However, only limited evidence has been available in dermatomyositis-associated panniculitis, mostly that in anti- melanoma differentiation-associated protein 5 antibody-positive disease. We present a rare case of a patients with dermatomyositis with extensive panniculitis on the trunk whose serum IgG autoantibodies reacted with both subunits of small ubiquitin-like modifier activating enzymes (SAEs), SAE1 and SAE2. The onset of panniculitis coincided with increased disease activity, including disease-related skin manifestations, fever, dysphagia, and muscle weakness in the extremities. These symptoms responded well to a high dose of systemic steroid, but even upon receiving a high-dose intravenous immunoglobulin, the panniculitic lesions and pruritic erythema flared with tapering of steroid dose, further requiring tacrolimus and mycophenolate mofetil to achieve disease remission. To our knowledge, this is the third reported case of anti-SAE autoantibody-positive dermatomyositis with panniculitis. We aim to extend the understanding of the current limitation and further perspective in the clinical management of the extremely rare skin manifestation associated with dermatomyositis., (© 2023 Japanese Dermatological Association.)

Differences in lower limb kinematics between males and females during functional activities may be attributed to sex differences in the incidence of patellofemoral pain, which is more common in females. To better comprehend the knee joint motion, it is necessary to understand both inter-segmental coordination patterns and angular amplitude. This exploratory study aimed to assess sex differences in pelvis-thigh and thigh-shank coordination patterns in the frontal and horizontal planes during walking. Data regarding the kinematic characteristics of the pelvis, thigh, and shank segments were collected from 26 males and 26 females performing walking at self-selected speeds using a 3D motion capture system. Furthermore, we compared the kinematics of the pelvis, thigh, and shank during walking as well as the pelvis-thigh and thigh-shank coordination patterns in the frontal and horizontal planes during the stance phase between males and females. Compared to males, females had greater thigh adduction (p < 0.001) and internal rotation (p < 0.001) throughout the stance phase; significantly greater frequency of the pelvis-thigh anti-phase pattern in the frontal plane in the early (p = 0.002) and mid-stance (p = 0.003); and significantly greater thigh-shank anti-phase pattern in the frontal plane in the early (p = 0.001) and mid-stance (p = 0.015). These results suggest the presence of sex differences in the inter-segmental coordination of the pelvis and lower limb during walking. However, as this study could not determine a causal relationship between female sex and knee joint injury, further longitudinal studies are needed to determine the effects of differences in coordination patterns on the pathophysiology of the injury and pain generation., 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 © 2023 Elsevier Ltd. All rights reserved.)

Toxoplasma gondii is a highly prevalent obligate apicomplexan parasite that is important in clinical and veterinary medicine. It is known that glycerophospholipids phosphatidylserine (PtdSer) and phosphatidylethanolamine (PtdEtn), especially their expression levels and flip-flops between cytoplasmic and exoplasmic leaflets, in the membrane of T. gondii play important roles in efficient growth in host mammalian cells, but their distributions have still not been determined because of technical difficulties in studying intracellular lipid distribution at the nanometer level. In this study, we developed an electron microscopy method that enabled us to determine the distributions of PtdSer and PtdEtn in individual leaflets of cellular membranes by using quick-freeze freeze-fracture replica labeling. Our findings show that PtdSer and PtdEtn are asymmetrically distributed, with substantial amounts localized at the luminal leaflet of the inner membrane complex (IMC), which comprises flattened vesicles located just underneath the plasma membrane (see Figs. 2B and 7). We also found that PtdSer was absent in the cytoplasmic leaflet of the inner IMC membrane, but was present in considerable amounts in the cytoplasmic leaflet of the middle IMC membrane, suggesting a barrier-like mechanism preventing the diffusion of PtdSer in the cytoplasmic leaflets of the two membranes. In addition, the expression levels of both PtdSer and PtdEtn in the luminal leaflet of the IMC membrane in the highly virulent RH strain were higher than those in the less virulent PLK strain. We also found that the amount of glycolipid GM3, a lipid raft component, was higher in the RH strain than in the PLK strain. These results suggest a correlation between lipid raft maintenance, virulence, and the expression levels of PtdSer and PtdEtn in T. gondii., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

As medical device development becomes increasingly global, the opportunities and potential advantages offered by international clinical trial and regulatory approval strategies are also growing. In particular, medical device clinical trials involving sites in both the United States and Japan and intended to support marketing in both countries may warrant particular consideration, given the similarities in their regulatory systems, patients and clinical practice patterns, and market sizes. Since 2003, the US-Japan Harmonization By Doing (HBD) initiative has been focused on identifying and addressing clinical and regulatory barriers to medical devices access in both countries via collaboration between governmental, academic, and industry stakeholders. Through the efforts of HBD participants, US-Japanese clinical trials have been conducted and the resulting data have supported regulatory approval for marketing in both countries. Based on these experiences, this paper outlines some of the key factors to consider when developing a global clinical trial involving US and Japanese participation. These considerations include the mechanisms for consultation with regulatory authorities on clinical trial strategies, the regulatory framework for clinical trial notification and approval, recruitment and conduct of clinical sites, and lessons learned from specific US-Japanese clinical trial experiences. The goal of this paper is to promote global access to promising medical technologies by assisting potential clinical trial sponsors in understanding when an international strategy may be appropriate and successful., Competing Interests: Declaration of competing interest None., (Published by Elsevier Inc.)

Objectives: Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive rapidly progressive interstitial lung disease (RP-ILD) is a life-threatening disease, the aetiology of which remains unclear. To detect potential diagnostic markers, a transcriptome analysis of the lung sample from a patient with anti-MDA5 antibody-positive RP-ILD was performed., Methods: RNA sequencing analyses of an autopsy lung sample from a 74-year-old woman with anti-MDA5 antibody-positive RP-ILD was performed and compared with an age- and sex-matched normal lung sample. Genes with changes of gene expression ≥5-fold were considered differentially expressed genes and analysed by Metascape. The levels of leukaemia inhibitory factor (LIF) were measured in the serum samples from 12 cases of anti-MDA5 antibody-positive ILD, 12 cases of anti-aminoacyl tRNA synthetase (ARS) antibody-positive ILD, 10 cases of anti-transcription intermediary factor 1γ/anti-Mi-2 antibody DM and 12 healthy volunteers., Results: Gene ontology enrichment analysis on the RNA sequencing data showed a strong association with antigen binding. Upregulated expressions of IL-1β, IL-6 and LIF were also detected. Serum LIF levels were significantly elevated in anti-MDA5 antibody-positive ILD patients {median 32.4 pg/ml [interquartile range (IQR) 13.2-125.7]} when compared with anti-ARS antibody-positive ILD patients [4.9 pg/ml (IQR 3.1-19.7), P < 0.05] and DM patients [5.3 pg/ml (IQR 3.9-9.7), P < 0.05]., Conclusion: Our present study suggested that upregulation of LIF might be a new potential disease marker specific for anti-MDA5 antibody-positive ILD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Context: Excessive hip adduction and internal rotation are abnormal movements that may lead to the onset and progression of patellofemoral pain. Previous studies have reported that lower dynamic frontal plane hip joint stiffness in the gait of women is associated with the magnitude of hip adduction and internal rotation angles. However, the factors contributing to the lack of dynamic frontal plane hip joint stiffness in the gait of young women are unclear. This study aims to investigate the factors affecting dynamic frontal plane hip joint stiffness during the weight-acceptance phase of the gait of healthy young women., Design: Cross-sectional study., Methods: This study included 30 healthy women between the ages of 18 and 30 years. The pelvic width/femur length ratio was calculated by dividing the pelvic width by the femur length. Data on hip kinematics and kinetics and activation of the gluteus maximus and medius, tensor fasciae latae, and adductor longus muscles during gait were collected using a motion capture system, force plates, and surface electromyography. Stepwise multiple regression analysis was conducted to determine the extent to which each independent factor affected dynamic frontal plane hip joint stiffness., Results: In healthy young women, decreased dynamic frontal plane hip joint stiffness was associated with decreased muscle activity of the gluteus maximus during the gait, as well as greater pelvic width/femur length ratio., Conclusions: Women with a relatively great pelvic width relative to femur length may have more difficulty in producing dynamic frontal plane hip joint stiffness. However, increasing the muscle activity of the gluteus maximus may contribute to increased dynamic frontal plane hip joint stiffness.

Idiopathic inflammatory myopathies (IIMs) are characterized by inflammation of muscles and other organs. Several myositis-specific autoantibodies (MSAs) have been identified in IIMs and were found to be associated with distinct clinical features. Although MSAs are valuable for the diagnosis of IIMs, the pathogenic roles of these antibodies remain unknown. To investigate the pathogenesis of IIMs, several animal models of experimental myositis have been established. Classical murine models of autoimmune myositis, experimental autoimmune myositis, and C protein-induced myositis are established by immunization with muscle-specific antigens, myosin, and skeletal C protein, respectively. Furthermore, a murine model of experimental myositis was generated by immunization with a murine recombinant histidyl-tRNA synthetase, Jo-1, in which muscle and lung inflammation reflecting anti-synthetase syndrome are induced depending on acquired immunity. Recently, the transfer of human IgGs from patients with immune-mediated necrotizing myopathy, comprising anti-signal recognition particles and anti-3-hydroxy-3-methylglutaryl coenzyme A reductase antibodies, was found to induce complement-mediated myositis in recipient mice. CD8 + T cell-mediated myositis can be established depending on autoimmunity against transcriptional intermediary factor 1γ (TIF1γ), an autoantigen for MSAs induced by recombinant human TIF1γ immunization. These new murine models reflecting MSA-related IIMs are useful tools for accurately understanding the pathological mechanisms underlying IIMs.

Background: Antigen-stimulated naïve T cells differentiate into effector and memory T cells, of which resident memory T (T RM ) cells reside permanently in organ tissues. Involvement of T RM cells has been indicated in pathological conditions of various skin diseases. CD122, which is the β chain subunit of interleukin (IL)- 2 and IL-15 receptors, is expressed on immune cells including T RM cells., Objective: To investigate whether CD122 signaling in skin CD8 + T RM cells mediates the development of mucocutaneous graft-versus-host disease (GVHD)., Methods: We used a genetically modified mouse expressing a membrane-bound form of chicken ovalbumin (OVA) under the control of the keratin 14 promoter, which develops GVHD-like erosive mucocutaneous disease resulting in sclerodermatous disease after transfer of OVA-specific T cell-receptor-transgenic CD8 + OT-I cells. Mice with mucocutaneous GVHD were treated with an anti-CD122 blocking antibody., Results: Administration of an anti-CD122 blocking antibody suppresses the development of acute/chronic GVHD-like mucocutaneous disease in our murine model via the reduction of CD122-expressing memory CD8 + T cells, including skin, memory autoaggressive CD8 + T cells. Moreover, blockade of CD122, even after the establishment of acute GVHD, inhibited the development of chronic GVHD-like sclerodermatous disease via the reduction of epidermal and dermal T RM autoaggressive CD8 + T cells., Conclusion: Skin memory CD8 + T cells in particular mediate the development of mucocutaneous GVHD, and blockade of CD122 may be an effective treatment strategy, especially for sclerodermatous GVHD., Competing Interests: Disclosure of potential conflict of interest NK, RT, YI, RK, TN and NO have declared that no conflict of interest exists. NT and JYT are employees and managing partners of JN Biosciences LLC., (Copyright © 2023 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Cancers induce the production of acute phase proteins such as serum amyloid alpha (SAA) in the liver and cause inflammation in various host organs. Despite the well-known coincidence of acute phase response and inflammation, the direct roles of SAA proteins in inflammation in the cancer context remains incompletely characterized, particularly in vivo . Here, we investigate the in vivo significance of SAA proteins in liver inflammation in the 4T1 murine breast cancer model. 4T1 cancers elevate the expression of SAA1 and SAA2, the two major murine acute phase proteins in the liver. The elevation of Saa1-2 correlates with the up-regulation of immune cell-related genes including neutrophil markers. To examine this correlation in detail, we generate mice that lack Saa1-2 and investigate immune-cell phenotypes. RNA-seq experiments reveal that deletion of Saa1-2 does not strongly affect 4T1-induced activation of immune cell-related genes in the liver. Flow cytometry experiments demonstrate the dispensable roles of SAA1-2 in cancer-dependent neutrophil infiltration to the liver. Consistently, 4T1-induced gene expression changes in bone marrow do not require Saa1-2 . This study clarifies the negligible contribution of SAA1-2 proteins in liver inflammation in the 4T1 breast cancer model., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 He, Konishi, Harata, Nakamura, Mizuno, Yoda, Toi, Kawaguchi and Kawaoka.)

Background: For pharmacists expected to encounter the deaths of many of their patients in the near future, it is important to understand the perception of a "good death" for patients with cancer who are likely to be aware of the circumstances of their poor prognosis. In this study, we clarified pharmacists' perceptions of a "good death" and considered the differences in perception among patients with cancer, oncologists, and oncology nurses., Methods: From April to June 2022, an anonymous questionnaire survey was conducted on pharmacists working in hospitals and pharmacies and on members of the Japanese Society for Pharmaceutical Palliative Care and Sciences. The questionnaire consisted of 57 questions, called attributes, developed by Miyashita et al. to investigate the perception of "good death" in Japanese cancer medicine. The importance of those attributes was investigated using a 7-point Likert scale., Results: Three thousand four hundred thirty-two pharmacists were made aware of this survey, and 207 participated in the survey. The responses of pharmacists to the 57 questions were very similar to those of the oncologists. Among them, "Fighting against disease until one's last moment" and "Not making trouble for others" had very low importance, which was the most significantly different from the responses of patients with cancer. "Fighting against disease until one's last moment" tended to be significantly underestimated by pharmacists engaged in patient guidance and interview compared to that by pharmacists not engaged in the duty (p = 0.02). Also, when we compared pharmacists with or without qualifications related to cancer and palliative care, there was no significant difference in the importance of "Fighting against disease until one's last moment." However, the importance of "Not making trouble for others" for qualified pharmacists was significantly underestimated (p = 0.04)., Conclusion: Since pharmacists understand the limits of chemotherapy, they may want to be close to the patient but may not strongly agree with the "Fighting against cancer" component that patients with cancer prefer. It may be necessary to reconsider better ways of approaching the wishes and satisfaction of patients with cancer under the care of medical professionals in the field of oncology., (© 2023. The Author(s).)

The spatially organized gene expression program within the liver specifies hepatocyte functions according to their relative distances to the bloodstream (i.e., zonation), contributing to liver homeostasis. Despite the knowledge that solid cancers remotely disrupt liver homeostasis, it remains unexplored whether solid cancers affect liver zonation. Here, using spatial transcriptomics, we thoroughly investigate the abundance and zonation of hepatic genes in cancer-bearing mice. We find that breast cancers affect liver zonation in various distinct manners depending on biological pathways. Aspartate metabolism and triglyceride catabolic processes retain relatively intact zonation patterns, but the zonation of xenobiotic catabolic process genes exhibits a strong disruption. The acute phase response is induced in zonated manners. Furthermore, we demonstrate that breast cancers activate innate immune cells in particular neutrophils in distinct zonated manners, rather than in a uniform fashion within the liver. Collectively, breast cancers disorganize hepatic transcriptomes in zonated manners, thereby disrupting zonated functions of the liver., (© 2023. The Author(s).)

Langerhans cells (LCs) are skin-resident cells with potent antigen-presenting cell capabilities, which reportedly play some roles in the development of psoriasis, an inflammatory skin disease mediated by IL-17A‒producing cells, T helper 17 cells, and TCR-γδ low T cells. LCs in psoriatic skin lesions but not in normal skin express PD-L1, which binds to PD-1, an immune checkpoint molecule, to negatively regulate immune reactions. The aim of this study is to elucidate the regulatory role of LCs through the PD-1/PD-L1 axis in a murine model of imiquimod-induced psoriasis-like dermatitis. Imiquimod application on wild-type C57BL/6J mice induced PD-L1 expression on LCs both in the ear skin and skin-draining lymph nodes. To further identify the functional role of PD-L1 expressed on LCs, we generated conditional knockout mice lacking PD-L1 expression on LCs (Pd-l1-cKO mice). Pd-l1-cKO mice presented significantly more severe imiquimod-induced psoriasis-like dermatitis than their control littermates. Flow cytometric analysis showed that the frequency of activated IL-17A‒producing γδ low T cells was increased in the ear skin samples, and IL-17A production by CCR6 + migrating γδ low T cells increased in the skin-draining lymph nodes in imiquimod-applied Pd-l1-cKO mice than in control littermates. Collectively, LCs disrupt the exacerbation of psoriasis through PD-L1., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

COA-Cl, a novel adenosine-like nucleic acid analog, has recently been shown to exert neuroprotective effects and to increase dopamine levels both in vivo and in vitro. Therefore, we hypothesized that COA-Cl could protect dopaminergic neurons against toxic insults. Thus, the present study aimed to investigate the protective effects of COA-Cl against hydrogen peroxide (H 2 O 2 )- and 6-hydroxydopamine (6-OHDA)-induced toxicity in PC12 cells and to elucidate the possible mechanisms. PC12 cells were incubated with COA-Cl (100 μM) with or without H 2 O 2 or 6-OHDA (200 μM) for 24 h. Treatment with COA-Cl attenuated the decrease in cell viability, SOD activity and the Bcl-2/Bax ratio caused by H 2 O 2 . In addition, COA-Cl attenuated the increase in LDH release, ROS production, caspase-3 activity, and apoptosis induced by H 2 O 2 . Further, COA-Cl enhanced the protection of PC12 cells against the toxicity caused by 6-OHDA, as evidenced by an increase in cell viability and the Bcl-2/Bax ratio, and a decrease in LDH release. Our results are the first to demonstrate that COA-Cl potentially protects PC12 cells against toxicity induced by H 2 O 2 and 6-OHDA, implying that COA-Cl could be a promising neuroprotective agent for the treatment of Parkinson's disease., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Lumbopelvic region rotation relative flexibility (LRRF), which is defined as lumbopelvic region that is relatively less stiffness than the hip region, is associated with low back pain (LBP) symptoms. However, how LRRF is influenced by lumbopelvic region motion during walking is unclear., Research Question: What is the influence of LBP and LRRF on coordination patterns of the thorax, pelvis, and femur during walking?, Methods: The presence of LRRF was determined based on whether the lumbopelvic rotation occurred in the first 50% of knee flexion or hip external rotation movement. Participants with LBP and LRRF were classified into the LBP group. Participants with LRRF but without LBP were classified into the early pelvis rotation (ROT) group, and those without LBP and relative flexibility were classified as controls. The thorax-pelvis coordination and pelvis-femur coordination during the stance cycles were calculated from the segmental angles obtained by three-dimensional motion analysis using a modified vector coding technique., Results: In the sagittal plane, the thorax-pelvis coordination of the LBP group showed more anti-phase patterns at both the early stance and midstance compared with controls and the ROT group. In the sagittal and horizontal planes, pelvis-femur coordination of the LBP and ROT groups showed more in-phase patterns during the early stance and midstance compared with controls., Significance: Regardless of LBP, the presence of LRRF alters the intersegmental coordination during walking. In individuals with LRRF, stiffness of the hip may increase during walking. People who have LRRF without LBP may develop LBP in the future, and it is important for prevention to identify these differences in kinematics during walking., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Autophagy is regulated by phosphoinositides. We have previously shown that phosphatidylinositol 4-phosphate (PtdIns(4)P) is localized in the autophagosomal membrane. Additionally, in yeast cells, phosphatidylinositol 4-kinases Pik1p and Stt4p play important roles in the formation of the autophagosome and its fusion with the vacuole, respectively. In this study, we analyzed the primary role of PtdIns(4)P phosphatases in yeast autophagy. The PtdIns(4)P labeling densities in the membranes of the vacuoles, mitochondria, nucleus, endoplasmic reticulum, and plasma membrane dramatically increased in the phosphatase deletion mutants sac1∆ and sjl3∆, and the temperature-sensitive mutant sac1 ts /sjl3∆ at the restrictive temperature. GFP-Atg8 processing assay indicated defective autophagy in the sac1∆ and sac1 ts /sjl3∆ mutants. In contrast to the localization of PtdIns(4)P in the luminal leaflet of autophagosomal membranes in the wild-type yeast, PtdIns(4)P was localized in both the luminal and cytoplasmic leaflets of the autophagosomal membranes in the sac1∆ strain. In addition, the number of autophagic bodies in the vacuole significantly decreased in the sac1∆ strain, although autophagosomes were present in the cytoplasm. In the sac1 ts /sjl3∆ strain, the number of autophagosomes in the cytoplasm dramatically decreased at the restrictive temperature. Considering that the numbers of autophagosomes and autophagic bodies in the sjl3∆ strain were comparable to those in the wild-type yeast, we found that the autophagosome could not be formed when PtdIns(4)P phosphatase activities of both Sac1p and Sjl3p were diminished. Together, these results indicate that the turnover of PtdIns(4)P by phosphatases is essential for autophagosome biogenesis., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Erdheim-Chester disease, a rare non-Langerhans histiocytosis, involves multiple organs, including kidney. Renal dysfunction sometimes occurs, and is attributed to ureteral obstruction and renal artery stenosis by histiocytic infiltration. However, to our knowledge, case reports of end-stage renal disease requiring renal replacement therapy due to Erdheim-Chester disease are very few. Here, we report a 69-year-old woman who was diagnosed with Erdheim-Chester disease 10 years ago. She had multiple organ involvement, such as bone, skin, heart, pituitary gland, kidney, and retroperitoneum. She had been treated with interferon-alpha, but discontinued after 2 years due to depression and repeated infection. She did not desire treatment with other drugs, so we continued supportive care. Her renal function gradually deteriorated, and hemodialysis was initiated 4 years ago. Subsequently, she is still doing well without any major symptoms. This report describes an unusual case of Erdheim-Chester disease requiring maintenance hemodialysis that longer prognosis than expected was obtained regardless of multiple organ involvement and no specific treatment after interferon-alpha cessation., (© 2022. Japanese Society of Nephrology.)

Cancers disrupt host homeostasis in various manners but the identity of host factors underlying such disruption remains largely unknown. Here we show that nicotinamide-N-methyltransferase (NNMT) is a host factor that mediates metabolic dysfunction in the livers of cancer-bearing mice. Multiple solid cancers distantly increase expression of Nnmt and its product 1-methylnicotinamide (MNAM) in the liver. Multi-omics analyses reveal suppression of the urea cycle accompanied by accumulation of amino acids, and enhancement of uracil biogenesis in the livers of cancer-bearing mice. Importantly, genetic deletion of Nnmt leads to alleviation of these metabolic abnormalities, and buffers cancer-dependent weight loss and reduction of the voluntary wheel-running activity. Our data also demonstrate that MNAM is capable of affecting urea cycle metabolites in the liver. These results suggest that cancers up-regulate the hepatic NNMT pathway to rewire liver metabolism towards uracil biogenesis rather than nitrogen disposal via the urea cycle, thereby disrupting host homeostasis., (© 2022. The Author(s).)

A line blotting assay (LB) is currently used to detect myositis-specific autoantibodies (MSAs) in patients with idiopathic inflammatory myopathies (IIMs), because of its simplicity; however, the sensitivity and specificity of this assay is low. The aim of this study is to evaluate the accuracy of the commercial LB in detection of antinuclear matrix protein 2 (NXP2) antibody. Seventy-seven serum samples from patients with IIMs, in which anti-NXP2 antibodies were detected through immunoprecipitation and western blotting (IP-WB) using K562 cell lysate, were enrolled. All samples were assessed by LB and IP-WB using recombinant human NXP2 whole protein (rNXP2) produced by insect cells, and the positive rates of each assay were compared. Thirty-two samples (41.6%) showed false-negativity by LB, which includes 11 samples with negative results by IP-WB using rNXP2. Relative intensities of IP-WB using cell lysate were significantly higher in the samples with positive results by both LB and IP-WB using rNXP2, compared to samples with positive by IP-WB using rNXP2 but negative by LB. Three of 11 samples with negative results by both LB and IP-WB using rNXP2 revealed high antibody titers. Further, differences in post-transcriptional SUMOylation were observed between recombinant and natural NXP2 proteins. In conclusion, the LB showed low sensitivity for detection of anti-NXP2 antibody, an effect exacerbated at low titers of anti-NXP2 antibodies. Moreover, there appears to be differences in the reactivities of antibodies to recombinant and natural NXP2 proteins with different post-transcriptional modifications., (© 2021 Japanese Dermatological Association.)

Purpose: The relationship between duty hours (DH) and the performance of postgraduate residents is needed to establish appropriate DH limits. This study explores their relationship using the General Medicine In-training Examination (GM-ITE)., Materials and Methods: In this cross-sectional study, GM-ITE examinees of 2019 had participated. We analyzed data from the examination and questionnaire, including DH per week (eight categories). We examined the association between DH and GM-ITE score, using random-intercept linear models with and without adjustments., Results: Five thousand five hundred and ninety-three participants (50.7% PGY-1, 31.6% female, 10.0% university hospitals) were included. Mean GM-ITE scores were lower among residents in Category 2 (45-50 h; mean score difference, -1.05; p  < 0.001) and Category 4 (55-60 h; -0.63; p  = 0.008) compared with residents in Category 5 (60-65 h; Reference). PGY-2 residents in Categories 2-4 had lower GM-ITE scores compared to those in Category 5. University residents in Category 1 and Category 5 showed a large mean difference (-3.43; p  = 0.01)., Conclusions: DH <60-65 h per week was independently associated with lower resident performance, but more DH did not improve performance. DH of 60-65 h per week may be the optimal balance for a resident's education and well-being.

Objectives: Myositis-specific autoantibodies (MSAs) define distinct clinical subsets of idiopathic inflammatory myopathies (IIMs). The anti-nuclear matrix protein 2 (NXP2) antibody, a MSA detected in juvenile/adult IIMs, has been reported to be associated with a high risk of subcutaneous calcinosis, subcutaneous oedema and internal malignancies. The study aimed to clarify the clinical features of anti-NXP2 antibody-positive IIMs in detail., Methods: This was a multicentre retrospective observational study on 76 anti-NXP2 antibody-positive patients. The antibody was detected via a serological assay using immunoprecipitation and western blotting. The patients were selected from 162 consecutive Japanese patients with IIMs., Results: The cohort of anti-NXP2 antibody-positive IIMs included 29 juvenile patients and 47 adult patients. Twenty-seven (35.5%) patients presented with polymyositis phenotype without dermatomyositis-specific skin manifestations (heliotrope rash or Gottron sign/papules); this was more common in the adults than children (48.9% vs 15.8%, P < 0.01). Nine (11.8%) patients had subcutaneous calcinosis, and 20 (26.3%) patients had subcutaneous oedema. In addition, the proportion of patients with muscle weakness extending to the distal limbs was high (36 patients [47.4%]) in this cohort. Adult patients had a higher prevalence of malignancy than the general population (age-standardized incidence ratio of malignancies: 22.4)., Conclusion: Anti-NXP2 antibody-positive IIMs, which include dermatomyositis sine dermatitis, are characterized by atypical skin manifestations and extensive muscular involvement., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Although bisphosphonates are well known to cause kidney disease, there are very few published cases of focal segmental glomerulosclerosis (FSGS) following treatment with minodronate. Here we report the case of an 86-year-old woman who developed acute kidney injury and nephrotic syndrome after receiving monthly oral minodronate for 24 months. Kidney biopsy revealed cellular variant FSGS. Treatment was initiated with the discontinuation of minodronate followed by intravenous methylprednisolone pulse and prednisolone at 35 mg/day. Subsequently, the patient's renal function gradually worsened, requiring initiation of hemodialysis. However, renal function and proteinuria improved markedly and hemodialysis was withdrawn 1 month after the initiation of steroid therapy. This is, to our knowledge, the first published case of FSGS induced by long-term use of minodronate, and also the first case of cellular variant FSGS induced by bisphosphonates although collapsing variant of FSGS is commonly caused by bisphosphonates. Our study indicates that patients on bisphosphonates should be closely monitored for proteinuria and renal impairment, regardless of the type of bisphosphonate., (© 2021. Japanese Society of Nephrology.)

Dermatomyositis, an idiopathic inflammatory myopathy, is characterized by cutaneous itchy manifestations, which are frequently refractory and recurrent even after intensive immunosuppressive treatments. To evaluate the effectiveness and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in treating skin-dominant dermatomyositis in which myositis and interstitial lung disease are absent or in remission, we performed this prospective, single-arm, interventional study. A total of five Japanese patients (one male and four females, median [range] age, 64 [37-71] years) with refractory dermatomyositis-associated cutaneous manifestations were recruited and treated with a 12-week course of oral apremilast. Among five enrolled patients, three experienced diarrhea with full-dose apremilast (30 mg twice daily), two of whom withdrew from the study and recovered quickly afterwards. A total of three evaluable female patients (median [range] age, 65 [64-71] years) received apremilast treatment for 12 weeks. A 39.4% reduction from baseline Cutaneous Dermatomyositis Disease Area and Severity Index total activity score, but not the damage score, at week 12 was observed in all three patients. Visual analog scale of itching, and quality of life by Dermatology Life Quality Index were slightly improved in one and two apremilast-treated patients, respectively. As apremilast was effective, with expected and recoverable digestive adverse events (diarrhea), in patients with refractory and recurrent dermatomyositis-associated cutaneous manifestations in this first phase Ib study, it can be suggested as a possible treatment when aggressive immunosuppressive therapies with high-dose systemic corticosteroid and/or immunosuppressive agents for other manifestations, myositis, and interstitial lung disease, are not required., (© 2021 Japanese Dermatological Association.)

The combination of a cobalt-dioxolene core that exhibits valence tautomerism (VT) with pyridine-3,5-dicarboxylic acid functionalized with chains bearing two, four, or six oxyethylene units led to new complexes ConEGEspy (n = 2, 4, and 6). These complexes commonly form violet crystals of the low-spin (ls)-[Co III (nEGEspy) 2 (3,6-DTBSQ)(3,6-DTBCat)] (ls-[Co III ], 3,6-DTBSQ = 3,6-di-tert-butyl semiquinonato, 3,6-DTBCat = 3,6-di-tert-butyl catecholato). Interestingly, violet crystals of Co2EGEspy in the ls-[Co III ] transitioned into a green liquid, accompanied by an almost complete VT shift (94 %) to the high-spin (hs)-[Co II (nEGEspy) 2 (3,6-DTBSQ) 2 ] (hs-[Co II ]) upon melting. In contrast, violet crystals of Co4EGEspy and Co6EGEspy in the ls-[Co III ] exhibited partial VT (33 %) and only a 9.3 % VT shift after melting, respectively. These data demonstrate the tunability of the synchronicity of the molecular VT and macroscopic solid-liquid transitions by optimizing the tethered chains, thus establishing a new strategy for coupling bistable molecules with the macroscopic world., (© 2021 Wiley-VCH GmbH.)