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Haiyan Li,1 Zhenhua Yang,1 Shuang Zhang,1 Lin Xu,1 Yudong Wei,1 Jun Jiang,2 Luzelena Caro,3 Hwa-Ping Feng,3 Jacqueline B McCrea,3 Meng Li,2 Shuang Xie,2 Jiangdian Wang,2 Xu Min Zhao,2 Shengmei Mu2 1Drug Clinical Trial Center, Peking University Third Hospital, Beijing, People’s Republic of China; 2Department of Infectious Diseases, MSD (China) R&D, Beijing, People’s Republic of China; 3Department of Infectious Diseases, Merck & Co., Inc., Kenilworth, NJ, USACorrespondence: Haiyan LiDrug Clinical Trial Center, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, People’s Republic of ChinaTel +86 108 226 6226Email haiyanli1027@hotmail.comPurpose: The burden of hepatitis C virus infection is particularly high in Asian countries, and new treatments are urgently needed. The purpose of this study was to characterize the pharmacokinetics (PK) and safety of the fixed-dose combination tablet of elbasvir/grazoprevir in healthy Chinese participants.Patient and Methods: In this Phase I, single-site, open-label, 3-period study in healthy Chinese adults, participants received a single tablet of elbasvir 50 mg/grazoprevir 100 mg, followed by blood sampling for up to 96 hrs (http://www.chinadrugtrials.org.cn/ CTR20160034; Protocol PN071). Participants then received 1 tablet daily for 10 days, followed by a minimum 10-day washout, after which participants received a single dose of 2 tablets (elbasvir 100 mg/grazoprevir 200 mg). Elbasvir and grazoprevir PK were assessed following single and multiple doses. Safety and tolerability were also evaluated.Results: Twelve participants (50% male) were enrolled in and completed the study. Following single-dose oral administration of elbasvir 50 mg/grazoprevir 100 mg or elbasvir 100 mg/grazoprevir 200 mg, the median Tmax was 3– 4 hrs and elimination half-life was 18 hrs (elbasvir) and 30 hrs (grazoprevir). Multiple-dose administration resulted in AUC0– 24 accumulation ratios of 1.58 (elbasvir) and 2.35 (grazoprevir). Both elbasvir 50 mg/grazoprevir 100 mg and 100 mg/200 mg regimens were generally well tolerated.Conclusion: Single-dose administration of elbasvir 50 mg/grazoprevir 100 mg or 100 mg/200 mg and once-daily administration of elbasvir 50 mg/grazoprevir 100 mg for 10 days has been adequately characterized, with PK values within the expected range, and was generally well tolerated in healthy Chinese male and female participants.Keywords: elbasvir, grazoprevir, healthy volunteers, hepatitis C virus, pharmacokinetics

Xue-Min Zhao, 1 Ping Zhuang, 1–3 Yong-jie Li, 1 Yu-qing Zhang, 1 Jian-yu Li, 1 Yun-peng Wang, 1 Ji-ping Li 1 1Beijing Institute of Functional Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Center of Parkinson’s Disease, Beijing Institute for Brain Disorders, Beijing, People’s Republic of China; 3Key Laboratory of Neurodegenerative Diseases (Capital Medical University), Ministry of Education, Beijing, People’s Republic of ChinaCorrespondence: Ping ZhuangBeijing Institute of Functional Neurosurgery, Xuanwu Hospital, Capital Medical University, No. 45 Changchun Street, Xicheng District, Beijing 100053, People’s Republic of ChinaTel +86 10 83198887Fax +86 10 83199238Email zhuangping833@gmail.comPurpose: The aim of this study was to compare the neuronal firing rate and oscillatory activity of the subthalamic nucleus (STN) between the more affected (MA) and the less affected (LA) hemispheres in Parkinson’s disease (PD).Patients and Methods: We recorded and analyzed the intra-operative microelectrode recordings (MER) from the STN of 24 PD subjects. Lateralized Unified Parkinson’s Disease Rating Scale (UPDRS) III sub-scores (item 20– 26) were calculated. The STN corresponding to the MA side was designated as the MA STN while the other side as the LA STN. Single unit characteristics including interspike intervals were identified and spectral analyses were assessed. Further, the mean spontaneous firing rate (MSFR) of neurons was calculated. The correlations between clinical symptoms and neuronal activity were analyzed.Results: The firing rate in the MA and LA sides were 43.18 ± 0.74 Hz and 36.94 ± 1.32 Hz, respectively, with an increase of 16.9% in the MA group. The number of neurons that oscillated in the Tremor-Frequency Band (TFB), β-Frequency Band (βFB), and the non-oscillatory cells in the MA group were 43, 115, and 62 versus 78, 68, and 54 in the LA group, respectively. The proportions of the three types of neurons were different between both groups. The firing rate of the STN neurons and the UPDRS III sub-scores were positively correlated. Additionally, we observed a positive correlation between the percentage of βFB oscillatory neurons and bradykinesia score.Conclusion: The firing rate of the STN in the MA hemisphere is higher than in the LA side, following disease progression and there seems to be an increase in firing rate. The βFB oscillatory neurons are at a larger proportion in the MA group while there were larger percentage of TFB oscillatory cells in the LA group. The proportion of βFB oscillatory neurons is selectively correlated with the severity of bradykinesia.Keywords: Parkinson’s disease, subthalamic nucleus, intra-operative microelectrode recordings, tremor-frequency band, β-frequency band, βFB

Yuan Zhuang, Bao-Ying Yuan, Yong Hu, Gen-Wen Chen, Li Zhang, Xiao-Mei Zhao, Yi-Xing Chen,* Zhao-Chong Zeng* Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi-Xing Chen; Zhao-Chong ZengDepartment of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People’s Republic of ChinaTel +86-139-1605-6575Fax +86-21-6404-8472Email chen.yixing@zs-hospital.sh.cn; zeng.zhaochong@zs-hospital.sh.cnPurpose: The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are inflammatory indexes that may reflect immune response to tumors and prognosis. We investigated the prognostic values of pre-treatment and post-treatment NLR and PLR and changes in those ratios in patients with small hepatocellular carcinoma (sHCC) treated with stereotactic body radiation therapy (SBRT).Patients and methods: Sixty patients who received SBRT were retrospectively reviewed. NLR and PLR were calculated by division of neutrophil and platelet counts, respectively, by lymphocyte counts. Independent factors for progression-free survival (PFS) and overall survival (OS) were determined by the Kaplan–Meier method, log-rank test, and Cox multivariate regression. Hazard ratios (HRs) and 95% confidence intervals (CIs) were also calculated.Results: The median follow-up was 36.9 (range: 4.1–73.5) months. Median PFS was 21.4 (range: 1.8–66.9) months. The 1-year and 2-year PFS rates were 76.7% and 55.0%, respectively. The 1-year and 2-year OS rates were 95.0% and 78.3%, respectively. In multivariate analysis, post-treatment PLR ≥263.0 indicated both poor PFS (HR: 3.70; 95% CI: 1.07–12.76, p=0.038) and OS (HR: 3.23; 95% CI: 1.01–9.11, p=0.043) for sHCC patients treated with SBRT. In addition, the presence of hepatitis infection and a low level of red blood cell count were also proved to be significantly associated with patients’ poor prognosis (pp=0.029).Conclusion: High post-treatment PLR and change in NLR ≥2.7-fold were associated with poor prognosis in patients treated with SBRT and might be considered as reliable and independent prognostic biomarkers for patients with sHCC.Keywords: stereotactic body radiation therapy, hepatocellular carcinoma, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, progression-free survival

Aquatic organisms in the environment are frequently exposed to a variety of organic chemicals, while these biological species may show different sensitivities to different chemical groups present in the environment. This study evaluated species sensitivity, hazards, and risks of six classes of organic chemicals in the aquatic environment. None of the taxonomic groups were the most sensitive or tolerant to all chemicals, as one group sensitive to one class of chemicals might possess adaptations to other chemical groups. Polychlorinated biphenyls were generally the most toxic chemical group, followed by polybrominated diphenyl ethers, polycyclic aromatic hydrocarbons, and pharmaceuticals and personal care products, while per- and polyfluoroalkyl substances and phthalate esters were the less toxic chemical groups. The hazard of organic chemicals was closely related to their physicochemical properties, including hydrophobicity and molecular weight. It was shown that 20% of the evaluated chemicals exhibited medium or high ecological risks with the worst-case scenario in the Pearl River Estuary. This novel work represented a comprehensive comparison of chemical hazards and species sensitivity among different classes of organic chemicals, and the reported results herein have provided scientific evidence for ecological risk assessment and water quality management to protect aquatic ecosystems against organic chemicals.

Xylitol, as an important food additive and fine chemical, has a wide range of applications, including food, medicine, chemical, and feed. This review paper focuses on the research progress of xylitol biosynthesis, from overcoming the limitations of traditional chemical hydrogenation and xylose bioconversion, to the full biosynthesis of xylitol production using green and non-polluting glucose as substrate. In the review, the molecular strategies of wild strains to increase xylitol yield, as well as the optimization strategies and metabolic reconfiguration during xylitol biosynthesis are discussed. Subsequently, on the basis of existing studies, the paper further discusses the current status of research and future perspectives of xylitol production using glucose as a single substrate. The evolution of raw materials from xylose-based five-carbon sugars to glucose is not only cost-saving, but also safe and environmentally friendly, which brings new opportunities for the green industrial chain of xylitol., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Objective: This study aimed to compare the neuropsychological function in early adolescence between children born small for gestational age (SGA) or large for gestational age (LGA) and those born appropriate for gestational age (AGA)., Methods: This retrospective cohort study utilized data from the Adolescent Brain Cognitive Development study in 2016-18. Children born of singleton pregnancy with complete information of birth weight and delivery week were enrolled. Their neuropsychological functioning were assessed by the brain structural magnetic resonance imaging (MRI), combined with cognitive and behavioral measurements. Linear mixed-effects models and subgroup analyses were performed., Results: Among 5,922 children aged 9-11, children born SGA and LGA demonstrated similar cognitive and behavioral performances as children born AGA (P > 0.05). In the MRI measurement, brain area and volume were lower among SGA children compared to AGA children (t=-5.626, Cohen's d = 0.448, P < 0.001; t=-6.071, Cohen's d = 0.427, P < 0.001); brain area and volume were higher among LGA children compared to AGA children (t = 8.562, Cohen's d = 0.470, P < 0.001; t = 8.562, Cohen's d = 0.470, P < 0.001). Cortical thickness was of no statistical difference (P > 0.05). These associations were confirmed by sensitivity analyses and propensity score matching., Conclusion: Children born of SGA and LGA status were associated with altered brain area and volume structure in early adolescence., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cancer is a systemic heterogeneous disease involving complex molecular networks. Tumor formation involves an epithelial-mesenchymal transition (EMT), which promotes both metastasis and plasticity of cancer cells. Recent experiments have proposed that cancer cells can be transformed into adipocytes via a combination of drugs. However, the underlying mechanisms for how these drugs work, from a molecular network perspective, remain elusive. To reveal the mechanism of cancer-adipose conversion (CAC), this study adopts a systems biology approach by combing mathematical modeling and molecular experiments, based on underlying molecular regulatory networks. Four types of attractors are identified, corresponding to epithelial (E), mesenchymal (M), adipose (A) and partial/intermediate EMT (P) cell states on the CAC landscape. Landscape and transition path results illustrate that intermediate states play critical roles in the cancer to adipose transition. Through a landscape control approach, two new therapeutic strategies for drug combinations are identified, that promote CAC. These predictions are verified by molecular experiments in different cell lines. The combined computational and experimental approach provides a powerful tool to explore molecular mechanisms for cell fate transitions in cancer networks. The results reveal underlying mechanisms of intermediate cell states that govern the CAC, and identified new potential drug combinations to induce cancer adipogenesis., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Ischemic stroke is one of the most disabling and fatal diseases around the world. The damaged brain tissues will undergo excessive autophagy, vascular endothelial cells injury, blood-brain barrier (BBB) impairment and neuroinflammation after ischemic stroke. However, there is no unified viewpoint on the underlying mechanism of brain damage. Transforming growth factor-β1 (TGF-β1), as a multi-functional cytokine, plays a crucial role in the intricate pathological processes and helps maintain the physiological homeostasis of brain tissues through various signaling pathways after ischemic stroke. In this review, we summarize the protective role of TGF-β1 in autophagic flux, BBB, vascular remodeling, neuroinflammation and other aspects after ischemic stroke. Based on the review, we believe that TGF-β1 could serve as a key target for treating ischemic stroke., Competing Interests: Declaration of competing interest Authors declare that the research is conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Five undescribed monoterpene-chalcone conjugates (1-5), one undescribed hypothetical precursor of diarylheptanoid (6), two undescribed diarylheptanoids (7-8), and fourteen known compounds (9-22) were isolated from the seeds of Alpinia katsumadai. Their structures were elucidated through the interpretation of HRESIMS, NMR, ECD, and X-ray diffraction data. MTT assays on human cancer cell lines (HepG2, A549, SGC7901, and SW480) revealed that compounds 3-8, 11, and 13 exhibited broad-spectrum antiproliferative activities with IC 50 values ranging from 3.59 to 21.78 μM. B cell lymphoma 2 was predicted as the target of sumadain C (11) by network pharmacology and verified by homogeneous time-resolved fluorescence assay and molecular docking., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Small open reading frames (smORFs) shorter than 100 codons are widespread and perform essential roles in microorganisms, where they encode proteins active in several cell functions, including signal pathways, stress response, and antibacterial activities. However, the ecology, distribution and role of small proteins in the global microbiome remain unknown. Here, we construct a global microbial smORFs catalog (GMSC) derived from 63,410 publicly available metagenomes across 75 distinct habitats and 87,920 high-quality isolate genomes. GMSC contains 965 million non-redundant smORFs with comprehensive annotations. We find that archaea harbor more smORFs proportionally than bacteria. We moreover provide a tool called GMSC-mapper to identify and annotate small proteins from microbial (meta)genomes. Overall, this publicly-available resource demonstrates the immense and underexplored diversity of small proteins., (© 2024. The Author(s).)

Genetic variations are instrumental for unraveling phage evolution and deciphering their functional implications. Here, we explore the underlying fine-scale genetic variations in the gut phageome, especially structural variations (SVs). By using virome-enriched long-read metagenomic sequencing across 91 individuals, we identified a total of 14,438 nonredundant phage SVs and revealed their prevalence within the human gut phageome. These SVs are mainly enriched in genes involved in recombination, DNA methylation, and antibiotic resistance. Notably, a substantial fraction of phage SV sequences share close homology with bacterial fragments, with most SVs enriched for horizontal gene transfer (HGT) mechanism. Further investigations showed that these SV sequences were genetic exchanged between specific phage-bacteria pairs, particularly between phages and their respective bacterial hosts. Temperate phages exhibit a higher frequency of genetic exchange with bacterial chromosomes and then virulent phages. Collectively, our findings provide insights into the genetic landscape of the human gut phageome.

The established recognition of N6-methyladenosine (m6A) modification as an indispensable regulatory agent in human cancer is widely accepted. However, the understanding of m6A's role and the mechanisms underlying its contribution to gefitinib resistance is notably limited. Herein, using RT-qPCR, Western blot, Cell proliferation and apoptosis, as well as RNA m6A modification assays, we substantiated that heightened FTO (Fat Mass and Obesity-associated protein) expression substantially underpins the emergence of gefitinib resistance in NSCLC cells. This FTO-driven gefitinib resistance is hinged upon the co-occurrence of PELI3 (Pellino E3 Ubiquitin Protein Ligase Family Member 3) expression and concurrent autophagy activation. Manipulation of PELI3 expression and autophagy activation, including its attenuation, was efficacious in both inducing and overcoming gefitinib resistance within NSCLC cells, as validated in vitro and in vivo. In summary, this study has successfully elucidated the intricate interplay involving FTO-mediated m6A modification, its consequential downstream effect on PELI3, and the concurrent involvement of autophagy in fostering the emergence of gefitinib resistance within the therapeutic context of NSCLC., Competing Interests: Declaration of competing Interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Candida is a polyphyletic genus of asexually reproducing yeasts in the Saccharomycotina with more than 400 species that occur in almost all families of the subclass and its name is strongly connected with the infectious disease candidiasis. During the last two decades, approximately half of the Candida species have been reassigned into more than 36 already existing genera and 14 newly proposed genera, but the polyphyletic feature of the genus largely remained. Candida auris is an important, globally emerging opportunistic pathogen that has caused life-threatening outbreaks in healthcare facilities worldwide. This species belongs to the Candida auris-Candida haemuli (CAH) clade in the Metschnikowiaceae , a clade that contains multidrug-resistant clinically relevant species, but also species isolated from natural environments. The clade is phylogenetically positioned remotely from the type species of the genus Candida that is Candida vulgaris (currently interpreted as a synonym of Candida tropicalis ) and belongs to the family Debaryomycetaceae . Although previous phylogenetic and phylogenomic studies confirmed the position of C. auris in the Metschnikowiaceae , these analyses failed to resolve the position of the CAH clade within the family and its delimitation from the genera Clavispora and Metschnikowia . To resolve the position of the CAH clade, phylogenomic and comparative genomics analyses were carried out to address the phylogenetic position of C. auris and related species in the Metschnikowiaceae using several metrics, such as the average amino acid identity (AAI) values, the percentage of conserved proteins (POCP) and the presence-absence patterns of orthologs (PAPO). Based on those approaches, 13 new genera are proposed for various Candida and Hyphopichia species, including members of the CAH clade in the Metschnikowiaceae . As a result, C. auris and related species are reassigned to the genus Candidozyma . Fifty-five new combinations and nine new species are introduced and this will reduce the polyphyly of the genus Candida . Citation : Liu F, Hu Z-D, Zhao X-M, et al. 2024. Phylogenomic analysis of the Candida auris-Candida haemuli clade and related taxa in the Metschnikowiaceae, and proposal of thirteen new genera, fifty-five new combinations and nine new species. Persoonia 52: 22-43. https://doi.org/10.3767/persoonia.2024.52.02 ., Competing Interests: The authors declare that there is no conflict of interest., (© 2024 Naturalis Biodiversity Center & Westerdijk Fungal Biodiversity Institute.)

A correct classification of fungi, including yeasts, is of prime importance to understand fungal biodiversity and to communicate about this diversity. Fungal genera are mainly defined based on phenotypic characteristics and the results of single or multigene-based phylogenetic analyses. However, because yeasts often have less phenotypic characters, their classification experienced a strong move towards DNA-based data, from short ribosomal sequences to multigene phylogenies and more recently to phylogenomics. Here, we explore the usefulness of various genomics-based parameters to circumscribe fungal genera more correctly taking the yeast domain as an example. Therefore, we compared the results of a phylogenomic analysis, average amino acid identity (AAI) values, the presence of conserved signature indels (CSIs), the percentage of conserved proteins (POCP) and the presence-absence patterns of orthologs (PAPO). These genome-based metrics were used to investigate their usefulness in demarcating 13 hitherto relatively well accepted genera in Saccharomycetaceae , namely Eremothecium , Grigorovia , Kazachstania , Kluyveromyces , Lachancea , Nakaseomyces , Naumovozyma , Saccharomyces , Tetrapisispora , Torulaspora , Vanderwaltozyma , Zygosaccharomyces and Zygotorulaspora. As a result, most of these genera are supported by the genomics-based metrics, but the genera Kazachstania , Nakaseomyces and Tetrapisispora were shown to be genetically highly diverse based on the above listed analyses. Considering the results obtained for the presently recognized genera, a range of 80-92 % POCP values and a range of 60-70 % AAI values might be valuable thresholds to discriminate genera in Saccharomycetaceae. Furthermore, the genus-specific genes identified in the PAPO analysis and the CSIs were found to be useful as synapomorphies to characterize and define genera in Saccharomycetaceae . Our results indicate that the combined monophyly-based phylogenomic analysis together with genomic relatedness indices and synapomorphies provide promising approaches to delineating yeast genera and likely those of filamentous fungi as well. The genera Kazachstania , Nakaseomyces and Tetrapisispora are revised and we propose eight new genera and 41 new combinations. Citation : Liu F, Hu Z-D, Yurkov A, et al. 2024. Saccharomycetaceae: delinaeation of fungal genera based on phylogenomic analyses, genomic relatedness indices and genomics-based synapomorphies. Persoonia 52: 1-21. https://doi.org/10.3767/persoonia.2024.52.01., Competing Interests: The authors declare that there is no conflict of interest., (© 2024 Naturalis Biodiversity Center & Westerdijk Fungal Biodiversity Institute.)

Twin births are related with maternal and fetal adverse outcomes. Little was known about the comparability of the cognitive, behavioral development and brain structure between twins and singletons in early adolescence. This retrospective cohort study was based on data from the United States population-based, prospective, longitudinal observational Adolescent Brain Cognitive Development study. Children with complete twin status information were enrolled, and the exposure variable was twin status. Primary outcomes were cognitive, behavioral development and brain structure in early adolescence. Cognitive and behavioral outcomes were assessed by using the NIH Toolbox and Child Behavioral Checklist, respectively. Brain structure was evaluated by the cortical thickness, area, and volume extracted from the magnetic resonance imaging (MRI) data. Subgroup analyses were conducted by prematurity, birth weight, with sibling, genetic profiles, and twin types (zygosity). From 1st September 2016 to 15th November 2018, 11545 children (9477 singletons and 2068 twins) aged 9-10 years were enrolled. Twins showed mildly lower cognitive performance (|t|> 5.104, P-values < 0.001, False Discovery Rate [FDR] < 0.001), better behavioral outcome (|t|> 2.441, P-values < 0.015, FDR < 0.042), such as lower scores for multiple psychiatric disorders and behavioral issues, and smaller cortical volume (t = - 3.854, P-values < 0.001, FDR < 0.001) and cortical area (t = - 3.872, P-values < 0.001, FDR < 0.001). The observed differences still held when stratified for prematurity, birth weight, presence of siblings, genetic profiles, and twin types (zygosity). Furthermore, analyses on the two-year follow-up data showed consistent results with baseline data. Twin status is associated with lower cognitive and better behavioral development in early adolescence accompanied by altered brain structure. Clinicians should be aware of the possible difference when generalizing results from adolescent twin samples to singletons., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Direct interspecies electron transfer (DIET) is essential for maintaining the function and stability of anaerobic microbial consortia. However, only limited natural DIET modes have been identified and DIET engineering remains highly challenging. In this study, an unnatural DIET between Shewanella oneidensis MR-1 (SO, electron donating partner) and Rhodopseudomonas palustris (RP, electron accepting partner) was artificially established by a facile living cell-cell click chemistry strategy. By introducing alkyne- or azide-modified monosaccharides onto the cell outer surface of the target species, precise covalent connections between different species in high proximity were realized through a fast click chemistry reaction. Remarkably, upon covalent connection, outer cell surface C-type cytochromes mediated DIET between SO and RP was achieved and identified, although this was never realized naturally. Moreover, this connection directly shifted the natural H 2 mediated interspecies electron transfer (MIET) to DIET between SO and RP, which delivered superior interspecies electron exchange efficiency. Therefore, this work demonstrated a naturally unachievable DIET and an unprecedented MIET shift to DIET accomplished by cell-cell distance engineering, offering an efficient and versatile solution for DIET engineering, which extends our understanding of DIET and opens up new avenues for DIET exploration and applications., (© 2024 Wiley-VCH GmbH.)

Novel antibiotics are urgently needed to combat the antibiotic-resistance crisis. We present a machine-learning-based approach to predict antimicrobial peptides (AMPs) within the global microbiome and leverage a vast dataset of 63,410 metagenomes and 87,920 prokaryotic genomes from environmental and host-associated habitats to create the AMPSphere, a comprehensive catalog comprising 863,498 non-redundant peptides, few of which match existing databases. AMPSphere provides insights into the evolutionary origins of peptides, including by duplication or gene truncation of longer sequences, and we observed that AMP production varies by habitat. To validate our predictions, we synthesized and tested 100 AMPs against clinically relevant drug-resistant pathogens and human gut commensals both in vitro and in vivo. A total of 79 peptides were active, with 63 targeting pathogens. These active AMPs exhibited antibacterial activity by disrupting bacterial membranes. In conclusion, our approach identified nearly one million prokaryotic AMP sequences, an open-access resource for antibiotic discovery., Competing Interests: Declaration of interests C.F.-N. provides consulting services to Invaio Sciences and is a member of the Scientific Advisory Boards of Nowture S.L. and Phare Bio. The de la Fuente Lab has received research funding or in-kind donations from United Therapeutics, Strata Manufacturing PJSC, and Procter & Gamble, none of which were used in support of this work. An invention disclosure associated with this work has been submitted., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A hitherto unknown class of C 4 -symmetric C aryl -C β (C 3 , C 8 , C 13 , C 18 ) axially chiral porphyrins has been synthesized and the application of their iridium (Ir) complexes in catalytic asymmetric C(sp 3 )-H functionalization is documented. Cyclotetramerization of enantioenriched axially chiral 2-hydroxymethyl-3-naphthyl pyrroles under mild acidic conditions affords, after oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), the C 4 -symmetric α,α,α,α-atropenantiomer as an only isolable diastereomer. Both regioisomeric Ir(Por*)(CO)(Cl) complexes catalyze the carbene C-H insertion reaction affording the same enantiomer, albeit with slight difference in enantioselectivity. With the optimum Ir-complex 3 e, the 2-substituted arylacetic acid derivatives were generated from diazo compounds and cyclohexadiene in excellent yields and enantioselectivities., (© 2024 Wiley-VCH GmbH.)

In the present study, the mitochondrial genomic characteristics of Acanthopsetta nadeshnyi have been reported and have depicted the phylogenetic relationship among Pleuronectidae. Combined with a comparative analysis of 13 PCGs, the TN93 model was used to review the neutral evolution and habitat evolution catalysis of the mitogenome to verify the distancing and purification selectivity of the mitogenome in Pleuronectidae. At the same time, a species differentiation and classification model based on mitogenome analysis data was established. This study is expected to provide a new perspective on the phylogenetic relationship and taxonomic status of A. nadeshnyi and lay a foundation for further exploration of environmental and biological evolutionary mechanisms.

Identifying viruses from metagenomes is a common step to explore the virus composition in the human gut. Here, we introduce VirRep, a hybrid language representation learning framework, for identifying viruses from human gut metagenomes. VirRep combines a context-aware encoder and an evolution-aware encoder to improve sequence representation by incorporating k-mer patterns and sequence homologies. Benchmarking on both simulated and real datasets with varying viral proportions demonstrates that VirRep outperforms state-of-the-art methods. When applied to fecal metagenomes from a colorectal cancer cohort, VirRep identifies 39 high-quality viral species associated with the disease, many of which cannot be detected by existing methods., (© 2024. The Author(s).)

Chlorinated polyfluorinated ether sulfonate, commercially known as F-53B, has been associated with adverse birth outcomes. However, the reproductive toxicology of F-53B on the placenta remains poorly understood. To address this gap, we examined the impact of F-53B on placental injury and its underlying molecular mechanisms in vivo. Pregnant C57BL/6 J female mice were randomly allocated to three groups: the control group, F-53B 0.8 µg/kg/day group, and F-53B 8 µg/kg/day group. After F-53B exposure through free drinking water from gestational day (GD) 0.5-14.5, the F-53B 8 µg/kg/day group exhibited significant increases in placental weights and distinctive histopathological alterations, including inflammatory cell infiltration, heightened syncytiotrophoblast knots, and a loosened trophoblastic basement membrane. Within the F-53B 8 µg/kg/day group, placental tissue exhibited increased apoptosis, as indicated by increased caspase3 activation. Furthermore, F-53B potentially induced the NF-κB signaling pathway activation through IκB-α phosphorylation. Subsequently, this activation upregulated the expression of inflammatory cytokines and components of the NLRP3 inflammasome, including activated caspase1, IL-1β, IL-18, and cleaved gasdermin D (GSDMD), ultimately leading to pyroptosis in the mouse placenta. Our findings reveal a pronounced inflammatory injury in the placenta due to F-53B exposure, suggesting potential reproductive toxicity at concentrations relevant to the human population. Further toxicological and epidemiological investigations are warranted to conclusively assess the reproductive health risks posed by F-53B., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: We aim to compare the effects of proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) on the gut microbiota through longitudinal analysis., Design: Healthy volunteers were randomly assigned to receive either PPI (n=23) or H2RA (n=26) daily for seven consecutive days. We collected oral (saliva) and faecal samples before and after the intervention for metagenomic next-generation sequencing. We analysed intervention-induced alterations in the oral and gut microbiome including microbial abundance and growth rates, oral-to-gut transmissions, and compared differences between the PPI and H2RA groups., Results: Both interventions disrupted the gut microbiota, with PPIs demonstrating more pronounced effects. PPI usage led to a significantly higher extent of oral-to-gut transmission and promoted the growth of specific oral microbes in the gut. This led to a significant increase in both the number and total abundance of oral species present in the gut, including the identification of known disease-associated species like Fusobacterium nucleatum and Streptococcus anginosus . Overall, gut microbiome-based machine learning classifiers could accurately distinguish PPI from non-PPI users, achieving an area under the receiver operating characteristic curve (AUROC) of 0.924, in contrast to an AUROC of 0.509 for H2RA versus non-H2RA users., Conclusion: Our study provides evidence that PPIs have a greater impact on the gut microbiome and oral-to-gut transmission than H2RAs, shedding light on the mechanism underlying the higher risk of certain diseases associated with prolonged PPI use., Trial Registration Number: ChiCTR2300072310., Competing Interests: Competing interests: None declared., (© 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.)

Reyanning Mixture is one of the superior Chinese patent medicine varieties of &quot;Qin medicine&quot;. Based on the idea of quality by design(QbD), the extraction process of the Reyanning Mixture was optimized. The caffeic acid, polydatin, resveratrol, and emodin were used as critical quality attributes(CQAs). The material-liquid ratio, extraction temperature, and extraction time were taken as critical process parameters(CPPs) by the Plackett-Burman test. The mathematical model was established by the star design-effect surface method, and the design space was constructed and verified. The optimal extraction process of the Reyanning Mixture was obtained as follows: material-liquid ratio of 11.84 g·mL~(-1), extraction temperature at 81 ℃, and two extractions. A partial least-square(PLS) quantitative model for CQAs was established by using near-infrared spectroscopy(NIRS) combined with high-performance liquid chromatography(HPLC) under the optimal extraction process. The results showed that the correlation coefficients of the correction set(R&#95;c) and validation set(R&#95;p) of the quantitative models of four CQAs were more than 0.9. The root mean square error of the correction set(RMSEC) were 0.744, 6.71, 3.95, and 1.53 μg·mL~(-1), respectively, and the root mean square error of the validation set(RMSEP) were 0.709, 5.88, 2.92, and 1.59 μg·mL~(-1), respectively. Therefore, the optimized extraction process of the Reyanning Mixture is reasonable, feasible, stable, and reliable. The NIRS quantitative model has a good prediction, which can be used for the rapid content determination of CQAs during extraction. They can provide an experimental basis for the process research and quality control of Reyanning Mixture.

Atherosclerotic disease is a chronic disease that predominantly affects the elderly and is the most common cause of cardiovascular death worldwide. Atherosclerosis is closely related to processes such as abnormal lipid transport and metabolism, impaired endothelial function, inflammation, and oxidative stress. Coenzyme Q10 (CoQ10) is a key component of complex Ⅰ in the electron transport chain and an important endogenous antioxidant that may play a role in decelerating the progression of atherosclerosis. Here, the different forms of CoQ10 presence in the electron transport chain are reviewed, as well as its physiological role in regulating processes such as oxidative stress, inflammatory response, lipid metabolism and cellular autophagy. It was also found that CoQ10 plays beneficial effects in atherosclerosis by mitigating lipid transportation, endothelial inflammation, metabolic abnormalities, and thrombotic processes from the perspectives of molecular mechanisms, animal experiments, and clinical evidence. Besides, the combined use of CoQ10 with other drugs has better synergistic therapeutic effects. It seems reasonable to suggest that CoQ10 could be used in the treatment of atherosclerotic cardiovascular diseases while more basic and clinical studies are needed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A new labdane diterpene ( 1 ), two new norsesquiterpenoids ( 2 - 3 ), as well as eight known terpenoids ( 4 - 11 ) were isolated from the seeds of Alpinia galanga (Zingiberaceae). Their structures and absolute configurations were elucidated by 1D, 2D NMR, MS, and comparison of their experimental and calculated electronic circular dichroism (ECD). The acetylcholinesterase (AChE) inhibitory activities of all the isolated compounds ( 1 - 11 ) were evaluated and the result showed that compounds 6 and 9 had inhibitory activity against AChE, with IC 50 values at 295.70 and 183.91 μM, whereas other compounds did not show any inhibitory activity.

Objective: To explore the predictive value of pulmonary effective arterial elastance (Ea) in patients with heart failure (HF). Methods: This is a retrospective cohort study, which retrospectively included 284 patients with HF who underwent right heart catheterization at Heart Failure Center in Fuwai Hospital between September 2013 and February 2022. Data regarding baseline clinical characteristics, hemodynamic profiles, and prognosis were collected. Ea was calculated as mean pulmonary arterial pressure/stroke volume. Patients were divided into Ea<0.555 group and Ea≥0.555 group according to the median value of Ea (0.555 mmHg/ml, 1 mmHg=0.133 kPa). The primary outcome was the primary clinical event, set as the first occurrence of a series of composite events, including all-cause death, heart transplantation, left ventricular assist device implantation, and HF rehospitalization. Event-free survival was defined as the absence of primary clinical events. Spearman correlation analysis was used to calculate the correlation coefficient between Ea and parameters reflective of right heart function. The Kaplan-Meier analysis was used to compare the different groups for the estimation of outcomes with the log-rank test. We used Cox proportional-hazards regression models to estimate hazard ratios ( HR ) for primary clinical event. Subgroup analysis was performed based on the age, gender, New York Heart Association (NYHA) functional class, left ventricular ejection fraction, presence of pulmonary hypertension, and serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) values. We used receiver operating characteristic (ROC) curve to calculate the area under the curve ( AUC ) of Ea for predicting event-free survival in patients with HF. Results: The median age was 51 years, and 206 (72.5%) patients were male. Ea and pulmonary vascular resistance (PVR) were significantly correlated ( r =0.698, P< 0.001). The correlation between Ea and pulmonary arterial elastance (PAC) were even more significant ( r =-0.888, P <0.001). Compared with Ea<0.555 group, Ea≥0.555 group presented with higher serum NT-proBNP values (4 443 (1 792, 8 554) ng/L vs. 1 721 (480, 4 528)ng/L, P <0.001), higher PVR (3.4 (2.5, 4.7) Wood vs. 1.4 (0.9, 2.2) Wood, P <0.001), lower cardiac output (3.0 (2.3, 3.9) L/min vs. 4.3 (3.8, 4.9) L/min, P <0.001), and lower PAC (1.6 (1.3, 2.0) ml/mmHg vs. 4.0 (3.0, 6.0) ml/mmHg, P <0.001). The median follow-up time was 392 (166, 811) days. The Kaplan-Meier survival curve demonstrated a lower event-free survival rate in the Ea≥0.555 group compared to the Ea<0.555 group ( P log-rank <0.001). After multivariate adjustment, Ea ( HR =1.734, P <0.001) remained significantly associated with the primary outcome. Subgroup analysis indicated that Ea was associated with the primary outcome across all subgroups. The AUC was 0.724 ( P <0.001) for Ea to predict event-free survival calculated from ROC analysis. Conclusions: Ea is closely related to parameters reflective of right ventricular afterload. Increased Ea is an independent predictor of adverse outcomes in patients with HF.

Monolayer (ML) Janus III-VI compounds have attracted the use of multiple competitive platforms for future-generation functional electronics, including non-volatile memories, field effect transistors, and sensors. In this work, the electronic and interfacial properties of ML Ga 2 STe-metal (Au, Ag, Cu, and Al) contacts are systematically investigated using first-principles calculations combined with the non-equilibrium Green's function method. The ML Ga 2 STe-Au/Ag/Al contacts exhibit weak electronic orbital hybridization at the interface, while the ML Ga 2 STe-Cu contact exhibits strong electronic orbital hybridization. The Te surface is more conducive to electron injection than the S surface in ML Ga 2 STe-metal contact. Quantum transport calculations revealed that when the Te side of the ML Ga 2 STe is in contact with Au, Ag and Cu electrodes, p-type Schottky contacts are formed. When in contact with the Al electrode, an n-type Schottky contact is formed with an electron SBH of 0.079 eV. When the S side of ML Ga 2 STe is in contact with Au and Al electrodes, p-type Schottky contacts are formed, and when it is in contact with Ag and Cu electrodes, n-type Schottky contacts are formed. Our study will guide the selection of appropriate metal electrodes for constructing ML Ga 2 STe devices.

Current metagenome assembled human gut phage catalogs contained mostly fragmented genomes. Here, comprehensive gut virome detection procedure is developed involving virus-like particle (VLP) enrichment from ≈500 g feces and combined sequencing of short- and long-read. Applied to 135 samples, a Chinese Gut Virome Catalog (CHGV) is assembled consisting of 21,499 non-redundant viral operational taxonomic units (vOTUs) that are significantly longer than those obtained by short-read sequencing and contained ≈35% (7675) complete genomes, which is ≈nine times more than those in the Gut Virome Database (GVD, ≈4%, 1,443). Interestingly, the majority (≈60%, 13,356) of the CHGV vOTUs are obtained by either long-read or hybrid assemblies, with little overlap with those assembled from only the short-read data. With this dataset, vast diversity of the gut virome is elucidated, including the identification of 32% (6,962) novel vOTUs compare to public gut virome databases, dozens of phages that are more prevalent than the crAssphages and/or Gubaphages, and several viral clades that are more diverse than the two. Finally, the functional capacities are also characterized of the CHGV encoded proteins and constructed a viral-host interaction network to facilitate future research and applications., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Four new steroidal glycosides (1-4), including two steroidal saponins named lililancifoloside B and C (1-2), one pregnane glycoside named lililancifoloside D (3), and one C22-steroidal lactone glycoside named lililancifoloside E (4), together with five known ones (5-9), were isolated from the bulbs of Lilium lancifolium Thunb. By using spectroscopic analysis, including 1D, 2D NMR, and HR-ESI-MS, the structures of 1-4 were elucidated. All isolates were tested for their cytotoxic potential against the MCF-7, MDA-MB-231, HepG2, and A549 cell lines. Compound 6 distinguished out among them, IC 50 values of 3.31, 5.23, 1.78, and 1.49 μM against the four cell lines, respectively. Other compounds such as compound 3, 5, and 9 have also shown specific cytotoxic activity. Next, studies showed that compound 6 might cause HepG2 cells to undergo a cell cycle arrest during the G2/M phase and apoptosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A enantioselective tandem transformation, concerning asymmetric allylic decarboxylative addition and cyclization of N -nosylimines with vinylethylene carbonates (VECs), in the presence of [Rh(C 2 H 4 ) 2 Cl] 2 , chiral sulfoxide- N -olefin tridentate ligand has been developed. The reaction of VECs with various substituted N -nosylimines proceeded smoothly under mild conditions, providing highly functionalized oxazolidine frameworks in good to high yields with good to excellent enantioselectivity.

The foregut, located at the front of the digestive tract, serves a vital role in insects by storing and grinding food into small particles. The innermost layer of the foregut known as the chitinous intima, comes into direct contact with the food and acts as a protective barrier against abrasive particles. Knickkopf (Knk) is required for chitin organization in the chitinous exoskeleton, tracheae and wings. Despite its significance, little is known about the biological function of Knk in the foregut. In this study, we found that LmKnk was stably expressed in the foregut, and highly expressed before molting in Locusta migratoria. To ascertain the biological function of LmKnk in the foregut, we synthesized specific double-stranded LmKnk (dsLmKnk) and injected it into locusts. Our findings showed a significant decrease in the foregut size, along with reduced food intake and accumulation of residues in the foregut after dsLmKnk injection. Morphological observations revealed that newly formed intima became thinner and lacked chitin lamella. Furthermore, fluorescence immunohistochemistry revealed that LmKnk was located in the apical region of new intima and epithelial cells. Taken together, this study provides insights into the biological function of LmKnk in the foregut, and identifies the potential target gene for exploring biological pest management strategies., (© 2024 Institute of Zoology, Chinese Academy of Sciences.)

The brain is constituted of heterogeneous types of neuronal and non-neuronal cells, which are organized into distinct anatomical regions, and show precise regulation of gene expression during development, aging and function. In the current database release, STAB2 provides a systematic cellular map of the human and mouse brain by integrating recently published large-scale single-cell and single-nucleus RNA-sequencing datasets from diverse regions and across lifespan. We applied a hierarchical strategy of unsupervised clustering on the integrated single-cell transcriptomic datasets to precisely annotate the cell types and subtypes in the human and mouse brain. Currently, STAB2 includes 71 and 61 different cell subtypes defined in the human and mouse brain, respectively. It covers 63 subregions and 15 developmental stages of human brain, and 38 subregions and 30 developmental stages of mouse brain, generating a comprehensive atlas for exploring spatiotemporal transcriptomic dynamics in the mammalian brain. We also augmented web interfaces for querying and visualizing the gene expression in specific cell types. STAB2 is freely available at https://mai.fudan.edu.cn/stab2., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Berberine has been demonstrated to alleviate cerebral ischemia/reperfusion injury, but its neuroprotective mechanism has yet to be understood. Studies have indicated that ischemic neuronal damage was frequently driven by autophagic/lysosomal dysfunction, which could be restored by boosting transcription factor EB (TFEB) nuclear translocation. Therefore, this study investigated the pharmacological effects of berberine on TFEB-regulated autophagic/lysosomal signaling in neurons after cerebral stroke. A rat model of ischemic stroke and a neuronal ischemia model in HT22 cells were prepared using middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation (OGD), respectively. Berberine was pre-administered at a dose of 100[Formula: see text]mg/kg/d for three days in rats and 90[Formula: see text][Formula: see text]M in HT22 neurons for 12[Formula: see text]h. 24[Formula: see text]h after MCAO and 2[Formula: see text]h after OGD, the penumbral tissues and OGD neurons were obtained to detect nuclear and cytoplasmic TFEB, and the key proteins in the autophagic/lysosomal pathway were examined using western blot and immunofluorescence, respectively. Meanwhile, neuron survival, infarct volume, and neurological deficits were assessed to evaluate the therapeutic efficacy. The results showed that berberine prominently facilitated TFEB nuclear translocation, as indicated by increased nuclear expression in penumbral neurons as well as in OGD HT22 cells. Consequently, both autophagic activity and lysosomal capacity were simultaneously augmented to alleviate the ischemic injury. However, berberine-conferred neuroprotection could be greatly counteracted by lysosomal inhibitor Bafilomycin A1 (Baf-A1). Meanwhile, autophagy inhibitor 3-Methyladenine (3-MA) also slightly neutralized the pharmacological effect of berberine on ameliorating autophagic/lysosomal dysfunction. Our study suggests that berberine-induced neuroprotection against ischemic stroke is elicited by enhancing autophagic flux via facilitation of TFEB nuclear translocation in neurons.

Mendelian randomization (MR) is an effective approach for revealing causal risk factors that underpin complex traits and diseases. While MR has been more widely applied under two-sample settings, it is more promising to be used in one single large cohort given the rise of biobank-scale datasets that simultaneously contain genotype data, brain imaging data, and matched complex traits from the same individual. However, most existing multivariable MR methods have been developed for two-sample setting or a small number of exposures. In this study, we introduce a one-sample multivariable MR method based on partial least squares and Lasso regression (MR-PL). MR-PL is capable of considering the correlation among exposures (e.g., brain imaging features) when the number of exposures is extremely upscaled, while also correcting for winner's curse bias. We performed extensive and systematic simulations, and demonstrated the robustness and reliability of our method. Comprehensive simulations confirmed that MR-PL can generate more precise causal estimates with lower false positive rates than alternative approaches. Finally, we applied MR-PL to the datasets from UK Biobank to reveal the causal effects of 36 white matter tracts on 180 complex traits, and showed putative white matter tracts that are implicated in smoking, blood vascular function-related traits, and eating behaviors., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

PIWI-interacting RNAs (piRNAs) are highly expressed in various cardiovascular diseases. However, their role in cardiomyocyte death caused by ischemia/reperfusion (I/R) injury, especially necroptosis, remains elusive. In this study, a heart necroptosis-associated piRNA (HNEAP) is found that regulates cardiomyocyte necroptosis by targeting DNA methyltransferase 1 (DNMT1)-mediated 5-methylcytosine (m 5 C) methylation of the activating transcription factor 7 (Atf7) mRNA transcript. HNEAP expression level is significantly elevated in hypoxia/reoxygenation (H/R)-exposed cardiomyocytes and I/R-injured mouse hearts. Loss of HNEAP inhibited cardiomyocyte necroptosis and ameliorated cardiac function in mice. Mechanistically, HNEAP directly interacts with DNMT1 and attenuates m 5 C methylation of the Atf7 mRNA transcript, which increases Atf7 expression level. ATF7 can further downregulate the transcription of Chmp2a, an inhibitor of necroptosis, resulting in the reduction of Chmp2a level and the progression of cardiomyocyte necroptosis. The findings reveal that piRNA-mediated m 5 C methylation is involved in the regulation of cardiomyocyte necroptosis. Thus, the HNEAP-DNMT1-ATF7-CHMP2A axis may be a potential target for attenuating cardiac injury caused by necroptosis in ischemic heart disease., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Patients with hepatobiliary tumors who accept radiotherapy are at risk for radiation-induced liver fibrosis. MicroRNAs (miRNAs) have been implicated in the pathogenesis of radiation-induced liver damage and possess potential as novel biomarkers and therapeutic targets. However, the role of miR-146a-5p in radiation-induced liver fibrosis is less well understood. The current study was designed to evaluate the role of miR-146a-5p in radiation-induced liver fibrosis in mice and to investigate the possible mechanisms involved in miR-146a-5p-mediated effects. The experiments were performed on Institute of Cancer Research (ICR) mice which received fractionated radiation (30 Gy in 5 fractions) to the liver. The results show radiation could induce histopathological changes, liver dysfunction and fibrosis accompanied with decreased miR-146a-5p expression. miR-146a-5p agomir treatment resulted in recovery of liver function and reduced the amount of alpha-smooth muscle actin (α-SMA), collagen 1, protein tyrosine phosphatase receptor type A (PTPRA) and phosphorylated SRC in the livers of irradiated mice. Therefore, our study reveals that miR-146a-5p inhibits the progression of hepatic fibrosis after radiation treatment. And the beneficial role of miR-146a-5p may be relevant to PTPRA-SRC signaling pathway., (©2023 by Radiation Research Society. All rights of reproduction in any form reserved.)

The aim of this study was to investigate the clinical characteristics and prognosis of patients hospitalized with heart failure with preserved ejection fraction (HFpEF) and low N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. Seven hundred ninety consecutive patients hospitalized with HFpEF from 2006 to 2017 were enrolled. Clinical characteristics and outcomes were compared between low NT-proBNP group (<300 ng/L) and elevated NT-proBNP group (≥300 ng/L). 108 HFpEF patients (13.7%) presented with low NT-proBNP levels. Age, body mass index, atrial fibrillation, New York Heart Association functional class, and albumin were independent predictors of low NT-proBNP levels in HFpEF patients. During the median follow-up duration of 1103 days, 11 patients (10.2%) in low NT-proBNP group suffered from primary endpoint event. Elevated NT-proBNP group had a higher risk of all-cause death or heart transplantation than low NT-proBNP group (adjusted HR [95%CI]: 2.36 [1.24,4.49], P = .009). Stratified analyses showed that the association between NT-proBNP (elevated NT-proBNP group vs low NT-proBNP group) and risk of all-cause death or heart transplantation was stronger in non-atrial fibrillation patients than in atrial fibrillation patients (P value for interaction = .025). Furthermore, the associations between NT-proBNP and risk of all-cause death or heart transplantation were stronger in younger and male patients than in older and female patients. However, both subgroups only reached borderline significant (P values for interaction = .062 and .084, respectively). Our findings suggest that low NT-proBNP levels were common in patients hospitalized with HFpEF. Patients with HFpEF and low NT-proBNP levels had a better prognosis than those with elevated NT-proBNP levels, particularly in younger, male, and non-atrial fibrillation patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Cytosine base editors (CBEs), which enable precise C-to-T substitutions, have been restricted by potential safety risks, including DNA off-target edits, RNA off-target edits and additional genotoxicity such as DNA damages induced by double-strand breaks (DSBs). Though DNA and RNA off-target edits have been ameliorated via various strategies, evaluation and minimization of DSB-associated DNA damage risks for most CBEs remain to be resolved. Here we demonstrate that YE1, an engineered CBE variant with minimized DNA and RNA off-target edits, could induce prominent DSB-associated DNA damage risks, manifested as γH2AX accumulation in human cells. We then perform deaminase engineering for two deaminases lamprey LjCDA1 and human APOBEC3A, and generate divergent CBE variants with eliminated DSB-associated DNA damage risks, in addition to minimized DNA/RNA off-target edits. Furthermore, the editing scopes and sequence preferences of APOBEC3A-derived CBEs could be further diversified by internal fusion strategy. Taken together, this study provides updated evaluation platform for DSB-associated DNA damage risks of CBEs and further generates a series of safer toolkits with diversified editing signatures to expand their applications., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

In recent years, the two-dimensional (2D) semiconductor α-In 2 Se 3 has great potential for applications in the fields of electronics and optoelectronics due to its spontaneous iron electrolysis properties. Through ab initio electronic structure calculations and quantum transport simulations, the interface properties and transport properties of α-In 2 Se 3 /Au contacts with different polarization directions are studied, and a two-dimensional α-In 2 Se 3 asymmetric metal contact design is proposed. When α-In 2 Se 3 is polarized upward, it forms an n-type Schottky contact with Au. While when α-In 2 Se 3 is polarized downward, it forms a p-type Schottky contact with Au. More importantly, significant rectification effect is found in the asymmetric Au/α-In 2 Se 3 /Au field-effect transistor. The carrier transports under positive and negative bias voltages are found to be dominated by thermionic excitation and tunneling, respectively. These findings provide guidance for the further design of 2D α-In 2 Se 3 -based transistors., (© 2023. The Author(s).)

The abnormal initiation of autophagy flux in neurons after ischemic stroke caused dysfunction of autophagy-lysosome, which not only led to autophagy flux blockage, but also resulted in autophagic death of neurons. However, the pathological mechanism of neuronal autophagy-lysosome dysfunction did not form a unified viewpoint until now. In this review, taking the autophagy lysosomal dysfunction of neurons as a starting point, we summarized the molecular mechanisms that led to neuronal autophagy lysosomal dysfunction after ischemic stroke, which would provide theoretical basis for the clinical treatment of ischemic stroke., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To investigate the effect of electroacupuncture(EA) stimulation on proliferation and diffe-rentiation of endogenous neural stem cells as well as Jagged1/Notch1 pathway in AD model mice, so as to explore its mechanism underlying amelioration of AD., Methods: A total of 40 6-week-old male APP/PS1 transgenic AD mice were randomly divided into EA group ( n =20) and AD model group ( n =20), and other 20 normal C57BL/6J mice of the same age were used as the normal control group. The mice in the EA group received EA (10 Hz, 2 mA) at "Baihui"(GV20), "Fengfu"(GV16) and bilateral "Shenshu" (BL23) for 20 min, once daily, 6 days a week for 16 weeks. The mice's learning-memory ability was detected by Morris water maze tests. The Aβ senile plaques in the hippocampal CA1 region were detected by Congo red staining, the immunofluorescence double label of BrdU, neuronal nuclear antigen (NeuN) and astrocyte specific protein GFAP in dentate gyrus of hippocampus was performed for detecting the proliferation and differentiation of the endogenous neural stem cells. The expression levels of Nestin (neuron specific protein) and GFAP were detected by Western blot, and those of Jagged1 and Notch1 mRNAs and proteins in the hippocampus were detected by real-time fluorescence quantifative PCR and Western blot., Results: Compared with the normal control group, the escape latencies at 2 nd , 3 rd and 4 th day, and Aβ senile plaques were significantly increased ( P <0.05, P <0.01), whereas the platform crossing times and time spent in the target quadrant, the expression levels of Jagged1 mRNA and Nestin protein were remarkably down-regulated ( P <0.05) in the model group. Following EA intervention, the escape latencies at the 3 rd and 4 th day, Aβ senile plaques, immunofluorescence density of BrdU/GFAP, and GFAP protein expression were pronouncedly decreased ( P <0.05, P <0.01), while the platform crossing times, platform quadrant residence time, immunofluorescence density of BrdU/NeuN, expression levels of Jagged1 and Notch1 mRNAs and proteins and Nestin protein evidently increased ( P <0.05, P <0.01), suggesting an enhancement of proliferation and diffe-rentiation of endogenous neural stem cells into neurons and a suppression of the proliferation and differentiation towards astrocytes in the hippocampus., Conclusion: EA at GV20, GV16 and BL23 can improve the learning-memory ability, promote the proliferation and differentiation of endogenous neural stem cells towards neurons and inhibit the proliferation and differentiation of endogenous neural stem cells towards astrocytes in the hippocampus, which may be achieved by regulating Jagged1/Notch1 pathway.

Background: A growing body of neuroimaging studies has reported common neural abnormalities among mental disorders in adults. However, it is unclear whether the distinct disorder-specific mechanisms operate during adolescence despite the overlap among disorders., Methods: We studied a large cohort of more than 11 000 preadolescent (age 9-10 yr) children from the Adolescent Brain and Cognitive Development cohort. We adopted a regrouping approach to compare cortical thickness (CT) alterations and longitudinal changes between healthy controls ( n = 4041) and externalizing ( n = 1182), internalizing ( n = 1959) and thought disorder ( n = 347) groups. Genome-wide association study (GWAS) was performed on regional CT across 4468 unrelated European youth., Results: Youth with externalizing or internalizing disorders exhibited increased regional CT compared with controls. Externalizing ( p = 8 × 10 -4 , Cohen d = 0.10) and internalizing disorders ( p = 2 × 10 -3 , Cohen d = 0.08) shared thicker CT in the left pars opercularis. The somatosensory and the primary auditory cortex were uniquely affected in externalizing disorders, whereas the primary motor cortex and higher-order visual association areas were uniquely affected in internalizing disorders. Only youth with externalizing disorders showed decelerated cortical thinning from age 10-12 years. The GWAS found 59 genome-wide significant associated genetic variants across these regions. Cortical thickness in common regions was associated with glutamatergic neurons, while internalizing-specific regional CT was associated with astrocytes, oligodendrocyte progenitor cells and GABAergic neurons., Limitations: The sample size of the GWAS was relatively small., Conclusion: Our study provides strong evidence for the presence of specificity in CT, developmental trajectories and underlying genetic underpinnings among externalizing and internalizing disorders during early adolescence. Our results support the neurobiological validity of the regrouping approach that could supplement the use of a dimensional approach in future clinical practice., Competing Interests: Competing interests: B.J. Sahakian reports grants from Lundbeck Foundation and Leverhulme Trust; royalties from PopReach; consulting fees from Cambridge Cognition; and honoraria from the Alberta Psychiatric Association. She is a member of the Human Brain Project Science and Infrastructure Advisory Board, the academic representative for the National Institute for Health and Care Excellence guidelines on harmful gambling, and a member of the EBRAINS Science and Technology Committee. T.W. Robbins reports consultancies with Cambridge Cognition, Arcadia, Greenfield Bioventures, Heptares, Takeda, Lundbeck, Merck, Sharp and Dohme; and royalties from Cambridge Cognition. Research Grants with Shionogi and GlaxoSmithKline and editorial honoraria with Springer Nature and Elsevier. L. Palaniyappan reports personal fees from Janssen Canada, Otsuka Canada, SPMM Course Limited UK and the Canadian Psychiatric Association; book royalties from Oxford University Press; and investigator-initiated educational grants from Janssen Canada, Sunovion and Otsuka Canada outside the submitted work. He is also co-editor-in-chief of JPN; he was not involved in the review or decision to accept this manuscript for publication. None of the above-listed companies or funding agencies had any influence on the content of this article. No other competing interests were declared., (© 2023 CMA Impact Inc. or its licensors.)

DNA methylation plays a crucial role in the survival of bacteriophages (phages), yet the understanding of their genome methylation remains limited. In this study, DNA methylation patterns are analyzed in 8848 metagenome-assembled high-quality phages from 104 fecal samples using single-molecule real-time sequencing. The results demonstrate that 97.60% of gut phages exhibit methylation, with certain factors correlating with methylation densities. Phages with higher methylation densities appear to have potential viability advantages. Strikingly, more than one-third of the phages possess their own DNA methyltransferases (MTases). Increased MTase copies are associated with higher genome methylation densities, specific methylation motifs, and elevated prevalence of certain phage groups. Notably, the majority of these MTases share close homology with those encoded by gut bacteria, suggesting their exchange during phage-bacterium interactions. Furthermore, these MTases can be employed to accurately predict phage-host relationships. Overall, the findings indicate the widespread utilization of DNA methylation by gut DNA phages as an evasion mechanism against host defense systems, with a substantial contribution from phage-encoded MTases., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Objective: To analyze the associated factors with stimulation-induced seizures (SIS) and the relevant factors in predicting surgical outcomes., Methods: We analyzed 80 consecutive epilepsy patients explored by stereo-electroencephalography with routine electrical stimulation mapping (ESM). If seizures induced by ESM, patients were classified as SIS-positive (SIS-P); otherwise, SIS-negative (SIS-N). Patients received radical surgery were further classified as favorable (Engel I) and unfavorable (Engel II-IV) groups., Results: Of the 80 patients included, we identified 44 (55.0%) and 36(45.0%) patients in the SIS-P and SIS-N groups, respectively. Multivariate analysis revealed that the seizure onset pattern (SOP) of preceding repetitive epileptiform discharges following LVFA (PRED→LVFA) (OR 3.319, 95% CI 1.200-9.183, P = 0.021) and pathology of focal cortical dysplasia (FCD) type II (OR 3.943, 95% CI 1.093-14.226, P = 0.036) were independent factors influencing whether the electrical stimulation can induce a seizure. Among the patients received radical surgery, there were 55 and 15 patients in the favorable and unfavorable groups separately. Multivariate analysis revealed that the SOP of PRED→LVFA induced seizures by stimulation (OR 11.409, 95% CI 1.182-110.161, P = 0.035) and bilateral implantation (OR 0.048, 95% CI 0.005-0.497, P = 0.011) were independent factors affecting surgical outcomes. The previous epilepsy surgery had a trend to be a negative factor with SIS (OR 0.156, 95% CI 0.028-0.880, P = 0.035) and surgical outcomes (OR 0.253, 95% CI 0.053-1.219, P = 0.087)., Conclusion: ESM is a highly valuable method for localizing the seizure onset zone. The SOP of PRED→LVFA and FCD type II were associated with elicitation of SIS by ESM, whereas a previous epilepsy surgery showed a negative association. Furthermore, the SOP of PRED→LVFA together with SIS in the same patient predicted favorable surgical outcomes, whereas bilateral electrode implantation predicted unfavorable outcomes., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Objective: To investigate the risk factors of microvascular invasion (MVI) in China liver cancer staging system stage Ⅰa (CNLC Ⅰa) hepatocellular carcinoma (HCC), and develop a nomogram for predicting MVI based on clinical and radiographic data. Methods: This retrospective study focused on CNLC Ⅰa HCC patients who underwent radical resection at the Cancer Hospital, Chinese Academy of Medical Sciences from January 2016 to December 2020. Patients' clinical characteristics and laboratory test results and pre-surgery gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging results were collected. The clinical and radiographic risk factors for MVI were identified by univariate and multivariate logistic regression analyses and used for the construction of the predictive nomogram. The nomogram model was then internally validated, and its performance was assessed. Results: A total of 104 patients were divided into the MVI-positive group ( n =28) and the MVI-negative group ( n =76). Multivariate logistic regression analysis at the P <0.1 level identified serum alpha-ferroprotein >7 ng/ml, total bilirubin >21 μmol/L, prothrombin time >12.5 s, non-smooth margin, and incomplete or absent capsule as risk factors of MVI, based on which a nomogram model was built. The model achieved an area under the curve (AUC) value of 0.867 (95% confidence interval, 0.791-0.944) in the internal validation. The sensitivity and specificity of the nomogram model were 0.786 and 0.829, respectively, with the prediction curve nearly overlapping the ideal curve. Based on the Hosmer-Lemeshow test, the predicted and real results were not significantly different ( P =0.956). Conclusions: The probability of MVI of CNLC Ⅰa HCC can be objectively predicted by the monogram model that quantifies the clinical and radiographic risk factors. The model can also help clinicians select individualized surgical plans to improve the long-term prognosis of patients.

Background: The fungal component of the human gut microbiome, also known as the mycobiome, plays a vital role in intestinal ecology and human health. However, the overall structure of the gut mycobiome as well as the inter-individual variations in fungal composition remains largely unknown. In this study, we collected a total of 3363 fungal sequencing samples from 16 cohorts across three continents, including 572 newly profiled samples from China., Results: We identify and characterize four mycobiome enterotypes using ITS profiling of 3363 samples from 16 cohorts. These enterotypes exhibit stability across populations and geographical locations and significant correlation with bacterial enterotypes. Particularly, we notice that fungal enterotypes have a strong age preference, where the enterotype dominated by Candida (i.e., Can&#95;type enterotype) is enriched in the elderly population and confers an increased risk of multiple diseases associated with a compromised intestinal barrier. In addition, bidirectional mediation analysis reveals that the fungi-contributed aerobic respiration pathway associated with the Can&#95;type enterotype might mediate the association between the compromised intestinal barrier and aging., Conclusions: We show that the human gut mycobiome has stable compositional patterns across individuals and significantly correlates with multiple host factors, such as diseases and host age. Video Abstract., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: To assess the link between serum potassium ( K + ) and all-cause mortality in hospitalized heart failure (HF) patients., Methods: Hospitalized HF patients (n = 3114) were analyzed at the Fuwai Hospital Heart Failure Center. Before discharge, HF patients were divided into four groups according to the K + level quartiles: K + ≤ 3.96 mmol/L (Q1), 3.96 < K + ≤ 4.22 mmol/L (Q2), 4.22 < K + ≤ 4.52 mmol/L (Q3), and K + > 4.52 mmol/L (Q4). At 90 days, 2 years, and maximal follow-up, all-cause mortality was the primary outcome., Results: Patients with HF in the Q4 group had worse cardiac function, higher N-terminal pro-B-type natriuretic peptide levels, lower left ventricular ejection fractions and lower estimated glomerular filtration rates than patients in the Q2 group. In the multivariate-adjusted Cox analysis, the mortality assessed during the 90-day, 2-year, and maximal follow-up examinations increased in the Q4 group of HF patients but not in the Q1 and Q3 groups. The Q4 group had a 28% (hazard ratio [HR]: 1.28, 95% confidence interval [CI]: 1.09-1.49, p = 0.002) higher risk of all-cause mortality at maximum follow-up. Hypokalemia and hyperkalemia were linked to increased HF mortality risk at the 90-day, 2-year, and maximal follow-up periods., Conclusions: Serum K + levels had a J-shaped association with all-cause mortality in HF patients. Both hypokalemia and a K + level of > 4.52 mmol/L were associated with increased all-cause mortality in the short term and long term, suggesting a narrow target K + range in HF patients., Clinical Trial Registration: Unique Identifier: NCT02664818; URL: clinicaltrials.gov., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2023 The Author(s). Published by IMR Press.)