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Background: Combination immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) leads to high response rates and improved survival in patients with advanced cutaneous melanoma (CM). Less is known about the efficacy of this combination in acral lentiginous melanoma (ALM)., Objectives: To determine the efficacy of combination immune checkpoint blockade targeting PD-1 and CTLA-4 in a diverse, real-world population of patients with ALM., Methods: This multi-institutional retrospective study analysed patients with histologically confirmed ALM treated with a combination of PD-1 and CTLA-4 inhibitors between 2010 and 2022. The primary objective of the study was the objective response rate (ORR) as per the RECIST criteria. The secondary objectives were progression-free survival (PFS) and overall survival (OS)., Results: In total, 109 patients with advanced ALM treated with combined PD-1 and CTLA-4 blockade in any line of treatment were included. The majority of patients had stage IV disease (n = 81; 74.3%). The ORR for the entire cohort was 18.3% [95% confidence interval (CI) 11.6-26.9], with 9 (8.3%) complete and 11 (10.1%) partial responses. A further 22 patients (20.2%) had stable disease, and the disease control rate was 38.5%. Median PFS was 4.2 months (95% CI 3.25-5.62), while median OS was 17 months (95% CI 12.4-23.1). Ninety-five patients (87.2%) had a treatment-related adverse event, with 40.4% (n = 44/109) experiencing at least one grade 3 or 4 toxicity. Elevated lactate dehydrogenase (P = 0.04), ≥ 2 lines of prior treatment (P = 0.03) and Asian ethnicity (P = 0.04) were associated with worse OS, while Hispanic/Latino ethnicity was associated with better OS (P = 0.02)., Conclusions: Combination PD-1 and CTLA-4 blockade is less effective for ALM than for CM, despite similar toxicity. In particular, Asian patients appear to derive less benefit from this regimen. Novel treatment approaches are needed for this rare melanoma subtype., Competing Interests: Conflicts of interest: Unrelated to this work, C.M.C. has worked as the Principal Investigator with DeepX Health on melanoma diagnostic imaging technology. The funding was paid to his institution. G.K.I. is on advisory boards for BMS, Merck, Regeneron, Array, Castle Biosciences, Sanofi, Replimune and Pfizer. Institutional research support funds were provided by Regeneron, Array, Idera, Replimune, Xencor, InstilBio, Pfizer and Checkmate Pharmaceuticals. K.B.K. has received honoraria for serving as a speaker and member of an advisory board for Bristol Myers Squibb. He is also an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for Melanoma Management and was not involved in the editorial review or the decision to publish this article. A.R.M. has received grants/research fundings from Kyowa, Miragen, Regeneron, Corbus, Sun Pharma, Incyte, Pfizer Inc, Merck & Co., Priovant Therapeutics, Eli Lilly, Elorac, Novartis, Janssen, Soligenix, Argenx, Palvella and AbbVie; and has served as a consultant for Kyowa, Eli Lilly, Momenta, UCB, Regeneron, Incyte, PHELEC, Soligenix, Clarivate, Argenx, Janssen, Bristol Myers Squibb, Boehringer Ingelheim and Pfizer. He has two provisional intellectual property (IP)/patents and one filed IP/patent (‘Methods and materials for assessing and treating cutaneous squamous cell carcinoma’ provisional 63-423254; ‘Use of oral Jaki in lichen planus’ provisional 63/453,065; and ‘Topical ruxolitinib in lichen planus’ wo2022072814a1, respectively). Y.G.N. is on the consulting/advisory board for Merck, BMS, Pfizer, Immunocore, Mallinkrodt, InterVenn Bio and Novartis. She is a speaker for Immunocore and Pfizer. The other authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. 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.)

Context: Experimental evidence indicates that resistin, an adipokine, negatively impacts muscle metabolism by hindering myogenesis., Objective: To explore resistin's potential as a biomarker of muscle health in humans by examining the relationship between circulating resistin levels and sarcopenia in older adults., Design and Setting: A case-control study conducted in a geriatric clinical unit., Participants: The study included 247 individuals aged 65 and older who underwent comprehensive geriatric evaluations., Main Outcome Measures: Sarcopenia was defined based on Asian-specific thresholds, with serum resistin concentrations measured using an enzyme-linked immunosorbent assay., Results: After adjusting for sex, age, fat mass, smoking, osteoarthritis, and diabetes, participants with sarcopenia, low muscle mass, and weak muscle strength exhibited at least 27.0% higher circulating resistin concentrations than controls (P = 0.002 to 0.003). Elevated serum resistin levels were inversely associated with skeletal muscle mass, gait speed, and the short physical performance battery score, and positively associated with the time to complete five chair stands (P = 0.019 to 0.048). Higher serum resistin levels were linked to an increased risk of sarcopenia, low muscle mass, and weak muscle strength (all P = 0.005). Finally, participants in the highest resistin quartile had at least three times higher odds of having adverse muscle outcomes compared to those in the lowest quartile (P = 0.007 to 0.029)., Conclusion: This study is to establish a link between blood resistin levels and sarcopenia, suggesting that circulating resistin may serve as a potential biomarker reflecting poor muscle health in humans., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. 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. See the journal About page for additional terms.)

Background: The MEK inhibitor, selumetinib, reduces plexiform neurofibroma (PN) in pediatric patients with neurofibromatosis type 1 (NF1). Its safety and efficacy in adults with PN and effectiveness in other NF1 manifestations (eg, neurocognitive function, growth reduction, and café-au-lait spots) are unknown., Methods: This open-label, phase II trial enrolled 90 pediatric or adult NF1 patients with inoperable, symptomatic, or potentially morbid, measurable PN (≥3 cm). Selumetinib was administered at doses of 20 or 25 mg/m2 or 50 mg q 12 hours for 2 years. Pharmacokinetics, PN volume, growth parameters, neurocognitive function, café-au-lait spots, and quality of life (QoL) were evaluated., Results: Fifty-nine children and 30 adults (median age, 16 years; range, 3-47) received an average of 22 ± 5 (4-26) cycles of selumetinib. Eighty-eight (98.9%) out of 89 per-protocol patients showed volume reduction in the target PN (median, 40.8%; 4.2%-92.2%), and 81 (91%) patients showed partial response (≥20% volume reduction). The response lasted until cycle 26. Scores of neurocognitive functions (verbal comprehension, perceptual reasoning, processing speed, and full-scale IQ) significantly improved in both pediatric and adult patients (P < .05). Prepubertal patients showed increases in height score and growth velocity (P < .05). Café-au-lait spot intensity decreased significantly (P < .05). Improvements in QoL and pain scores were observed in both children and adults. All adverse events were CTCAE grade 1 or 2 and were successfully managed without drug discontinuation., Conclusions: Selumetinib decreases PN volume in the majority of pediatric and adult NF1 patients while also showing efficacy in nonmalignant diverse NF1 manifestations., Trial Registration: Cris.nih.go.kr Identifier (KCT0003700)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Urbanization is a leading factor effecting global biodiversity, driving rapid evolutionary processes in the local biota. Species that adapt and proliferate in city environments can become pests, with human activities facilitating their dispersal and excessive outbreaks. Here we present the first genome data of Plecia longiforceps, a lovebug pest in Eastern Asia with intensive aggregations recently occurring in the Seoul Metropolitan Area of Korea. PacBio HiFi and ONT Pore-C sequencing data were used to construct a highly continuous assembly with a total size of 707 Mb and 8 major pseudochromosomes, its integrity supported by the N50 length of 98.1 Mb and 96.8% BUSCO completeness. Structural and functional annotation using transcriptome data and ab initio predictions revealed a high proportion (69.3%) of repeat sequences, and synteny analysis with Bibio marci showed high levels of genomic collinearity. The genome will serve as an essential resource for both population genomics and molecular research on lovebug dispersal and outbreaks, and also implement studies on the eco-evolutionary processes of insects in urbanizing habitats., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Objectives: Certain studies propose that antibiotic use may influence rheumatoid arthritis (RA) incidence, but the clear association between antibiotics and RA remains unclear. Therefore, this study aimed to examine the relationship between antibiotics and RA risk to provide additional epidemiological evidence., Methods: This population-based retrospective cohort study was conducted with adults aged 40 years or older using the Korean National Health Insurance Service (NHIS) database. Antibiotic exposure was measured from 2003 to 2007. Study participants were followed up from January 1, 2008, to December 31, 2019. Multivariable Cox hazard regression was utilized to evaluate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for the risk of RA according to accumulative days of antibiotic use and the number of antibiotic classes used, respectively., Results: During 3,395 590 person-years of follow-up, 29 274 cases of RA were identified. Participants who used antibiotics for 91 or more days had a higher risk of RA (aHR, 1.79; 95% CI, 1.67-1.92) than antibiotic non-users. Additionally, individuals who used four or more kinds of antibiotic classes had a higher risk of RA (aHR, 1.61; 95% CI, 1.51-1.71) than those who did not prescribe antibiotics. The risk of RA was positively associated with both higher cumulative days of antibiotic exposure and a larger number of drug classes. These trends were maintained in sensitivity analyses, including variations in antibiotic exposure periods., Conclusion: Our findings suggest a possible association between the long-term use of antibiotics and RA incidence. Further studies are necessary for a clearer understanding of this association., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Severe fever with thrombocytopenia syndrome virus (SFTSV) poses a significant public health challenge in East Asia, necessitating a deeper understanding of its evolutionary dynamics to effectively manage its spread and pathogenicity. This study provides a comprehensive analysis of the genetic diversity, recombination patterns, and selection pressures across the SFTSV genome, utilizing an extensive dataset of 2041 sequences from various hosts and regions up to November 2023. Employing maximum likelihood and Bayesian evolutionary analysis by sampling trees (BEAST), we elucidated the phylogenetic relationships among nine distinct SFTSV genotypes (A, B1, B2, B3, B4, C, D, E, and F), revealing intricate patterns of viral evolution and genotype distribution across China, South Korea, and Japan. Furthermore, our analysis identified 34 potential reassortments, underscoring a dynamic genetic interplay among SFTSV strains. Genetic recombination was observed most frequently in the large segment and least in the small segment, with notable recombination hotspots characterized by stem-loop hairpin structures, indicative of a structural propensity for genetic recombination. Additionally, selection pressure analysis on critical viral genes indicated a predominant trend of negative selection, with specific sites within the RNA-dependent RNA polymerase and glycoprotein genes showing positive selection. These sites suggest evolutionary adaptations to host immune responses and environmental pressures. This study sheds light on the intricate evolutionary mechanisms shaping SFTSV, offering insights into its adaptive strategies and potential implications for vaccine development and therapeutic interventions., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press.)

Delineating the intricate interplay between promoter-proximal and -distal regulators is crucial for understanding the function of transcriptional mediator complexes implicated in the regulation of gene expression. The present study aimed to develop a computational method for accurately modeling the spatial proximal and distal regulatory interactions. Our method combined regression-based models to identify key regulators through gene expression prediction and a graph-embedding approach to detect coregulated genes. This approach enabled a detailed investigation of the gene regulatory mechanisms for germinal center B cells, accompanied by dramatic rearrangements of the genome structure. We found that while the promoter-proximal regulatory elements were the principal regulators of gene expression, the distal regulators fine-tuned transcription. Moreover, our approach unveiled the presence of modular regulators, such as cofactors and proximal/distal transcription factors, which were co-expressed with their target genes. Some of these modules exhibited abnormal expression patterns in lymphoma. These findings suggest that the dysregulation of interactions between transcriptional and architectural factors is associated with chromatin reorganization failure, which may increase the risk of malignancy. Therefore, our computational approach helps decipher the transcriptional cis -regulatory code spatially interacting., (© The Author(s) 2024. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

Stem cell homeostasis is pivotal for continuous and programmed formation of organs in plants. The precise control of meristem proliferation is mediated by the evolutionarily conserved signaling that encompasses complex interactions among multiple peptide ligands and their receptor-like kinases. Here, we identified compensation mechanisms involving the CLAVATA1 (CLV1) receptor and its paralogs, BARELY ANY MERISTEMs (BAMs), for stem cell proliferation in two Solanaceae species, tomato and groundcherry. Genetic analyses of higher-order mutants deficient in multiple receptor genes, generated via CRISPR-Cas9 genome editing, reveal that tomato SlBAM1 and SlBAM2 compensate for slclv1 mutations. Unlike the compensatory responses between orthologous receptors observed in Arabidopsis , tomato slclv1 mutations do not trigger transcriptional upregulation of four SlBAM genes. The compensation mechanisms within receptors are also conserved in groundcherry, and critical amino acid residues of the receptors associated with the physical interaction with peptide ligands are highly conserved in Solanaceae plants. Our findings demonstrate that the evolutionary conservation of both compensation mechanisms and critical coding sequences between receptor-like kinases provides a strong buffering capacity during stem cell homeostasis in tomato and groundcherry., Competing Interests: The authors declare that they have no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nanjing Agricultural University.)

Background: Reactive astrogliosis is a hallmark of various brain pathologies, including neurodegenerative diseases and glioblastomas. However, the specific intermediate metabolites contributing to reactive astrogliosis remain unknown. This study investigated how glioblastomas induce reactive astrogliosis in the neighboring microenvironment and explore 11C-acetate PET as an imaging technique for detecting reactive astrogliosis., Methods: Through in vitro, mouse models, and human tissue experiments, we examined the association between elevated 11C-acetate uptake and reactive astrogliosis in gliomas. We explored acetate from glioblastoma cells, which triggers reactive astrogliosis in neighboring astrocytes by upregulating MAO-B and monocarboxylate transporter 1 (MCT1) expression. We evaluated the presence of cancer stem cells in the reactive astrogliosis region of glioblastomas and assessed the correlation between the volume of 11C-acetate uptake beyond MRI and prognosis., Results: Elevated 11C-acetate uptake is associated with reactive astrogliosis and astrocytic MCT1 in the periphery of glioblastomas in human tissues and mouse models. Glioblastoma cells exhibit increased acetate production as a result of glucose metabolism, with subsequent secretion of acetate. Acetate derived from glioblastoma cells induces reactive astrogliosis in neighboring astrocytes by increasing the expression of MAO-B and MCT1. We found cancer stem cells within the reactive astrogliosis at the tumor periphery. Consequently, a larger volume of 11C-acetate uptake beyond contrast-enhanced MRI was associated with a worse prognosis., Conclusions: Our results highlight the role of acetate derived from glioblastoma cells in inducing reactive astrogliosis and underscore the potential value of 11C-acetate PET as an imaging technique for detecting reactive astrogliosis, offering important implications for the diagnosis and treatment of glioblastomas., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. 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.)

Reliable cell type annotations are crucial for investigating cellular heterogeneity in single-cell omics data. Although various computational approaches have been proposed for single-cell RNA sequencing (scRNA-seq) annotation, high-quality cell labels are still lacking in single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) data, because of extreme sparsity and inconsistent chromatin accessibility between datasets. Here, we present a novel automated cell annotation method that transfers cell type information from a well-labeled scRNA-seq reference to an unlabeled scATAC-seq target, via a parallel graph neural network, in a semi-supervised manner. Unlike existing methods that utilize only gene expression or gene activity features, HyGAnno leverages genome-wide accessibility peak features to facilitate the training process. In addition, HyGAnno reconstructs a reference-target cell graph to detect cells with low prediction reliability, according to their specific graph connectivity patterns. HyGAnno was assessed across various datasets, showcasing its strengths in precise cell annotation, generating interpretable cell embeddings, robustness to noisy reference data and adaptability to tumor tissues., (© The Author(s) 2024. Published by Oxford University Press.)

Background and Aims: The optimal follow-up surveillance strategy for high-risk diabetic patients with had undergone percutaneous coronary intervention (PCI) remains unknown., Methods: The POST-PCI (Pragmatic Trial Comparing Symptom-Oriented versus Routine Stress Testing in High-Risk Patients Undergoing Percutaneous Coronary Intervention) study was a randomized trial comparing a follow-up strategy of routine functional testing at 1 year vs. standard care alone after high-risk PCI. Randomization was stratified according to diabetes status. The primary outcome was a composite of death from any cause, myocardial infarction, or hospitalization for unstable angina at 2 years., Results: Among 1706 randomized patients, participants with diabetes (n = 660, 38.7%) had more frequent comorbidities and a higher prevalence of complex anatomical or procedural characteristics than those without diabetes (n = 1046, 61.3%). Patients with diabetes had a 52% greater risk of primary composite events [hazard ratio (HR) 1.52; 95% confidence interval (CI) 1.02-2.27; P = .039]. The 2-year incidences of the primary composite outcome were similar between strategies of routine functional testing or standard care alone in diabetic patients (7.1% vs. 7.5%; HR 0.94; 95% CI 0.53-1.66; P = .82) and non-diabetic patients (4.6% vs. 5.1%; HR 0.89; 95% CI 0.51-1.55; P = .68) (interaction term for diabetes: P = .91). The incidences of invasive coronary angiography and repeat revascularization after 1 year were higher in the routine functional-testing group than the standard-care group irrespective of diabetes status., Conclusions: Despite being at higher risk for adverse clinical events, patients with diabetes who had undergone high-risk PCI did not derive incremental benefit from routine surveillance stress testing compared with standard care alone during follow-up., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Numerous studies have been dedicated to genetically engineering crops to enhance their yield and quality. One of the key requirements for generating genetically modified plants is the reprogramming of cell fate. However, the efficiency of shoot regeneration during this process is highly dependent on genotypes, and the underlying molecular mechanisms remain poorly understood. Here, we identified microRNA396 (miR396) as a negative regulator of shoot regeneration in tomato. By selecting two genotypes with contrasting shoot regeneration efficiencies and analyzing their transcriptome profiles, we found that miR396 and its target transcripts, which encode GROWTH-REGULATING FACTORs (GRFs), exhibit differential abundance between high- and low-efficiency genotypes. Suppression of miR396 functions significantly improved shoot regeneration rates along with increased expression of GRF s in transformed T0 explants, suggesting that miR396 is a key molecule involved in the determination of regeneration efficiency. Notably, we also showed that co-expression of a miR396 suppressor with the gene-editing tool can be employed to generate gene-edited plants in the genotype with a low capacity for shoot regeneration. Our findings show the critical role of miR396 as a molecular barrier to shoot regeneration in tomato and suggest that regeneration efficiency can be improved by blocking this single microRNA., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nanjing Agricultural University.)

Context: Recent studies suggest that hypothyroidism is a risk factor for dementia. Based on existing literature, it is unclear if treatment or compliance to treatment is associated with decreased dementia risk in hypothyroidism patients., Objective: To determine the association between thyroid hormone medication adherence and risk of dementia., Methods: A population-based cohort study following patients with newly diagnosed hypothyroidism until incidence of dementia, death, or December 31, 2020, whichever came earliest. The study comprised 41 554 older adults age 50 and above with newly diagnosed hypothyroidism between 2004 and 2008 who underwent health screening. Risk of dementia was evaluated using multivariable-adjusted Cox proportional hazards regression., Results: Among 5188 men (12.5%) and 36 366 (87.5%) women, 2120 cases of incident dementia were identified. After stratification of the participants according to the interquartile range of the medication possession ratio (MPR), the fourth quartile (highest adherence) showed a 14% lower risk of overall dementia compared with the first quartile (lowest adherence) (adjusted hazard ratio 0.86; 95% CI 0.76-0.97). No consistent association was observed between thyroid hormone medication adherence and vascular dementia. After a dichotomous stratification of the MPR, higher MPR (≥0.8) showed a lower risk of Alzheimer disease (adjusted hazard ratio 0.91; 95% CI 0.84-0.99) than lower MPR (<0.8)., Conclusion: Better adherence to thyroid hormone medication may be beneficial in preventing incident dementia, especially Alzheimer disease, in older adults with newly diagnosed hypothyroidism. Along with the resolution of hypothyroid symptoms and the reduction of cardiovascular risk factors, the reduction of dementia risk may be another potential benefit of thyroid hormone medication., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: After coronary sinus (CS) lead extraction in patients with cardiac resynchronization therapy (CRT), occlusion of the branch vessel from which CS lead was extracted is a major obstacle to re-implantation, particularly if that vessel is the only optimal vessel for resynchronization., Case Summary: A 75-year-old female who underwent CRT implantation 11 years prior presented with worsening dyspnoea, right ventricle-only pacing rhythm, and increased CS lead pacing threshold. Because she was a CRT responder, we decided to replace the malfunctioning CS lead. After successful extraction, the vessel from which CS lead was extracted was not visualized, and guidewire re-insertion attempts failed. No other branch vessels suitable for re-implantation were observed. Fortunately, distal portion of the target vessel was viewed by a retrograde flow of contrast. A guidewire was advanced retrograde into the target vein via a connecting vessel, and the distal end of the guidewire was snared around CS ostium and then pulled out of the sheath. A new CS lead was inserted through the distal end of the guidewire and successfully implanted antegrade into the same target vein using a veno-venous loop of the guidewire ('anti-dromic snare technique'). The patient was discharged 2 days after the procedure without complications., Discussion: Antegrade re-implantation of CS lead may not be possible after extracting CS leads with long dwell times, possibly due to extraction-induced vessel occlusion. If the occluded vessel is the only proper vessel for CS lead re-implantation, the anti-dromic snare technique could be a safe and effective bail-out strategy., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Aims: Wind pollination has evolved repeatedly in flowering plants, yet the identification of a wind pollination syndrome as a set of integrated floral traits can be elusive. Thalictrum (Ranunculaceae) comprises temperate perennial herbs that have transitioned repeatedly from insect to wind pollination while also exhibiting mixed pollination, providing an ideal system to test for evolutionary correlation between floral morphology and pollination mode in a biotic to abiotic continuum. Moreover, the lack of floral organ fusion across this genus allows testing for specialization to pollination vectors in the absence of this feature., Methods: We expanded phylogenetic sampling in the genus from a previous study using six chloroplast loci, which allowed us to test whether species cluster into distinct pollination syndromes based on floral morphology. We then used multivariate analyses on floral traits followed by ancestral state reconstruction of the emerging flower morphotypes and determined whether these traits are evolutionarily correlated under a Bayesian framework with Brownian motion., Key Results: Floral traits fell into five distinct clusters, which were reduced to three after considering phylogenetic relatedness and were largely consistent with flower morphotypes and associated pollination vectors. Multivariate evolutionary analyses found a positive correlation between the lengths of floral reproductive structures (styles, stigmas, filaments and anthers). Shorter reproductive structures tracked insect-pollinated species and clades in the phylogeny, whereas longer structures tracked wind-pollinated ones, consistent with selective pressures exerted by biotic vs. abiotic pollination vectors, respectively., Conclusions: Although detectable suites of integrated floral traits across Thalictrum were correlated with wind or insect pollination at the extremes of the morphospace distribution, a presumed intermediate, mixed pollination mode morphospace was also detected. Thus, our data broadly support the existence of detectable flower morphotypes from convergent evolution underlying the evolution of pollination mode in Thalictrum, presumably via different paths from an ancestral mixed pollination state., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Motivation: DNA-based data storage is one of the most attractive research areas for future archival storage. However, it faces the problems of high writing and reading costs for practical use. There have been many efforts to resolve this problem, but existing schemes are not fully suitable for DNA-based data storage, and more cost reduction is needed., Results: We propose whole encoding and decoding procedures for DNA storage. The encoding procedure consists of a carefully designed single low-density parity-check code as an inter-oligo code, which corrects errors and dropouts efficiently. We apply new clustering and alignment methods that operate on variable-length reads to aid the decoding performance. We use edit distance and quality scores during the sequence analysis-aided decoding procedure, which can discard abnormal reads and utilize high-quality soft information. We store 548.83 KB of an image file in DNA oligos and achieve a writing cost reduction of 7.46% and a significant reading cost reduction of 26.57% and 19.41% compared with the two previous works., Availability and Implementation: Data and codes for all the algorithms proposed in this study are available at: https://github.com/sjpark0905/DNA-LDPC-codes., (© The Author(s) 2023. Published by Oxford University Press.)

Objectives: Comparisons of long-term clinical outcomes of mitral valve replacement (MVR) between bovine pericardial and porcine bioprostheses are conflicting, with limited research in large-scale real-world clinical settings. This study examined clinical outcomes in MVR according to bioprosthesis type using a national administrative claims database., Methods: This study included adult patients undergoing bioprosthetic MVR between 2003 and 2018 using administrative health care data from the Korean National Health Insurance Service database. Propensity score matching with competing risk analysis was used to compare the clinical outcomes according to the type of bioprosthesis. The end points were death, cardiac death, and valve-related events, including the incidence of reoperation, endocarditis, systemic thromboembolism, and major bleeding., Results: A total of 3151 patients underwent bioprosthetic MVR with bovine pericardial (n = 1628, 51.7%) or porcine (n = 1523, 48.3%) bioprostheses. After matching, 1170 pairs were included in the final analysis. During follow-up (median 4.49 years, interquartile range 1.87 -8.75 years), death occurred in 1178 patients (6.8%/patient-year), comprising 730 (4.3%/patient-year) cardiac death. No significant differences were noted between the bovine and porcine groups in the cumulative incidences of death from any cause [adjusted hazard ratio (aHR), 1.00; 95% confidence interval (CI), 0.87-1.14], cardiac mortality (aHR, 0.96; 95% CI, 0.81-1.14), or reoperation (aHR, 1.01; 95% CI, 0.72-1.41)., Conclusions: This study on a nationwide comparison between bovine and porcine bioprostheses in MVR found no significant differences in clinical outcomes including mortality, and valve-related reoperation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Aims: Insertable cardiac monitors (ICMs) are indicated for long-term monitoring of unexplained syncope or palpitations, and for detection of bradycardia, ventricular tachycardia, and/or atrial fibrillation (AF). The aim of our study was to evaluate the safety and clinical value associated with a new generation ICM (Confirm Rx™, Abbott, Illinois, USA), featuring a new remote monitoring system based on smartphone patient applications., Methods and Results: The SMART Registry is an international prospective observational study. The main endpoints were ICM safety (incidence of serious adverse device and procedure-related events (SADEs) at 1 month), ICM clinical value (incidence of device-detected true arrhythmias and of clinical diagnoses and interventions), and patient-reported experience measurements (PREMs). A total of 1400 subjects were enrolled. ICM indications included syncope (49.1%), AF (18.8%), unexplained palpitations (13.6%), risk of ventricular arrhythmia (6.6%), and cryptogenic stroke (6.0%). Freedom from SADEs at 1 month was 99.4% (95% Confidence Interval: 98.8-99.7%). In the 6-month monitoring period, the ICM detected true cardiac arrhythmias in 45.7% of patients and led to clinical interventions in a relevant proportion of patients; in particular, a pacemaker implant was performed after bradycardia detection in 8.9% of subjects who received an ICM for syncope and oral anticoagulation therapy was indicated after AF detection in 15.7% of subjects with cryptogenic stroke. PREMs showed that 78.2% of subjects were satisfied with the remote monitoring patient app., Conclusion: The evaluated ICM is associated with an excellent safety profile and high diagnostic yield. Patients reported positive experiences associated with the use of their smartphone for the device remote monitoring., Competing Interests: Conflict of interest: W.L., A.G., and C.S.H. are employees of Abbott. All remaining authors have declared no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Limited data are available regarding the efficacy of thoracoscopic ablation as the first procedure for persistent atrial fibrillation (AF). We sought to compare the long-term efficacy of thoracoscopic ablation vs. radiofrequency (RF) catheter ablation as the first procedure for persistent AF., Methods and Results: Between February 2011 and December 2020, 575 patients who underwent ablation for persistent AF were studied. Among them, thoracoscopic ablation was performed in 281 patients, RF catheter ablation in 228, and hybrid ablation in 66. Rhythm, clinical, and safety outcomes during 7-year follow-up were compared. The patients who underwent thoracoscopic ablation were older, had a higher prevalence of stroke, and had a larger left atrial volume than those who underwent RF catheter ablation. In the propensity score-matched population (n = 306), incidences of atrial tachyarrhythmia recurrence were 51.4% in the thoracoscopic ablation group and 62.5% in the RF catheter ablation group [adjusted hazard ratio (HR) 0.869, 95% confidence interval (CI) 0.618-1.223, P = 0.420]. Stroke and total procedural adverse events were not significantly different between thoracoscopic and RF catheter ablation (2.7 vs. 2.5%, P = 0.603, and 7.1 vs. 4.8%, P = 0.374, respectively). The hybrid ablation group showed similar rhythm outcomes compared with both the thoracoscopic and the RF catheter ablation groups. At the redo procedure, pulmonary vein gaps were more frequently observed in the RF catheter ablation group (32.6%) than in the thoracoscopic ablation group (7.9%) and in the hybrid ablation group (8.8%) (P < 0.001)., Conclusion: As a first procedure in persistent AF, thoracoscopic ablation and RF catheter ablation showed comparable efficacy, clinical, and safety outcomes during long-term follow-up., Competing Interests: Conflict of interest None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective: To compare the risk of blindness and vision-threatening ocular comorbidities in patients with Behçet's disease (BD) vs the general population., Methods: Using 2002-2017 Korea National Health Insurance Service database, we did a population-based cohort study comparing newly diagnosed BD patients and age- and sex-matched non-BD controls at a 1:5 ratio. The primary outcome was blindness, defined as a best-corrected visual acuity of ≤20/500 in the better-seeing eye. Secondary outcomes were vision-threatening ocular comorbidities (cataract, glaucoma and retinal disorders) that require surgical interventions and incident uveitis. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs. We performed subgroup analyses by sex and BD diagnosis age., Results: We included 31 228 BD patients and 156 140 controls. During a follow-up of 9.39 years, the incidence rate of blindness per 1000 person-years was 0.24 in BD and 0.02 in controls with an HR of 10.73 (95% CI 7.10, 16.22). The HR for secondary outcomes was 2.06 (95% CI 1.98, 2.15) for cataract surgery, 5.43 (4.57, 6.45) for glaucoma surgery and 2.71 (2.39, 3.07) for retinal surgery. The HR of incident uveitis was 6.19 (95% CI 5.83, 6.58). Males suffered a disproportionately higher risk of blindness than females due to greater severity rather than a lower incidence of uveitis. The risk of uveitis and blindness decreased as BD diagnosis age increased., Conclusions: In this large population-based cohort study, BD patients compared with the general population have a 10.73-fold risk of blindness in 10 years and also a substantially higher risk of diverse ocular comorbidities that pose potential threats to vision., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Inflammatory bowel diseases could be diagnosed in major measure by diagnostic imaging; however, radiation exposure in the intestine may also contribute to the progression of these pathologies. To better understand the impact of radiation in the presence of bowel disease, we administered dextran sodium sulfate (DSS) to C57BL/6 mice to induce colitis and exposed to radiation at abdominal area. We observed that abdominal irradiation (13 Gy) aggravates the DSS-induced decrease in survival rate (0%), body weight (74.54 ± 3.59%) and colon length (4.98 ± 0.14 cm). Additionally, abdominal irradiation markedly increased in colonic inflammation levels (3.16 ± 0.16) compared with that of DSS-induced sham mice. Furthermore, abdominal irradiation also increased the mRNA expression levels of inflammatory genes, such as cyclooxygenase-2 (13.10 folds), interleukin-6 (48.83 folds) and tumor necrosis factor-alpha (42.97 folds). We conclude that abdominal irradiation aggravates the detrimental effects of DSS-induced colitis in mice, which might be a useful guideline for inflammatory bowel disease patients., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Euphorbia peplus (petty spurge) is a small, fast-growing plant that is native to Eurasia and has become a naturalized weed in North America and Australia. Euphorbia peplus is not only medicinally valuable, serving as a source for the skin cancer drug ingenol mebutate, but also has great potential as a model for latex production owing to its small size, ease of manipulation in the laboratory, and rapid reproductive cycle. To help establish E. peplus as a new model, we generated a 267.2-Mb Hi-C-anchored PacBio HiFi nuclear genome assembly with a BUSCO score of 98.5%, a genome annotation based on RNA-seq data from six organs, and publicly accessible tools including a genome browser and an interactive organ-specific expression atlas. Chromosome number is highly variable across Euphorbia species. Using a comparative analysis of our newly sequenced E. peplus genome with other Euphorbiaceae genomes, we show that variation in Euphorbia chromosome number between E. peplus and Euphorbia lathyris is likely due to fragmentation and rearrangement rather than chromosomal duplication followed by diploidization of the duplicated sequence. Moreover, we found that the E. peplus genome is relatively compact compared with related members of the genus in part due to restricted expansion of the Ty3 transposon family. Finally, we identify a large gene cluster that contains many previously identified enzymes in the putative ingenol mebutate biosynthesis pathway, along with additional gene candidates for this biosynthetic pathway. The genomic resources we have created for E. peplus will help advance research on latex production and ingenol mebutate biosynthesis in the commercially important Euphorbiaceae family., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

N 6-methyladenosine (m6A) RNA methylation has been shown to play a crucial role in plant development and floral transition. Two recent studies have identified FIONA1 as an m6A methyltransferase that regulates the floral transition in Arabidopsis through influencing the stability of CONSTANS (CO), SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1), and FLOWERING LOCUS C (FLC). In this study, we confirmed that FIONA1 is an m6A methyltransferase that installs m6A marks in a small group of mRNAs. Furthermore, we show that, in addition to its role in influencing the stability of CO, SOC1, and FLC, FIONA1-mediated m6A methylation influences the splicing of FLC, a key floral repressor, and the stability of SQUAMOSA PROMOTER-BINDING PROTEIN-LIKE 3 (SPL3) and SEPALLATA3 (SEP3), floral activators, which together play a vital role in floral transition in Arabidopsis. Our study confirms the function of FIONA1 as an m6A methyltransferase and suggests a close molecular link between FIONA1-mediated m6A methylation and the splicing of FLC and the destabilization of SPL3 and SEP3 in flowering time control., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: The incidence of infective endocarditis related to cardiac implantable electronic devices (CIEDs) has gradually increased. The risk associated with dental procedures in patients with CIED implantation and the need for prevention of infective endocarditis remain unclear. The present study investigated the incidence and risk of infective endocarditis associated with invasive dental procedures in patients with CIEDs., Methods and Results: We analysed a nationwide population-based cohort of patients with CIEDs who underwent dental procedures. We performed a self-controlled case series analysis and evaluated the incidence rate ratio of infective endocarditis 3 months after dental procedures. Of a total of 62 019 patients who underwent CIED implantation, 32 536 patients underwent at least one dental procedure during follow-up, and the mean number of dental procedures was 3.4 per patient. They were 152 infections with an incidence of 445 per 100 000 person-years in the dental procedure period and 500 events at an incidence of 255 per 100 000 person-years in the non-dental procedure period. The CIED-related infective endocarditis in the dental procedure period occurred significantly more frequently than during non-dental procedure periods (odds ratio, 1.75; 95% confidence interval, 1.48-2.05; P < 0.001). The mean time interval from dental procedure to infective endocarditis was 59.6 ± 47.3 days., Conclusion: Invasive dental procedures are associated with an increased risk of infective endocarditis in those who underwent CIED implantation. Appropriate preventive therapy might be needed in these patients., Competing Interests: Conflict of interest: None declared., (© 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.)

To compare the measurement results of a portable survey meter with a soil-based dose rate assessment method, the gamma absorbed dose rates in the air were measured at 27 sites. The soil-based gamma absorbed dose rates in the air were calculated using established conversion factors and the activity concentrations of 226Ra, 232Th and 40K of the soil at the sites. The gamma absorbed dose rate averages of the portable survey meter, and computing from the activity concentrations in the soil were 65.8 ± 4.26 and 64.8 ± 3.68 nGy⋅h-1, respectively. A significant positive correlation was found in the comparison between the evaluated gamma absorbed dose rates from soil radioactivity and in the air. Conversion factors based on the local soils converting to the absorbed dose rate were computed from the portable survey meter data and the soil activity concentrations, and it was compared with others., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aims: This study aimed to assess the impact of valvular/subvalvular calcium burden on procedural and long-term outcomes in patients undergoing transcatheter aortic valve replacement (TAVR) for severe aortic stenosis (AS)., Methods and Results: In this prospective observational cohort study, we included patients with AS undergoing TAVR between March 2010 and December 2019. Calcium burden at baseline was quantified using multidetector computed tomography and the patients were classified into tertile groups according to the amount of calcium. Procedural outcomes [paravalvular leakage (PVL) or permanent pacemaker insertion (PPI)] and 12-month clinical outcomes (composite of death, stroke, or rehospitalization, and all-cause mortality) were assessed. A total of 676 patients (age, 79.8 ± 5.4 years) were analysed. The 30-day rates of moderate or severe PVL (P-for-trend = 0.03) and PPI (P-for-trend = 0.002) proportionally increased with the tertile levels of calcium volume. The 12-month rate of primary composite outcomes was 34.2% in low-tertile, 23.9% in middle-tertile, and 25.8% in high-tertile groups (log-rank P = 0.02). After multivariable adjustment, the risk for primary composite outcomes at 12 months was not significantly different between the tertile groups of calcium volume [reference = low-tertile; middle-tertile, hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.54-1.22; P = 0.31; high-tertile, HR 0.93; 95% CI 0.56-1.57; P = 0.80]. A similar pattern was observed for all-cause mortality., Conclusion: The rates of PVL and PPI proportionally increased according to the levels of valvular/subvalvular calcium volume, while the adjusted risks for composite outcomes and mortality at 12 months were not significantly different., Competing Interests: Conflict of interest: None declared., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

An optimal size of post-embryonic root apical meristem (RAM) is achieved by a balance between cell division and differentiation. Despite extensive research, molecular mechanisms underlying the coordination of cell division and differentiation are still fragmentary. Here, we report that ORESARA 15 (ORE15), an Arabidopsis PLANT A/T-RICH SEQUENCE-AND ZINC-BINDING PROTEIN (PLATZ) transcription factor preferentially expressed in the RAM, determines RAM size. Primary root length, RAM size, cell division rate, and stem cell niche activity were reduced in an ore15 loss-of-function mutant but enhanced in an activation-tagged line overexpressing ORE15, compared with wild type. ORE15 forms mutually positive and negative feedback loops with auxin and cytokinin signalling, respectively. Collectively, our findings imply that ORE15 controls RAM size by mediating the antagonistic interaction between auxin and cytokinin signalling-related pathways., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Complications like complete atrioventricular block (CAVB) and paravalvular leakage (PVL) following rapid deployment aortic valve (AV) replacement (RDAVR) remain unresolved. Selecting an optimal size of the valve might be important to minimize the incidence of these complications. We sought to determine the impact of prosthesis size relative to the anatomic profile of the AV on the occurrence of CAVB or PVL after RDAVR., Methods: Preoperative computed tomographic (CT) images were evaluated in patients receiving RDAVR (INTUITY ELITE) between February 2016 and December 2019. The occurrence of CAVB requiring permanent pacemaker implantation and PVL (≥ mild) was evaluated. The relative size of implants against the cross-sectional dimensions of recipients' AV annulus and left ventricular outflow tract (LVOT) were calculated., Results: Among 187 eligible patients, CAVB and PVL (≥ mild) occurred in 12 (6.4%) and 11 patients (5.9%), respectively. CAVB was associated with oversized RDAVR (RDAVR frame width minus average diameter of LVOT calculated from the cross-sectional area [ΔLVOTarea]: odds ratio, 2.05; 95% confidence interval, 1.28-3.30): this was with an area under the curve of 0.78 (P = 0.005). The projected probability of CAVB was <3% when the ΔLVOTarea was <1.3. In contrast, PVL was associated with under-sized RDAVR (RDAVR size divided by the longest diameter of AV annulus [index Annlong]: odds ratio, 0.64; 95% confidence interval, 0.51-0.79): This was with an area under curve of 0.94 (P < 0.001)., Conclusions: CT parameters of the AV annulus and LVOT are highly reliable in the prediction of CAVB or PVL after RDAVR. Our data might justify CT-based sizing of prosthesis for RDAVR., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: Right mini-thoracotomy approach may enhance the visualization of mitral valve (MV) visualization during redo MV surgery, thereby minimizing the risk of reoperative median sternotomy. We described the clinical outcomes of redo MV surgery by mini-thoracotomy and full-sternotomy approach., Methods: Of 730 consecutive adult patients who underwent redo MV surgery between 2002 and 2018 at our institution, we identified 380 patients (age: 56.0 [14.8] years) after excluding those who underwent concomitant aortic valve or coronary artery surgeries., Results: The clinical outcomes in patients who underwent mini-thoracotomy (MINI group; n = 168) and full-sternotomy (STERN group; n = 218) were described. The early and overall mortality in the MINI group was 4.3% (7/162) and 17.3% (28/162), with the rates of early major complications as follows: low cardiac output syndrome, 5.6% (9/162); early stroke, 6.8% (11/162); new-onset dialysis, 6.2% (10/162); prolonged ventilation, 15.4% (25/162); and postoperative bleeding requiring exploration, 7.4% (12/162). In the STERN group, the early mortality was 11.0% (24/218), whereas the risk of low cardiac output syndrome, early stroke, new-onset dialysis, prolonged ventilation, and postoperative bleeding was 12.4% (27/218), 14.2% (31/218), 17.0% (37/218), 33.0% (72/218), and 10.1% (22/218), respectively. The duration of intensive care unit and hospital stay was 2.0 [range 1.0, 3.0] and 8.0 [6.0, 13.0], respectively, in the MINI group and 3.0 [2.0, 7.0] and 14.0 [8.0, 29.0], respectively, in the STERN group., Conclusions: Mini-thoracotomy may be a viable alternative to conventional sternotomy for redo MV surgery., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Acylsugars are a class of plant defense compounds produced across many distantly related families. Members of the horticulturally important morning glory (Convolvulaceae) family produce a diverse sub-class of acylsugars called resin glycosides (RGs), which comprise oligosaccharide cores, hydroxyacyl chain(s), and decorating aliphatic and aromatic acyl chains. While many RG structures are characterized, the extent of structural diversity of this class in different genera and species is not known. In this study, we asked whether there has been lineage-specific diversification of RG structures in different Convolvulaceae species that may suggest diversification of the underlying biosynthetic pathways. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was performed from root and leaf extracts of 26 species sampled in a phylogeny-guided manner. LC-MS/MS revealed thousands of peaks with signature RG fragmentation patterns with one species producing over 300 signals, mirroring the diversity in Solanaceae-type acylsugars. A novel RG from Dichondra argentea was characterized using Nuclear Magnetic Resonance spectroscopy, supporting previous observations of RGs with open hydroxyacyl chains instead of closed macrolactone ring structures. Substantial lineage-specific differentiation in utilization of sugars, hydroxyacyl chains, and decorating acyl chains was discovered, especially among Ipomoea and Convolvulus - the two largest genera in Convolvulaceae. Adopting a computational, knowledge-based strategy, we further developed a high-recall workflow that successfully explained ~72% of the MS/MS fragments, predicted the structural components of 11/13 previously characterized RGs, and partially annotated ~45% of the RGs. Overall, this study improves our understanding of phytochemical diversity and lays a foundation for characterizing the evolutionary mechanisms underlying RG diversification., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved.)

Aims: We evaluated the long-term prognostic value of invasively assessing coronary physiology after heart transplantation in a large multicentre registry., Methods and Results: Comprehensive intracoronary physiology assessment measuring fractional flow reserve (FFR), the index of microcirculatory resistance (IMR), and coronary flow reserve (CFR) was performed in 254 patients at baseline (a median of 7.2 weeks) and in 240 patients at 1 year after transplantation (199 patients had both baseline and 1-year measurement). Patients were classified into those with normal physiology, reduced FFR (FFR ≤ 0.80), and microvascular dysfunction (either IMR ≥ 25 or CFR ≤ 2.0 with FFR > 0.80). The primary outcome was the composite of death or re-transplantation at 10 years. At baseline, 5.5% had reduced FFR; 36.6% had microvascular dysfunction. Baseline reduced FFR [adjusted hazard ratio (aHR) 2.33, 95% confidence interval (CI) 0.88-6.15; P = 0.088] and microvascular dysfunction (aHR 0.88, 95% CI 0.44-1.79; P = 0.73) were not predictors of death and re-transplantation at 10 years. At 1 year, 5.0% had reduced FFR; 23.8% had microvascular dysfunction. One-year reduced FFR (aHR 2.98, 95% CI 1.13-7.87; P = 0.028) and microvascular dysfunction (aHR 2.33, 95% CI 1.19-4.59; P = 0.015) were associated with significantly increased risk of death or re-transplantation at 10 years. Invasive measures of coronary physiology improved the prognostic performance of clinical variables (χ2 improvement: 7.41, P = 0.006). However, intravascular ultrasound-derived changes in maximal intimal thickness were not predictive of outcomes., Conclusion: Abnormal coronary physiology 1 year after heart transplantation was common and was a significant predictor of death or re-transplantation at 10 years., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: We investigated the real-life effectiveness and safety of vedolizumab (VDZ) induction therapy among Korean patients with Crohn disease (CD) or ulcerative colitis (UC) for whom anti-tumor necrosis factor therapy previously failed., Methods: Adult patients who started VDZ induction therapy at 16 centers were prospectively enrolled in the Korean VDZ nationwide registry. The coprimary outcomes were clinical remission, defined as a Crohn's Disease Activity Index score <150 points and a partial Mayo score ≤2 points with a combined rectal bleeding and stool frequency subscore ≤1 point at week 14 and endoscopic remission defined as a Mayo endoscopic subscore ≤1 point. We also analyzed predictors of clinical remission., Results: Between August 2017 and November 2019, a total of 158 patients (80 with CD and 78 with UC) received VDZ induction therapy. Clinical remission rates among patients with CD and patients with UC were 44.1% and 44.0%, respectively. Among patients with UC, the endoscopic remission rate was 32.4%. Clinical response and remission rates showed increasing trends during induction therapy. Multivariable analysis revealed that clinical response at week 6 was the only predictor of clinical remission at week 14 for both patients with CD and patients with UC. Among patients who experienced 1 or more adverse events (n = 71; 44.9%), disease exacerbation (n = 28; 17.7%) was the most common adverse event., Conclusions: Among Korean patients with CD or UC for whom anti-tumor necrosis factor therapy failed, VDZ induction therapy was effective and safe. The early clinical response was associated with clinical remission after VDZ induction therapy., (© 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Ribosomal RNA (rRNA) methylation is a pivotal process in the assembly and activity of ribosomes, which in turn play vital roles in the growth, development and stress responses of plants. Although few methyltransferases responsible for rRNA methylation have been identified in plant chloroplasts, the nature and function of these enzymes in chloroplasts remain largely unknown. In this study, we characterized ArabidopsisRsmD (At3g28460), an ortholog of the methyltransferase responsible for N2-methylguanosine (m2G) modification of 16S rRNA in Escherichia coli. Confocal microscopic analysis of an RsmD- green fluorescent protein fusion protein revealed that RsmD is localized to chloroplasts. Primer extension analysis indicated that RsmD is responsible for m2G methylation at position 915 in the 16S rRNA of Arabidopsis chloroplasts. Under cold stress, rsmd mutant plants exhibited retarded growth, i.e. had shorter roots, lower fresh weight and pale-green leaves, compared with wild-type (WT) plants. However, these phenotypes were not detected in response to drought or salt stress. Notably, the rsmd mutant was hypersensitive to erythromycin or lincomycin and accumulated fewer chloroplast proteins compared with the WT, suggesting that RsmD influences translation in chloroplasts. Complementation lines expressing RsmD in the rsmd mutant background recovered WT phenotypes. Importantly, RsmD harbored RNA methyltransferase activity. Collectively, the findings of this study indicate that RsmD is a chloroplast 16S rRNA methyltransferase responsible for m2G915 modification that plays a role in the adaptation of Arabidopsisto cold stress., (© The Author(s) 2021. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Motivation: In DNA storage systems, there are tradeoffs between writing and reading costs. Increasing the code rate of error-correcting codes may save writing cost, but it will need more sequence reads for data retrieval. There is potentially a way to improve sequencing and decoding processes in such a way that the reading cost induced by this tradeoff is reduced without increasing the writing cost. In past researches, clustering, alignment and decoding processes were considered as separate stages but we believe that using the information from all these processes together may improve decoding performance. Actual experiments of DNA synthesis and sequencing should be performed because simulations cannot be relied on to cover all error possibilities in practical circumstances., Results: For DNA storage systems using fountain code and Reed-Solomon (RS) code, we introduce several techniques to improve the decoding performance. We designed the decoding process focusing on the cooperation of key components: Hamming-distance based clustering, discarding of abnormal sequence reads, RS error correction as well as detection and quality score-based ordering of sequences. We synthesized 513.6 KB data into DNA oligo pools and sequenced this data successfully with Illumina MiSeq instrument. Compared to Erlich's research, the proposed decoding method additionally incorporates sequence reads with minor errors which had been discarded before, and thus was able to make use of 10.6-11.9% more sequence reads from the same sequencing environment, this resulted in 6.5-8.9% reduction in the reading cost. Channel characteristics including sequence coverage and read-length distributions are provided as well., Availability and Implementation: The raw data files and the source codes of our experiments are available at: https://github.com/jhjeong0702/dna-storage., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Recent studies have reported that thyroid hormone levels are associated with metabolic syndrome (MetS) even in euthyroid subjects. However, the association between thyroid autoimmunity and MetS is uncertain. This study aimed to investigate the relationship between thyroid autoimmunity and MetS in a large cohort study of euthyroid subjects., Methods: A total of 4775 participants aged ≥19 years from the Korea National Health and Nutrition Examination Survey VI (2013-2015) with anti-thyroid peroxidase antibody (TPOAb) results and normal thyroid functions were included in this study. Subjects were grouped according to thyroid autoimmunity (positivity of TPOAb). We estimated the odds ratios (ORs) for MetS according to TPOAb positivity using logistic regression models, adjusted for potential confounders., Results: Of the study subjects, 25% (n = 1206) were diagnosed with MetS. Subjects with MetS showed higher median TPOAb levels (6.3 vs 6.8 IU/mL, P < 0.001) and higher positivity of TPOAb (5 vs 7%, P = 0.002) than those without MetS. There was a significant difference in prevalence of MetS depending on the TPOAb positivity (25% vs 33%, P = 0.002). Subjects with TPOAb positive had a significantly greater risk of abdominal obesity (OR 1.675, 95% CI: 1.302-2.154, P < 0.001), low high-density lipoprotein cholesterol (OR: 1.603, 95% CI: 1.244-2.066, P < 0.001) and elevated blood pressure (OR: 1.418, 95% CI: 1.099-1.829, P = 0.007) as compared to those with TPOAb negative. Positivity of TPOAb was a significant risk factor for MetS even after adjusting for confounding variables including age, sex, household income, education, smoking, alcohol consumption, walking activity, thyroid-stimulating hormone and free thyroxine (OR: 1.389, 95% CI: 1.048-1.841, P = 0.022)., Conclusion: In euthyroid subjects, thyroid autoimmunity is associated with MetS. Further large longitudinal studies are needed to clarify causality.

Summary: Microorganisms infect and contaminate eukaryotic cells during the course of biological experiments. Because microbes influence host cell biology and may therefore lead to erroneous conclusions, a computational platform that facilitates decontamination is indispensable. Recent studies show that next-generation sequencing (NGS) data can be used to identify the presence of exogenous microbial species. Previously, we proposed an algorithm to improve detection of microbes in NGS data. Here, we developed an online application, OpenContami, which allows researchers easy access to the algorithm via interactive web-based interfaces. We have designed the application by incorporating a database comprising analytical results from a large-scale public dataset and data uploaded by users. The database serves as a reference for assessing user data and provides a list of genera detected from negative blank controls as a 'blacklist', which is useful for studying human infectious diseases. OpenContami offers a comprehensive overview of exogenous species in NGS datasets; as such, it will increase our understanding of the impact of microbial contamination on biological and pathological traits., Availability and Implementation: OpenContami is freely available at: https://openlooper.hgc.jp/opencontami/., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2021. Published by Oxford University Press.)

Aims: To evaluate the impact of coronary artery calcium (CAC) score, minimal lumen area (MLA), and length of coronary artery stenosis on the diagnostic performance of the machine-learning-based computed tomography-derived fractional flow reserve (ML-FFR)., Methods and Results: In 471 patients with coronary artery disease, computed tomography angiography (CTA) and invasive coronary angiography were performed with fractional flow reserve (FFR) in 557 lesions at a single centre. Diagnostic performances of ML-FFR, computational fluid dynamics-based CT-FFR (CFD-FFR), MLA, quantitative coronary angiography (QCA), and visual stenosis grading were evaluated using invasive FFR as a reference standard. Diagnostic performances were analysed according to lesion characteristics including the MLA, length of stenosis, CAC score, and stenosis degree. ML-FFR was obtained by automated feature selection and model building from quantitative CTA. A total of 272 lesions showed significant ischaemia, defined by invasive FFR ≤0.80. There was a significant correlation between CFD-FFR and ML-FFR (r = 0.99, P < 0.001). ML-FFR showed moderate sensitivity and specificity in the per-patient analysis. Diagnostic performances of CFD-FFR and ML-FFR did not decline in patients with high CAC scores (CAC > 400). Sensitivities of CFD-FFR and ML-FFR showed a downward trend along with the increase in lesion length and decrease in MLA. The area under the curve (AUC) of ML-FFR (0.73) was higher than those of QCA and visual grading (AUC = 0.65 for both, P < 0.001) and comparable to those of MLA (AUC = 0.71, P = 0.21) and CFD-FFR (AUC = 0.73, P = 0.86)., Conclusion: ML-FFR showed comparable results to MLA and CFD-FFR for the prediction of lesion-specific ischaemia. Specificities and accuracies of CFD-FFR and ML-FFR decreased with smaller MLA and long lesion length., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: The associations between high-density lipoprotein cholesterol (HDL-C) levels and all-cause mortality are unclear in young adults (<45 years) and in Asian populations., Methods: In total, 15 860 253 Korean adults underwent routine health examinations during 2009-10 and were followed until June 2018 for all-cause mortality. Hazard ratios (HRs) were calculated using Cox proportional hazard models., Results: During a mean 8.4 years of follow-up, 555 802 individuals died. U-curve associations were found between HDL-C levels and mortality, irrespective of sex or age. The HDL-C ranges associated with the lowest mortality were 40-59 and 50-69 mg/dL (1.03-1.54 and 1.29-1.80 mmol/L) in men aged <65 and ≥65 years, respectively, and the corresponding ranges were 40-69 and 50-79 mg/dL (1.03-1.80 and 1.29-2.06 mmol/L) in women aged <45 and ≥45 years, respectively. For HDL-C ranges of 60-149 mg/dL (1.55-3.86 mmol/L), each 39 mg/dL (1 mmol/L) increase in HDL-C was associated with higher mortality [men: HR = 1.39; 95% confidence interval (CI) = 1.36-1.42; women: HR = 1.15, 95% CI = 1.11-1.18], adjusting for age. These positive associations were generally stronger at younger than older ages, whereas inverse associations for HDL-C ranges <60 mg/dL (1.55 mmol/L) were strongest in middle age (45-64 years). The U-curve associations were generally unchanged after adjustment for various confounders., Conclusions: Korean adults showed U-curve associations of HDL-C with mortality, regardless of sex, and age. Younger adults had a lower optimal range and a stronger positive association with mortality than older adults in the high HDL-C range. Even moderately high HDL-C levels are not necessarily a sign of good health, especially in young adults., (© The Author(s) 2020; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Skin necrosis is one of the most severe complications following filler injections, and can result in permanent aesthetic defects. Although an increasing number of studies have addressed the management of dermal filler complications, no study has described the spectrum of microbial pathogens. The aim of this study was to delineate the bacterial profile and prognostic factors of filler-related skin necrosis by reviewing the clinical and microbiological features of these patients. A retrospective medical record review of patients undergoing treatment for skin necrosis induced by fillers was conducted. In total, 10 cases were identified, with injection sites being the nasolabial fold (70%; n = 7), nasal dorsum (20%; n = 2) and nasal tip (10%; n = 1). Reviewing the culture results, the true culture-positive rate was found to be 50% after cases of contamination were excluded. To avoid permanent sequelae, all physicians should be aware of possible secondary infections when treating filler-induced skin necrosis., (© 2021 British Association of Dermatologists.)

Background and Aims: Robust evidence regarding the impact of disease activity on pregnancy outcomes in women with inflammatory bowel disease [IBD] is crucial for both clinicians and patients in preparing a birth plan. We sought to perform a systematic review and meta-analysis to assess the pooled influences of disease activity on pregnancy outcomes in women with IBD., Methods: We searched MEDLINE, EMBASE and the COCHRANE library to identify articles comparing pregnancy outcomes between active and inactive IBD at the time of conception or during pregnancy. A meta-analysis was performed using a random-effects model to pool estimates and report odds ratios [ORs]., Results: A total of 28 studies were identified as eligible for the meta-analysis. In women with active IBD, the pooled ORs for low birth weight [LBW], preterm birth, small for gestational age [SGA], spontaneous abortion and stillbirths were respectively 3.81 (95% confidence interval [CI] 1.81-8.02), 2.42 [95% CI 1.74-3.35], 1.48 [95% CI 1.19-1.85], 1.87 [95% CI 1.17-3.0] and 2.27 [95% CI 1.03-5.04] compared to women with inactive IBD. In the subgroup analysis based on disease type, women with active ulcerative colitis had an increased risk of LBW, preterm birth and spontaneous abortion. Women with active Crohn's disease had a higher risk of preterm birth, SGA and spontaneous abortion., Conclusions: Active IBD during the periconception period and pregnancy is associated with an increased risk of adverse pregnancy outcomes. Our data suggest that pregnancy should be planned when the disease is quiescent, and continuous disease control is important even during pregnancy., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Systemic contact dermatitis (SCD) develops when a person who was previously sensitized to an allergen is exposed to the same allergen via the systemic route. In East Asia, the use of lacquer for polishing furniture is common and a part of the traditional culture. Contact exposure to tableware polished with Rhus lacquer may lead to sensitization. In Korea, SCD is commonly observed after systemic exposure to Rhus, a nutritious food item consumed because of the common belief of it improving the immune system. In this study, we reviewed the medical records of 21 Korean patients with SCD caused by Rhus ingestion. We found that the most significant epidemiological factor for SCD was the season of the year. Furthermore, 66.67% of the patients presented with leucocytosis and 23.81% showed increased liver enzyme levels. It is important to educate people on the risks associated with the systemic ingestion of Rhus., (© 2020 British Association of Dermatologists.)

Objective: Patients with RA commonly use gastrointestinal (GI) protective drugs for treatment and prevention of drug-associated GI injuries. However, how these drugs affect the gut microbiota in RA patients remains unknown. The objective of this study was to examine the gut microbiota of RA patients according to use of GI protective drugs such as proton pump inhibitors (PPIs), histamine 2-receptor antagonists and rebamipide., Methods: Faecal samples were obtained from 15 healthy controls and 32 RA patients who were receiving PPI, histamine 2-receptor antagonist or rebamipide. Bacterial DNA was extracted from the faecal samples and 16S rRNA sequencing was performed. Microbial composition and function were analysed using Quantitative Insights Into Microbial Ecology and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States., Results: RA patients exhibited reduced diversity and altered composition of the gut microbiota compared with healthy controls. The gut microbiota of RA patients receiving acid-suppressing drugs, particularly PPIs, was distinct from that of RA patients receiving rebamipide (PPI vs rebamipide, P = 0.005). Streptococcus was enriched in RA patients receiving PPI, while Clostridium bolteae was enriched in RA patients receiving rebamipide. The gut microbiota of PPI users was abundant with microbial functional pathway involved in the production of virulence factors. This featured microbial function was positively correlated with relative abundance of Streptococcus, the differentially abundant taxa of PPI users., Conclusion: The gut microbiota of RA patients receiving PPIs was distinguishable from that of those receiving rebamipide. The enriched virulent function in the gut microbiota of PPI users suggests that inappropriate PPI use may be harmful in RA patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The sterile insect technique (SIT) and male annihilation technique (MAT) are important tools for the control of Queensland fruit fly (Q-fly), Bactrocera tryoni (Froggatt) (Diptera: Tephritidae), a major insect pest of horticultural crops in Australia. In MAT, mature Q-fly males are attracted to a toxic bait using Cuelure, a synthetic analog of raspberry ketone (RK). Substantial improvements in control could be achieved by simultaneous use of SIT and MAT, but this requires suppression of the Cuelure response in released sterile flies. Recent studies report that prerelease feeding with RK during the first 48 h after emergence can reduce the response of mature Q-fly males to Cuelure, but the mechanism underpinning this is unknown. Here, to test whether reduced sensory sensitivity to Cuelure is involved, we evaluated the effects of RK supplements, adult diet (yeast-supplemented diet throughout adult stage vs yeast-supplemented diet only for 48 h), and age on electroantennogram (EAG) and electropalpogram (EPG) responses of Q-flies to Cuelure stimuli. EAG responses did not vary with RK supplements, sex, or age of Q-flies fed yeast-supplemented diet throughout the adult stage, but the responses of Q-flies fed other diet regime decreased with age. EPG responses of both sexes of Q-flies were affected by RK supplements, age, and their interaction, but without patterns that might indicate reduced maxillary palp response of RK supplemented flies to Cuelure. Our findings do not support the hypothesis that reduced Cuelure response of male Q-flies fed RK supplements is explained by reduced electrophysiological response in antennae or maxillary palps., (© The Author(s) 2020. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Methylated non-CpGs (mCpHs) in mammalian cells yield weak enrichment signals and colocalize with methylated CpGs (mCpGs), thus have been considered byproducts of hyperactive methyltransferases. However, mCpHs are cell type-specific and associated with epigenetic regulation, although their dependency on mCpGs remains to be elucidated. In this study, we demonstrated that mCpHs colocalize with mCpGs in pluripotent stem cells, but not in brain cells. In addition, profiling genome-wide methylation patterns using a hidden Markov model revealed abundant genomic regions in which CpGs and CpHs are differentially methylated in brain. These regions were frequently located in putative enhancers, and mCpHs within the enhancers increased in correlation with brain age. The enhancers with hypermethylated CpHs were associated with genes functionally enriched in immune responses, and some of the genes were related to neuroinflammation and degeneration. This study provides insight into the roles of non-CpG methylation as an epigenetic code in the mammalian brain genome., (© The Author(s) 2020. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.)

Motivation: Glycan microarrays are capable of illuminating the interactions of glycan-binding proteins (GBPs) against hundreds of defined glycan structures, and have revolutionized the investigations of protein-carbohydrate interactions underlying numerous critical biological activities. However, it is difficult to interpret microarray data and identify structural determinants promoting glycan binding to glycan-binding proteins due to the ambiguity in microarray fluorescence intensity and complexity in branched glycan structures. To facilitate analysis of glycan microarray data alongside protein structure, we have built the Glycan Microarray Database (GlyMDB), a web-based resource including a searchable database of glycan microarray samples and a toolset for data/structure analysis., Results: The current GlyMDB provides data visualization and glycan-binding motif discovery for 5203 glycan microarray samples collected from the Consortium for Functional Glycomics. The unique feature of GlyMDB is to link microarray data to PDB structures. The GlyMDB provides different options for database query, and allows users to upload their microarray data for analysis. After search or upload is complete, users can choose the criterion for binder versus non-binder classification. They can view the signal intensity graph including the binder/non-binder threshold followed by a list of glycan-binding motifs. One can also compare the fluorescence intensity data from two different microarray samples. A protein sequence-based search is performed using BLAST to match microarray data with all available PDB structures containing glycans. The glycan ligand information is displayed, and links are provided for structural visualization and redirection to other modules in GlycanStructure.ORG for further investigation of glycan-binding sites and glycan structures., Availability and Implementation: http://www.glycanstructure.org/glymdb., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Dual specificity LAMMER kinase has been reported to be conserved across species ranging from yeasts to animals and has multiple functions. Candida albicans undergoes dimorphic switching between yeast cells and hyphal growth forms as its key virulence factors. Deletion of KNS1, which encodes for LAMMER kinase in C. albicans, led to pseudohyphal growth on YPD media and defects in filamentous growth both on spider and YPD solid media containing 10% serum. These cells exhibited expanded central wrinkled regions and specifically reduced peripheral filaments. Among the several stresses tested, the kns1Δ strains showed sensitivity to cell-wall and DNA-replicative stress. Under fluorescent microscopy, an increase in chitin decomposition was observed near the bud necks and septa in kns1Δ cells. When the expression levels of genes for cell wall integrity (CWI) and the DNA repair mechanism were tested, the kns1 double-deletion cells showed abnormal patterns compared to wild-type cells; The transcript levels of genes for glycosylphosphatidylinositol (GPI)-anchored proteins were increased upon calcofluor white (CFW) treatment. Under DNA replicative stress, the expression of MluI-cell cycle box binding factor (MBF)-targeted genes, which are expressed during the G1/S transition in the cell cycle, was not increased in the kns1 double-deletion cells. This strain showed increased adhesion to the surface of an agar plate and zebrafish embryo. These results demonstrate that Kns1 is involved in dimorphic transition, cell wall integrity, response to DNA replicative stress, and adherence to the host cell surface in C. albicans., (© The Author(s) 2019. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Aggregation of amyloid beta and loss of cholinergic innervation in the brain are predominant components of Alzheimer's disease pathology and likely underlie cognitive impairment. Acetylcholinesterase inhibitors are one of the few treatment options for Alzheimer's disease, where levels of available acetylcholine are enhanced to counteract the cholinergic loss. However, these inhibitors show limited clinical efficacy. One potential explanation for this is a concomitant dysregulation of cholinergic receptors themselves as a consequence of the amyloid beta pathology. We tested this hypothesis by examining levels of M1 muscarinic acetylcholine receptors in the temporal cortex from seven Alzheimer's disease and seven non-disease age-matched control brain tissue samples (control: 85 ± 2.63 years old, moderate Alzheimer's disease: 84 ± 2.32 years old, P -value = 0.721; eight female and six male patients). The samples were categorized into two groups: 'control' (Consortium to Establish a Registry for Alzheimer's Disease diagnosis of 'No Alzheimer's disease', and Braak staging pathology of I-II) and 'moderate Alzheimer's disease' (Consortium to Establish a Registry for Alzheimer's Disease diagnosis of 'possible/probable Alzheimer's disease', and Braak staging pathology of IV). We find that in comparison to age-matched controls, there is a loss of M1 muscarinic acetylcholine receptors in moderate Alzheimer's disease tissue (control: 2.17 ± 0.27 arbitrary units, n  = 7, Mod-AD: 0.83 ± 0.16 arbitrary units, n  = 7, two-tailed t -test, t  = 4.248, P  = 0.00113). Using a functional rat cortical brain slice model, we find that postsynaptic muscarinic acetylcholine receptor function is dysregulated by aberrant amyloid beta-mediated activation of metabotropic glutamate receptor 5. Crucially, blocking metabotropic glutamate receptor 5 restores muscarinic acetylcholine receptor function and object recognition memory in 5XFAD transgenic mice. This indicates that the amyloid beta-mediated activation of metabotropic glutamate receptor 5 negatively regulates muscarinic acetylcholine receptor and illustrates the importance of muscarinic acetylcholine receptors as a potential disease-modifying target in the moderate pathological stages of Alzheimer's disease., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Although the importance of chloroplast RNA splicing and ribosome maturation (CRM) domain-containing proteins has been established for chloroplast RNA metabolism and plant development, the functional role of CRM proteins in mitochondria remains largely unknown. Here, we investigated the role of a mitochondria-targeted CRM protein (At3g27550), named CFM9, in Arabidopsis thaliana. Confocal analysis revealed that CFM9 is localized in mitochondria. The cfm9 mutant exhibited delayed seed germination, retarded growth and shorter height compared with the wild type under normal conditions. The growth-defect phenotypes were more manifested upon high salinity, dehydration or ABA application. Complementation lines expressing CFM9 in the mutant background fully recovered the wild-type phenotypes. Notably, the mutant had abnormal mitochondria, increased hydrogen peroxide and reduced respiration activity, implying that CFM9 is indispensable for normal mitochondrial function. More important, the splicing of many intron-containing genes in mitochondria was defective in the mutant, suggesting that CFM9 plays a crucial role in the splicing of mitochondrial introns. Collectively, our results provide clear evidence emphasizing that CFM9 is an essential factor in the splicing of mitochondrial introns, which is crucial for mitochondrial biogenesis and function and the growth and development of Arabidopsis., (� The Author(s) 2019. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)