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This single-center retrospective study aimed to analyze the variability of macrolide resistance (MR) in 68 patients with Mycobacterium avium complex pulmonary disease. Among 25 patients treated without macrolides, 13 (52%) reverted to macrolide-susceptible (MS) profiles. Only one (2%) of 43 patients who continued macrolide treatment showed this change. We compared 30 MR isolates with recent specimens. Among them, seven shifted to MS (five attributed to clonally related strains; two resulting from reinfection or polyclonal infection).

Objectives: To evaluate the safety, tolerability, pharmacokinetics (PK), biomarker response and efficacy of E6742 in a phase I/II study in patients with systemic lupus erythematosus (SLE)., Methods: Two sequential cohorts of patients with SLE were enrolled and randomised to 12 weeks of two times per day treatment with E6742 (100 or 200 mg; n=8 or 9) or placebo (n=9). The primary endpoint was safety, the secondary endpoints were PK and interferon gene signature (IGS), and the exploratory endpoints were efficacy and biomarker., Results: The proportion of patients with any treatment-emergent adverse events (TEAEs) was 58.8% in the E6742 group (37.5% (3/8 patients) for 100 mg; 77.8% (7/9 patients) for 200 mg) and 66.7% (6/9 patients) in the placebo group. No Common Terminology Criteria for Adverse Events≥Grade 3 TEAEs occurred. PK parameters were similar to these in previous phase I studies in healthy adults. The IGS and levels of proinflammatory cytokines after ex-vivo challenge with a Toll-like receptor 7/8 agonist were immediately decreased by E6742 treatment. The response rate of the British Isles Lupus Assessment Group-based Composite Lupus Assessment at week 12 was 37.5% (3/8 patients) for E6742 100 mg, 57.1% (4/7 patients) for E6742 200 mg and 33.3% (3/9 patients) for placebo group., Conclusions: E6742 had a favourable safety profile and was well tolerated, with suppression of IGS responses and preliminary efficacy signals in patients with SLE. These results provide the first clinical evidence to support E6742 in the treatment of SLE, and support larger, longer-term clinical trials., Trial Registration Number: NCT05278663., Competing Interests: Competing interests: YT has received grants from Mitsubishi-Tanabe, Eisai, Chugai and Taisho; speaker fees and/or honoraria from Eli Lilly, AstraZeneca, Abbvie, Gilead, Chugai, Behringer-Ingelheim, GlaxoSmithKline, Eisai, Taisho, Bristol-Myers Squibb, Pfizer and Taiho. AK has received grants from Chugai; consulting fees from Eisai; speaker fees and/or honoraria from Asahi Kasei, Astellas, Eisai, GlaxoSmithKline, Chugai, Eli Lilly, BoehringerIngelheim, Pfizer and Bristol-Myers Squibb. TA has received grants from GlaxoSmithKline; consulting fees from GlaxoSmithKline, AstraZeneca, Boehringer-Ingelheim, Novartis, Otsuka and Eisai; speaker fees and/or honoraria from AbbVie, Alexion, Asahi Kasei, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Gilead Sciences, GlaxoSmithKline, Janssen, Novartis, Boehringer-Ingelheim, Mitsubishi-Tanabe, Pfizer, Taiho and UCB. TI has received grants from Asahi Kasei; consulting fees from Eisai; speaker fees and/or honoraria from Astellas, Chugai, Janssen, Ono and Sanofi. FT, MA and SY are employees of Eisai. SA has received grants from Chugai and Otsuka; consulting fees from Eisai., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Regnase-1 is an RNase that plays a critical role in negatively regulating immune responses by destabilizing inflammatory messenger RNAs (mRNAs). Dysfunction of Regnase-1 can be a major cause of various inflammatory diseases with tissue injury and immune cell infiltration into organs. This study focuses on the role of the RNase activity of Regnase-1 in developing inflammatory diseases. We have constructed mice with a single point mutation at the catalytic center of the Regnase-1 RNase domain, which lacks endonuclease activity. D141N mutant mice demonstrated systemic inflammation, immune cell infiltration into various organs, and progressive development of lung granuloma. CD4+ T cells, mainly affected by this mutation, upregulated the mTORC1 pathway and facilitated the autoimmune trait in the D141N mutation. Moreover, serine/threonine kinase Pim2 contributed to lung inflammation in this mutation. Inhibition of Pim2 kinase activity ameliorated granulomatous inflammation, immune cell infiltration, and proliferation in the lungs. Additionally, Pim2 inhibition reduced the expression of adhesion molecules on CD4+ T cells, suggesting a role for Pim2 in facilitating leukocyte adhesion and migration to inflamed tissues. Our findings provide new insights into the role of Regnase-1 RNase activity in controlling immune functions and underscore the therapeutic relevance of targeting Pim2 to modulate abnormal immune responses., (© 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.)

Regulatory T cells (Tregs) are crucial immune cells for tissue repair and regeneration. However, their potential as a cell-based regenerative therapy is not yet fully understood. Here, we show that local delivery of exogenous Tregs into injured mouse bone, muscle, and skin greatly enhances tissue healing. Mechanistically, exogenous Tregs rapidly adopt an injury-specific phenotype in response to the damaged tissue microenvironment, upregulating genes involved in immunomodulation and tissue healing. We demonstrate that exogenous Tregs exert their regenerative effect by directly and indirectly modulating monocytes/macrophages (Mo/MΦ) in injured tissues, promoting their switch to an anti-inflammatory and pro-healing state via factors such as interleukin (IL)-10. Validating the key role of IL-10 in exogenous Treg-mediated repair and regeneration, the pro-healing capacity of these cells is lost when Il10 is knocked out. Additionally, exogenous Tregs reduce neutrophil and cytotoxic T cell accumulation and IFN-γ production in damaged tissues, further dampening the pro-inflammatory Mo/MΦ phenotype. Highlighting the potential of this approach, we demonstrate that allogeneic and human Tregs also promote tissue healing. Together, this study establishes exogenous Tregs as a possible universal cell-based therapy for regenerative medicine and provides key mechanistic insights that could be harnessed to develop immune cell-based therapies to enhance tissue healing., (© 2024. The Author(s).)

Transforming growth factor-β-activated kinase 1 (TAK1) plays a pivotal role in innate and adaptive immunity. TAK1 is essential for the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB pathways downstream of diverse immune receptors, including toll-like receptors (TLRs). Upon stimulation with TLR ligands, TAK1 is activated via recruitment to the lysine 63-linked polyubiquitin chain through TAK1-binding protein 2 (TAB2) and TAB3. However, the physiological importance of TAB2 and TAB3 in macrophages is still controversial. A previous study has shown that mouse bone marrow-derived macrophages (BMDMs) isolated from mice double deficient for TAB2 and TAB3 produced tumor necrosis factor (TNF)-α and interleukin (IL)-6 to the similar levels as control wild-type BMDMs in response to TLR ligands such as lipopolysaccharide (LPS) or Pam3CSK4, indicating that TAB2 and TAB3 are dispensable for TLR signaling. In this study, we revisited the role of TAB2 and TAB3 using an improved mouse model. We observed a significant impairment in the production of pro-inflammatory cytokines and chemokine in LPS- or Pam3CSK4-treated BMDMs deficient for both TAB2 and TAB3. Double deficiency of TAB2 and TAB3 resulted in the decreased activation of NF-κB and MAPK pathways as well as the slight decrease in TAK1 activation in response to LPS or Pam3CSK4. Notably, the TLR-mediated expression of inhibitor of NF-κB (IκB)ζ was severely compromised at the protein and messenger RNA (mRNA) levels in the TAB2/TAB3 double-deficient BMDMs, thereby impeding IL-6 production. Our results suggest that TAB2 and TAB3 play a redundant and indispensable role in the TLR signaling pathway., (© 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.)

Climate change has profound impacts on forest ecosystem dynamics and could lead to the emergence of novel ecosystems via changes in species composition, forest structure, and potentially a complete loss of tree cover. Disturbances fundamentally shape those dynamics: the prevailing disturbance regime of a region determines the inherent variability of a system, and its climate-mediated change could accelerate forest transformation. We used the individual-based forest landscape and disturbance model iLand to investigate the resilience of three protected temperate forest landscapes on three continents-selected to represent a gradient from low to high disturbance activity-to changing climate and disturbance regimes. In scenarios of sustained strong global warming, natural disturbances increased across all landscapes regardless of projected changes in precipitation (up to a sevenfold increase in disturbance rate over the 180-year simulation period). Forests in landscapes with historically high disturbance activity had a higher chance of remaining resilient in the future, retaining their structure and composition within the range of variability inherent to the system. However, the risk of regime shift and forest loss was also highest in these systems, suggesting forests may be vulnerable to abrupt change beyond a threshold of increasing disturbance activity. Resilience generally decreased with increasing severity of climate change. Novelty in tree species composition was more common than novelty in forest structure, especially under dry climate scenarios. Forests close to the upper tree line experienced high novelty in structure across all three study systems. Our results highlight common patterns and processes of forest change, while also underlining the diverse and context-specific responses of temperate forest landscapes to climate change. Understanding past and future disturbance regimes can anticipate the magnitude and direction of forest change. Yet, even across a broad gradient of disturbance activity, we conclude that climate change mitigation is the most effective means of maintaining forest resilience., (© 2024 The Author(s). Global Change Biology published by John Wiley & Sons Ltd.)

Limited infiltration and activity of natural killer (NK) and T cells within the tumor microenvironment (TME) correlate with poor immunotherapy responses. Here, we examined the role of the endonuclease Regnase-1 on NK cell anti-tumor activity. NK cell-specific deletion of Regnase-1 (Reg1 ΔNK ) augmented cytolytic activity and interferon-gamma (IFN-γ) production in vitro and increased intra-tumoral accumulation of Reg1 ΔNK -NK cells in vivo, reducing tumor growth dependent on IFN-γ. Transcriptional changes in Reg1 ΔNK -NK cells included elevated IFN-γ expression, cytolytic effectors, and the chemokine receptor CXCR6. IFN-γ induced expression of the CXCR6 ligand CXCL16 on myeloid cells, promoting further recruitment of Reg1 ΔNK -NK cells. Mechanistically, Regnase-1 deletion increased its targets, the transcriptional regulators OCT2 and IκBζ, following interleukin (IL)-12 and IL-18 stimulation, and the resulting OCT2-IκBζ-NF-κB complex induced Ifng transcription. Silencing Regnase-1 in human NK cells increased the expression of IFNG and POU2F2. Our findings highlight NK cell dysfunction in the TME and propose that targeting Regnase-1 could augment active NK cell persistence for cancer immunotherapy., Competing Interests: Declaration of interests Y.N. and H.N. declare they are employees and shareholders of Otsuka Pharmaceutical Co., Ltd. E.V. is an employee of Innate Pharma., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Endometriosis is a multifaceted gynecological condition that poses diagnostic challenges and affects a significant number of women worldwide, leading to pain, infertility, and a reduction in patient quality of life (QoL). Traditional diagnostic methods, such as the revised American Society for Reproductive Medicine (r-ASRM) classification, have limitations, particularly in preoperative settings. The Numerical Multi-Scoring System of Endometriosis (NMS-E) has been proposed to address these shortcomings by providing a comprehensive preoperative diagnostic tool that integrates findings from pelvic examinations and transvaginal ultrasonography., Methods: This retrospective study aims to validate the effectiveness of the NMS-E in predicting surgical outcomes and correlating with the severity of endometriosis. Data from 111 patients at Nippon Medical School Hospital were analyzed to determine the correlation between NMS-E scores, including E-score-a severity indicator-traditional scoring systems, surgical duration, blood loss, and clinical symptoms. This study also examined the need to refine parameters for deep endometriosis within the NMS-E to enhance its predictive accuracy for disease severity., Results: The mean age of the patient cohort was 35.1 years, with the majority experiencing symptoms such as dysmenorrhea, dyspareunia, and chronic pelvic pain. A statistically significant positive correlation was observed between the NMS-E's E-score and the severity of endometriosis, particularly in predicting surgical duration (Spearman correlation coefficient: 0.724, p < 0.01) and blood loss (coefficient: 0.400, p < 0.01). The NMS-E E-score also correlated strongly with the r-ASRM scores (coefficient: 0.758, p < 0.01), exhibiting a slightly more excellent predictive value for surgical duration than the r-ASRM scores alone. Refinements in the methodology for scoring endometriotic nodules in uterine conditions improved the predictive accuracy for surgical duration (coefficient: 0.752, p < 0.01)., Conclusions: Our findings suggest that the NMS-E represents a valuable preoperative diagnostic tool for endometriosis, effectively correlating with the disease's severity and surgical outcomes. Incorporating the NMS-E into clinical practice could significantly enhance the management of endometriosis by addressing current diagnostic limitations and guiding surgical planning.

Natural ecosystems store large amounts of carbon globally, as organisms absorb carbon from the atmosphere to build large, long-lasting, or slow-decaying structures such as tree bark or root systems. An ecosystem's carbon sequestration potential is tightly linked to its biological diversity. Yet when considering future projections, many carbon sequestration models fail to account for the role biodiversity plays in carbon storage. Here, we assess the consequences of plant biodiversity loss for carbon storage under multiple climate and land-use change scenarios. We link a macroecological model projecting changes in vascular plant richness under different scenarios with empirical data on relationships between biodiversity and biomass. We find that biodiversity declines from climate and land use change could lead to a global loss of between 7.44-103.14 PgC (global sustainability scenario) and 10.87-145.95 PgC (fossil-fueled development scenario). This indicates a self-reinforcing feedback loop, where higher levels of climate change lead to greater biodiversity loss, which in turn leads to greater carbon emissions and ultimately more climate change. Conversely, biodiversity conservation and restoration can help achieve climate change mitigation goals., (© 2024. Isbell, Arce-Plata, Di Marco, Harfoot, Johnson, Mori, Weng, Ferrier. Parts of this work were authored by US Federal Government authors and are not under copyright protection in the US; foreign copyright protection may apply.)

The cellular and molecular mechanisms of atherosclerosis are still unclear. Type 2 innate lymphocytes (ILC2) exhibit anti-inflammatory properties and protect against atherosclerosis. This study aimed to elucidate the pathogenesis of atherosclerosis development using atherosclerosis model mice (ApoE KO mice) and mice deficient in IL-33 receptor ST2 (ApoEST2 DKO mice). Sixteen-week-old male ApoE KO and ApoEST2 DKO mice were subjected to an 8-week regimen of a high-fat, high-sucrose diet. Atherosclerotic foci were assessed histologically at the aortic valve ring. Chronic inflammation was assessed using flow cytometry and real-time polymerase chain reaction. In addition, saturated fatty acids (palmitic acid) and IL-33 were administered to human aortic endothelial cells (HAECs) to assess fatty acid metabolism. ApoEST2 DKO mice with attenuated ILC2 had significantly worse atherosclerosis than ApoE KO mice. The levels of saturated fatty acids, including palmitic acid, were significantly elevated in the arteries and serum of ApoEST2 DKO mice. Furthermore, on treating HAECs with saturated fatty acids with or without IL-33, the Oil Red O staining area significantly decreased in the IL-33-treated group compared to that in the non-treated group. IL-33 potentially prevented the accumulation of saturated fatty acids within atherosclerotic foci.

Toll-like receptors (TLRs) are an evolutionarily conserved family in the innate immune system and are the first line of host defense against microbial pathogens by recognizing pathogen-associated molecular patterns (PAMPs). TLRs, categorized into cell surface and endosomal subfamilies, recognize diverse PAMPs, and structural elucidation of TLRs and PAMP complexes has revealed their intricate mechanisms. TLRs activate common and specific signaling pathways to shape immune responses. Recent studies have shown the importance of post-transcriptional regulation in TLR-mediated inflammatory responses. Despite their protective functions, aberrant responses of TLRs contribute to inflammatory and autoimmune disorders. Understanding the delicate balance between TLR activation and regulatory mechanisms is crucial for deciphering their dual role in immune defense and disease pathogenesis. This review provides an overview of recent insights into the history of TLR discovery, elucidation of TLR ligands and signaling pathways, and their relevance to various diseases., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This article reports the results of the 16th National Survey conducted by the Japan Society for Endoscopic Surgery (JSES) for 2020 and 2021. Laparoscopic cholecystectomy was first introduced to Japan in 1990 and has rapidly become popular because of its minimally invasive nature. Since then, the number of objective organs and indications for laparoscopic surgery have gradually expanded. In 2021, 290 787 patients underwent endoscopic surgery in all surgical domains. Of these, 124 614, 110 757, 23 156, 21 771, 6543, 2614, 535, 465, 247, and 58 underwent abdominal, obstetric and gynecologic, thoracic, urological, pediatric, orthopedic, bariatric, mammary and thyroid gland, cardiovascular, and plastic surgery, respectively. Owing to the impact of the coronavirus disease 2019 (COVID-19) infection spread, the incidence of many surgeries decreased in 2020, and levels are only now gradually recovering. However, despite the impact of COVID-19, robot-assisted surgeries were increasingly applied. The rate of complications did not change significantly, indicating that the procedure was performed safely, even with the spread of COVID-19., (© 2024 Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

Understanding the regeneration and succession of belowground communities, particularly in forests, is vital for maintaining ecosystem health. Despite its importance, there is limited knowledge regarding how fungal communities change over time during ecosystem development, especially under different forest restoration strategies. In this study, we focused on two restoration methods used in northern Japan: monoculture planting and natural regeneration. We examined the responses of the fungal community to monoculture plantations (active tree planting) and naturally regenerated (passive regeneration) forests over a 50-year chronosequence, using natural forests as a reference. Based on DNA metabarcoding, we assessed the richness of fungal Operational Taxonomic Units (OTUs) and their dissimilarity. Our findings revealed that soil fungal richness remained stable after natural regeneration but declined in monoculture plantations, from 354 to 247 OTUs. While the compositional dissimilarity of fungal assemblages between monoculture plantations and natural forests remained consistent regardless of the time since tree planting, it significantly decreased after natural regeneration, suggesting recovery to a state close to the reference level. Notably, the composition of key functional fungal groups-saprotrophic and ectomycorrhizal- has increasingly mirrored that of natural forests over time following passive natural regeneration. In summary, our study suggests that monoculture plantations may not be effective for long-term ecosystem function and service recovery because of their limited support for soil fungal diversity. These results underscore the importance of natural regeneration in forest restoration and management strategies., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The immune system has a critical role in orchestrating tissue healing. As a result, regenerative strategies that control immune components have proved effective 1,2 . This is particularly relevant when immune dysregulation that results from conditions such as diabetes or advanced age impairs tissue healing following injury 2,3 . Nociceptive sensory neurons have a crucial role as immunoregulators and exert both protective and harmful effects depending on the context 4-12 . However, how neuro-immune interactions affect tissue repair and regeneration following acute injury is unclear. Here we show that ablation of the Na V 1.8 nociceptor impairs skin wound repair and muscle regeneration after acute tissue injury. Nociceptor endings grow into injured skin and muscle tissues and signal to immune cells through the neuropeptide calcitonin gene-related peptide (CGRP) during the healing process. CGRP acts via receptor activity-modifying protein 1 (RAMP1) on neutrophils, monocytes and macrophages to inhibit recruitment, accelerate death, enhance efferocytosis and polarize macrophages towards a pro-repair phenotype. The effects of CGRP on neutrophils and macrophages are mediated via thrombospondin-1 release and its subsequent autocrine and/or paracrine effects. In mice without nociceptors and diabetic mice with peripheral neuropathies, delivery of an engineered version of CGRP accelerated wound healing and promoted muscle regeneration. Harnessing neuro-immune interactions has potential to treat non-healing tissues in which dysregulated neuro-immune interactions impair tissue healing., (© 2024. The Author(s).)

Accurate predictions of ecosystem functions and nature's contributions to people (NCP) are needed to prioritize environmental protection and restoration in the Anthropocene. However, our ability to predict NCP is undermined by approaches that rely on biophysical variables and ignore those describing biodiversity, which have strong links to NCP. To foster predictive mapping of NCP, we should harness the latest methods in biodiversity modeling. This field advances rapidly, and new techniques with promising applications for predicting NCP are still underutilized. Here, we argue that employing recent advances in biodiversity modeling can enhance the accuracy and scope of NCP maps and predictions. This enhancement will contribute significantly to the achievement of global objectives to preserve NCP, for both the present and an unpredictable future., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Periodontitis, which is induced by repeated bacterial invasion and the ensuing immune reactions that follow, is the leading cause of tooth loss. Periodontal tissue is comprised of four different components, each with potential role in pathogenesis, however, most studies on immune responses focus on gingival tissue. Here, we present a modified ligature-induced periodontitis model in male mice to analyze the pathogenesis, which captures the complexity of periodontal tissue. We find that the inflammatory response in the peri-root tissues and the expression of IL-6 and RANKL by Thy-1.2 - fibroblasts/stromal cells are prominent throughout the bone destruction phase, and present already at an early stage. The initiation phase is characterized by high levels of ST2 (encoded by Il1rl1) expression in the peri-root tissue, suggesting that the IL-33/ST2 axis is involved in the pathogenesis. Both Il1rl1- and Il33-deficient mice exhibit exacerbated bone loss in the acute phase of periodontitis, along with macrophage polarization towards a classically activated phenotype and increased neutrophil infiltration, indicating a protective role of the IL-33/ST2 axis in acute inflammation. Thus, our findings highlight the hidden role of the peri-root tissue and simultaneously advance our understanding of the etiology of periodontitis via implicating the IL-33/ST2 axis., (© 2024. The Author(s).)

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by inflammation in multiple organs. A few treatments for SLE currently exist, including antimalarials, glucocorticoids, immunosuppressants, and two recently approved antibody agents; however, an unmet medical need remains for SLE. In addition, developing new drugs targeting SLE is a challenge since no specific biomarkers exist for the prediction of disease progression or drug response. A new drug candidate, E6742, is a specific antagonist of the toll-like receptors 7/8. To address the challenges for drug development in SLE, the process of developing E6742 utilizes a unique system of the Japan Agency for Medical Research and Development (AMED), the Cyclic Innovation for Clinical Empowerment (CiCLE) program. In the CiCLE program, a Phase 1 study in healthy adults was completed (NCT04683185) and a Phase 1/2 study in patients with SLE is on-going (NCT05278663). One of the potential benefits of this program is to conduct academia-led clinical research to identify specific biomarkers for E6742 in parallel with clinical studies (UMIN000042037). The aim of this review is to present current progress within the strategic collaboration of the AMED CiCLE program that optimize clinical development for patients with SLE.

Objectives: Platelets and low-density neutrophils (LDNs) are major players in the immunopathogenesis of SLE. Despite evidence showing the importance of platelet-neutrophil complexes (PNCs) in inflammation, little is known about the relationship between LDNs and platelets in SLE. We sought to characterize the role of LDNs and Toll-like receptor 7 (TLR7) in clinical disease., Methods: Flow cytometry was used to immunophenotype LDNs from SLE patients and controls. The association of LDNs with organ damage was investigated in a cohort of 290 SLE patients. TLR7 mRNA expression was assessed in LDNs and high-density neutrophils (HDNs) using publicly available mRNA sequencing datasets and our own cohort using RT-PCR. The role of TLR7 in platelet binding was evaluated in platelet-HDN mixing studies using TLR7-deficient mice and Klinefelter syndrome patients., Results: SLE patients with active disease have more LDNs, which are heterogeneous and more immature in patients with evidence of kidney dysfunction. LDNs are platelet bound, in contrast to HDNs. LDNs settle in the peripheral blood mononuclear cell (PBMC) layer due to the increased buoyancy and neutrophil degranulation from platelet binding. Mixing studies demonstrated that this PNC formation was dependent on platelet-TLR7 and that the association results in increased NETosis. The neutrophil:platelet ratio is a useful clinical correlate for LDNs, and a higher NPR is associated with past and current flares of LN., Conclusions: LDNs sediment in the upper PBMC fraction due to PNC formation, which is dependent on the expression of TLR7 in platelets. Collectively, our results reveal a novel TLR7-dependent crosstalk between platelets and neutrophils that may be an important therapeutic opportunity for LN., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Climate change is increasing the frequency and severity of short-term (~1 y) drought events-the most common duration of drought-globally. Yet the impact of this intensification of drought on ecosystem functioning remains poorly resolved. This is due in part to the widely disparate approaches ecologists have employed to study drought, variation in the severity and duration of drought studied, and differences among ecosystems in vegetation, edaphic and climatic attributes that can mediate drought impacts. To overcome these problems and better identify the factors that modulate drought responses, we used a coordinated distributed experiment to quantify the impact of short-term drought on grassland and shrubland ecosystems. With a standardized approach, we imposed ~a single year of drought at 100 sites on six continents. Here we show that loss of a foundational ecosystem function-aboveground net primary production (ANPP)-was 60% greater at sites that experienced statistically extreme drought (1-in-100-y event) vs. those sites where drought was nominal (historically more common) in magnitude (35% vs. 21%, respectively). This reduction in a key carbon cycle process with a single year of extreme drought greatly exceeds previously reported losses for grasslands and shrublands. Our global experiment also revealed high variability in drought response but that relative reductions in ANPP were greater in drier ecosystems and those with fewer plant species. Overall, our results demonstrate with unprecedented rigor that the global impacts of projected increases in drought severity have been significantly underestimated and that drier and less diverse sites are likely to be most vulnerable to extreme drought., Competing Interests: Competing interests statement:The authors declare no competing interest.

Biodiversity-ecosystem functioning (BEF) research has provided strong evidence and mechanistic underpinnings to support positive effects of biodiversity on ecosystem functioning, from single to multiple functions. This research has provided knowledge gained mainly at the local alpha scale (i.e. within ecosystems), but the increasing homogenization of landscapes in the Anthropocene has raised the potential that declining biodiversity at the beta (across ecosystems) and gamma scales is likely to also impact ecosystem functioning. Drawing on biodiversity theory, we propose a new statistical framework based on Hill-Chao numbers. The framework allows decomposition of multifunctionality at gamma scales into alpha and beta components, a critical but hitherto missing tool in BEF research; it also allows weighting of individual ecosystem functions. Through the proposed decomposition, new BEF results for beta and gamma scales are discovered. Our novel approach is applicable across ecosystems and connects local- and landscape-scale BEF assessments from experiments to natural settings., (© 2023 The Authors. Ecology Letters published by John Wiley & Sons Ltd.)

Problem: In women of reproductive age, endometriosis may contribute to dysmenorrhea, chronic pelvic pain, dyspareunia, infertility, adenomyosis, and endometrial ovarian cyst (EOC). Recent studies have shown that chronic inflammation occurs in the pelvis of endometriosis patients and that this inflammation is exacerbated by immunosuppression, leading to survival endometrial debris. However, the detailed immunological mechanisms underlying the aggravation of inflammation and immunosuppression in endometriosis patients remain unclear., Method of Study: We investigate the alarmins (high-mobility group box-1, IL-33, IL-1α, and S100B protein), proinflammatory cytokines (IL-6 and IL-1β), and immune cells (CD8 + T cells, CD4 + T cells, natural killer cells, natural killer T cells, dendritic cells, and macrophages) in peritoneal fluid of patients with EOC using enzyme-linked immunosorbent assay, electrochemiluminescence, and flow cytometry. Then, we analyzed the correlation between these factors and the aggravating indicators of endometriosis, tumor size and revised American Society for Reproductive Medicine (r-ASRM) score., Results: Unexpectedly, there was no correlation between each alarmin level and aggravating indicators. However, the expression of pattern recognition receptors, toll-like receptor 4, and receptor of advanced glycation end-products on macrophages was inversely correlated with aggravating indicators., Conclusions: The aggravation of endometriosis is associated with a decrease in alarmin receptors but not alarmin levels. Investigation of innate immune systems, such as alarmins and their receptors, may help elucidate new mechanisms of endometriosis., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Mitochondrial DNA (mtDNA) leakage into the cytoplasm can occur when cells are exposed to noxious stimuli. Specific sensors recognize cytoplasmic mtDNA to promote cytokine production. Cytoplasmic mtDNA can also be secreted extracellularly, leading to sterile inflammation. However, the mode of secretion of mtDNA out of cells upon noxious stimuli and its relevance to human disease remain unclear. Here, we show that pyroptotic cells secrete mtDNA encapsulated within exosomes. Activation of caspase-1 leads to mtDNA leakage from the mitochondria into the cytoplasm via gasdermin-D. Caspase-1 also induces intraluminal membrane vesicle formation, allowing for cellular mtDNA to be taken up and secreted as exosomes. Encapsulation of mtDNA within exosomes promotes a strong inflammatory response that is ameliorated upon exosome biosynthesis inhibition in vivo. We further show that monocytes derived from patients with Behçet's syndrome (BS), a chronic systemic inflammatory disorder, show enhanced caspase-1 activation, leading to exosome-mediated mtDNA secretion and similar inflammation pathology as seen in BS patients. Collectively, our findings support that mtDNA-containing exosomes promote inflammation, providing new insights into the propagation and exacerbation of inflammation in human inflammatory diseases., (© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

Background: Pancreatitis is known to be an important risk factor for pancreatic ductal adenocarcinoma (PDAC). However, the exact molecular mechanisms of how inflammation promotes PDAC are still not fully understood. Regnase-1, an endoribonuclease, regulates immune responses by degrading mRNAs of inflammation-related genes. Herein, we investigated the role of Regnase-1 in PDAC., Methods: Clinical significance of intratumor Regnase-1 expression was evaluated by immunohistochemistry in 39 surgically-resected PDAC patients. The functional role of Regnase-1 was investigated by pancreas-specific Regnase-1 knockout mice and Kras-mutant Regnase-1 knockout mice. The mechanistic studies with gene silencing, RNA immunoprecipitation sequencing (RIP-seq) and immune cell reconstitution were performed in human/mouse PDAC cell lines and a syngeneic orthotopic tumor transplantation model of KrasG12D-mutant and Trp53-deficient PDAC cells., Results: Regnase-1 expression was negatively correlated with the clinical outcomes and an independent predictor of poor relapse-free and overall survival in PDAC patients. Pancreas-specific Regnase-1 deletion in mice promoteed pancreatic cancer with PMN-MDSC infiltration and shortened their survival. A syngeneic orthotopic PDAC model exhibited that Regnase-1 downregulation accelerated tumor progression via recruitment of intratumor CD11b + MDSCs. Mechanistically, Regnase-1 directly negatively regulated a variety of chemokines/cytokines important for MDSC recruitment and activation, including CXCL1, CXCL2, CSF2, and TGFβ, in pancreatic cancer cells. We subsequently showed that IL-1β-mediated Regnase-1 downregulation recruited MDSCs to tumor sites and promoted pancreatic cancer progression via mitigation of cytotoxic T lympohocytes-mediated antitumor immunity., Conclusions: IL-1b-mediated Regnase-1 downregulation induces MDSCs and promotes pancreatic cancer through the evasion of anticancer immunity., (© 2023. Italian National Cancer Institute ‘Regina Elena’.)

International collaborations aim to solve global environmental issues. Academic work and science-policy interfaces are instrumental in this pursuit, although scholars often overlook their significance. There is a need for fair credit distribution, transparency, and diversity in academia and policy reports. Recognizing these factors can enhance inclusivity and equity, driving solutions., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Loss-of-function mutations in the lysosomal nucleoside transporter SLC29A3 cause lysosomal nucleoside storage and histiocytosis: phagocyte accumulation in multiple organs. However, little is known about the mechanism by which lysosomal nucleoside storage drives histiocytosis. Herein, histiocytosis in Slc29a3-/- mice was shown to depend on Toll-like receptor 7 (TLR7), which senses a combination of nucleosides and oligoribonucleotides (ORNs). TLR7 increased phagocyte numbers by driving the proliferation of Ly6Chi immature monocytes and their maturation into Ly6Clow phagocytes in Slc29a3-/- mice. Downstream of TLR7, FcRγ and DAP10 were required for monocyte proliferation. Histiocytosis is accompanied by inflammation in SLC29A3 disorders. However, TLR7 in nucleoside-laden splenic monocytes failed to activate inflammatory responses. Enhanced production of proinflammatory cytokines was observed only after stimulation with ssRNAs, which would increase lysosomal ORNs. Patient-derived monocytes harboring the G208R SLC29A3 mutation showed enhanced survival and proliferation in a TLR8-antagonist-sensitive manner. These results demonstrated that TLR7/8 responses to lysosomal nucleoside stress drive SLC29A3 disorders., (© 2023 Shibata et al.)

Aim: Minimally invasive surgery (MIS) has been introduced as an alternative to more radical surgical procedures. The Japan Society of Gynecologic and Obstetric Endoscopy and Minimally Invasive Therapy conducted a cross-sectional questionnaire survey to ascertain the status of MIS for endometrial cancer., Methods: The survey was conducted between May 10 and June 30, 2022. The questionnaire included information on personal attributes, academic affiliations, qualifications, hysterectomies, and intraoperative procedures performed., Results: The total number of questionnaire respondents was 436 (9.2% of the membership). The hysterectomy methods and percentage performed were as follows: simple total hysterectomy (equivalent to benign surgery), 3%; simple total hysterectomy with care to avoid shaving the cervix, 31%; extended total hysterectomy, 48%; and modified radical hysterectomy, 15%. An analysis of hysterectomies performed using MIS for endometrial cancer by qualified gynecologists of endoscopy or board-certified gynecologic oncologists showed a tendency not to choose simple total hysterectomy compared to the gynecologists who did not hold certification (p = 0.019, p = 0.045, and p = 0.010, respectively). Additionally, 67% of respondents did not use uterine manipulators, and 59% of the respondents did not perform lymph node dissection following the guidelines for treating endometrial cancer in Japan., Conclusion: This study provided the current status of MIS for endometrial cancer in Japan. The hysterectomy method, use of uterine manipulators, and criteria for omitting lymph node dissection were generally in agreement with the guidelines. Currently, an extra-fascial simple hysterectomy, including at least not shaving the cervix, was a major method for early invasive endometrial cancer using MIS., (© 2023 The Authors. Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.)

Primary succession and microtopography result in environmental changes and are important processes influencing the community assembly of soil fungi in the Arctic region. In glacier forefields that contain a series of moraine ridges, both processes contribute synchronously to fungal spatial diversity. To reveal the synergistic effects of succession and microtopography, we investigated the fungal community structure and environmental variables in the moraines of the Arklio Glacier, Ellesmere Island. The study sites were established at four locations from the top to the bottom of the ridge slope within each of the three moraine ridges of different post-glacial ages. The location-dependent community composition was equally diverse in both the initial and later stages of succession, suggesting that successional time could alter the effects of microtopography on the fungal community. Moreover, our results suggest that fungal communities at different locations follow different successional trajectories, even if they have passed through the same time lapse. Such a synergistic effect of succession and microtopography of moraines does not allow for parallel changes in fungal communities among moraines or among locations, suggesting that the moraine series contributes substantially to fungal spatial diversity in the glacier forefield., (© The Author(s) 2023. Published by Oxford University Press on behalf of FEMS.)

Lung infection during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via the angiotensin-I-converting enzyme 2 (ACE2) receptor induces a cytokine storm. However, the precise mechanisms involved in severe COVID-19 pneumonia are unknown. Here, we showed that interleukin-10 (IL-10) induced the expression of ACE2 in normal alveolar macrophages, causing them to become vectors for SARS-CoV-2. The inhibition of this system in hamster models attenuated SARS-CoV-2 pathogenicity. Genome-wide association and quantitative trait locus analyses identified a IFNAR2-IL10RB readthrough transcript, COVID-19 infectivity-enhancing dual receptor (CiDRE), which was highly expressed in patients harboring COVID-19 risk variants at the IFNAR2 locus. We showed that CiDRE exerted synergistic effects via the IL-10-ACE2 axis in alveolar macrophages and functioned as a decoy receptor for type I interferons. Collectively, our data show that high IL-10 and CiDRE expression are potential risk factors for severe COVID-19. Thus, IL-10R and CiDRE inhibitors might be useful COVID-19 therapies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Biodiversity changes, such as decline in species richness and biotic homogenization, can have grave consequences for ecosystem functionality. Careful investigation of biodiversity-ecosystem multifunctionality linkages with due consideration of conceptual and technical challenges is required to make the knowledge practically useful in managing social-ecological systems. In this paper, we introduced different methods to assess perspectives regarding the issue of diversity-multifunctionality, including a possible multifunctional redundancy/uniqueness, and the influences of the number and identity of functions on multifunctionality. In particular, we aimed to align methods with detecting the mechanisms underpinning diversity-multifunctional relationships that are free from statistical biases. Based on a set of novel methods that excluded analytical biases resulting from differences in the number and identities of multiple functions considered, we found that a substantial portion of species disproportionately supported ecosystem functions and that the diversity effects on multifunctionality were more markedly observed when more functions were considered. These results jointly emphasize that individual species are, to some extent, both functionally unique as well as redundant, highlighting the complexity and necessity for managed assemblages to retain high levels of diversity. We also observed that the relative magnitude of uniqueness or redundancy can differ between species and functions and therefore should be defined in a multifunctional context. We further found that only a small subset of species was identified as significantly less important, especially at low levels of multifunctionality. Taken together, given the low level of multifunctional redundancy we identified, we stress that unraveling the hierarchical roles of biodiversity at different levels, such as individual species and their assemblages, should be a high research priority, in both theory and practice., (© 2023 The Authors. Ecology published by Wiley Periodicals LLC on behalf of The Ecological Society of America.)

As interest in natural capital grows and society increasingly recognizes the value of biodiversity, we must discuss how ecosystem observations to detect changes in biodiversity can be sustained through collaboration across regions and sectors. However, there are many barriers to establishing and sustaining large-scale, fine-resolution ecosystem observations. First, comprehensive monitoring data on both biodiversity and possible anthropogenic factors are lacking. Second, some in situ ecosystem observations cannot be systematically established and maintained across locations. Third, equitable solutions across sectors and countries are needed to build a global network. Here, by examining individual cases and emerging frameworks, mainly from (but not limited to) Japan, we illustrate how ecological science relies on long-term data and how neglecting basic monitoring of our home planet further reduces our chances of overcoming the environmental crisis. We also discuss emerging techniques and opportunities, such as environmental DNA and citizen science as well as using the existing and forgotten sites of monitoring, that can help overcome some of the difficulties in establishing and sustaining ecosystem observations at a large scale with fine resolution. Overall, this paper presents a call to action for joint monitoring of biodiversity and anthropogenic factors, the systematic establishment and maintenance of in situ observations, and equitable solutions across sectors and countries to build a global network, beyond cultures, languages, and economic status. We hope that our proposed framework and the examples from Japan can serve as a starting point for further discussions and collaborations among stakeholders across multiple sectors of society. It is time to take the next step in detecting changes in socio-ecological systems, and if monitoring and observation can be made more equitable and feasible, they will play an even more important role in ensuring global sustainability for future generations. This article is part of the theme issue 'Detecting and attributing the causes of biodiversity change: needs, gaps and solutions'.

Fundamental axes of variation in plant traits result from trade-offs between costs and benefits of resource-use strategies at the leaf scale. However, it is unclear whether similar trade-offs propagate to the ecosystem level. Here, we test whether trait correlation patterns predicted by three well-known leaf- and plant-level coordination theories - the leaf economics spectrum, the global spectrum of plant form and function, and the least-cost hypothesis - are also observed between community mean traits and ecosystem processes. We combined ecosystem functional properties from FLUXNET sites, vegetation properties, and community mean plant traits into three corresponding principal component analyses. We find that the leaf economics spectrum (90 sites), the global spectrum of plant form and function (89 sites), and the least-cost hypothesis (82 sites) all propagate at the ecosystem level. However, we also find evidence of additional scale-emergent properties. Evaluating the coordination of ecosystem functional properties may aid the development of more realistic global dynamic vegetation models with critical empirical data, reducing the uncertainty of climate change projections., (© 2023. The Author(s).)

Tight regulation of Toll-like receptor (TLR)-mediated inflammatory responses is important for innate immunity. Here, we show that T-cell death-associated gene 51 (TDAG51/PHLDA1) is a novel regulator of the transcription factor FoxO1, regulating inflammatory mediator production in the lipopolysaccharide (LPS)-induced inflammatory response. TDAG51 induction by LPS stimulation was mediated by the TLR2/4 signaling pathway in bone marrow-derived macrophages (BMMs). LPS-induced inflammatory mediator production was significantly decreased in TDAG51-deficient BMMs. In TDAG51-deficient mice, LPS- or pathogenic Escherichia coli infection-induced lethal shock was reduced by decreasing serum proinflammatory cytokine levels. The recruitment of 14-3-3ζ to FoxO1 was competitively inhibited by the TDAG51-FoxO1 interaction, leading to blockade of FoxO1 cytoplasmic translocation and thereby strengthening FoxO1 nuclear accumulation. TDAG51/FoxO1 double-deficient BMMs showed significantly reduced inflammatory mediator production compared with TDAG51- or FoxO1-deficient BMMs. TDAG51/FoxO1 double deficiency protected mice against LPS- or pathogenic E. coli infection-induced lethal shock by weakening the systemic inflammatory response. Thus, these results indicate that TDAG51 acts as a regulator of the transcription factor FoxO1, leading to strengthened FoxO1 activity in the LPS-induced inflammatory response., (© 2023 The Authors.)

On the basis of postoperative histopathological findings, a 29-year-old nulliparous woman was diagnosed as having ovotesticular disorder of sex development (DSD). She had undergone unilateral gonadectomy at age 6 years and vulvoplasty and vaginoplasty at age 8 years. Her karyotype was 46, XX. She had dyspareunia because of a narrow vagina, but her uterus and left gonad were normal. Spontaneous ovulation was confirmed, but sexual intercourse was impossible because of dyspareunia, despite vaginal self-dilatation with a vaginal dilator. Artificial insemination was initiated; however, five cycles failed to yield a viable pregnancy. We decided to perform in vitro fertilization (IVF), which resulted in conception. During IVF we administered intravenous anesthesia before oocyte collection to reduce her distress due to insufficient lumen expansion after vaginoplasty. The patient delivered a healthy male infant weighing 2,558 g at 37 weeks of gestation via cesarean section, which was performed because of gestational hypertension. This is the eighth report of a viable neonate born from a patient with ovotesticular DSD after gonadectomy and the first such pregnancy achieved by IVF. Therefore, IVF may be an effective option for infertile patients with ovotesticular DSD. Additionally, to prevent dyspareunia, self-management of the plastic vagina is important during the peri- and postoperative periods of early vaginoplasty.

Aims: Microsomal prostaglandin E synthase-1 (mPGES-1)/prostaglandin E2 (PGE2) induces angiogenesis through the prostaglandin E2 receptor (EP1-4). Among immune cells, regulatory T cells (Tregs), which inhibit immune responses, have been implicated in angiogenesis, and PGE2 is known to modulate the function and differentiation of Tregs. We hypothesized that mPGES-1/PGE2-EP signalling could contribute to recovery from ischaemic conditions by promoting the accumulation of Tregs., Methods and Results: Wild-type (WT), mPGES-1-deficient (mPges-1-/-), and EP4 receptor-deficient (Ep4-/-) male mice, 6-8 weeks old, were used. Hindlimb ischaemia was induced by femoral artery ligation. Recovery from ischaemia was suppressed in mPges-1-/- mice and compared with WT mice. The number of accumulated forkhead box protein P3 (FoxP3)+ cells in ischaemic muscle tissue was decreased in mPges-1-/- mice compared with that in WT mice. Expression levels of transforming growth factor-β (TGF-β) and stromal cell derived factor-1 (SDF-1) in ischaemic tissue were also suppressed in mPges-1-/- mice. The number of accumulated FoxP3+ cells and blood flow recovery were suppressed when Tregs were depleted by injecting antibody against folate receptor 4 in WT mice but not in mPges-1-/- mice. Recovery from ischaemia was significantly suppressed in Ep4-/- mice compared with that in WT mice. Furthermore, mRNA levels of Foxp3 and Tgf-β were suppressed in Ep4-/- mice. Moreover, the number of accumulated FoxP3+ cells in ischaemic tissue was diminished in Ep4-/- mice compared with that in Ep4+/+ mice., Conclusion: These findings suggested that mPGES-1/PGE2 induced neovascularization from ischaemia via EP4 by promoting the accumulation of Tregs. Highly selective EP4 agonists could be useful for the treatment of peripheral artery disease., Competing Interests: Conflict of interest: The authors declare no conflicts of interest associated with this manuscript., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Endometriosis-associated pain is an essential factor in deciding surgical indications of endometriosis. However, there is no quantitative method to diagnose the intensity of local pain in endometriosis (especially deep endometriosis). This study aims to examine the clinical significance of the pain score, a preoperative diagnostic scoring system for endometriotic pain that can be performed only with pelvic examination, devised for the above purpose. The data from 131 patients from a previous study were included and evaluated using the pain score. This score measures the pain intensity in each of the seven areas of the uterus and its surroundings via a pelvic examination using a numeric rating scale (NRS) which contains 10 points. The maximum value was then defined as the max pain score. This study investigated the relationship between the pain score and clinical symptoms of endometriosis or endometriotic lesions related to deep endometriosis. The preoperative max pain score was 5.93 ± 2.6, which significantly decreased to 3.08 ± 2.0 postoperatively ( p = 7.70 × 10 -20 ). Regarding preoperative pain scores for each area, those of the uterine cervix, pouch of Douglas, and left and right uterosacral ligament areas were high (4.52, 4.04, 3.75, and 3.63, respectively). All scores decreased significantly after surgery (2.02, 1.88, 1.75, and 1.75, respectively). The correlations between the max pain score and dysmenorrhea, dyspareunia, perimenstrual dyschezia (pain with defecation), and chronic pelvic pain were 0.329, 0.453, 0.253, and 0.239, respectively, and were strongest with dyspareunia. Regarding the pain score of each area, the combination of the pain score of the pouch of Douglas area and the VAS score of dyspareunia showed the strongest correlation (0.379). The max pain score in the group with deep endometriosis (endometrial nodules) was 7.07 ± 2.4, which was significantly higher than the 4.97 ± 2.3 score obtained in the group without ( p = 1.71 × 10 -6 ). The pain score can indicate the intensity of endometriotic pain, especially dyspareunia. A local high value of this score could suggest the presence of deep endometriosis, depicted as endometriotic nodules at that site. Therefore, this method could help develop surgical strategies for deep endometriosis.

Understanding the variability of microbial niches and their interaction with abiotic and biotic factors in the Arctic can provide valuable insights into microbial adaptations to extreme environments. This study investigates the structure and diversity of soil bacterial communities obtained from sites with varying vegetation coverage and soil biogeochemical properties in the low Arctic tundra and explores how bacteria interact under different environmental parameters. Our findings reveal differences in bacterial composition and abundance among three bacterial niche breadths (specialists, common taxa, and generalists). Co-occurrence network analysis revealed Rhizobiales and Ktedonobacterales as keystone taxa that connect and support other microbes in the habitat. Low-elevation indicators, such as vascular plants and moisture content, were correlated with two out of three generalist modular hubs and were linked to a large proportion of generalists' distribution (18%). Structural equation modeling revealed that generalists' distribution, which influenced the remaining microbial communities, was mainly regulated by vegetation coverage as well as other abiotic and biotic factors. These results suggest that elevation-dependent environmental factors directly influence microbial community structure and module formation through the regulation of generalists' distribution. Furthermore, the distribution of generalists was mainly affected by macroenvironment filtering, whereas the distribution of specialists was mainly affected by microenvironment filtering (species-engineered microbial niche construction). In summary, our findings highlight the strong top-down control exerted by vegetation on generalists' distribution, which in turn shapes the overall microbial community structure in the low Arctic tundra., (© 2023. The Author(s).)

Causal effects of biodiversity on ecosystem functions can be estimated using experimental or observational designs - designs that pose a tradeoff between drawing credible causal inferences from correlations and drawing generalizable inferences. Here, we develop a design that reduces this tradeoff and revisits the question of how plant species diversity affects productivity. Our design leverages longitudinal data from 43 grasslands in 11 countries and approaches borrowed from fields outside of ecology to draw causal inferences from observational data. Contrary to many prior studies, we estimate that increases in plot-level species richness caused productivity to decline: a 10% increase in richness decreased productivity by 2.4%, 95% CI [-4.1, -0.74]. This contradiction stems from two sources. First, prior observational studies incompletely control for confounding factors. Second, most experiments plant fewer rare and non-native species than exist in nature. Although increases in native, dominant species increased productivity, increases in rare and non-native species decreased productivity, making the average effect negative in our study. By reducing the tradeoff between experimental and observational designs, our study demonstrates how observational studies can complement prior ecological experiments and inform future ones., (© 2023. The Author(s).)

We previously showed that the ribonuclease Regnase-1 (Reg1) in keratinocytes plays a role in mitigating skin inflammation by downregulating proinflammatory cytokines. In this study, we explored whether Reg1 also has a protective role against skin carcinogenesis. The chemically induced two-stage carcinogenesis protocol revealed that epidermis-specific Reg1-deficient (Reg1-knockout [Reg1-cKO]) mice developed skin tumors with shorter latency and more multiplicity than control mice. In addition, repeated UVB irradiation readily provoked solar keratosis-like lesions in Reg1-cKO mice. Increased levels of cyclooxygenase 2, whose mRNA (Ptgs2) is reportedly a target of Reg1, have been known to be associated with the development of squamous cell carcinomas. Indeed, Ptgs2 mRNA levels were upregulated in the skin of Reg1-cKO mice after treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate. The level of prostaglandin E2 was higher in 12-O-tetradecanoylphorbol-13-acetate‒treated Reg1-cKO mouse skin than in control mice skin. Moreover, in vivo inhibition of cyclooxygenase 2 attenuated the 12-O-tetradecanoylphorbol-13-acetate‒induced epidermal thickening in Reg1-cKO mice. Finally, REG1 knockdown in human squamous cell carcinomas lines enhanced PTGS2 mRNA levels after 12-O-tetradecanoylphorbol-13-acetate treatment. In conclusion, epidermal Reg1 plays a regulatory role not only in skin inflammation but also in tumor promotion through the downregulation of cyclooxygenase 2. Therefore, forced expression of Reg1 under inflammatory conditions may be relevant to preventing skin cancer., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The patterns of successional change of decomposer communities is unique in that resource availability predictably decreases as decomposition proceeds. Saproxylic (i.e. deadwood-dependent) beetles are a highly diverse and functionally important decomposer group, and their community composition is affected by both deadwood characteristics and other environmental factors. Understanding how communities change with faunal succession through the decomposition process is important as this process influences terrestrial carbon dynamics. Here, we evaluate how beta-diversity of saproxylic beetle communities change with succession, as well as the effects of different major drivers of beta-diversity, such as deadwood tree species, spatial distance between locations, climate and forest structure. We studied spatial beta-diversity (i.e. dissimilarity of species composition between deadwood logs in the same year) of saproxylic beetle communities over 8 years of wood decomposition. Our study included 379 experimental deadwood logs comprising 13 different tree species in 30 forest stands in Germany. We hypothesized that the effects of tree species dissimilarity, measured by phylogenetic distance, and climate on beta-diversity decrease over time, while the effects of spatial distance between logs and forest structure increase. Observed beta-diversity of saproxylic beetle communities increased over time, whereas standardized effects sizes (SES; based on null models) of beta-diversity decreased indicating higher beta-diversity than expected during early years. Beta-diversity increased with increasing phylogenetic distance between tree species and spatial distance among regions, and to a lesser extent with spatial distance within regions and differences in climate and forest structure. Whereas effects of space, climate and forest structure were constant over time, the effect of phylogenetic distance decreased. Our results show that the strength of the different drivers of saproxylic beetle community beta-diversity changes along deadwood succession. Beta-diversity of early decay communities was strongly associated with differences among tree species. Although this effect decreased over time, beta-diversity remained high throughout succession. Possible explanations for this pattern include differences in decomposition rates and fungal communities between logs or the priority effect of early successional communities. Our results suggest that saproxylic beetle diversity can be enhanced by promoting forests with diverse tree communities and structures., (© 2022 The Authors. Journal of Animal Ecology published by John Wiley & Sons Ltd on behalf of British Ecological Society.)

The RNA-binding protein (RBP) Regnase-1 is an endonuclease that regulates immune responses by modulating target mRNA stability. Regnase-1 degrades a group of inflammation-associated mRNAs, which contributes to a balanced immune response and helps prevent autoimmune diseases. Regnase-1 also cleaves its own mRNA by binding stem-loop (SL) RNA structures in its 3'UTR. To understand how this autoregulation is important for immune responses, we generated mice with a 2-bp genome deletion in the target SL of the Regnase-1 3'-untranslated region (3'UTR). Deletion of these nucleotides inhibited SL formation and limited Regnase-1-mediated mRNA degradation. Mutant mice had normal hematopoietic cell differentiation. Biochemically, mutation of the 3'UTR SL increased Regnase-1 mRNA stability and enhanced both Regnase-1 mRNA and protein levels in mouse embryonic fibroblasts (MEFs). The expression of Il6, a Regnase-1 target gene, was constitutively suppressed at steady-state in mutant MEFs. Additionally, Regnase-1 protein expression in mutant MEFs was significantly elevated compared to that in wild-type MEFs at steady state and upon proinflammatory cytokine stimulation. These data suggest a negative feedback mechanism for Regnase-1 expression and represent a unique mouse model to probe Regnase-1 overexpression in vivo., (© 2023 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

Background and Aims: Insufficient liver regeneration causes post-hepatectomy liver failure and small-for-size syndrome. Identifying therapeutic targets to enhance hepatic regenerative capacity remains urgent. Recently, increased IL-33 was observed in patients undergoing liver resection and in mice after partial hepatectomy (PHx). The present study aims to investigate the role of IL-33 in liver regeneration after PHx and to elucidate its underlying mechanisms., Approach and Results: We performed PHx in IL-33 -/- , suppression of tumorigenicity 2 (ST2) -/- , and wild-type control mice, and found deficiency of IL-33 or its receptor ST2 delayed liver regeneration. The insufficient liver regeneration could be normalized in IL-33 -/- but not ST2 -/- mice by recombinant murine IL-33 administration. Furthermore, we observed an increased level of serotonin in portal blood from wild-type mice, but not IL-33 -/- or ST2 -/- mice, after PHx. ST2 deficiency specifically in enterochromaffin cells recapitulated the phenotype of delayed liver regeneration observed in ST2 -/- mice. Moreover, the impeded liver regeneration in IL-33 -/- and ST2 -/- mice was restored to normal levels by the treatment with (±)-2,5-dimethoxy-4-iodoamphetamine, which is an agonist of the 5-hydroxytrytamine receptor (HTR)2A. Notably, in vitro experiments demonstrated that serotonin/HTR2A-induced hepatocyte proliferation is dependent on p70S6K activation., Conclusions: Our study identified that IL-33 is pro-regenerative in a noninjurious model of liver resection. The underlying mechanism involved IL-33/ST2-induced increase of serotonin release from enterochromaffin cells to portal blood and subsequent HTR2A/p70S6K activation in hepatocytes by serotonin. The findings implicate the potential of targeting the IL-33/ST2/serotonin pathway to reduce the risk of post-hepatectomy liver failure and small-for-size syndrome., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Because nontuberculous mycobacterial pulmonary disease is a considerable health burden, a simple and clinically applicable analytical protocol enabling the identification of subspecies and drug-resistant disease is required to determine the treatment strategy. We aimed to develop a simplified workflow consisting only of direct sequencing of mycobacterial growth indicator tube cultures (MGIT-seq). In total, 138 patients were prospectively enrolled between April 2021 and May 2022, and culture-positive MGIT broths were subjected to sequencing using MinION, a portable next-generation sequencer. Sequence analysis was conducted to identify species using core genome multilocus sequence typing and to predict macrolide and amikacin (AMK) resistance based on previously reported mutations in rrl, rrs , and erm (41). The results were compared to clinical tests for species identification and drug susceptibility. A total of 116 patients with positive MGIT cultures were included in the analysis. MGIT-seq yielded 99.1% accuracy in species-level identification and identified 98 isolates (84.5%) at the subspecies level. Macrolide and AMK resistance were detected in 19.4% and 1.9% of Mycobacterium avium complex (MAC) and Mycobacterium abscessus isolates. The predicted macrolide and AMK resistance was consistent with the results of conventional drug susceptibility tests, with specificities of 97.6% and 100.0%, respectively. Direct MGIT-seq has achieved comprehensive identification and drug resistance detection of nontuberculous mycobacteria, which could be applicable to determine the treatment strategy by a single test in clinical practice.

As Earth's climate has varied strongly through geological time, studying the impacts of past climate change on biodiversity helps to understand the risks from future climate change. However, it remains unclear how paleoclimate shapes spatial variation in biodiversity. Here, we assessed the influence of Quaternary climate change on spatial dissimilarity in taxonomic, phylogenetic, and functional composition among neighboring 200-kilometer cells (beta-diversity) for angiosperm trees worldwide. We found that larger glacial-interglacial temperature change was strongly associated with lower spatial turnover (species replacements) and higher nestedness (richness changes) components of beta-diversity across all three biodiversity facets. Moreover, phylogenetic and functional turnover was lower and nestedness higher than random expectations based on taxonomic beta-diversity in regions that experienced large temperature change, reflecting phylogenetically and functionally selective processes in species replacement, extinction, and colonization during glacial-interglacial oscillations. Our results suggest that future human-driven climate change could cause local homogenization and reduction in taxonomic, phylogenetic, and functional diversity of angiosperm trees worldwide.

Alcaligenes faecalis was previously identified as an intestinal lymphoid tissue-resident commensal bacteria, and our subsequent studies showed that lipopolysaccharide and its core active element (i.e., lipid A) have a potent adjuvant activity to promote preferentially antigen-specific Th17 response and antibody production. Here, we compared A. faecalis lipid A (ALA) with monophosphoryl lipid A, a licensed lipid A-based adjuvant, to elucidate the immunological mechanism underlying the adjuvant properties of ALA. Compared with monophosphoryl lipid A, ALA induced higher levels of MHC class II molecules and costimulatory CD40, CD80, and CD86 on dendritic cells (DCs), which in turn resulted in strong T cell activation. Moreover, ALA more effectively promoted the production of IL-6 and IL-23 from DCs than did monophosphoryl lipid A, thus leading to preferential induction of Th17 and Th1 cells. As underlying mechanisms, we found that the ALA-TLR4 axis stimulated both MyD88- and TRIF-mediated signaling pathways, whereas monophosphoryl lipid A was biased toward TRIF signaling. These findings revealed the effects of ALA on DCs and T cells and its induction pattern on signaling pathways., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Accurate diagnosis of retroflexed uterus in daily practice is essential because this condition is related to pelvic pain and deep endometriosis. Uterine flexion can be measured by transvaginal ultrasonography (TVUS), a cost-effective primary test, but the accuracy required for diagnosing retroflexed uterus is unclear. This study assessed the accuracy of TVUS for diagnosis of retroflexed uterus in patients with endometriosis and compared it with that of magnetic resonance imaging (MRI) -the gold standard for measuring the uterine axis., Methods: The study included 123 patients who underwent endometriosis surgery in our department between 2012 and 2017. Uterine flexion angles were measured by retrospectively examining TVUS and MRI images, and the correlation was analyzed. Analysis of anteverted and retroverted uterine subgroups identified aspects of diagnosing uterine flexion with TVUS., Results: Uterine flexion angles on TVUS were strongly positively correlated (r = 0.86) with MRI results. Additionally, TVUS yielded no false-positive diagnoses and 28 false-negative diagnoses of retroflexion. All false-negative diagnoses occurred in patients with anteverted retroflexed uteruses., Conclusions: TVUS was generally accurate for measuring uterine flexion angle, as indicated by its strong correlation with MRI. Misdiagnosis of anteverted retroflexed uterus was a limitation of using TVUS for retroflexion diagnosis.

Intensification of land use by humans has led to a homogenization of landscapes and decreasing resilience of ecosystems globally due to a loss of biodiversity, including the majority of forests. Biodiversity-ecosystem functioning (BEF) research has provided compelling evidence for a positive effect of biodiversity on ecosystem functions and services at the local (α-diversity) scale, but we largely lack empirical evidence on how the loss of between-patch β-diversity affects biodiversity and multifunctionality at the landscape scale (γ-diversity). Here, we present a novel concept and experimental framework for elucidating BEF patterns at α-, β-, and γ-scales in real landscapes at a forest management-relevant scale. We examine this framework using 22 temperate broadleaf production forests, dominated by Fagus sylvatica. In 11 of these forests, we manipulated the structure between forest patches by increasing variation in canopy cover and deadwood. We hypothesized that an increase in landscape heterogeneity would enhance the β-diversity of different trophic levels, as well as the β-functionality of various ecosystem functions. We will develop a new statistical framework for BEF studies extending across scales and incorporating biodiversity measures from taxonomic to functional to phylogenetic diversity using Hill numbers. We will further expand the Hill number concept to multifunctionality allowing the decomposition of γ-multifunctionality into α- and β-components. Combining this analytic framework with our experimental data will allow us to test how an increase in between patch heterogeneity affects biodiversity and multifunctionality across spatial scales and trophic levels to help inform and improve forest resilience under climate change. Such an integrative concept for biodiversity and functionality, including spatial scales and multiple aspects of diversity and multifunctionality as well as physical and environmental structure in forests, will go far beyond the current widely applied approach in forestry to increase resilience of future forests through the manipulation of tree species composition., (© 2022 John Wiley & Sons Ltd.)