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Abstract Photosynthesis converting solar energy to chemical energy is one of the most important chemical reactions on earth. In cyanobacteria, light energy is captured by antenna system phycobilisomes (PBSs) and transferred to photosynthetic reaction centers of photosystem II (PSII) and photosystem I (PSI). While most of the protein complexes involved in photosynthesis have been characterized by in vitro structural analyses, how these protein complexes function together in vivo is not well understood. Here we implemented STAgSPA, an in situ structural analysis strategy, to solve the native structure of PBS–PSII supercomplex from the cyanobacteria Arthrospira sp. FACHB439 at resolution of ~3.5 Å. The structure reveals coupling details among adjacent PBSs and PSII dimers, and the collaborative energy transfer mechanism mediated by multiple super-PBS in cyanobacteria. Our results provide insights into the diversity of photosynthesis-related systems between prokaryotic cyanobacteria and eukaryotic red algae but are also a methodological demonstration for high-resolution structural analysis in cellular or tissue samples.

Abstract Background The adenoids act as a reservoir of bacterial pathogens and immune molecules, and they are significantly involved in children with otitis media with effusion (OME). As an essential carrier of intercellular substance transfer and signal transduction, exosomes with different biological functions can be secreted by various types of cells. There remains significant uncertainty regarding the clinical relevance of exosomes to OME, especially in its pathophysiologic development. In this study, we will seek to determine the biological functions of exosomes in children with adenoid hypertrophy accompanied by OME (AHOME). Methods The diagnostic criteria for OME in children aged 4–10 years include a disease duration of at least 3 months, type B or C acoustic immittance, and varying degrees of conductive hearing loss. Adenoidal hypertrophy is diagnosed when nasal endoscopy shows at least 60% adenoidal occlusion in the nostrils or when nasopharyngeal lateral X-ray shows A/N > 0.6. Children who meet the indications for adenoidectomy surgery undergo adenoidectomy. Peripheral blood, nasopharyngeal swab, and adenoid tissue will be collected from patients, and the exosomes will be isolated from the samples. Following the initial collection, patients will undergo adenoidectomy and peripheral blood and nasopharyngeal swabs will be collected again after 3 months. Expected results This study aims to identify differences in exosomes from preoperative adenoid tissue and peripheral blood samples between children with AHOME and those with adenoid hypertrophy alone. Additionally, it seeks to determine changes in microbial diversity in adenoid tissue between these groups. Conclusions The findings are expected to provide new insights into the diagnosis and treatment of OME, to identify novel biomarkers, and to enhance our understanding of the pathophysiology of OME, potentially leading to the development of innovative diagnostic and therapeutic approaches.

Abstract Background Understanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis. Results Our study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota-associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA Il-10 −/− mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipient Il-10 −/− mice. Engraftment of human-to-mouse FMT stochastically varied with individual transplantation events more than mouse-adapted FMT. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamed Il-10 −/− host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant to Il-10 −/− mice than the distinct microbiota reassembled in non-inflamed WT hosts. Conclusions Our findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated by gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer. Video Abstract

Abstract The agriculture Internet of Things (IoT) has been widely applied in assisting pear farmers with pest and disease prediction, as well as precise crop management, by providing real-time monitoring and alerting capabilities. To enhance the effectiveness of agriculture IoT monitoring applications, clustering protocols are utilized in the data transmission of agricultural wireless sensor networks (AWSNs). However, the selection of cluster heads is a NP-hard problem, which cannot be solved effectively by conventional algorithms. Based on this, This paper proposes a novel AWSNs clustering model that comprehensively considers multiple factors, including node energy, node degree, average distance and delay. Furthermore, a novel high-performance cluster protocol based on Gaussian mutation and sine cosine firefly algorithm (GSHFA-HCP) is proposed to meet the practical requirements of different scenarios. The innovative Gaussian mutation strategy and sine–cosine hybrid strategy are introduced to optimize the clustering scheme effectively. Additionally, an efficient inter-cluster data transmission mechanism is designed based on distance between nodes, residual energy, and load. The experimental results show that compared with other four popular schemes, the proposed GSHFA-HCP protocol has significant performance improvement in reducing network energy consumption, extending network life and reducing transmission delay. In comparison with other protocols, GSHFA-HCP achieves optimization rates of 63.69%, 17.2%, 19.56%, and 35.78% for network lifespan, throughput, transmission delay, and packet loss rate, respectively.

Growing evidences indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two neurodegenerative disorders. The GGGGCC·GGCCCC repeat RNA expansion in chromosome 9 open reading frame 72 (C9orf72) is the most genetic cause of both ALS and FTD. According to the previous studies, GGGGCC·GGCCCC repeat undergoes the unconventional repeat-associated non-ATG translation, which produces dipeptide repeat (DPR) proteins. Although there is a growing understanding that C9orf72 DPRs have a strong ability to harm neurons and induce C9orf72-linked ALS/FTD, whether these DPRs can affect autophagy remains unclear. In the present study, we find that poly-GR and poly-PR, two arginine-containing DPRs which display the most cytotoxic properties according to the previous studies, strongly inhibit starvation-induced autophagy. Moreover, our data indicate that arginine-rich DPRs enhance the interaction between BCL2 and BECN1/Beclin 1 by inhibiting BCL2 phosphorylation, therefore they can impair autophagic clearance of neurodegenerative disease-associated protein aggregates under starvation condition in cells. Importantly, our study not only highlights the role of C9orf72 DPR in autophagy dysfunction, but also provides novel insight that pharmacological intervention of autophagy using SW063058, a small molecule compound that can disrupt the interaction between BECN1 and BCL2, may reduce C9orf72 DPR-induced neurotoxicity.

Poor seedling emergence is a challenge for direct seeding of rice under deep-sowing field conditions. Here we reveal that UDP-glucosyltransferase OsUGT75A promotes rice seedling emergence under deep-sowing conditions by increasing shoot length. Expression of OsUGT75A was higher in the middle regions of the shoot and in shoots under deep-sowing conditions. Levels of free abscisic acid (ABA) and jasmonates (JA) were higher in shoots of OsUGT75A mutants than in those of wild-type plants, and OsUGT75A mutants were more sensitive to ABA and JA treatments. Reduced shoot length was attributed to higher ABA INSENSITIVE 3 (OsABI3) expression and lower JASMONATE-ZIM domain protein (OsJAZ) expression in shoots. Shoot extension by OsUGT75A is achieved mainly by promotion of cell elongation. An elite haplotype of OsUGT75A associated with increased shoot length was identified among indica rice accessions. OsUGT75A acts to increase seedling emergence under deep-sowing conditions.

BackgroundTinnitus is a complex and heterogeneous disease that has been identified as a common manifestation of COVID-19. To gain a comprehensive understanding of tinnitus symptoms in individuals following COVID-19 infection, we conducted an online survey called the China Ear Nose and Throat Symptom Survey in the COVID-19 Pandemic (CENTSS) among the Chinese population. ObjectiveOur objective was to investigate tinnitus and ear-related symptoms after COVID-19 infection in the Chinese population, with the aim of providing a solid empirical foundation for improved health care. The findings from CENTSS can contribute to the development of enhanced management strategies for tinnitus in the context of long COVID. By gaining a better understanding of the factors contributing to tinnitus in individuals with COVID-19, health care providers can tailor interventions to address the specific needs of affected patients. Furthermore, this study serves as a basis for research on the long-term consequences of COVID-19 infection and its associated tinnitus symptoms. MethodsA quantitative, online, cross-sectional survey study design was used to explore the impact of the COVID-19 pandemic on experiences with tinnitus in China. Data were collected through an online questionnaire designed to identify the presence of tinnitus and its impacts. Descriptive statistics were used to analyze individuals' demographic characteristics, COVID-19 infection–related ear symptoms, and the cognitive and emotional implications of tinnitus. Univariable and multivariable logistic regression analyses were used to model the cross-sectional baseline associations between demographic characteristics, noise exposure, educational level, health and lifestyle factors, and the occurrence of tinnitus. ResultsBetween December 19, 2022, and February 1, 2023, we obtained responses from 1262 Chinese participants representing 24 regions, with an average age of 37 years. Among them, 540 patients (42.8%) reported experiencing ear-related symptoms after COVID-19 infection. Only 114 (9%) of these patients sought medical attention specifically for their ear symptoms, while 426 (33.8%) did not seek hospital care. Tinnitus emerged as the most prevalent and impactful symptom among all ear-related symptoms experienced after COVID-19 infection. Of the respondents, female participants (688/888, 77.78%), younger individuals (

Abstract Hereditary deafness is a common neurosensory disorder, and 148 non‐syndromic deafness genes have been identified to date. Gene therapy has been used to treat a variety of genetic diseases, but no gene therapy drug for hereditary deafness has been approved for clinical use. At present, several clinical trials of gene therapy for hereditary deafness are underway. However, few normative documents have been issued to guide the standardization of gene therapy for hearing loss, and this document is the first global gene therapy guideline for hereditary hearing loss. The guidelines were jointly developed and drafted by experienced audiologists, virologists and biologists who are vigorously involved in inner ear gene therapy research in the Hearing, Speech and Communication Subsociety of Biophysical Society of China, Audiology Development Foundation Of China and Audiology Subsociety of Jiangsu Medical Association. These guidelines cover preclinical research and clinical practice of gene therapy for hereditary deafness, including indications, key points of pre‐clinical research, patient selection criteria, pre‐clinical preparation, drug efficacy, drug safety evaluation criteria, ethical review, etc. We hope that the guidelines will promote the standardization of clinical practice related to gene therapy for hereditary deafness in China and around the world.

Abstract Background Inflammatory bowel disease (IBD) patients experience recurrent episodes of intestinal inflammation and often follow an unpredictable disease course. Mucosal colonization with adherent-invasive Escherichia coli (AIEC) are believed to perpetuate intestinal inflammation. However, it remains unclear if the 24-year-old AIEC in vitro definition fully predicts mucosal colonization in vivo. To fill this gap, we have developed a novel molecular barcoding approach to distinguish strain variants in the gut and have integrated this approach to explore mucosal colonization of distinct patient-derived E. coli isolates in gnotobiotic mouse models of colitis. Results Germ-free inflammation-susceptible interleukin-10-deficient (Il10 −/− ) and inflammation-resistant WT mice were colonized with a consortium of AIEC and non-AIEC strains, then given a murine fecal transplant to provide niche competition. E. coli strains isolated from human intestinal tissue were each marked with a unique molecular barcode that permits identification and quantification by barcode-targeted sequencing. 16S rRNA sequencing was used to evaluate the microbiome response to E. coli colonization. Our data reveal that specific AIEC and non-AIEC strains reproducibly colonize the intestinal mucosa of WT and Il10 −/− mice. These E. coli expand in Il10 −/− mice during inflammation and induce compositional dysbiosis to the microbiome in an inflammation-dependent manner. In turn, specific microbes co-evolve in inflamed mice, potentially diversifying E. coli colonization patterns. We observed no selectivity in E. coli colonization patterns in the fecal contents, indicating minimal selective pressure in this niche from host-microbe and interbacterial interactions. Because select AIEC and non-AIEC strains colonize the mucosa, this suggests the in vitro AIEC definition may not fully predict in vivo colonization potential. Further comparison of seven E. coli genomes pinpointed unique genomic features contained only in highly colonizing strains (two AIEC and two non-AIEC). Those colonization-associated features may convey metabolic advantages (e.g., iron acquisition and carbohydrate consumption) to promote efficient mucosal colonization. Conclusions Our findings establish the in vivo mucosal colonizer, not necessarily AIEC, as a principal dysbiosis driver through crosstalk with host and associated microbes. Furthermore, we highlight the utility of high-throughput screens to decode the in vivo colonization dynamics of patient-derived bacteria in murine models. Video Abstract

Abstract Photosynthetic organisms adapt to changing light conditions by manipulating their light harvesting complexes. Biophysical, biochemical, physiological and genetic aspects of these processes are studied extensively. The structural basis for these studies is lacking. In this study we address this gap in knowledge by focusing on phycobilisomes (PBS), which are large structures found in cyanobacteria and red algae. In this study we focus on the phycobilisomes (PBS), which are large structures found in cyanobacteria and red algae. Specifically, we examine red algae (Porphyridium purpureum) grown under a low light intensity (LL) and a medium light intensity (ML). Using cryo-electron microscopy, we resolve the structure of ML-PBS and compare it to the LL-PBS structure. The ML-PBS is 13.6 MDa, while the LL-PBS is larger (14.7 MDa). The LL-PBS structure have a higher number of closely coupled chromophore pairs, potentially the source of the red shifted fluorescence emission from LL-PBS. Interestingly, these differences do not significantly affect fluorescence kinetics parameters. This indicates that PBS systems can maintain similar fluorescence quantum yields despite an increase in LL-PBS chromophore numbers. These findings provide a structural basis to the processes by which photosynthetic organisms adapt to changing light conditions.

This paper analyzed the horizontal distribution and limitation of DIN, PO4-P and SiO3-Si based on the four surveys of Miaodao Archipelago sea area in August and October of 2018, April and June of 2019. The results showed that the concentration of DIN ranged from 0.82 μmol/L to 95.14 μmol/L with an average value of 5.27 μmol/L and the maximum was in August of 2018. The concentration of PO4-P ranged from "not detected" to 2.12 μmol/L with an average value of 0.19 μmol/L and the maximum was in October of 2018. The concentration of SiO3-Si ranged from 0.25 μmol/L to 48.93 μmol/L with an average value of 5.38 μmol/L and the maximum was in August of 2018. In general, the concentration of nutrients was higher in summer and was relatively scarce in spring. PO4-P was the limiting factor in August and October of 2018, June of 2019, while SiO3-Si and PO4-P were the limiting factors in April of 2019. The PO4-P limitation would limit the primary productivity of sea area and the aquaculture could be influenced. The low content of SiO3-Si was not conducive to the growth of diatoms, which indirectly promoted the reproduction of dinoflagellates, so that this area was easy to cause red tide in spring.

We modified the landscape connectivity calculation method and applied it to assess changes in temporal connectivity under different offsetting scenarios in the Yellow River Delta High-efficiency Ecological Economic Zone of China. We evaluated landscape connectivity based on resistance surfaces, least-cost distances, habitat areas, and the probability of dispersal between wetland patches in the landscape. The landscape connectivity declined between 1980 and 2015, with the degree of decline varying with the type of wetland. The cumulative percentages of freshwater marsh, salt marsh, and tidal marsh habitat areas that could be offset were 100 %, 100 %, and 34 %, respectively. However, the maximum landscape connectivity that was compensated for was only 1.2–10.4 %. When the offset patches were restored to freshwater marsh, the highest connectivity of coastal wetlands was achieved. There were substantial gaps between the area of habitat restoration offset required to achieve no net loss and the landscape connectivity that would ensure ecological effectiveness. The compensation area required to achieve no net loss of landscape connectivity was greater than that required to achieve no net loss of habitat area. We provide guidance for policy makers on how to implement offsetting to develop and manage green corridors, thus allowing movement that will ensure species’ survival. It was suggested that the passive restoration of isolated coastal wetland may be difficult to achieve. Policies that seek to increase landscape connectivity offsets can effectively promote population diffusion and migration, avoid habitat fragmentation, and are key to improving no net loss effectiveness.

Abstract OTOF mutations are the principal causes of auditory neuropathy. There are reports on Otof‐related gene therapy in mice, but there is no preclinical research on the drug evaluations. Here, Anc80L65 and the mouse hair cell‐specific Myo15 promoter (mMyo15) are used to selectively and effectively deliver human OTOF to hair cells in mice and nonhuman primates to evaluate the efficacy and safety of OTOF gene therapy drugs. A new dual‐AAV‐OTOF‐hybrid strategy to transfer full‐length OTOF is generated, which can stably restore hearing in adult OTOFp.Q939*/Q939* mice with profound deafness, with the longest duration being at least 150 days, and the best therapeutic effect without difference in hearing from wild‐type mice. An AAV microinjection method into the cochlea of cynomolgus monkeys without hearing impairment is further established and found the OTOF can be safely and effectively driven by the mMyo15 promoter in hair cells. In addition, the therapeutic dose of AAV drugs has no impact on normal hearing and does not cause significant systemic toxicity both in mouse and nonhuman primates. In summary, this study develops a potential gene therapy strategy for DFNB9 patients in the clinic and provides complete, standardized, and systematic research data for clinical research and application.

Abstract Regional bias of N 6-methyladenosine (m6A) mRNA modification avoiding splice site region, calls for an open hypothesis whether exon-intron boundary could affect m6A deposition. By deep learning modeling, we find that exon-intron boundary represses a proportion (12% to 34%) of m6A deposition at adjacent exons (~100 nt to splice site). Experiments validate that m6A signal increases once the host gene does not undergo pre-mRNA splicing to produce the same mRNA. Inhibited m6A sites have higher m6A enhancers and lower m6A silencers locally and show high heterogeneity at different exons genome-widely, with only a small proportion (12% to 15%) of exons showing strong inhibition, enabling more stable mRNAs and flexible protein coding. m6A is majorly responsible for why mRNAs with more exons be more stable. Exon junction complex (EJC) only partially contributes to this exon-intron boundary m6A inhibition in some short internal exons, highlighting additional factors yet to be identified.

Based on the environmental monitoring data of Laizhou Bay in May (spring) and October (autumn), 2020, this paper had studied the spatial distribution characteristics of inorganic nitrogen (DIN) and reactive phosphate (DIP), the condition of seawater quality and eutrophication in Laizhou Bay, and completed the correlation analysis of nutrient and environmental factors. The results showed that in spring, the concentration of DIN ranged from 0.115 mg/L to 1.830 mg/L, which was higher near shore than far shore and higher in the west than in the east. In autumn, the concentration of DIN ranged from 0.009 mg/L to 2.070 mg/L, and the high value area was located near the estuary of the Yellow River. The DIP concentration in spring and autumn ranged from not detected to 0.009 mg/L and form 0.000 4 mg/L to 0.012 9 mg/L, respectively. Due to the influence of phosphorus load reduction policies such as "phosphorus control" and "phosphorus limit", the DIP concentration had always been at a low level. Affected by DIN concentration, 35.7% and 30.7% of the survey sites exceeded the second-class seawater quality standard in spring and autumn, respectively. In spring, 1.4% of the survey sites were slightly eutrophicated, located near the estuary of Xiaoqing River. In autumn, 1.6% of the survey sites were slightly eutrophic, located near the estuary of the Yellow River. And the other sites did not reach eutrophication level. The distribution characteristics of nutrients in Laizhou Bay were significantly correlated with various environmental factors, and the spatial distribution was affected by many factors.

Abstract Objective Tinnitus is a highly prevalent hearing disorder, and the burden of tinnitus diagnosis and treatment is very heavy, especially in China. In order to better benefit the majority of tinnitus patients, we developed a new mobile app based on our patented invention – named the Fudan Tinnitus Relieving System (FTRS) – for tinnitus management. The FTRS app aims to alleviate patients’ tinnitus symptoms using customized sound therapy, to evaluate the treatment effect, to provide a doctor-patient communication platform, and to support tinnitus rehabilitation and auditory health. Methods In this study, we introduced the major functions of the FTRS app, analyzed the geographical distribution of users around China, and performed an analysis on the demographic and clinical characteristics of patients with tinnitus, including age and tinnitus position, duration, frequency, and severity in both men and women based on the user information collected by the FTRS. The data for 22,867 participants (males: 13,715; females: 9,152) were included in the statistical analysis. Results The FTRS app has been popular with tinnitus patients since its launch in May 2018 with its integrated pitch-matching test, individualized sound therapy, follow-up assessment, and provision of easy-to-understand science and education for tinnitus. The users were located throughout Mainland China but primarily concentrated in Shanghai, Jiangsu, Zhejiang, Guangdong, and Shandong provinces. We observed gender differences regarding age and tinnitus frequency, severity, and position among the app’s users. The FTRS has not only facilitated patients’ access to treatment at times and places that are convenient for them, but also provides a large amount of data based on user feedback in order to support clinical tinnitus research. Conclusions Compared with traditional face-to-face medical treatment, the FTRS greatly reduced medical costs and enabled patients with tinnitus to arrange their own treatment times. At the same time, the FTRS has provided standardized tinnitus data that have laid a foundation for clinical research on tinnitus. However, because of differences in the popularity and utilization of smart devices, FTRS user data might only reflect the situation of tinnitus patients who can effectively use smart devices. Therefore, the findings of this study need to be interpreted with caution.

Abstract Submergence stress represents a major obstacle limiting the application of direct seeding in rice cultivation. Under flooding conditions, coleoptile elongation can function as an escape strategy that contributes to submergence tolerance during seed germination in rice; however, the underlying molecular bases have yet to be fully determined. Herein, we report that natural variation of rice coleoptile length subjected to submergence is determined by the glucosyltransferase encoding gene OsUGT75A. OsUGT75A regulates coleoptile length via decreasing free abscisic acid (ABA) and jasmonic acid (JA) levels by promoting glycosylation of these two phytohormones under submergence. Moreover, we find that OsUGT75A accelerates coleoptile length through mediating the interactions between JASMONATE ZIMDOMAIN (OsJAZ) and ABSCISIC ACID-INSENSITIVE (OsABI) proteins. Last, we reveal the origin of the haplotype that contributes to coleoptile length in response to submergence and transferring this haplotype to indica rice can enhance coleoptile length in submergence conditions. Thus, we propose that OsUGT75A is a useful target in breeding of rice varieties suitable for direct seeding cultivation.

PINK1 (PTEN induced kinase 1) and PRKN-mediated mitophagy is an important mitochondrial quality control pathway which selectively degrades damaged mitochondria and is tightly associated with neurodegenerative diseases, including Parkinson disease and amyotrophic lateral sclerosis. The current model of PINK1-PRKN-mediated mitophagy is that PRKN ubiquitinates multiple outer mitochondrial membrane (OMM) proteins, and then the ubiquitin chains on the OMM interact with autophagy receptors which bind Atg8-family protein labeled phagophores. However, little work has been focused on the PRKN-mediated ubiquitination of inner mitochondrial membrane (IMM) proteins during mitophagy. Our recent work revealed that PRKN binds and ubiquitinates PHB2 (prohibitin 2), an essential IMM protein which was previously recognized as a mitophagy receptor, after the OMM is ruptured by proteasomal degradation. Using biochemical and microscopy approaches, we found that mutations of PRKN-targeted ubiquitination sites on PHB2 decrease the recognition of damaged mitochondria by the phagophore and the clearance of damaged mitochondria. In conclusion, our findings revealed a critical role for PRKN-PHB2 interaction in mitochondrial quality control by regulating IMM-associated recognition of mitochondria by the autophagy machinery.

BackgroundCarbapenem-resistant Klebsiella pneumoniae (CRKP) is epidemically transmitted globally, but few studies focused on the prevalence in district-level hospitals. In this study, we investigated CRKP strains collected from nine district hospitals from September 2019 to September 2020, aiming to determine the resistance mechanisms, virulence profiles, and molecular epidemiological characteristics of CRKP in district hospitals in Southwest China.MethodsA total of 51 CRKP strains were collected from 9 district-level hospitals. Matrix-assisted laser desorption/ionization-time of flight mass spectrometer was used for strain identification review, and the micro-broth dilution method was used for antibiotic sensitivity detection. Molecular epidemiological investigation of strains was performed by multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE) methods. PCR and efflux pump inhibition tests were used to detect CRKP resistance mechanisms. PCR and serum killing tests were used to detect capsular serotype, virulence-related genes, and virulence validation.ResultsThe CRKP strains in district hospitals presented high levels of MIC50 and MIC90 in carbapenem antibiotics especially ertapenem and meropenem. A total of 90.2% (46/51) CRKP strains were detected as carbapenemase producers, and the proportion of strains co-expressing carbapenemases was 11.8% (6/51). All CRKP strains were grouped into eight MLST types, and ST11 was the most prevalent genotype. A total of 11.8% (6/51) CRKP isolates were positive for the string test, and three strains of hypervirulent and carbapenem-resistant K. pneumoniae (HV-CRKP) were positive in serum killing test. The molecular typing of all the CRKP isolates was grouped into 29 different PFGE patterns, and 40 ST11 isolates belonged to 20 different PFGE clusters.ConclusionCRKP strains showed high-level antibiotic resistance and virulence phenotype in district hospitals in Southwest China, which suggested that we should immediately pay attention to the rapid dissemination of the CRKP in regional hospitals. Our study will provide new insights into the epidemiology of CRKP in regional hospitals, which will help regional hospitals develop nosocomial infection prevention and control policies tailored to local conditions.

Objective: This study aimed to investigate the clinical characteristics and outcomes of ear-nose-throat (ENT) symptoms in SARS-CoV-2 Omicron infected patients resulting from local transmission.Methods: A convenience sampling network survey was conducted among individuals infected with SARS-CoV-2 to examine the characteristics and progression of ENT symptoms associated with local transmission. The survey comprised 52 questions, and univariable and multivariable logistic regression analyses were employed to assess the rate, severity, and outcome of ENT symptoms across different genders and age groups.Results: Among the 1,366 individuals included in the investigation, a peak in new infections occurred on 20th December, and the majority (78.4%) were female. The most common symptoms reported were coughing (90.6%), nasal congestion (77.2%), and runny nose (74.3%). Otologic symptoms were predominantly represented by tinnitus (29.7%).Conclusion: The rate of specific symptoms showed a significant correlation with age and gender. It is crucial to provide timely medical intervention, especially for female patients. This study offers a comprehensive understanding of the symptom spectrum in individuals infected with the virus, providing valuable insights for the development of targeted symptom management strategies.

The multiple mechanisms of entrepreneurial intention are still an open issue, and few have explored whether the relationship between entrepreneurial intention and proactive personality is influenced by entrepreneurial passion. This study aims to reveal the mediation role of entrepreneurial passion between proactive personality and entrepreneurial intention with the application of the classic structural equation modeling. A questionnaire survey was conducted on Chinese undergraduates and 647 questionnaires were collected for the further analysis. The main findings shed light on the mechanisms that underpin entrepreneurial passion and contribute to the growing body of knowledge on entrepreneurial intention and will raise implications for both academic entrepreneurial theory and practice.

Based on 4 cruises in August and October 2018, February and May 2019,water quality and zooplankton at 59 stations in Miaodao Archipelago were investigated. The community structure, spatial and temporal distribution of zooplankton collected by type I net and the correlation with various environmental factors were analyzed statistically. The results showed that: a total of 93 species of zooplankton were identified in Miaodao Archipelago, including 13 categories, the species of copepods and planktonic larvae were 25 respectively, accounting for 53.8% in total. The dominant species in different seasons were different, and Calanus sinicus was dominant in all seasons. The abundance of zooplankton ranged from 3.0 to 2 720 ind/m3, with an average of 122.41 ind/m3, and the biomass ranged from 0.25 to 3 106.75 mg/m3, with an average of 172.15 mg/m3. The Shannon-Wiener index varied from 0.058 to 3.670, with an average of 1.431, the Pielou evenness index varied from 0.030 to 0.922, with an average of 0.467, and the Margalef index varied from 0.362 to 7.964, with an average of 2.358. The results of Pearson correlation analysis and canonical correspondence analysis showed that the distribution of zooplankton was influenced by various environmental factors, among which temperature and salinity were the most important factors.

Summary: Functional cochlear hair cells (HCs) innervated by spiral ganglion neurons (SGNs) are essential for hearing, whereas robust models that recapitulate the peripheral auditory circuity are still lacking. Here, we developed cochlear organoids with functional peripheral auditory circuity in a staging three-dimensional (3D) co-culture system by initially reprogramming cochlear progenitor cells (CPCs) with increased proliferative potency that could be long-term expanded, then stepwise inducing the differentiation of cochlear HCs, as well as the outgrowth of neurites from SGNs. The function of HCs and synapses within organoids was confirmed by a series of morphological and electrophysiological evaluations. Single-cell mRNA sequencing revealed the differentiation trajectories of CPCs toward the major cochlear cell types and the dynamic gene expression during organoid HC development, which resembled the pattern of native HCs. We established the cochlear organoids with functional synapses for the first time, which provides a platform for deciphering the mechanisms of sensorineural hearing loss.

Autophagy is a critical protein and organelle quality control system, which regulates cellular homeostasis and survival. Growing pieces of evidence suggest that autophagic dysfunction is strongly associated with many human diseases, including neurological diseases and cancer. Among various autophagic regulators, microphthalmia (MiT)/TFE transcription factors, including transcription factor EB (TFEB), have been shown to act as the master regulators of autophagosome and lysosome biogenesis in both physiological and pathological conditions. According to the previous studies, chlorpromazine (CPZ), an FDA-approved antipsychotic drug, affects autophagy in diverse cell lines, but the underlying mechanism remains elusive. In our present study, we find that CPZ treatment induces TFEB nuclear translocation through Rag GTPases, the upstream regulators of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Meanwhile, CPZ treatment also blocks autophagosome–lysosome fusion. Notably, we find a significant accumulation of immature autophagosome vesicles in CPZ-treated cells, which may impede cellular homeostasis due to the dysfunction of the autophagy–lysosome pathway. Interestingly and importantly, our data suggest that the expression of the active form of Rag GTPase heterodimers helps in reducing the accumulation of autophagosomes in CPZ-treated cells, further suggesting a major contribution of the Rag GTPase–mTORC1–TFEB signaling axis in CPZ-induced autophagic impairment.

Aminoglycoside antibiotics (AGAs) are widely used in life-threatening infections, but they accumulate in cochlear hair cells (HCs) and result in hearing loss. Increases in adenosine triphosphate (ATP) concentrations and P2X7 receptor expression were observed after neomycin treatment. Here, we demonstrated that P2X7 receptor, which is a non-selective cation channel that is activated by high ATP concentrations, may participate in the process through which AGAs enter hair cells. Using transgenic knockout mice, we found that P2X7 receptor deficiency protects HCs against neomycin-induced injury in vitro and in vivo. Subsequently, we used fluorescent gentamicin–Fluor 594 to study the uptake of AGAs and found fluorescence labeling in wild-type mice but not in P2rx7−/− mice in vitro. In addition, knocking-out P2rx7 did not significantly alter the HC count and auditory signal transduction, but it did inhibit mitochondria-dependent oxidative stress and apoptosis in the cochlea after neomycin exposure. We thus conclude that the P2X7 receptor may be linked to the entry of AGAs into HCs and is likely to be a therapeutic target for auditory HC protection.

Abstract Background Chronic subjective tinnitus poses significant challenges in clinical practice, and it is usually associated with hearing impairment, particularly with high-frequency sensorineural hearing loss (SNHL). Patients suffering from tinnitus with SNHL experience one of the most severe sensory disabilities, and this has devastating effects on their quality of life. Nowadays, mild to moderate SNHL can be managed with a properly fitted hearing aid (HA) that provides sound amplification, and several studies suggest that HAs may also benefit those with tinnitus. However, inadequate attention has been paid by medical personnel to the impact of HA use in residual hearing protection for patients with tinnitus and coexisting SNHL, and existing evidence is still at a preliminary stage. This study aims to identify and evaluate the efficacy of the use of HAs in both sound perception and residual hearing preservation among patients with tinnitus and coexisting SNHL. Methods and design The present study is a prospective, single-center, outcome assessor and data analyst-blinded, randomized, controlled trial. Eligible participants will be recruited and randomly allocated into the HA intervention group and the waiting list control group at a ratio of 1:1. The primary outcome is to evaluate the severity of tinnitus using the Tinnitus Handicap Inventory as a continuous variable at 6 months from randomization. Secondary outcome measures include changes in hearing status and mental states. The trial will last 6 months, with follow-up visits at 3 months and 6 months. Discussion This will be the first randomized, controlled trial to identify and evaluate HAs’ efficacy on residual hearing preservation among tinnitus patients with coexisting high-frequency SNHL in China. We are aiming for novelty and generalizability, and strengths of this study are that it will examine the effectiveness of HA in patients with tinnitus and hearing impairment and will further explore the residual hearing protection provided by HA treatment in the tinnitus group. Trial registration ClinicalTrials.gov NCT05343026. Registered on April 25, 2022

Abstract Mammalian sensory hair cells (HCs) have limited capacity for regeneration, which leads to permanent hearing loss after HC death. Here, we used in vitro RNA-sequencing to show that the Hippo signaling pathway is involved in HC damage and self-repair processes. Turning off Hippo signaling through Mst1/2 inhibition or Yap overexpression induces YAP nuclear accumulation, especially in supporting cells, which induces supernumerary HC production and HC regeneration after injury. Mechanistically, these effects of Hippo signaling work synergistically with the Notch pathway. Importantly, the supernumerary HCs not only express HC markers, but also have cilia structures that are able to form neural connections to auditory regions in vivo. Taken together, regulating Hippo suggests new strategies for promoting cochlear supporting cell proliferation, HC regeneration, and reconnection with neurons in mammals.

Gefitinib, a well-known epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for the targeted therapy of lung cancer, induces autophagy in association with drug resistance. However, it remains unclear whether gefitinib treatment can affect the selective form of autophagy (i.e., mitophagy) and be beneficial for the treatment of human diseases with decreased autophagy, such as neurodegenerative diseases. Here, we show that gefitinib treatment promotes PINK1/Parkin-mediated mitophagy in both nonneuronal and neuronal cells, and this effect is independent of EGFR. Moreover, we found that gefitinib treatment increases the recruitment of the autophagy receptor optineurin (OPTN) to damaged mitochondria, which is a downstream signaling event in PINK1/Parkin-mediated mitophagy. In addition, gefitinib treatment significantly alleviated neuronal damage in TBK1-deficient neurons, resulting in impeded mitophagy. In conclusion, our study suggests that gefitinib promotes PINK1/Parkin-mediated mitophagy via OPTN and may be beneficial for the treatment of neurodegenerative diseases that are associated with defective mitophagy.

The prevalence of obesity and type 2 diabetes is growing at an alarming rate, including among pregnant women. Low-calorie sweeteners (LCSs) have increasingly been used as an alternative to sugar to deliver a sweet taste without the excessive caloric load. However, there is little evidence regarding their biological effects, particularly during development. Here, we used a mouse model of maternal LCS consumption to explore the impact of perinatal LCS exposure on the development of neural systems involved in metabolic regulation. We report that adult male, but not female, offspring from both aspartame- and rebaudioside A–exposed dams displayed increased adiposity and developed glucose intolerance. Moreover, maternal LCS consumption reorganized hypothalamic melanocortin circuits and disrupted parasympathetic innervation of pancreatic islets in male offspring. We then identified phenylacetylglycine (PAG) as a unique metabolite that was upregulated in the milk of LCS-fed dams and the serum of their pups. Furthermore, maternal PAG treatment recapitulated some of the key metabolic and neurodevelopmental abnormalities associated with maternal LCS consumption. Together, our data indicate that maternal LCS consumption has enduring consequences on the offspring’s metabolism and neural development and that these effects are likely to be mediated through the gut microbial co-metabolite PAG.

ABSTRACT Several studies have compared metagenome inference performance in different human body sites; however, none specifically reported on the vaginal microbiome. Findings from other body sites cannot easily be generalized to the vaginal microbiome due to unique features of vaginal microbial ecology, and investigators seeking to use metagenome inference in vaginal microbiome research are “flying blind” with respect to potential bias these methods may introduce into analyses. We compared the performance of PICRUSt2 and Tax4Fun2 using paired 16S rRNA gene amplicon sequencing and whole-metagenome sequencing data from vaginal samples from 72 pregnant individuals enrolled in the Pregnancy, Infection, and Nutrition (PIN) cohort. Participants were selected from those with known birth outcomes and adequate 16S rRNA gene amplicon sequencing data in a case-control design. Cases experienced early preterm birth (

Abstract Extensive research have been devoted to the exploration of multifunctional theranostic agents for cancer, but the poor tumor specificity and unsatisfactory treatment efficacy are some of the critical obstacles for their clinical translations. Herein, ferrocene‐carbon dot‐crosslinked nanoparticles (Fc‐CD NPs) were designed and fabricated for achieving highly specific and photothermal‐augmented chemodynamic therapy (CDT). The Fc‐CD NPs were found not only to inherit the immanent fluorescence, photoacoustic, and photothermal properties of carbon dots (CDs), but also be endowed with CDT that could occur selectively in tumor microenvironment (TME) due to the presence of Fc for triggering Fenton reaction. Moreover, the enlarged particle size of Fc‐CD NPs facilitated their effective accumulation at tumor sites, thus realizing great improvement for antitumor treatment outcomes. Once docking at tumor and being exposed to 660 nm laser irradiation, significantly amplified CDT effect of Fc‐CD NPs was observed due to heat‐accelerating generation of reactive oxygen species (ROS). More interestingly, since the produced ROS could in turn alleviate the thermal‐resistance of photothermal therapy (PTT), the therapeutic efficiency of integrated PTT and CDT was synergized to the maximum extent. This study on the one hand provides a facile approach to fabricate CDs‐based multifunctional theranostic nanoplatform with enhanced tumor accumulation and specificity, on the other hand emphasizes the merits of synergizing mutually beneficial therapeutic modalities for more efficient cancer therapy.

Abstract Background: As nurse practitioners and physician assistants (APPs) become more prevalent in delivering pediatric care, their involvement in antimicrobial stewardship efforts increases in importance. This project aimed to create and assess the efficacy of a problem-based learning (PBL) approach to teaching APPs antimicrobial stewardship principles. Methods: A PBL education initiative was developed after communication with local APP leadership and focus group feedback. It was offered to all APPs associated with Lurie Children’s Hospital of Chicago. Participants completed a survey which assessed opinions on antimicrobial stewardship and included knowledge-based questions focused on antimicrobial stewardship. Prescriptions for skin and soft tissue infections associated with APPs were recorded via chart review before and after the education campaign. Results: Eighty APPs participated in the initial survey and teaching initiative with 44 filling out the 2-week follow-up and 29 filling out the 6-month follow-up. Subjective opinions of antimicrobial stewardship and comfort with basic principles of AS increased from pre-intervention. Correct responses to knowledge-based assessments increased from baseline after 2-week follow-up (p < 0.01) and were maintained at the 6-month follow-up (p = 0.03). Simple skin and soft tissue infection prescriptions for clindamycin went from 44.4% pre-intervention to 26.5% (p = 0.2) post-intervention. Conclusions: A PBL approach for APP education on antimicrobial stewardship can be effective in increasing knowledge and comfort with principles of antimicrobial stewardship. These changes are maintained in long-term follow-up. Changes in prescribing habits showed a strong trend towards recommended empiric therapy choice. Institutions should develop similar education campaigns for APPs.

Based on the survey data of surface sediments in Shandong coastal waters, the temporal and spatial variation characteristics of sediment granularity and its influencing factors were analyzed. The results showed that in 2020, the grain size of surface sediments in Shandong coastal waters gradually decreased from shore to sea, and silt content was the highest, with an average of 66.45%, sand content was the second, with an average of 26.78%, clay content was lower, with an average of 6.77%. There were significant differences in the spatial distribution of sediment grain fractions, including silty sand, sandy silty sand, silty sand and sand, and silty sand was dominant, accounting for 61.9% of the survey site. From 2016 to 2020, an overall coarsening trend of surface sediments in Shandong coastal waters was detected. And the trend was more obvious in the coastal waters of Rizhao, Qingdao, Weifang and Binzhou, followed by Dongying, and the lowest in Yantai and Weihai. The main influencing factors of the temporal and spatial characteristics of sediment granularity include provenance, regional hydrodynamic conditions (such as the Bohai Sea Current, Yellow Sea Current, Shandong Coastal Current, etc.), and coastal engineering construction, and furthermore, the specific influencing mechanism still needs further investigation and research. The research results could provide a reference for the analysis of changes in sediment types and the protection and utilization of coastal zones in the coastal waters of Shandong Province.

Emotional eating has emerged as a significant disordered eating and public health concern among adolescents. Despite the widespread prevalence of social networking site (SNS) use among this population, research investigating the influence of SNS use on adolescent eating behaviors remains limited. This study is to examine the impact of SNS use on emotional eating among Chinese adolescents, with a specific focus on exploring the mediating role of negative social comparisons and the moderating effect of perspective-taking. Data were obtained through an online survey involving 778 middle school students in China. The findings indicate that SNS use exerts a positive influence on adolescents’ engagement in emotional eating, with this association being mediated by the presence of negative social comparisons. Perspective-taking demonstrated a protective role in the context of adolescents’ utilization of social media platforms. For individuals characterized by high levels of perspective-taking, the effects of SNS use on negative social comparisons are mitigated, subsequently reducing its impact on emotional eating.

Low-calorie sweetener (LCS) consumption in children has increased dramatically due to its widespread presence in the food environment and efforts to mitigate obesity through sugar replacement. However, mechanistic studies on the long-term impact of early-life LCS consumption on cognitive function and physiological processes are lacking. Here, we developed a rodent model to evaluate the effects of daily LCS consumption (acesulfame potassium, saccharin, or stevia) during adolescence on adult metabolic, behavioral, gut microbiome, and brain transcriptomic outcomes. Results reveal that habitual early-life LCS consumption impacts normal postoral glucose handling and impairs hippocampal-dependent memory in the absence of weight gain. Furthermore, adolescent LCS consumption yielded long-term reductions in lingual sweet taste receptor expression and brought about alterations in sugar-motivated appetitive and consummatory responses. While early-life LCS consumption did not produce robust changes in the gut microbiome, brain region–specific RNA-Seq analyses reveal LCS-induced changes in collagen- and synaptic signaling–related gene pathways in the hippocampus and nucleus accumbens, respectively, in a sex-dependent manner. Collectively, these results reveal that habitual early-life LCS consumption has long-lasting implications for glucoregulation, sugar-motivated behavior, and hippocampal-dependent memory in rats, which may be based in part on changes in nutrient transporter, sweet taste receptor, and central gene pathway expression.

The composition of the gut microbiota in patients with anorexia nervosa (AN), and the ability of this microbial community to influence the host, remains uncertain. To achieve a broader understanding of the role of the intestinal microbiota in patients with AN, we collected fecal samples before and following clinical treatment at two geographically distinct eating disorder units (Center of Excellence for Eating Disorders [UNC-CH] and ACUTE Center for Eating Disorders [Denver Health]). Gut microbiotas were characterized in patients with AN, before and after inpatient treatment, and in non-eating disorder (non-ED) controls using shotgun metagenomic sequencing. The impact of inpatient treatment on the AN gut microbiota was remarkably consistent between eating disorder units. Although weight in patients with AN showed improvements, AN microbiotas post-treatment remained distinct from non-ED controls. Additionally, AN gut microbiotas prior to treatment exhibited more fermentation pathways and a lower ability to degrade carbohydrates than non-ED controls. As the intestinal microbiota can influence nutrient metabolism, our data highlight the complex microbial communities in patients with AN as an element needing further attention post inpatient treatment. Additionally, this study defines the effects of renourishment on the AN gut microbiota and serves as a platform to develop precision nutrition approaches to potentially mitigate impediments to recovery.

Epidemiological studies in adults have shown that exposure to ambient air pollution (AAP) is associated with the composition of the adult gut microbiome, but these relationships have not been examined in infancy. We aimed to determine if 6-month postnatal AAP exposure was associated with the infant gut microbiota at 6 months of age in a cohort of Latino mother-infant dyads from the Southern California Mother’s Milk Study (n = 103). We estimated particulate matter (PM2.5 and PM10) and nitrogen dioxide (NO2) exposure from birth to 6-months based on residential address histories. We characterized the infant gut microbiota using 16S rRNA amplicon sequencing at 6-months of age. At 6-months, the gut microbiota was dominated by the phyla Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria. Our results show that, after adjusting for important confounders, postnatal AAP exposure was associated with the composition of the gut microbiota. As an example, PM10 exposure was positively associated with Dialister, Dorea, Acinetobacter, and Campylobacter while PM2.5 was positively associated with Actinomyces. Further, exposure to PM10 and PM2.5 was inversely associated with Alistipes and NO2 exposure was positively associated with Actinomyces, Enterococcus, Clostridium, and Eubacterium. Several of these taxa have previously been linked with systemic inflammation, including the genera Dialister and Dorea. This study provides the first evidence of significant associations between exposure to AAP and the composition of the infant gut microbiota, which may have important implications for future infant health and development.

Japanese chestnut (Castanea crenata Sieb. et Zucc) is an economically and ecologically important chestnut species in East Asia. Here, we presented a high-quality chromosome-level reference genome of the Japanese chestnut cultivar ‘Tsukuba’ by combining Nanopore long reads and Hi-C sequencing. The final assembly has a size of 718.30 Mb and consists of 12 pseudochromosomes ranging from 41.03 to 92.03 Mb, with a BUSCO complete gene percentage of 97.6%. A total of 421.37 Mb repetitive sequences and 46,744 gene models encoding 46,463 proteins were predicted in the genome. Genome evolution analysis showed that Japanese chestnut is closely related to Chinese chestnut and these species shared a common ancestor ~6.5 million years ago. This high-quality Japanese chestnut genome represents an important resource for the chestnut genomics community and will improve our understanding of chestnut biology and evolution.

Abstract Background The inner ear organ is a delicate tissue consisting of hair cells (HCs) and supporting cells (SCs).The mammalian inner ear HCs are terminally differentiated cells that cannot spontaneously regenerate in adults. Epithelial non‐hair cells (ENHCs) in the utricle include HC progenitors and SCs, and the progenitors share similar characteristics with SCs in the neonatal inner ear. Methods We applied single‐cell sequencing to whole mouse utricles from the neonatal period to adulthood, including samples from postnatal day (P)2, P7 and P30 mice. Furthermore, using transgenic mice and immunostaining, we traced the source of new HC generation. Results We identified several sensory epithelial cell clusters and further found that new HCs arose mainly through differentiation from Sox9+ progenitor cells and that only a few cells were produced by mitotic proliferation in both neonatal and adult mouse utricles. In addition, we identified the proliferative cells using the marker UbcH10 and demonstrated that in adulthood the mitotically generated HCs were primarily found in the extrastriola. Moreover, we observed that not only Type II, but also Type I HCs could be regenerated by either mitotic cell proliferation or progenitor cell differentiation. Conclusions Overall, our findings expand our understanding of ENHC cell fate and the characteristics of the vestibular organs in mammals over the course of development.

BackgroundDelaying atrial fibrillation (AF) progression is a key goal in cardiovascular treatment. However, numbers of previously published studies on delayed AF progression are relatively limited. The purpose of this study was to determine whether a cryoballoon catheter ablation (CA) strategy could delay AF progression compared to anti-arrhythmic drug (AAD) treatment in patients with paroxysmal AF.MethodsA total of 204 subjects were enrolled in the trial, including 102 in the cryoballoon CA group and 102 in the AAD group. Participants were followed up with for 36 months. The primary study endpoint was the first occurrence of persistent atrial tachyarrhythmia, while secondary endpoints included the event rates of persistent atrial tachyarrhythmia at 1 and 2 years. The primary safety endpoint was serious adverse events.ResultsOverall, the 36-month follow-up was completed by 154 subjects (75.5%). At 3 years, documented progression from paroxysmal AF to persistent atrial tachyarrhythmia had occurred in 2 of the 102 patients assigned to undergo cryoballoon CA [2.203% (95% confidence interval (CI), 0.554–8.537)] and in 17 of the 102 patients assigned to receive AADs [20.223% (95% CI, 13.040–30.604)] [hazard ratio (HR), 0.107; 95% CI, 0.043–0.262; P < 0.001]. Lower rates of progression in the cryoballoon CA group compared to the AAD group were already obvious at 1 year [1.053% (95% CI, 0.149–7.238) vs. 5.284% (95% CI, 2.233–12.237)] [HR, 0.193; (95% CI, 0.039–0.956; P = 0.09)] and 2 years [2.203% (95% CI, 0.554–8.537) vs. 12.430% (95% CI, 7.066–21.371)] (HR, 0.169; 95% CI, 0.057–0.501, P < 0.001). Serious adverse events occurred in 7 of the 102 patients (6.9%) in the cryoballoon CA group and 9 of the 102 patients (8.8%) in the AAD group.ConclusionCryoballoon CA was superior to AAD therapy in preventing the occurrence of persistent atrial tachyarrhythmia in patients with paroxysmal AF who had not received prior rhythm control therapy. Serious adverse events were rare.

Plantation’s nutrient cycling can regulate and affect the material cycling of ecosystems, which is the key to maintain the sustainable development of the plantation ecosystem. However, the current understanding of the nutrient cycling characteristics of the “leave-root-litter-soil” continuum of dryland plantation ecosystems is limited. Therefore, in the Longzhong Loess Plateau of China, we selected nine typical dryland plantations to carry related research, including two evergreen (Platycladus orientalis (13-years and 50-years) and Pinus tabuliformis) and four deciduous (Caragana korshinskii (13-years, 35-years and 55-years), Armeniaca sibirica, Populus hopeiensis and Tamarix chinensis) tree species, and measured C, N, P and K contents of green leaves, fine roots, leaf litter and surface soil (0–20 cm). Results showed tree species and afforestation years strongly changed C, N, P and K contents and ratios of green leaves, fine roots, leaf litter and soil components, and also significantly affected leaf N, P and K reabsorption efficiencies. The average N, P and K contents of four components and soil available nitrogen (AN), available phosphorus (AP) and available potassium (AK) contents in deciduous plantations were higher than those in evergreen plantations, resulting in the lower C:N:P:K stoichiometry of deciduous plantations than evergreen plantations. Especially in 55-years C. korshinskii plantation, its soil C, N, AN, AP and AK contents were higher than those in A. sibirica, P. hopeiensis, P. orientalis and P. tabuliformis plantations. Moreover, soil C, N, P, AN, AP and AK contents in C. korshinskii plantations increased significantly with the increase of afforestation years. Thus, C. korshinskii was more suitable for ecological restoration in drylands. Due to the P limitation in plantations, P reabsorption efficiency was higher than N reabsorption efficiency, and significantly negatively correlated with P contents of four components. And green leaves had the homeostasis to soil AP, which may be the nutrient utilization strategies for plantations to alleviate P limitation. Correlation analysis revealed that the C cycling appeared in green leave-fine root and green leave-leaf litter, the N cycling appeared in green leave-leaf litter-soil-fine root, and the P cycling and K cycling appeared in green leave-leaf litter- soil and leaf litter-fine root. These results will provide guidance for ecological restoration and plantation management in drylands.

Abstract The gut microbiota plays an important role in human health and disease. Stool, rectal swab and rectal mucosal tissue samples have been used in individual studies to survey the microbial community but the consequences of using these different sample types are not completely understood. In this study, we report differences in stool, rectal swab and rectal mucosal tissue microbial communities with shotgun metagenome sequencing of 1397 stool, swab and mucosal tissue samples from 240 participants. The taxonomic composition of stool and swab samples was distinct, but less different to each other than mucosal tissue samples. Functional profile differences between stool and swab samples are smaller, but mucosal tissue samples remained distinct from the other two types. When the taxonomic and functional profiles were used for inference in association with host phenotypes of age, sex, body mass index (BMI), antibiotics or non-steroidal anti-inflammatory drugs (NSAIDs) use, hypothesis testing using either stool or rectal swab gave broadly significantly correlated results, but inference performed on mucosal tissue samples gave results that were generally less consistent with either stool or swab. Our study represents an important resource for determination of how inference can change for taxa and pathways depending on the choice of where to sample within the human gut.

Software for accurate prediction of protein-ligand binding affinity can be a key enabling tool for small molecule drug discovery. Free energy perturbation (FEP) is a computational technique that can be used to compute binding affinity differences between molecules in a congeneric series. It has shown promise in reliably generating accurate predictions and is now widely used in the pharmaceutical industry. However, the high computational cost and use of commercial software, together with the technical challenges to setup, run, and analyze the simulations, limits the usage of FEP. Here, we use an automated FEP workflow which uses the open-source OpenMM package. To enable effective application of FEP, we compared the performance of different water models, partial charge assignments, and AMBER protein forcefields in eight benchmark test cases previously assembled for FEP validation studies.

The relationship between neuroticism and mobile phone use is a hot research topic in the academic community. The purpose of this study was to investigate the roles of self-emotional assessment and love status in the mechanism through which college students’ neuroticism influences mobile phone use.We construct a moderated mediation model, and taking 869 Chinese college students as the research object and testing the mediating role of self-emotional assessment and the moderating role of love status. The results show that: (1) neuroticism was significantly positively related to mobile phone use and significantly negatively related to self-emotional assessment; self-emotional assessment was significantly positively related to mobile phone use; (2) self-emotional assessment had a masking effect on the relationship between neuroticism and mobile phone use; (3) love status not only moderated the relationship between self-emotional assessment and mobile phone use but also moderated the process through which self-emotional assessment masked the effect of neuroticism on mobile phone use. Our research expands the literature on the mechanisms underlying the effects of neuroticism on mobile phone use, enriches the understanding of the pertinent boundary conditions, and provides a better explanatory basis for the mobile phone use of college students.

Objective: Tinnitus is highly prevalent in the population, but there are currently few effective therapeutic interventions. Mobile applications (apps) might be helpful in tinnitus diagnosis and treatment by offering sound or music tools as well as questionnaires. We assessed the efficacy of a free, publicly available smartphone app (Fudan Tinnitus Relieving System, FTRS) for self-management of tinnitus and related symptoms. Methods: Among a total of 3564 participants recruited primarily online, 2744 patients had complete information at baseline and were an average of 37 years old and were 59.84 % male. Web-administered self-report measures THI, HADS, AIS, and other multi-dimensional scales were conducted at baseline and at 1 month and 2 months following treatment. Data from 54 participants who completed continuous follow-up were used for the final efficacy analysis and longitudinal analysis. Results: Following the intent-to-treat principle, t-tests revealed that the distribution of patients and the tinnitus features of patients of different genders were heterogeneous. One-way ANOVA showed that after using the FTRS app, THI scores showed a decreasing trend (p

BackgroundQuestionnaires have been used in the past 2 decades to predict the diagnosis of vertigo and assist clinical decision-making. A questionnaire-based machine learning model is expected to improve the efficiency of diagnosis of vestibular disorders. ObjectiveThis study aims to develop and validate a questionnaire-based machine learning model that predicts the diagnosis of vertigo. MethodsIn this multicenter prospective study, patients presenting with vertigo entered a consecutive cohort at their first visit to the ENT and vertigo clinics of 7 tertiary referral centers from August 2019 to March 2021, with a follow-up period of 2 months. All participants completed a diagnostic questionnaire after eligibility screening. Patients who received only 1 final diagnosis by their treating specialists for their primary complaint were included in model development and validation. The data of patients enrolled before February 1, 2021 were used for modeling and cross-validation, while patients enrolled afterward entered external validation. ResultsA total of 1693 patients were enrolled, with a response rate of 96.2% (1693/1760). The median age was 51 (IQR 38-61) years, with 991 (58.5%) females; 1041 (61.5%) patients received the final diagnosis during the study period. Among them, 928 (54.8%) patients were included in model development and validation, and 113 (6.7%) patients who enrolled later were used as a test set for external validation. They were classified into 5 diagnostic categories. We compared 9 candidate machine learning methods, and the recalibrated model of light gradient boosting machine achieved the best performance, with an area under the curve of 0.937 (95% CI 0.917-0.962) in cross-validation and 0.954 (95% CI 0.944-0.967) in external validation. ConclusionsThe questionnaire-based light gradient boosting machine was able to predict common vestibular disorders and assist decision-making in ENT and vertigo clinics. Further studies with a larger sample size and the participation of neurologists will help assess the generalization and robustness of this machine learning method.

ABSTRACT Recent rapid and large-scale urbanization has had a profound impact on human lifestyles and is associated with an increased risk of many diseases. Recent studies have revealed large differences in the human gut microbiota across populations in countries at different stages of urbanization. However, few studies have analyzed the impact of ongoing urbanization within the same geographic region. In this study, we sampled 214 participants in communities of different urbanization levels within two provinces of China and reconstructed draft prokaryotic genomes with metagenome sequences. The genomes were clustered into 447 species-level operational taxonomic units (OTUs), among which 196 did not have genomes in public reference databases according to the GTDB-Tk pipeline. The novel OTUs comprised 19.1% abundance in rural participants and 16.0% in urban participants, increasing the proportion of classified reads from 47.6% to 65.3% across all samples. Among the unknown OTUs, 26 OTUs present in rural samples were absent in urban participants, while 70 unknown OTUs were more abundant in rural than urban participants, suggesting potential loss and growth suppression of novel human symbionts during urbanization. Moreover, there were a higher number of genes, especially transporters, identified in genomes assembled from urban samples. This change in gene functionality indicates that urbanization not only altered the community structure of the human gut microbiota but also impacted its functional capacity. Taken together, these data show a dramatic change in the microbiota with urbanization and suggest the importance of cataloging microbial diversity from rural populations while these communities still exist. IMPORTANCE Previous studies have reported the differences in human gut microbiota across populations of different urbanization levels, but most of the studies focused on populations across different geographic regions. In this study, we analyzed the impact of ongoing urbanization in neighborhoods within the same geographic region. By assembling shotgun metagenome sequences, we reconstructed prokaryotic genomes from human gut microbiota and found that the novel bacterial OTUs were less abundant and less prevalent in urban participants than in rural participants, indicating potential loss and suppression of novel human symbionts during urbanization. Genes, including transporters and antibiotic resistance genes, were enriched in genomes of urban origins, suggesting change in functional potential of the microbiota. These findings suggest the significant influence of urbanization on human gut microbiota and the necessity of exploring the microbial diversity of rural populations.

Abstract This paper presents the response to anthropogenic forcing in the GISS‐E2.1 climate models for the 21st century Shared Socioeconomic Pathways emission scenarios within the Coupled Model Intercomparison Project Phase 6 (CMIP6). The experiments were performed using an updated and improved version of the NASA Goddard Institute for Space Studies (GISS) coupled general circulation model that includes two different versions for atmospheric composition: A non‐interactive version (NINT) with prescribed composition and a tuned aerosol indirect effect and the One‐Moment Aerosol model (OMA) version with fully interactive aerosols which includes a parameterized first indirect aerosol effect on clouds. The effective climate sensitivities are 3.0°C and 2.9°C for the NINT and OMA models, respectively. Each atmospheric version is coupled to two different ocean general circulation models: The GISS ocean model (E2.1‐G) and HYCOM (E2.1‐H). We describe the global mean responses for all future scenarios and spatial patterns of change for surface air temperature and precipitation for four of the marker scenarios: SSP1‐2.6, SSP2‐4.5, SSP4‐6.0, and SSP5‐8.5. By 2100, global mean warming ranges from 1.5°C to 5.2°C relative to 1,850–1,880 mean temperature. Two high‐mitigation scenarios SSP1‐1.9 and SSP1‐2.6 limit the surface warming to below 2°C by the end of the 21st century, except for the NINT E2.1‐H model that simulates 2.2°C of surface warming. For the high emission scenario SSP5‐8.5, the range is 4.6–5.2°C at 2100. Due to about 15% larger effective climate sensitivity and stronger transient climate response in both NINT and OMA CMIP6 models compared to CMIP5 versions, there is a stronger warming by 2100 in the SSP emission scenarios than in the comparable Representative Concentration Pathway (RCP) scenarios in CMIP5. Changes in sea ice area are highly correlated to global mean surface air temperature anomalies and show steep declines in both hemispheres, with the largest sea ice area decreases occurring during September in the Northern Hemisphere in both E2.1‐G (−1.21 × 106 km2/°C) and E2.1‐H models (−0.94 × 106 km2/°C). Both coupled models project decreases in the Atlantic overturning stream function by 2100. The largest decrease of 56%–65% in the 21st century overturning stream function is produced in the warmest scenario SSP5‐8.5 in the E2.1‐G model, comparable to the reduction in the corresponding CMIP5 GISS‐E2 RCP8.5 simulation. Both low‐end scenarios SSP1‐1.9 and SSP1‐2.6 also simulate substantial reductions of the overturning (9%–37%) with slow recovery of about 10% by the end of the 21st century (relative to the maximum decrease at the middle of the 21st century).