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Pulmonary arterial hypertension (PAH) is characterized by the severe obstruction of the small pulmonary arteries and concomitant high pulmonary arterial pressure, resulting in progressive right ventricular failure. Previously, we demonstrated that long-term interleukin (IL)-33 administration in mice induces severe occlusive medial hypertrophy of pulmonary arteries (PA) in the lungs, which is mediated by group 2 innate lymphoid cells (ILC2s). In response to IL-33, ILC2s accumulate around the blood vessels and produce IL-5, leading to perivascular eosinophil recruitment. In this study, we characterized IL-33-induced medial hypertrophy of PA. We demonstrated that long-term IL-33 administration causes an increase in right ventricular pressure. In IL-33-deficient mice, medial hypertrophy of PA mediated by eggs of Schistosoma mansoni was attenuated, accompanied by a partial reduction in ILC2s, eosinophils, and CD4 + T cells. In addition, proteomic analysis revealed dramatic changes in the urine samples from mice treated with IL-33 or S. mansoni eggs. Resistin-like alpha (RELMα), a pulmonary hypertension-related molecule, was commonly detected in the urine in both treatments. Large amounts of RELMα were observed in the lungs of the IL-33-treated mice. These observations suggest that IL-33-induced medial hypertrophy of PA is a useful model for studying the mechanism underlying the development of PAH and finding biomarkers to indicate the onset of PAH., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Masashi Ikutani reports financial support was provided by Hiroshima University. Shoichi Shimizu reports financial support was provided by University of Occupational and Environmental Health, Japan. Koki Okada reports financial support was provided by Hiroshima University. Koshi Imami reports financial support was provided by RIKEN. Tadakatsu Inagaki reports financial support was provided by National Cerebral and Cardiovascular Center Research Institute. Yoshikazu Nakaoka reports financial support was provided by National Cerebral and Cardiovascular Center Research Institute. Yoshio Osada reports financial support was provided by University of Occupational and Environmental Health, Japan. Susumu Nakae reports financial support was provided by Hiroshima University., (Copyright © 2024 Elsevier Inc. All rights reserved.)

We previously reported that Plasmodium yoelii 17XNL (Py), a non-lethal rodent malarial parasite, could suppress collagen-induced arthritis (CIA) and increase the production of T cell-derived interleukin (IL)-10. However, it remained unclear whether IL-10 is essential for the Py-induced suppression of CIA. Male IL-10 knockout (KO) DBA/1 J mice were immunized with bovine type II collagen (CII) and subsequently infected with Py at one week post-immunization. The development of arthritis was evaluated by an arthritis score up to 6 weeks post-immunization. At 3 weeks post-immunization, cytokine production from splenocytes and serum anti-CII IgG/IgG1/IgG2a levels were compared between non-infected control mice and Py-infected mice. Py infection inhibited the development of CIA in IL-10KO mice until 4 weeks post-immunization, after which the arthritis score reached levels comparable with the control mice. Both pro-arthritic (IL-17 and TNF-α) and anti-arthritic (IFN-γ and IL-4) cytokines were down-regulated during the periods of parasitemia, while no significant differences were observed in levels of anti-CII IgG antibodies. Our findings indicate that Py alleviates CIA via IL-10-independent mechanisms., (Copyright © 2024. Published by Elsevier B.V.)

Mast cells (MCs) are tissue-resident cells of hematopoietic origin that play an important role in host's defense mechanism against nematodes. However, excessive activation of these cells contributes to the development of certain allergic diseases. Immunoglobin E (IgE) is one of the well-known molecules that activate MCs. Even in the absence of specific antigens, the binding of highly cytokinergic IgE to FcεRI on MCs prolongs their survival and induces cytokine production without enhancing their degranulation. In the present study, we examined the effects of the members of the interleukin-10 (IL-10) family of cytokines on IgE-mediated MCs functions. The receptors including Il10r1, Il10r2, and Il20r2, but not Il20r1, Il22r1 or Il28r1, were constitutively expressed in mouse bone marrow cell-derived cultured MCs (BMCMCs), suggesting that IL-10 may influence MCs function. Indeed, we found that only IL-10 could influence upon BMCMCs function; IL-10 enhanced prolongation of survival, promoted IL-6 and/or IL-13 production dependently of STAT1 and STAT3, and suppressed tumor necrosis factor production independently of STAT1 and STAT3 on IgE-stimulated BMCMCs. Moreover, the IL-10-mediated enhancement of IL-6 production by IgE-stimulated BMCMCs promotes Th17 cell expansion. These results suggest that IL-10 has a dual role as an anti-inflammatory and pro-inflammatory cytokine in MCs functions., (© 2024. The Author(s).)

Interleukin-33 (IL-33) is an alarmin released upon epithelial tissue damage. It functions as a nuclear factor for regulating gene expression. We hypothesised that IL-33 is involved in the formation of decubitus ulcers through damaged epidermis. Therefore, this study aimed to clarify the mechanism of IL-33 action in decubitus ulcer formation. IL-33 knockout (KO), soluble stimulation-2 (ST2) transgenic, and wild-type (WT) mice were used to construct an ischemia-reperfusion (I/R) injury as a decubitus model. The ulcer area was significantly reduced in IL-33 KO mice compared to WT mice but was not reduced in ST2 transgenic mice. Anti-IL-33 receptor (transmembrane ST2) antibodies effectively prevented ulcer formation; however, an anti-IL-33 neutralising antibody was ineffective. The number of infiltrating macrophages was higher, while that of neutrophils and mast cells was lower in IL-33 KO mice than in WT mice. The number of M2 macrophages increased in IL-33 KO mice. Characterisation of gene expression levels revealed significantly reduced interleukin-1 beta (IL-1β) and increased C-C motif chemokine ligand 17 expression in IL-33 KO mice. Macrophages isolated from ulcers in WT or IL-33 KO mice stimulated with exogenous IL-33 produced comparable amounts of IL-1β. In conclusion, our study indicates that IL-33 is released in response to I/R injury in the skin, contributing to inflammatory macrophage and mast cell infiltration and stimulation, resulting in IL-1β production and the massive infiltration of effector cells, including neutrophils, which finally induces decubitus ulcer formation. These results suggest that suppressing IL-33 expression could be beneficial for treating early-phase decubitus ulcers., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Translocator protein (TSPO) is a mitochondrial outer membrane protein expressed on a variety of immune cells, including macrophages, dendritic cells, and T cells, in addition to neurons and steroid-producing cells. Previous studies of TSPO ligands have suggested that TSPO is involved in multiple cellular functions, including steroidogenesis, immunomodulation, and cell proliferation. Currently, there are limited reports on the effects of TSPO or TSPO ligands on T cell-mediated immune responses. We here investigated the involvement of TSPO/TSPO ligand in T cell responses using a 2,4-dinitro-1-fluorobenzene (DNFB)-induced contact hypersensitivity (CH) model. Treatment with Ro5-4864, a TSPO ligand, during DNFB sensitization reduced the number and activation status of CD4+ and CD8+ T cells in draining lymph nodes and alleviated skin inflammation after DNFB challenge. Adoptive transfer of Ro5-4864-treated mouse-derived DNFB-sensitized T cells to naïve mice inhibited CH responses after DNFB challenge. Ro5-4864-treated sensitized T cells showed lower proliferative responses when stimulated with DNFB-pulsed antigen-presenting cells compared to control-treated sensitized T cells. Ro5-4864 also suppressed cell proliferation, as well as adenosine triphosphate and lactate production, during T cell activation. Moreover, the inhibitory effects of Ro5-4864 on T cell responses were conserved in TSPO-deficient cells. Our results suggest that Ro5-4864 inhibits CH responses by suppressing energy metabolism, at least via glycolysis, to reduce the T cell primary response in a TSPO-independent manner., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Society for Immunology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

This review explores the transformative impact of omics technologies on allergy and asthma research in recent years, focusing on advancements in high-throughput technologies related to genomics and transcriptomics. In particular, the rapid spread of single-cell RNA sequencing has markedly advanced our understanding of the molecular pathology of allergic diseases. Furthermore, high-throughput genome sequencing has accelerated the discovery of monogenic disorders that were previously overlooked as ordinary intractable allergic diseases. We also introduce microbiomics, proteomics, lipidomics, and metabolomics, which are quickly growing areas of research interest, although many of their current findings remain inconclusive as solid evidence. By integrating these omics data, we will gain deeper insights into disease mechanisms, leading to the development of precision medicine approaches that promise to enhance treatment outcomes., Competing Interests: Disclosure statement Supported in part by the Japanese Agency for Medical Research and Development (AMED) (grant JP24ek0410106 [to H.M.]) and a Health, Labor and Welfare Sciences Research Grant (grant 24FE2002 [to H.M.]). Disclosure of potential conflict of interest: H. Saito reports having received a consultation fee from Teikoku Seiyaku, Co, Ltd. H. Morita reports consulting and/or advisory board agreements with Sanofi, LEO Pharma, and Otsuka Pharmaceutical Co, Ltd. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Discrimination faced by Asian American trainees in medical school include those reported by female trainees. This study aims to characterize the microaggressions faced by Asian American woman medical students., Methods: We use a mixed methods approach to characterize the experiences of Asian Americans in United States (US) medical schools through an anonymous online survey and participation in focus groups., Results: Among our 305 participants, 65.9 ​% were women. More women experienced microaggressions than men (p ​< ​0.001). Compared to men, women reported significantly higher rates of supervisors having higher expectations of them, implying they were submissive, and describing them as too quiet. Women felt that their experiences with microaggressions were entangled with being Asian and a woman, but could not distinguish which identity was being targeted., Conclusion: The intersectionality of being Asian American and a woman in medical training has not been explored. We found that this duality intensified experiences of microaggressions., Competing Interests: Declaration of competing interest All authors have no financial interests related to this study to disclose., (Published by Elsevier Inc.)

Background & Aims: In recent times, the complexity of food styles and meal content has increased, leading to significant variations in macronutrient composition between meals. This phenomenon has coincided with a rise in obesity rates. We aimed to determine whether a large variation in macronutrient composition between meals results in reduced fat oxidation., Methods: A cross-over study was conducted with 13 healthy young men, using whole-body indirect calorimetry to test 24-h energy metabolic responses under three conditions: regular meals (R), high-carbohydrate breakfast (CB), or high-fat breakfast (FB), each with different macronutrient contents. The R condition included three meals daily with the same macronutrient composition. The CB condition included a high-carbohydrate meal at breakfast, high-fat meal at lunch, and high-carbohydrate meal at dinner. The FB condition included a high-fat meal at breakfast, high-carbohydrate meal at lunch, and high-carbohydrate meal at dinner. The daily macronutrient compositions were similar across the three conditions, except that CB and FB had larger variations in carbohydrate-fat balance between meals than R. The participants were tested in random order. During the dietary intervention, we compared 24-h whole-body metabolic parameters, including substrate oxidation (e.g., 24 h respiratory quotient [RQ])., Results: No significant differences were observed in the measures of energy expenditure among the three conditions. However, after adjusting for the sleeping RQ on a preceding day, the estimated 24hRQ was lower under the FB condition (0.845) than under the R (0.854, P = 0.0077 vs. FB) and CB conditions (0.853, P = 0.016 vs. FB). No difference was observed in the magnitude of the 5-h RQ change from lunch to dinner under the CB condition and in the magnitude of change from breakfast to lunch under the FB condition., Conclusions: A large variation in the carbohydrate-fat balance between meals does not decrease daily fat oxidation. An FB may increase daily fat oxidation compared to a CB when the daily food quotient is constant, but this increase may not be owing to the upregulation of fat burning on a daily basis., Competing Interests: Conflict of interest None of the authors has a direct conflict of interest to declare., (Copyright © 2024 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Interaction of mast cells (MCs) with fibroblasts is essential for MC maturation within tissue microenvironments, although the underlying mechanism is incompletely understood. Through a phenotypic screening of >30 mouse lines deficient in lipid-related genes, we found that deletion of the lysophosphatidic acid (LPA) receptor LPA 1 , like that of the phospholipase PLA2G3, the prostaglandin D 2 (PGD 2 ) synthase L-PGDS, or the PGD 2 receptor DP1, impairs MC maturation and thereby anaphylaxis. Mechanistically, MC-secreted PLA2G3 acts on extracellular vesicles (EVs) to supply lysophospholipids, which are converted by fibroblast-derived autotaxin (ATX) to LPA. Fibroblast LPA 1 then integrates multiple pathways required for MC maturation by facilitating integrin-mediated MC-fibroblast adhesion, IL-33-ST2 signaling, L-PGDS-driven PGD 2 generation, and feedforward ATX-LPA 1 amplification. Defective MC maturation resulting from PLA2G3 deficiency is restored by supplementation with LPA 1 agonists or PLA2G3-modified EVs. Thus, the lipid-orchestrated paracrine circuit involving PLA2G3-driven lysophospholipid, eicosanoid, integrin, and cytokine signaling fine-tunes MC-fibroblast communication, ensuring MC maturation., Competing Interests: Declaration of interests J.C. has an employment relationship with Neurocrine Biosciences, Inc. as a Distinguished Scholar, unrelated to the current manuscript., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Achieving gender equity in academic medicine is not only a matter of social justice but also necessary in promoting an innovative and productive academic community. The purpose of this study was to assess gender distribution in dual MD/PhD academic programme faculty members across North America., Methods: Academic metrics were analysed to quantify the relative career success of academic faculty members in MD/PhD programmes. Measured parameters included academic and leadership ranks along with nominal research factors such as peer-reviewed research publications, H-index, citation number and years of active research., Results: Χ² analysis revealed a statistically significant (p<0.0001, χ²=114.5) difference in the gender distribution of faculty and leadership across North American MD/PhD programmes. Men held 74.2% of full professor positions, 64% of associate professor positions, 59.4% of assistant professor positions and 62.8% of lecturer positions. Moreover, men occupied a larger share of faculty leadership roles with a statistically significant disparity across all ranks (p<0.001, χ²=20.4). A higher proportion of men held positions as department chairs (79.6%), vice chairs (69.1%) and programme leads (69.4%)., Conclusion: Gender disparity was prevalent in the MD/PhD programmes throughout North America with women achieving a lower degree of professional stature than men. Ultimately, steps must be taken to support women faculty to afford them better opportunities for academic and professional advancement., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

A pleiotropic immunoregulatory cytokine, TGF-β, signals via the receptor-regulated SMADs: SMAD2 and SMAD3, which are constitutively expressed in normal cells. Here, we show that selective repression of SMAD3 induces cDC differentiation from the CD115 + common DC progenitor (CDP). SMAD3 was expressed in haematopoietic cells including the macrophage DC progenitor. However, SMAD3 was specifically down-regulated in CD115 + CDPs, SiglecH - pre-DCs, and cDCs, whereas SMAD2 remained constitutive. SMAD3-deficient mice showed a significant increase in cDCs, SiglecH - pre-DCs, and CD115 + CDPs compared with the littermate control. SMAD3 repressed the mRNA expression of FLT3 and the cDC-related genes: IRF4 and ID2. We found that one of the SMAD transcriptional corepressors, c-SKI, cooperated with phosphorylated STAT3 at Y705 and S727 to repress the transcription of SMAD3 to induce cDC differentiation. These data indicate that STAT3 and c-Ski induce cDC differentiation by repressing SMAD3: the repressor of the cDC-related genes during the developmental stage between the macrophage DC progenitor and CD115 + CDP., (© 2024 Yoon et al.)

Pathways programs are critical to promoting access and success for careers in healthcare for students from immigrant backgrounds. Three cases are presented that demonstrate the successful elements of pathways programs. Excellence in pediatrics requires the inclusion of talent from immigrant communities. Community capacity building and systems level change can be achieved through coliberatory practice of mutual action, investment, and benefit. Navigation, mentorship, and structural support for educational, social, and monetary capital are key components of pathways programs., (Copyright © 2024 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Introduction: Prostaglandin D2 (PGD2), which is produced mainly by Th2 cells and mast cells, promotes a type-2 immune response by activating Th2 cells, mast cells, eosinophils, and group 2 innate lymphoid cells (ILC2s) via its receptor, chemoattractant receptor-homologous molecules on Th2 cells (CRTH2). However, the role of CRTH2 in models of airway inflammation induced by sensitization without adjuvants, in which both IgE and mast cells may play major roles, remain unclear., Methods: Wild-type (WT) and CRTH2-knockout (KO) mice were sensitized with ovalbumin (OVA) without an adjuvant and then challenged intranasally with OVA. Airway inflammation was assessed based on airway hyperresponsiveness (AHR), lung histology, number of leukocytes, and levels of type-2 cytokines in the bronchoalveolar lavage fluid (BALF)., Results: AHR was significantly reduced after OVA challenge in CRTH2 KO mice compared to WT mice. The number of eosinophils, levels of type-2 cytokines (IL-4, IL-5, and IL-13) in BALF, and IgE concentration in serum were decreased in CRTH2 KO mice compared to WT mice. However, lung histological changes were comparable between WT and CRTH2 KO mice., Conclusion: CRTH2 is responsible for the development of asthma responses in a mouse model of airway inflammation that features prominent involvement of both IgE and mast cells., (© 2024 S. Karger AG, Basel.)

Severely immunodeficient mice are useful for understanding the pathogenesis of certain tumors and for developing therapeutic agents for such tumors. In addition, engraftment of these mice with human hematopoietic cells can yield information that helps us understand the in vivo molecular mechanisms underlying actual human viral infections. In our present research, we discovered a novel, severely immunodeficient strain of mice having a mutation in exon 57 of the Prkdc gene (Prkdc Δex57/Δex57 ) in an inbred colony of B10.S/SgSlc mice. Those Prkdc Δex57/Δex57 mice showed thymic hypoplasia and lack of mature T cells and B cells in peripheral lymphoid tissues, resulting in very low levels of production of serum immunoglobulins. In addition, those mice were highly susceptible to influenza viruses due to the lack of acquired immune cells. On the other hand, since they had sufficient numbers of NK cells, they rejected tumor transplants, similarly to Prkdc +/+ mice. Next, we generated Foxn1 nu/nu Prkdc Δex57/Δex57 Il2rg -/- (NPG) mice on the BALB/cSlc background, which lack all lymphocytes such as T cells, B cells and innate lymphoid cells, including NK cells. As expected, these mice were able to undergo engraftment of human tumor cell lines. These findings suggest that Prkdc Δex57/Δex57 mice will be useful as a novel model of immunodeficiency, while NPG mice will be useful for xenografting of various malignancies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Yumie Takagi reports financial support was provided by Japan SLC, Inc.Katsuko Sudo reports financial support was provided by Tokyo Medical University.Sachiko Yamaguchi, Masashi Ikutani and Susumu Nakae report financial support was provided by Hiroshima University.Shuzo Urata and Jiro Yasuda report financial support was provided by Nagasaki University.Tatsukuni Ohno reports financial support was provided by Tokyo Dental College.Sachiko Hirose reports financial support was provided by Toin University.Kiyoshi Matsumoto reports financial support was provided by Shinshu University.Takeshi Kuramoto reports financial support was provided by Tokyo University of Agriculture.Tadao Serikawa reports financial support was provided by Kyoto University., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Intestinal stem cells (ISCs) maintain the epithelial lining of the intestines, but mechanisms regulating ISCs and their niche after damage remain poorly understood. Utilizing radiation injury to model intestinal pathology, we report here that the Interleukin-33 (IL-33)/ST2 axis, an immunomodulatory pathway monitored clinically as an intestinal injury biomarker, regulates intrinsic epithelial regeneration by inducing production of epidermal growth factor (EGF). Three-dimensional imaging and lineage-specific RiboTag induction within the stem cell compartment indicated that ISCs expressed IL-33 in response to radiation injury. Neighboring Paneth cells responded to IL-33 by augmenting production of EGF, which promoted ISC recovery and epithelial regeneration. These findings reveal an unknown pathway of niche regulation and crypt regeneration whereby the niche responds dynamically upon injury and the stem cells orchestrate regeneration by regulating their niche. This regenerative circuit also highlights the breadth of IL-33 activity beyond immunomodulation and the therapeutic potential of EGF administration for treatment of intestinal injury., (© 2023. Springer Nature Limited.)

Background: We previously reported the response rate of a phase II OGSG1602 study on panitumumab in chemotherapy-naive frail or elderly patients with RAS wild-type unresectable colorectal cancer (CRC) [Terazawa T, Kato T, Goto M, et al. Oncologist. 2021;26(1):17]. Herein, we report a survival analysis., Methods: Patients aged ≥65 years and considered unsuitable for intensive chemotherapy or aged ≥76 years were enrolled. Primary tumors located from the cecum to the transverse colon were considered right-sided tumors (RSTs); those located from the splenic flexure to the rectum were considered left-sided tumors (LSTs)., Results: Among the 36 enrolled patients, 34 were included in the efficacy analysis, with 26 and 8 having LSTs and RSTs, respectively. The median progression-free survival (PFS) and overall survival (OS) were 6.0 [95% CI, 5.4-10.0] and 17.5 months (95% CI, 13.8-24.3), respectively. Although no significant differences existed in PFS between patients with LST and RST {6.6 (95% CI, 5.4-11.5) vs. 4.9 months [95% CI, 1.9-not available (NA), P = .120]}, there were significant differences in OS [19.3 (95% CI, 14.2-NA) vs.12.3 months (95% CI, 9.9-NA), P = .043]., Conclusion: Panitumumab showed favorable OS in frail or elderly patients with RAS wild-type CRC and no prior exposure to chemotherapy. Panitumumab may be optimal for patients with LSTs (UMIN Clinical Trials Registry Number UMIN000024528)., (© The Author(s) 2022. Published by Oxford University Press.)

This study aimed to assess the effectiveness of methods for evaluating the environmental and physical loads on workers in manufacturing plants, considering their locations. Participants were employees of DENSO CORPORATION's manufacturing facilities, and environmental sensors (for temperature and humidity) and BLE beacons were installed to cover the work area. Questionnaires were completed by the participants twice to assess their thermal comfort and fatigue in the work environment. The results showed that a regression prediction model with an adjusted R-squared of 0.418 for fixed-point temperature and 0.495 for perceived temperature was developed for thermal comfort. No linear relationship was found between environmental factors and fatigue, and a decision tree analysis was conducted. Relative humidity and activity level, along with temperature, were selected as predictor variables. The findings suggest that it is possible to estimate the work environment and workload without adding additional measurement-related burdens or challenges. This highlights the usefulness of the proposed method, which takes into account the environmental distribution throughout the work area rather than relying solely on conventional fixed-point observation data, for assessing workers' exposure to the environment and preventing occupational accidents.Clinical Relevance- The proposed approach, combining indoor localization with environmental status, can estimate the condition of workers and is expected to be a good solution for preventing occupational accidents and enhancing workers' health.

Introduction: Epidemiological studies demonstrated that cleaning work and frequent use of cleaning products are risk factors for asthma. Laundry detergents have been reported to have epithelial barrier-opening effects. However, whether laundry detergents directly induce airway inflammation and its mechanisms in vivo remain to be elucidated., Methods: Two commercial laundry detergents and two commonly used surfactants for cleaning and cosmetics (sodium lauryl sulfate and sodium dodecyl benzene sulfonate) were intranasally administered to mice. Lungs were analyzed using flow cytometry, histology, ELISA, and quantitative PCR. Human bronchial epithelial cells were stimulated with laundry detergents and analyzed using quantitative PCR and western blotting. Involvement of oxidative stress was assessed using an antioxidant. Dust samples from homes were analyzed to determine their detergent content by measuring their critical micelle concentration (CMC)., Results: The administered laundry detergents and surfactants-induced eosinophilic airway inflammation accompanied by increased IL-33 expression and activation of group 2 innate lymphoid cells (ILC2s). Detergent-induced eosinophilic airway inflammation was significantly attenuated in Rag2 -/- Il2rg -/- , Il33 -/- mice, and also in wild-type mice treated with NAC. Detergent-induced IL-33 expression in airways was attenuated by NAC treatment, both in vivo and in vitro. CMCs were found in all of the tested dust extracts, and they differed significantly among the homes., Conclusion: The laundry detergents and surfactants-induced eosinophilic airway inflammation in vivo through epithelial cell and ILC2 activation. They induced IL-33 expression in airway epithelial cells through oxidative stress. Furthermore, detergent residues were present in house dust and are presumably inhaled into the airway in daily life., (© 2023 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

High-frequency spectroscopy (HFS) is an analytical method that is sensitive to slight changes in the dielectric properties of materials. Since water has high permittivity, HFS can be used to detect changes in water content in materials. In this study, we employed HFS to measure human skin moisture during a water sorption-desorption test. Skin without any treatment showed a resonance peak at approximately 1150 MHz. Furthermore, the peak shifted to lower frequency immediately after the application of water to the skin and gradually returned to its original frequency as time progressed. The resonance frequency obtained via least-squares fitting showed that the applied water remained in the skin after 240 s from the beginning of the measurement. These results illustrated that HFS measurements can monitor the progression of decreasing moisture content in human skin during a water sorption-desorption test., (© 2023. The Author(s), under exclusive licence to The Japan Society for Analytical Chemistry.)

Accurate methods for the prediction of the total energy expenditure and physical activity level (PAL) in community-dwelling older adults have not been established. Therefore, we examined the validity of estimating the PAL using an activity monitor (Active style Pro HJA-350IT, [ASP]) and proposed correction formulae for such populations in Japan. Data for 69 Japanese community-dwelling adults aged 65 to 85 years were used. The total energy expenditure in free-living conditions was measured with the doubly labeled water method and the measured basal metabolic rate. The PAL was also estimated from metabolic equivalent (MET) values obtained with the activity monitor. Adjusted MET values were also calculated with the regression equation of Nagayoshi et al. (2019). The observed PAL was underestimated, but significantly correlated, with the PAL from the ASP. When adjusted using the Nagayoshi et al. regression equation, the PAL was overestimated. Therefore, we developed regression equations to estimate the actual PAL (Y) from the PAL obtained with the ASP for young adults (X) as follows: women: Y = 0.949 × X + 0.205, mean ± standard deviation of the prediction error = 0.00 ± 0.20; men: Y = 0.899 × X + 0.371, mean ± standard deviation of the prediction error = 0.00 ± 0.17.

Pregnant women are exposed to various microbes, some of which can harm the mother and/or fetus and can lead to life-long morbidity and even death. The syncytiotrophoblast (STB) covers the placental villi and comes into direct contact with pathogens contained in the maternal blood and plays a key role in placental host defense. However, the precise mechanisms whereby the STB recognizes and responds to pathogenic microbes remain unclear. In this study, we comprehensively analyzed the expression of functional pattern recognition receptors, which are responsible for tissue defense against pathogens, in a primary STB model differentiated from highly purified human term cytotrophoblasts (CTBs). Screening for mRNA expression and multiplex cytokine/chemokine production demonstrated that differentiated CTBs (dCTBs) predominantly expressed dsRNA receptors, including TLR3, MDA5, and RIG-I. We confirmed that term human placentas also expressed TLR3. Transcriptome analysis revealed common and unique responses of dCTBs to a synthetic dsRNA (polyinosinic-polycytidylic acid) compared with human peripheral mononuclear cells. Moreover, polyinosinic-polycytidylic acid induced the release of type I and type III IFNs (IFN-β, IFN-λ1, IFN-λ2, IFN-λ3), as well as mRNA expression of IFN-stimulated genes (IFIT1, MX1, and OAS1). dCTBs underwent apoptosis via the mitochondrial pathway in response to dsRNA stimulation. These results suggest that dsRNA receptors expressed on the STB are key players in antiviral defense in the placenta. Elucidation of the underpinnings of these defense processes can help us better understand the pathophysiology of viral infections during pregnancy., (Copyright © 2023 by The American Association of Immunologists, Inc.)

The bone marrow (BM) stromal cell antigen-2 (BST-2), also known as tetherin, CD317, PDCA-1, or HM1.24, is a membrane protein overexpressed in several types of tumors and may act as a promising target for cancer treatment via antibody-dependent cellular cytotoxicity. BST-2 is also expressed in human BM stromal cells (BMSC), which support B cell development. While the activity of BST-2 as an antiviral factor has been demonstrated, the expression patterns and the role of BST-2 on B-cell development and activation have not been investigated, especially in vivo. In this study, Bst2 knockout (Bst2 -/- ) mice were generated to assess the role of BST-2 on B cell development and activation. It was observed that BST-2 was not expressed in BMSC or all B cell progenitors even in wild-type mice and does not play a significant role in B cell development. In addition, the loss of BST-2 had no effect on B cell activation. Furthermore and in contrast to the well-known antiviral role of BST-2, infection of vesicular stomatitis Indiana virus to the BM cells collected from the Bst2 -/- mice produced less infectious virus compared with that from the WT mice. These results suggest that murine BST-2 is different from human BST-2 in the expression pattern, physiological function, in vivo, and might possess positive role on VSV replication., (© 2023 The Societies and John Wiley & Sons Australia, Ltd.)

Importance: The Latino Medical Student Association (LMSA) is a student-run national organization founded in 1972 dedicated to recruiting and retaining members enrolled in health professions programs through academic and social support activities. This study investigates the career impact of member participation in LMSA., Objective: To determine if engagement in LMSA at the individual and school levels contributes to retention, success, and commitment to underserved communities., Design: A voluntary online retrospective 18-question survey sent to LMSA-member medical students in the United States and Puerto Rico from the graduating classes of 2016-2021., Setting: Students in medical schools in the United States and Puerto Rico., Main Outcomes and Measures: There were 18 survey questions. A total of 112 anonymous responses were collected from March 2021 to September 2021. The survey queried levels of engagement with the LMSA and agreement on questions related to support, belonging, and career development., Results: There is a positive relationship between level of engagement in the LMSA and social belonging, peer support, career networking, community engagement, and career commitment to serve Latinx communities. These positive outcomes were enhanced for respondents reporting strong support for their respective school-based LMSA chapters. We did not find a significant relationship between participation in the LMSA and research experiences during medical school., Conclusions and Relevance: Participation in the LMSA is associated with positive individual support and career outcomes for members. Supporting the LMSA as a national organization and within school-based chapters can increase support for Latinx trainees and enhance career outcomes., Competing Interests: No competing financial interests exist., (© Sunny Nakae et al., 2023; Published by Mary Ann Liebert, Inc.)

Distinguishing primary central nervous system lymphoma (PCNSL) from glioblastoma, isocitrate dehydrogenase (IDH)-wildtype is sometimes hard. Because the role of operation on them varies, accurate preoperative diagnosis is crucial. In this study, we evaluated whether a specific kind of chemical exchange saturation transfer imaging, i.e., amide proton transfer-weighted (APTw) imaging, was useful to distinguish PCNSL from glioblastoma, IDH-wildtype. A total of 14 PCNSL and 27 glioblastoma, IDH-wildtype cases were evaluated. There was no significant difference in the mean APTw signal values between the two groups. However, the percentile values from the 1st percentile to the 20th percentile APTw signals and the width 1-100 APTw signals significantly differed. The highest area under the curve was 0.796, which was obtained from the width 1-100 APTw signal values. The sensitivity and specificity values were 64.3% and 88.9%, respectively. APTw imaging was useful to distinguish PCNSL from glioblastoma, IDH-wildtype. To avoid unnecessary aggressive surgical resection, APTw imaging is recommended for cases in which PCNSL is one of the differential diagnoses.

PolyADP-ribosylation is a posttranslational modification of proteins that results from enzymatic synthesis of poly(ADP-ribose) with NAD + as the substrate. A unique characteristic of polyADP-ribosylation is that the poly(ADP-ribose) chain can have 200 or more ADP-ribose residues in branched patterns, and the presence and variety of these chains can have substantive effects on protein function. To understand how polyADP-ribosylation affects biological processes, it is important to know the physiological level of poly(ADP-ribose) in cells. Under normal cell physiological conditions and in the absence of any exogenous DNA damaging agents, we found that the concentration of poly(ADP-ribose) in HeLa cells is approximately 0.04 pmol (25 pg)/10 6 cells, as measured with a double-antibody sandwich, enzyme-linked immunosorbent assay protocol that avoids artificial activation of PARP1 during cell lysis. Notably, this system demonstrated that the poly(ADP-ribose) level peaks in S phase and that the average cellular turnover of a single poly(ADP-ribose) is less than 40 s., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Interleukin-33 (IL-33) is a member of the IL-1 cytokine family that has been studied primarily in the context of type 2 immune responses. Recent reports suggest that IL-33 also enhances the func- tions of various immune cells and contributes to the development of different inflammatory diseas- es. Interestingly, IL-33 and its receptor ST2 axis exerted either inhibitory or promotional effects on alveolar bone loss in various periodontitis models. Using a mouse model of ligature-induced periodontitis, we found that the levels of mRNAs encoding IL-33 and other inflammatory cyto- kines (IL-1α, IL-1β, IL-6, and TNFα) were augmented in gingival tissues of wild-type (WT) mice, and that the alveolar bone loss amount was lower in IL-33-deficient than WT mice. The numbers and proportions of IFN-γ-producing CD8+ T and regulatory T cells were decreased while those of Th17 cells were increased in the draining lymph nodes of IL-33-deficient mice compared to WT mice. Additionally, the level of RNA encoding an osteoclastogenic molecule, i.e., receptor activa- tor of nuclear factor kappa-B ligand (RANKL), in ligated gingival tissue was higher in IL-33-defi- cient than WT mice. These results suggest that IL-33 is involved in alveolar bone loss in the ligature-induced periodontitis model, although IL-33 may inhibit osteoclast differentiation.

Many U.S. medical schools conduct holistic review of applicants to enhance the socioeconomic and experiential diversity of the physician workforce. The authors examined the role of first-generation college-graduate status on U.S. medical school application, acceptance, and matriculation, hypothesizing that first-generation (vs. continuing-generation) college graduates would be less likely to apply and gain acceptance to medical school.Secondary analysis of de-identified data from a retrospective national-cohort study was conducted for individuals who completed the 2001-2006 Association of American Medical Colleges (AAMC) Pre-Medical College Admission Test Questionnaire (PMQ) and the Medical College Admissions Test (MCAT). AAMC provided medical school application, acceptance, and matriculation data through 06/09/2013. Multivariable logistic regression models identified demographic, academic, and experiential variables independently associated with each outcome and differences between first-generation and continuing-generation students. Of 262,813 PMQ respondents, 211,216 (80.4%) MCAT examinees had complete data for analysis and 24.8% self-identified as first-generation college graduates. Of these, 142,847 (67.6%) applied to U.S. MD-degree-granting medical schools, of whom 86,486 (60.5%) were accepted, including 14,708 (17.0%) first-generation graduates; 84,844 (98.1%) acceptees matriculated. Adjusting for all variables, first-generation (vs. continuing-generation) college graduates were less likely to apply (odds ratio [aOR] 0.84; 95% confidence interval [CI], 0.82-0.86) and be accepted (aOR 0.86; 95% CI, 0.83-0.88) to medical school; accepted first-generation college graduates were as likely as their continuing-generation peers to matriculate. Students with (vs. without) paid work experience outside hospitals/labs/clinics were less likely to apply, be accepted, and matriculate into medical school. Increased efforts to mitigate structural socioeconomic vulnerabilities that may prevent first-generation college students from applying to medical school are needed. Expanded use of holistic review admissions practices may help decision makers value the strengths first-generation college graduates and other underrepresented applicants bring to medical educationand the physician workforce.

Introduction: Admissions and selection committees face challenges in identifying and mitigating biases in policies, processes, and discussions. Past bias training has focused on defining bias and presenting the negative impact of bias for committees., Methods: This interactive training used committee comments, reflection, and audience response to enhance the contextual recognition of bias in admissions and selection processes and practices. For each bias type, we presented specific mitigation strategies and examples. The workshop was offered at four medical schools between December 2020 and April 2021. Participants were committee members ( n = 126), largely medical school faculty, involved in MD, MD/PhD, and residency program selection at participating schools. A paired pre- and postworkshop assessment was conducted for each session to determine effectiveness of the workshop., Results: Mean scores for each of the postassessment items ranged from 4.0 to 4.2 and were statistically significantly different from the preassessment scores per respective item. The results of a paired two-way t test found that these pre- to postworkshop assessment score increases were statistically significant across all assessment questions ( p s < .001). Participants reported in their comments that the workshop was effective in establishing a safe and judgment-free learning environment to explore and identify biases and build skills and confidence for mitigating them., Discussion: Interactive and applied bias training can be an effective strategy to advance committee culture and practice in recognizing and mitigating bias. This workshop provides committees with ongoing tools for equity practice in selection and decision-making., (© 2022 Nakae et al.)

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by type 2 immune responses. Interleukin-25 (IL-25) is produced predominantly by epithelial cells. It can activate Th2 cells to produce type 2 cytokines such as IL-4, IL-5 and IL-13, contributing to host defense against nematodes. However, excessive/inappropriate production of IL-25 is considered to be involved in development of type 2 cytokine-associated allergic disorders such as asthma. On the other hand, the contribution of IL-25 to the pathogenesis of AD remains poorly understood. In the present study, we found that expression of Il25 mRNA was significantly increased in the skin of mice during oxazolone-induced chronic contact hypersensitivity (CHS), which is a mouse model of human AD. In addition, development of oxazolone-induced chronic CHS was significantly reduced in IL-25-deficient (Il25 -/- ) mice compared with wild-type mice on the C57BL/6, but not BALB/c, background, although IL-25 was not essential for IL-4 production by hapten-specific T cells. Therefore, IL-25 is crucial for development of chronic CHS, although that is partly dependent on the genetic background of the mice., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Susumu Nakae reports financial support was provided by Hiroshima University. Eri Shimura reports financial support was provided by Juntendo University. Hajime Suto reports financial support was provided by Juntendo University. Takafumi Numata reports financial support was provided by Tokyo Medical University. Sachiko Yamaguchi reports financial support was provided by Hiroshima University. Kazutoshi Harada reports financial support was provided by Tokyo Medical University. Ko Okumura reports financial support was provided by Juntendo University. Katsuko Sudo reports financial support was provided by Tokyo Medical University. Masashi Ikutani reports financial support was provided by Hiroshima University., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Deferred Action for Childhood Arrivals (DACA) provides a path for individuals who are undocumented to join the physician workforce. Indeed, recipients of DACA can play an important role in addressing health inequities in medicine. Although DACA has been in place since 2012, many medical schools remain unaware of it or are hesitant to consider recipients for admission. In a similar vein, the premedical community, including those with DACA status, may be unaware of their eligibility and the steps necessary to pursue medicine. Further education and outreach are needed to achieve institutional policies conducive to the inclusion and success of those undocumented in medicine., Methods: We created an hour-long workshop to empower learners with key knowledge relevant to DACA policy and its impact on medicine. We evaluated the workshop through pre- and postworkshop questionnaires assessing participant knowledge and attitudes based on the theory of planned behavior (TPB)., Results: A total of 112 participants engaged in our workshop. Ninety-one pretests and 61 posttests were completed by attendees. Data revealed a significant increase in performance on all knowledge-based and TPB questions, including intention to participate in future policy development. Moreover, participants reported appreciating the interactive nature of the session and expressed feelings of empowerment by their newfound knowledge base., Discussion: This workshop provides a promising foundation from which conversations and progress regarding DACA-related medical education policy can begin. Specifically, the workshop engages participants in the process of identifying actionable steps for overcoming barriers to inclusion and support., (© 2022 Garcia et al.)

Background: Many activity trackers have been developed, but steps can still be inconsistent from one monitor to another., Research Question: What are the differences and associations between the steps of 13 selected consumer-based and research-grade wearable devices during 1 standardized day in a metabolic chamber and 15-day free-living trials?, Methods: In total, 19 healthy adults between 21 and 50 years-old participated in this study. Participants were equipped with 12 accelerometer-based active trackers and one pedometer (Yamasa) in order to monitor the number of steps per day. The devices were worn on the waist (ActiGraph, Omron, Actimarker, Lifedorder, Withings, and Yamasa) or non-dominant wrist (Fitbit, Garmin, Misfit, EPSON, and Jawbone), or placed in a pocket (Omron CaloriScan, and TANITA). Participants performed structured activities over a 24 h period in a chamber (Standardized day), and steps were monitored in the same participants in free-living trials for 15 successive days using the same monitors (free-living days)., Results: When the 13 monitors were ranked by their steps, waist-worn ActiGraph was located at the center (7th) of the monitors both in the Standardized (12,252 ± 598 steps/day, mean ± SD) and free-living days (9295 ± 4027 steps/day). The correlation between the accelerometer-based devices was very high (r = 0.87-0.99). However, the steps of Yamasa was significantly lower in both trials than ActiGraph. The wrist-worn accelerometers had significantly higher steps than other devices both trials (P < 0.05). The differences between ActiGraph and Actimarker or Lifecorder was less than 100 steps/day in the Standardized day, and the differences between ActiGraph and Active Style Pro was less than 100 steps/day in the free-living days. Regression equation was also performed for inter-device compatibility., Significance: Step obtained from the wrist-worn, waist-worn, and pocket-type activity trackers were significantly different from each other but still highly correlated in free-living conditions., Competing Interests: Conflicts of Interest Shigeho Tanaka reported receiving research funding from Omron Health Care Inc. No other disclosures were reported., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

This research examined the effects of single-dose molecular hydrogen (H 2 ) supplements on acid-base status and local muscle deoxygenation during rest, high-intensity intermittent training (HIIT) performance, and recovery. Ten healthy, trained subjects in a randomized, double-blind, crossover design received H 2 -rich calcium powder (HCP) (1500 mg, containing 2.544 μg of H 2 ) or H 2 -depleted placebo (1500 mg) supplements 1 h pre-exercise. They performed six bouts of 7 s all-out pedaling (HIIT) at 7.5% of body weight separated by 40 s pedaling intervals, followed by a recovery period. Blood gases' pH, PCO 2 , and HCO 3 - saturation (S 2 saturation (S t O 2 ) were determined via time-resolved near-infrared spectroscopy in the vastus lateralis ( VL ) and rectus femoris ( RF ) muscles from rest to recovery. At rest, the HCP group had significantly higher PCO 2 concentrations and a slight tendency toward acidosis. During exercise, the first HIIT bout's peak power was significantly higher in HCP (839  ±  112 W) vs. Placebo (816  ±  108 W, 3 - concentrations and a slight tendency toward acidosis. During exercise, the first HIIT bout's peak power was significantly higher in HCP (839  ±  112 W) vs. Placebo (816  ±  108 W, p = 0.001), and HCP had a notable effect on significantly increased deoxy[Hb + Mb] concentration during HIIT exercise, despite no differences in heart rate response. The HCP group showed significantly greater O 2 extraction in VL and microvascular (Hb) volume in RF during HIIT exercise. The HIIT exercise provided significantly improved blood flow and muscle reoxygenation rates in both the RF and VL during passive recovery compared to rest in all groups. The HCP supplement might exert ergogenic effects on high-intensity exercise and prove advantageous for improving anaerobic HIIT exercise performance.

Protein targets of polyADP-ribosylation undergo covalent modification with high-molecular-weight, branched poly(ADP-ribose) (PAR) of lengths up to 200 or more ADP-ribose residues derived from NAD + . PAR polymerase 1 (PARP1) is the most abundant and well-characterized enzyme involved in PAR biosynthesis. Extensive studies have been carried out to determine how polyADP-ribosylation (PARylation) regulates cell proliferation during cell cycle, with conflicting conclusions. Since significant activation of PARP1 occurs during cell lysis in vitro, we changed the standard method for cell lysis, and using our sensitive ELISA system, quantified without addition of a PAR glycohydrolase inhibitor and clarified that the PAR level is significantly higher in S phase than that in G1. Under normal condition in the absence of exogenous DNA-damaging agent, PAR turns over with a half-life of <40 s; consistent with significant decrease of NAD + levels in S phase, which is rescued by PARP inhibitors, in line with the observed rapid turnover of PAR. PARP inhibitors delayed cell cycle in S phase and decreased cell proliferation. Our results underscore the importance of a suitable assay system to measure rapid PAR chain dynamics in living cells and aid our understanding of the function of PARylation during the cell cycle., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Mast cells are present in all vascularized tissues of the body. They are especially abundant in tissues that are in frequent contact with the surrounding environment and act as potential sources of inflammatory and/or regulatory mediators during development of various infections and diseases. Mature mast cells' cytoplasm contains numerous granules that store a variety of chemical mediators, cytokines, proteoglycans, and proteases. Mast cells are activated via various cell surface receptors, including FcϵRI, toll-like receptors (TLR), Mas-related G-protein-coupled receptor X2 (MRGPRX2), and cytokine receptors. IgE-mediated mast cell activation results in release of histamine and other contents of their granules into the extracellular environment, contributing to host defense against pathogens. TLRs, play a crucial role in host defense against various types of pathogens by recognizing pathogen-associated molecular patterns. On the other hand, excessive/inappropriate mast cell activation can cause various disorders. Here, we review the published literature regarding the known and potential inflammatory and regulatory roles of mast cells in cutaneous inflammation, including atopic dermatitis, psoriasis, and contact dermatitis GVHD, as well as in host defense against pathogens., 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 © 2022 Numata, Harada and Nakae.)

Group 2 innate lymphoid cells (ILC2s) are typically known for their ability to respond rapidly to parasitic infections and play a pivotal role in the development of certain allergic disorders. ILC2s produce cytokines such as Interleukin (IL)-5 and IL-13 similar to the type 2 T helper (Th2) cells. Recent findings have highlighted that ILC2s, together with IL-33 and eosinophils, participate in a considerably broad range of physiological roles such as anti-tumor immunity, metabolic regulation, and vascular disorders. Therefore, the focus of the ILC2 study has been extended from conventional Th2 responses to these unexplored areas of research. However, disease outcomes accompanied by ILC2 activities are paradoxical mostly in tumor immunity requiring further investigations. Although various environmental factors that direct the development, activation, and localization of ILC2s have been studied, IL-33/ILC2/eosinophil axis is presumably central in a multitude of inflammatory conditions and has guided the research in ILC2 biology. With a particular focus on this axis, we discuss ILC2s across different diseases., 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 © 2022 Ikutani and Nakae.)

Long-term senescent cells exhibit a secretome termed the senescence-associated secretory phenotype (SASP). Although the mechanisms of SASP factor induction have been intensively studied, the release mechanism and how SASP factors influence tumorigenesis in the biological context remain unclear. In this study, using a mouse model of obesity-induced hepatocellular carcinoma (HCC), we identified the release mechanism of SASP factors, which include interleukin-1β (IL-1β)- and IL-1β-dependent IL-33, from senescent hepatic stellate cells (HSCs) via gasdermin D (GSDMD) amino-terminal-mediated pore. We found that IL-33 was highly induced in senescent HSCs in an IL-1β-dependent manner in the tumor microenvironment. The release of both IL-33 and IL-1β was triggered by lipoteichoic acid (LTA), a cell wall component of gut microbiota that was transferred and accumulated in the liver tissue of high-fat diet-fed mice, and the release of these factors was mediated through cell membrane pores formed by the GSDMD amino terminus, which was cleaved by LTA-induced caspase-11. We demonstrated that IL-33 release from HSCs promoted HCC development via the activation of ST2-positive T reg cells in the liver tumor microenvironment. The accumulation of GSDMD amino terminus was also detected in HSCs from human NASH-associated HCC patients, suggesting that similar mechanism could be involved in a certain type of human HCC. These results uncover a release mechanism for SASP factors from sensitized senescent HSCs in the tumor microenvironment, thereby facilitating obesity-associated HCC progression. Furthermore, our findings highlight the therapeutic potential of inhibitors of GSDMD-mediated pore formation for HCC treatment.

Background: Platelets are thought to be involved in the pathophysiology of asthma, presumably through direct adhesion to inflammatory cells, including group 2 innate lymphoid cells (ILC2s). Here, we tried to elucidate the effects of platelet adhesion to ILC2s in vitro and in vivo, as well as the mechanisms involved., Methods: Alternaria-induced ILC2-dependent airway inflammation models using wild-type and c-mpl -/- mice were evaluated. Both purified CD41 + and CD41 - ILC2s were cultured with IL-2 and IL-33 to determine in vitro Type 2 (T2) cytokine production and cell proliferation. RNA-seq data of flow-cytometry-sorted CD41 + and CD41 - ILC2s were used to isolate ILC2-specific genes. Flow cytometry was performed to determine the expression of CD41 and adhesion-related molecules on ILC2s in both mouse and human tissues., Results: T2 inflammation and T2 cytokine production from ILC2s were significantly reduced in the c-mpl -/- mice compared to wild-type mice. Platelet-adherent ILC2s underwent significant proliferation and showed enhanced T2 cytokine production when exposed to IL-2 and IL-33. The functions of ILC2-specific genes were related to cell development and function. Upstream regulator analysis identified 15 molecules, that are thought to be involved in ILC2 activation. CD41 expression levels were higher in ILC2s from human PBMCs and mouse lung than in those from secondary lymphoid tissues, but they did not correlate with the P-selectin glycoprotein ligand-1 or CD24 expression level., Conclusion: Platelets spontaneously adhere to ILC2s, probably in the peripheral blood and airways, thereby potentiating ILC2s to enhance their responses to IL-33., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: We investigated the ability of magnetic resonance imaging (MRI) to distinguish primary central nervous system vasculitis (PCNSV) from glioblastoma to facilitate the development of an appropriate treatment for PCNSV., Methods: We enrolled patients who were treated for PCNSV or glioblastoma at our center between January 2007 and August 2018. We compared the diagnoses of the 2 conditions by retrospectively reviewing patients' data for contrast-enhanced MRI, perfusion MRI, flow-sensitive black-blood (FSBB) imaging, and 1 H-magnetic resonance spectroscopy (MRS)., Results: We evaluated 108 patients (6 PCNSV; 102 glioblastoma). We found a statistically significant correlation between diagnosis and the contrast pattern on MRI. Perivascular enhancement was observed in all cases of PCNSV as follows: ring-like, homogeneous, and irregular patterns were observed in 53 (60%), 18 (20%), and 17 (19%) cases of glioblastoma, respectively. We identified a statistically significant correlation between diagnosis and cerebral blood volume (CBV) in 3 patients with PCNSV who underwent perfusion MRI; and all had low CBVs. Among the 55 patients with glioblastoma who underwent perfusion MRI, low and high CBVs were detected in 3 and 52 patients, respectively. There was no significant correlation between diagnosis and FSBB findings. Evaluation of 1 H-MRS data showed statistically significant differences between PCNSV and glioblastoma as functions of neuronal amino acid levels on long echo time MRS, with a slightly different amino acid profile, including glutamine + glutamate on short echo time MRS., Conclusions: Contrast-enhanced MRI, perfusion MRI, and quantitative analysis of 1 H-MRS are valuable techniques for distinguishing PCNSV from glioblastoma before surgery., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: A common surgical approach for dominant insular lesions is to make a surgical corridor in asymptomatic cortices based on functional mapping. However, the surgical approach is difficult for posterior insular lesions in a dominant hemisphere because the posterior parts of the perisylvian cortices usually have verbal functions., Observations: We present the case of a 40-year-old male whose magnetic resonance images revealed the presence of contrast-enhancing lesions in the left posterior insula. Our surgical approach was to split the sylvian fissure as widely as possible, and partially resect Heschl's gyrus if the cortical mapping was negative for language tests. Because Heschl's gyrus did not have verbal functions, the gyrus was used as a surgical corridor. It was wide enough for the removal of the lesion; however, because intraoperative pathological diagnosis eliminated the possibility of brain tumors, further resection was discontinued. The tissues were histologically diagnosed as tuberculomas. Antituberculosis drugs were administered, and the residual lesions finally disappeared. According to the neurophysiological tests, the patient showed temporary impairment of auditory detection, but the low scores of these tests improved., Lessons: The transsylvian and trans-Heschl's gyrus approach can be a novel surgical option for excising dominant posterior insular lesions.

Paneth cells are intestinal epithelial cells that release antimicrobial peptides, such as α-defensin as part of host defense. Together with mesenchymal cells, Paneth cells provide niche factors for epithelial stem cell homeostasis. Here, we report two subtypes of murine Paneth cells, differentiated by their production and utilization of fucosyltransferase 2 (Fut2), which regulates α(1,2)fucosylation to create cohabitation niches for commensal bacteria and prevent invasion of the intestine by pathogenic bacteria. The majority of Fut2 - Paneth cells were localized in the duodenum, whereas the majority of Fut2 + Paneth cells were in the ileum. Fut2 + Paneth cells showed higher granularity and structural complexity than did Fut2 - Paneth cells, suggesting that Fut2 + Paneth cells are involved in host defense. Signaling by the commensal bacteria, together with interleukin 22 (IL-22), induced the development of Fut2 + Paneth cells. IL-22 was found to affect the α-defensin secretion system via modulation of Fut2 expression, and IL-17a was found to increase the production of α-defensin in the intestinal tract. Thus, these intestinal cytokines regulate the development and function of Fut2 + Paneth cells as part of gut defense., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

Cepharanthine (CEP) is a natural biscoclaurine alkaloid of plant origin and was recently demonstrated to have anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) activity. In this study, we evaluated whether natural analogues of CEP may act as potential anti-coronavirus disease 2019 drugs. A total of 24 compounds resembling CEP were extracted from the KNApSAcK database, and their binding affinities to target proteins, including the spike protein and main protease of SARS-CoV-2, NPC1 and TPC2 in humans, were predicted via molecular docking simulations. Selected analogues were further evaluated by a cell-based SARS-CoV-2 infection assay. In addition, the efficacies of CEP and its analogue tetrandrine were assessed. A comparison of the docking conformations of these compounds suggested that the diphenyl ester moiety of the molecules was a putative pharmacophore of the CEP analogues., (© 2021 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Eukaryotic protein kinases contain an Asp-Phe-Gly (DFG) motif, the conformation of which is involved in controlling the catalytic activity, at the N-terminus of the activation segment. The motif can be switched between active-state (DFG-in) and inactive-state (DFG-out) conformations: however, the mechanism of conformational change is poorly understood, partly because there are few reports of the DFG-out conformation. Here, a novel crystal structure of nonphosphorylated human mitogen-activated protein kinase kinase 1 (MEK1; amino acids 38-381) complexed with ATP-γS is reported in which MEK1 adopts the DFG-out conformation. The crystal structure revealed that the structural elements (the αC helix and HRD motif) surrounding the active site are involved in the formation/stabilization of the DFG-out conformation. The ATP-γS molecule was bound to the canonical ATP-binding site in a different binding mode that has never been found in previously determined crystal structures of MEK1. This novel ATP-γS binding mode provides a starting point for the design of high-affinity inhibitors of nonphosphorylated inactive MEK1 that adopts the DFG-out conformation.

Discovery of innate lymphoid cells (ILCs), which are non-T and non-B lymphocytes that have no antigen-specific receptors, changed the classical concept of the mechanism of allergy, which had been explained mainly as antigen-specific acquired immunity based on IgE and Th2 cells. The discovery led to dramatic improvement in our understanding of the mechanism of non-IgE-mediated allergic inflammation. Numerous studies conducted in the past decade have elucidated the characteristics of each ILC subset in various organs and tissues and their ontogeny. We now know that each ILC subset exhibits heterogeneity. Moreover, the functions and activating/suppressing factors of each ILC subset were found to differ among both organs and types of tissue. Therefore, in this review, we summarize our current knowledge of ILCs by focusing on the organ/tissue-specific features of each subset to understand their roles in various organs. We also discuss ILCs' involvement in human inflammatory diseases in various organs and potential therapeutic/preventive strategies that target ILCs., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)