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ABSTRACT Psychrobacter is an important bacterial genus that is widespread in Antarctic and marine environments. However, to date, only two complete Psychrobacter phage sequences have been deposited in the NCBI database. Here, the novel Psychrobacter phage vB_PmaS_Y8A, infecting Psychrobacter HM08A, was isolated from sewage in the Qingdao area, China. The morphology of vB_PmaS_Y8A was characterized by transmission electron microscopy, revealing an icosahedral head and long tail. The genomic sequence of vB_PmaS_Y8A is linear, double-stranded DNA with a length of 40,226 bp and 44.1% G+C content, and encodes 69 putative open reading frames. Two auxiliary metabolic genes (AMGs) were identified, encoding phosphoadenosine phosphosulfate reductase and MarR protein. The first AMG uses thioredoxin as an electron donor for the reduction of phosphoadenosine phosphosulfate to phosphoadenosine phosphate. MarR regulates multiple antibiotic resistance mechanisms in Escherichia coli and is rarely found in viruses. No tRNA genes were identified and no lysogeny-related feature genes were detected. However, many similar open reading frames (ORFs) were found in the host genome, which may indicate that Y8A also has a lysogenic stage. Phylogenetic analysis based on the amino acid sequences of whole genomes and comparative genomic analysis indicate that vB_PmaS_Y8A contains a novel genomic architecture similar only to that of Psychrobacter phage pOW20-A, although at a low similarity. vB_PmaS_Y8A represents a new family-level virus cluster with 22 metagenomic assembled viral genomes, here named Minviridae. IMPORTANCE Although Psychrobacter is a well-known and important bacterial genus that is widespread in Antarctic and marine environments, genetic characterization of its phages is still rare. This study describes a novel Psychrobacter phage containing an uncharacterized antibiotic resistance gene and representing a new virus family, Minviridae. The characterization provided here will bolster current understanding of genomes, diversity, evolution, and phage-host interactions in Psychrobacter populations.

Pseudoalteromonas is a ubiquitous and abundant genus of marine bacteria commonly associated with algae. In this study, a novel siphoviral-morphological bacteriophage, vB_PhoS_XC, was isolated from the coastal seawaters of Qingdao (China) during a bloom of the Ulva prolifera (U. prolifera) green tide. The morphology of this phage (icosahedron head 51 ± 1 nm in diameter; a tail length of 86 ± 1 nm) was characterized through transmission electron microscope. The biological properties of this virus showed a short latent period (45 minutes), a large burst size (241 virions per cell) and a relatively wide range of temperatures/pH level tolerance (-20°C to 45°C and pH 4 to pH 10, respectively). The vB_PhoS_XC has a 46,490-bp double-stranded DNA genome with a G+C content of 40.0%, and encodes 72 open reading frames (ORFs). Thirty-five of these ORFs were assigned into known functions based on BLAST-based algorithm against NR database of GenBank. In addition, eco-genomic analysis provides the evidence of vB_PhoS_XC accompanied by bloom of U. prolifera, and confirmed the high expression of two phosphatase-metabolism-related auxiliary metabolic genes (AMGs). This study provides new insights into the functional and ecological roles of the Pseudoalteromonas phage vB_PhoS_XC, shedding light on the virological study approach combined with traditional isolation and meta-omics data.

Indoor home dust microbial communities, important contributors to human health, are shaped by environmental factors, including farm-related exposures. Advanced metagenomic whole genome shotgun sequencing (WGS) improves detection and characterization of microbiota in the indoor built-environment dust microbiome, compared to conventional 16S rRNA amplicon sequencing (16S). We hypothesized that the improved characterization of indoor dust microbial communities by WGS will enhance detection of exposure-outcome associations. The objective of this study was to identify novel associations of environmental exposures with the dust microbiome from the homes of 781 farmers and farm spouses enrolled in the Agricultural Lung Health Study. We examined various farm-related exposures, including living on a farm, crop versus animal production, and type of animal production, as well as non-farm exposures, including home cleanliness and indoor pets. We assessed the association of the exposures on within-sample alpha diversity and between-sample beta diversity, and the differential abundance of specific microbes by exposure. Results were compared to previous findings using 16S. We found most farm exposures were significantly positively associated with both alpha and beta diversity. Many microbes exhibited differential abundance related to farm exposures, mainly in the phyla Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria. The identification of novel differential taxa associated with farming at the genera level, including Rhodococcus, Bifidobacterium, Corynebacterium, and Pseudomonas, was a benefit of WGS compared to 16S. Our findings indicate that characterization of dust microbiota, an important component of the indoor environment relevant to human health, is heavily influenced by sequencing techniques. WGS is a powerful tool to survey the microbial community that provides novel insights on the impact of environmental exposures on indoor dust microbiota. These findings can inform the design of future studies in environmental health.

The snow cover on the Qinghai-Xizang Plateau has a significant effect on surface energy and water exchange.Based on the meteorological data of Madoi， Maqu and Yakou stations in the east of Qinghai-Xizang Plateau， this paper compares and analyzes the surface energy and water characteristics in high snowfall years and low snowfall years.The results show that： In terms of surface radiation balance， the years or periods with high snow can reflect more upward shortwave radiation.At Madoi station， the upward shortwave radiation which is reflected in the high snowfall year is 2.3 times that in the low snowfall year.During the main snow period （from March to May） of Maqu station， 10.07 W·m-2 upward shortwave radiation was reflected in the high snowfall period than in the low snowfall period.The mean upward shortwave radiation of yakou station in the high snowfall year was 37.49 W·m-2 and 31.92 W·m-2 higher than that in the low snowfall years， respectively.The high snowfall years or periods can also reduce the emission of upward long wave radiation.The difference of upward longwave radiation between high snowfall year and low snowfall year at Madoi station is basically negative during the whole study period.In the two low snowfall years of Yakou station， from December to January and from the end of February to the beginning of April， the deeper the snow was， the lower the upward long-wave radiation value was.Therefore， the difference between the upward shortwave radiation and the upward long wave radiation makes the surface net radiation in high snowfall years less than that in low snowfall years.The value of the soil heat flux is very small in both high and low snowfall years， and the surface energy distribution is mainly composed of sensible heat flux and latent heat flux.Madoi station is dominated by sensible heat flux in low snowfall year and it is positive.While the sensible heat flux is negative in high snowfall years.From March to May in Maqu， the snowfall is more concentrated in high snowfall year， and the surface energy distribution is mainly latent heat.At the same time， the surface energy distribution is mainly sensible heat in low snowfall year.The time of soil heat flux from negative to positive in high snowfall years is later than that in low snowfall years.Due to the heat preservation effect of the snow cover， the soil temperature and the difference between surface temperature and atmospheric temperature in high snowfall years is higher than that in low snowfall years， furthermore， the mean value of atmospheric humidity is also higher than that in low snowfall years.After the soil entering the freezing stage， the change of soil moisture in each layer decreases with time.At the depth of 5 cm， the soil moisture in high snowfall years was significantly higher than that in low snowfall years.At Maqu station， the variation of soil moisture at 10 cm to 40 cm is more obvious in low snowfall years.For the soil freezing time 20~160 cm in Yakou station， the high snowfall year is later than the low snowfall year.

IntroductionVibrio is an important bacterial genus containing many pathogenic species. Although more and more Vibrio phages were isolated, the genome, ecology and evolution of Vibrio phages and their roles in bacteriophage therapy, have not been fully revealed.MethodsNovel Vibrio phage vB_ValR_NF infecting Vibrio alginolyticus was isolated from the coastal waters of Qingdao during the Ulva prolifera blooms, Characterization and genomic feature of phage vB_ValR_NF has been analysed using phage isolation, sequencing and metagenome method.Results and DiscussionPhage vB_ValR_NF has a siphoviral morphology (icosahedral head 114±1 nm in diameter; a tail length of 231±1 nm), a short latent period (30 minutes) and a large burst size (113 virions per cell), and the thermal/pH stability study showed that phage vB_ValR_NF was highly tolerant to a range of pHs (4-12) and temperatures (-20 - 45 °C), respectively. Host range analysis suggests that phage vB_ValR_NF not only has a high inhibitory ability against the host strain V. alginolyticus, but also can infect 7 other Vibrio strains. In addition, the phage vB_ValR_NF has a double-stranded 44, 507 bp DNA genome, with 43.10 % GC content and 75 open reading frames. Three auxiliary metabolic genes associated with aldehyde dehydrogenase, serine/threonine protein phosphatase and calcineurin-like phosphoesterase were predicted, might help the host V. alginolyticus occupy the survival advantage, thus improving the survival chance of phage vB_ValR_NF under harsh conditions. This point can be supported by the higher abundance of phage vB_ValR_NF during the U. prolifera blooms than in other marine environments. Further phylogenetic and genomic analysis shows that the viral group represented by Vibrio phage vB_ValR_NF is different from other well-defined reference viruses, and can be classified into a new family, named Ruirongviridae. In general, as a new marine phage infecting V. alginolyticus, phage vB_ValR_NF provides basic information for further molecular research on phage–host interactions and evolution, and may unravel a novel insight into changes in the community structure of organisms during the U. prolifera blooms. At the same time, its high tolerance to extreme conditions and excellent bactericidal ability will become important reference factors when evaluating the potential of phage vB_ValR_NF in bacteriophage therapy in the future.

Abstract Background Donor human milk is the best alternative for preterm infants when their mother’s own milk is insufficient or unavailable. The development of human milk banks in China started late, and in most of these banks, the amount of donor human milk is insufficient for clinical demand. Moreover, many mothers are reluctant to use donor human milk due to safety concerns. It is important to understand the potential supply and demand of donor human milk before establishing a new human milk bank. This study aimed to understand women’s acceptance of human milk banking in Wenzhou, southeastern China. Methods A cross-sectional study was conducted in three community health centers in Wenzhou, southeast China, in December 2020. Data were collected from 305 postpartum women selected through convenience sampling. Sociodemographic, perinatal and breastfeeding characteristics, awareness and knowledge of human milk banking and willingness to donate human milk, and to accept donor human milk were assessed. Multivariable logistic regression analysis was used to explore independent predictors of willingness to donate human milk and to accept donor human milk. Results Only 17% (52/305) of our participants had heard of human milk banking prior to this survey. The prevalence of willingness to donate human milk and use donor human milk in our study was 73.4% (224/305) and 44.6% (136/305), respectively. Employment (adjusted odds ratio [AOR] 2.30; 95% confidence interval [CI] 1.17, 4.50) and human milk banking knowledge (AOR 1.23; 95% CI 1.12, 1.35) were independent predictors of willingness to donate human milk. Monthly household income in the previous year (AOR 2.18; 95% CI 1.17, 4.06), awareness of human milk banking (AOR 2.41; 95% CI 1.24, 4.67) and knowledge of human milk banking (AOR 1.22; 95% CI 1.11, 1.35) were significantly associated with willingness to accept donor human milk. Conclusions In our study, awareness of human milk banks among women in the first year postpartum was low. More mothers were willing to donate human milk than to use donor human milk to feed their children. In our study, knowledge of human milk banking was a predictor of both willingness to donate human milk and willingness to use donor human milk. Programs with detailed information on human milk banking are needed to help mothers improve their knowledge and increase acceptance of human milk banking.

Abstract Background A major challenge of prospective cohort studies is attrition in follow-up surveys. This study investigated attrition in a prospective cohort comprised of medical graduates in China. We described status of attrition, identified participants with higher possibility of attrition, and examined if attrition affect the estimation of the key outcome measures. Methods The cohort study recruited 3,620 new medical graduates from four medical universities in central and western China between 2015 and 2019. Online follow-up surveys were conducted on an annual basis. Follow-up status was defined as complete (meaning that the participant completed all the follow-up surveys) and incomplete, while incomplete follow-up was further divided into ‘always-out’, ‘rejoin’ and ‘other’. Multivariable logistic and linear regressions were used to examine factors predicting attrition and the influence on the outcome measures of career development. Results 2364 (65.3%) participants completed all follow-up surveys. For those with incomplete follow-up, 520 (14.4%) were ‘always-out’, 276 (7.6%) rejoined in the 2020 survey. Willingness to participate in residency training (OR=0.80, 95%CI[0.66 - 0.98]) and willingness to provide sensitive information in the baseline survey predicted a lower rate of attrition (providing scores for university entrance exam OR=0.82, 95%CI[0.69 - 0.97]]; providing contact information (OR=0.46, 95%CI[0.32 - 0.66]); providing household income (OR=0.60, 95%CI[0.43 - 0.84]). Participants with compulsory rural service (OR=1.52, 95%CI[1.05 - 2.19]) and those providing university entrance scores (OR=1.64, 95%CI[1.15-2.33)) were more likely to rejoin in the follow-up survey. These factors associated with follow-up status did not have significant impact on key outcome measures of career development. Conclusions Graduates who were unwilling to participate in residency training or not providing sensitive information should be targeted early in the cohort study to reduce attrition. More information about the study should be provided to those graduates early to facilitate their understanding of the meaning in participation. On the contrary, medical graduates with compulsory rural service and those who provided university entrance scores were more likely to rejoin in the cohort. The research team should invest more effort in contacting those graduates and returned them to the cohort.

Abstract Background Silencing of the periostin gene (POSTN) can inhibit the biological process of several different cancers, and this inhibition may be related to down-regulation of PI3K/AKT signaling. However, the effect of POSTN on the progression, proliferation, and invasion of osteosarcoma (OS) remain unclear. Methods We used the Gene Expression Omnibus (GEO) database to screen datasets on in situ OS and lung metastases to identify core genes and potential pathways. We used additional bioinformatics tools to identify protein–protein interactions (PPIs) and gene networks, and selected the top seven genes whose expression had the strongest correlations with other genes. Results The results indicated that POSTN was a major hub gene. Subsequent analysis of gene expression profiles showed that POSTN was highly expressed in 262 cases with sarcoma and expression was closely related to poor prognosis. We also performed enrichment analysis to identify differentially expressed genes and used real-time PCR, western blotting, and immunohistochemistry analyses to measure POSTN expression in cells and tissues. Transfection of a POSTN-shRNA plasmid into cultured OS cells (Saos-2) effectively inhibited the proliferation, invasion, and migration of these cells. Taken together, our results suggest that POSTN may play a role in promoting the proliferation and metastasis of OS by activation of the PI3K/Akt signaling pathway. Conclusions Our results provide a preliminary characterization of the mechanism by which POSTN may regulate the migration and invasion of OS cells and also provide a theoretical basis for identifying biomarkers that have potential use for the diagnosis and treatment of OS.

The existing judicial reading comprehension datasets are relatively simple, and the answers to the questions can be obtained through single-step reasoning. However, the content of legal documents in actual scenarios is complex, making it problematic to infer correct results merely by single-step reasoning. To solve this type of issue, we promote the difficulties of questions included in Chinese Judicial Reading Comprehension (CJRC) dataset and propose two augmented versions, CJRC2.0 and CJRC3.0. These datasets are derived from Chinese judicial judgment documents in different fields and annotated by judicial professionals. Compared to CJRC, there are more types of judgment documents in the two datasets, and the questions become are more challenging to answer. For CJRC2.0, we only preserve complex questions that require to be solved by multi-step reasoning. Besides, we provide additional supporting facts to the answers. For CJRC3.0, we introduce a new question type, the multi-span question, which should be answered by extracting and combining multiple spans in the documents. We implement two powerful baselines to evaluate the difficulty of our proposed datasets. Our proposed datasets fill gaps in the field of explainable legal machine reading comprehension.

Background: Point-of-care testing (POCT) has applications across medical specialties and holds promise to improve patient care. While cardiovascular medicine has been attractive for POCT applications in recent years, little is known about how cardiovascular health professionals perceive them. Objective: The objective of our study was to examine differences in perceptions and attitudes towards POCTs between cardiovascular health professionals compared to other healthcare professionals. Methods: We surveyed healthcare professionals to assess perceptions of POCT usage and their benefits and concerns between October 2019 and March 2020. Questions regarding POCT perceptions were assessed on a 5-point Likert scale. Results: We received a total of 148 survey responses; of the responders, 52% were male, 59% were physicians, and 50% worked in a hospital setting. We found that cardiology professionals were less likely, compared to other specialties, to view POCTs as improving patient management or reducing errors. These cardiology professionals were not constrained by resources or a lack of investment opportunities to implement these technologies. Conclusion: This study provides a better understanding of perceptions about POCTs among healthcare specialists. To improve patient outcomes through the adoption and usage of POCTs, greater collaboration is advised among key industry and healthcare stakeholders.

Background and aimsThe disease burden attributable to metabolic risk factors is rapidly increasing in China, especially in older people. The objective of this study was to (i) estimate the pattern and trend of six metabolic risk factors and attributable causes in China from 1990 to 2019, (ii) ascertain its association with societal development, and (iii) compare the disease burden among the Group of 20 (G20) countries.MethodsThe main outcome measures were disability-adjusted life-years (DALYs) and mortality (deaths) attributable to high fasting plasma glucose (HFPG), high systolic blood pressure (HSBP), high low-density lipoprotein (HLDL) cholesterol, high body-mass index (HBMI), kidney dysfunction (KDF), and low bone mineral density (LBMD). The average annual percent change (AAPC) between 1990 and 2019 was analyzed using Joinpoint regression.ResultsFor all six metabolic risk factors, the rate of DALYs and death increased with age, accelerating for individuals older than 60 and 70 for DALYs and death, respectively. The AAPC value in rate of DALYs and death were higher in male patients than in female patients across 20 age groups. A double-peak pattern was observed for AAPC in the rate of DALYs and death, peaking at age 20–49 and at age 70–95 plus. The age-standardized rate of DALYs increased for HBMI and LBMD, decreased for HFPG, HSBP, KDF, and remained stable for HLDL from 1990 to 2019. In terms of age-standardized rate of DALYs, there was an increasing trend of neoplasms and neurological disorders attributable to HFPG; diabetes and kidney diseases, neurological disorders, sense organ diseases, musculoskeletal disorders, neoplasms, cardiovascular diseases, digestive diseases to HBMI; unintentional injuries to LBMD; and musculoskeletal disorders to KDF. Among 19 countries of Group 20, in 2019, the age-standardized rate of DALYs and death were ranked fourth to sixth for HFPG, HSBP, and HLDL, but ranked 10th to 15th for LBMD, KDF, and HBMI, despite the number of DALYs and death ranked first to second for six metabolic risk factors.ConclusionsPopulation aging continuously accelerates the metabolic risk factor driven disease burden in China. Comprehensive and tight control of metabolic risk factors before 20 and 70 may help to mitigate the increasing disease burden and achieve healthy aging, respectively.

Pseudomonas is a ubiquitous and ambiguous opportunistic pathogen, and plays an important ecological role in the ocean. Here, a new species, Pseudomonas phage vB_PsaP_M1, is described, which was isolated from the surface coastal waters of Qingdao, China. vB_PsaP_M1 contains a linear, double-stranded 89,387-bp genome with a GC content of 41.04% and encoding 184 putative open reading frames (ORFs). There were 50 conservative domains were predicted with BLASTp, including two auxiliary metabolic genes (Phosphate-inducible gene phoH and signal peptide peptidase A, sppA). Phylogenetic analysis of whole genome amino acid sequence and comparative genomic analysis showed that vB_PsaP_M1 has a distant evolutionary relationship with previously isolated viruses and can be grouped into a family-level novel viral cluster (VC_61) with eleven uncultured, assembled viral genomes, named as Psaeviridae. Psaeviridae contains two ORFs (ORFs 117 and 127), which were not detected in the genomes of other viral families, confirming the proposal for a new family. Combined with its ability to infect Pseudomonas and its representation of an unstudied viral family, vB_PsaP_M1 may be an important and novel model system for the study of interactions between viruses and host cells in marine ecosystems.

Abstract Background Pancreatic cancer has been a threateningly lethal malignant tumor worldwide. Despite the promising survival improvement in other cancer types attributing to the fast development of molecular precise medicine, the current treatment situation of pancreatic cancer is still woefully challenging since its limited response to neither traditional radiotherapy and chemotherapy nor emerging immunotherapy. The study is to explore potential responsible genes during the development of pancreatic cancer, thus identifying promising gene indicators and probable drug targets. Methods Different bioinformatic analysis were used to interpret the genetic events in pancreatic cancer development. Firstly, based on multiple cDNA microarray profiles from Gene Expression Omnibus (GEO) database, the genes with differently mRNA expression in cancer comparing to normal pancreatic tissues were identified, followed by being grouped based on the difference level. Then, GO and KEGG were performed to separately interpret the multiple groups of genes, and further Kaplan–Meier survival and Cox Regression analysis assisted us to scale down the candidate genes and select the potential key genes. Further, the basic physicochemical properties, the association with immune cells infiltration, mutation or other types variations besides expression gap in pancreatic cancer comparing to normal tissues of the selected key genes were analyzed. Moreover, the aberrant changed expression of key genes was validated by immunohistochemistry (IHC) experiment using local hospital tissue microarray samples and the clinical significance was explored based on TCGA clinical data. Results Firstly, a total of 22,491 genes were identified to express differently in cancer comparing to normal pancreatic tissues based on 5 cDNA expression profiles, and the difference of 487/22491 genes was over eightfold, and 55/487 genes were shared in multi profiles. Moreover, after genes interpretation which showed the > eightfold genes were mainly related to extracellular matrix structural constituent regulation, Kaplan–Meier survival and Cox-regression analysis were performed continually, and the result indicated that of the 55 extracellular locating genes, GPRC5A and IMUP were the only two independent prognostic indicators of pancreatic cancer. Further, detailed information of IMUP and GPRC5A were analyzed including their physicochemical properties, their expression and variation ratio and their association with immune cells infiltration in cancer, as well as the probable signaling pathways of genes regulation on pancreatic cancer development. Lastly, local IHC experiment performed on PAAD tissue array which was produced with 62 local hospital patients samples confirmed that GPRC5A and IMUP were abnormally up-regulated in pancreatic cancer, which directly associated with worse patients both overall (OS) and recurrence free survival (RFS). Conclusions Using multiple bioinformatic analysis as well as local hospital samples validation, we revealed that GPRC5A and IMUP expression were abnormally up-regulated in pancreatic cancer which associated statistical significantly with patients survival, and the genes’ biological features and clinical significance were also explored. However, more detailed experiments and clinical trials are obligatory to support their further potential drug-target role in clinical medical treatment.

Background: Telemedicine and commercial wearable devices capable of detecting atrial fibrillation (AF) have revolutionized arrhythmia care during coronavirus disease 2019. However, not much is known about virtual patient-provider interactions or device sharing behaviors. Objective: The purpose of this study was to characterize how participants with or at risk of AF are engaging with their providers in the context of telemedicine and using commercially wearable devices to manage their health. Methods: We developed a survey to describe participant behaviors around telemedicine encounters and commercial wearable device use. The survey was distributed to participants diagnosed with AF or those at risk of AF (as determined by being at least 65 years old and having a CHA2DS2-VASc stroke risk score of >2) in the University of Massachusetts Memorial Health Care system. Results: The survey was distributed to 23,530 patients, and there were 1222 (5.19%) participant responses. Among the participants, 327 (26.8%) had AF and 895 (73.2%) were at risk of AF. Neither device ownership nor device type use differed by AF status. After adjusting for covariates that may influence surveyed participant communication patterns, we found that participants with AF were more likely to share their wearable device-derived data with providers (adjusted odds ratio 1.87; 95% confidence interval 1.02–3.41). Rates of sharing physical activity or sleep data were low for both groups and did not differ by AF status. Conclusion: Compared with participants at risk of developing AF, those with AF were more likely to share heart rate and rhythm data from their commercial wearable devices with providers. However, both groups had similar rates of sharing physical activity and sleep data, telemedicine engagement, and technology use and ownership.

Abstract Background Marine bacteriophages play key roles in the community structure of microorganisms, biogeochemical cycles, and the mediation of genetic diversity through horizontal gene transfer. Recently, traditional isolation methods, complemented by high-throughput sequencing metagenomics technology, have greatly increased our understanding of the diversity of bacteriophages. Oceanospirillum, within the order Oceanospirillales, are important symbiotic marine bacteria associated with hydrocarbon degradation and algal blooms, especially in polar regions. However, until now there has been no isolate of an Oceanospirillum bacteriophage, and so details of their metagenome has remained unknown. Results Here, we reported the first Oceanospirillum phage, vB_OliS_GJ44, which was assembled into a 33,786 bp linear dsDNA genome, which includes abundant tail-related and recombinant proteins. The recombinant module was highly adapted to the host, according to the tetranucleotides correlations. Genomic and morphological analyses identified vB_OliS_GJ44 as a siphovirus, however, due to the distant evolutionary relationship with any other known siphovirus, it is proposed that this virus could be classified as the type phage of a new Oceanospirivirus genus within the Siphoviridae family. vB_OliS_GJ44 showed synteny with six uncultured phages, which supports its representation in uncultured environmental viral contigs from metagenomics. Homologs of several vB_OliS_GJ44 genes have mostly been found in marine metagenomes, suggesting the prevalence of this phage genus in the oceans. Conclusions These results describe the first Oceanospirillum phage, vB_OliS_GJ44, that represents a novel viral cluster and exhibits interesting genetic features related to phage–host interactions and evolution. Thus, we propose a new viral genus Oceanospirivirus within the Siphoviridae family to reconcile this cluster, with vB_OliS_GJ44 as a representative member.

Abstract As the core ingredient for spin polarization, the equilibrium spin distribution function that eliminates the collision terms is derived from the detailed balance principle. The kinetic theory for interacting fermionic systems is applied to the Nambu–Jona-Lasinio model at quark level. Under the semi-classical expansion with respect to $$\hbar $$ ħ , the kinetic equations for the vector and axial-vector distribution functions are obtained with collision terms. For an initially unpolarized system, spin polarization can be generated at the first order of $$\hbar $$ ħ from the coupling between the vector and axial-vector charges. Different from the classical transport theory, the collision terms in a quantum theory vanish only in global equilibrium with Killing condition.

Summary: Background: Tuberculosis is the leading cause of death from a single infectious agent among the HIV-negative population and ranks first among the HIV-positive population. However, few studies have assessed tuberculosis trends in Brazil, Russia, India, China and South Africa (BRICS) or with an emphasis on HIV status. This study assesses the time trends of tuberculosis mortality across the BRICS with an emphasis on HIV status from 1990 to 2019. Methods: We obtained tuberculosis data from the Global Burden of Disease 2019 study (GBD 2019). We calculated the relative proportion of tuberculosis to all communicable, maternal, neonatal, and nutritional diseases by HIV status across the BRICS. We used age-period-cohort modelling to estimate cohort and period effects in tuberculosis from 1990 to 2019, and calculated net drift (overall annual percentage change), local drift (annual percentage change in each age group), longitudinal age curves (expected longitudinal age-specific rate), and period (cohort) relative risks. Findings: There were 549,522 tuberculosis deaths across the BRICS in 2019, accounting for 39.3% of global deaths. Among HIV-negative populations, the age-standardised mortality rate (ASMR) of tuberculosis in BRICS remained far higher than that of high-income Asia Pacific countries, especially in India (36.1 per 100 000 in 2019, 95% UI [30.7, 42.6]) and South Africa (40.1 per 100 000 in 2019, 95% UI [36.8, 43.7]). China had the fastest ASMR reduction across the BRICS, while India maintained the largest tuberculosis death numbers with an annual decrease much slower than China's (-4.1 vs -8.0%). Among HIV-positive populations, the ASMR in BRICS surged from 0.24 per 100 000 in 1990 to 5.63 per 100 000 in 2005, and then dropped quickly to 1.70 per 100 000 in 2019. Brazil was the first country to reverse the upward trend of HIV/AIDS-tuberculosis (HIV-TB) mortality in 1995, and achieved the most significant reduction (-3.32% per year). The HIV-TB mortality in South Africa has realised much progress since 2006, but still has the heaviest HIV-TB burden across the BRICS (ASMR: 70.0 per 100 000 in 2019). We also found unfavourable trends among HIV-negative middle-aged (35-55) adults of India, men over 50 in the HIV-negative population and whole HIV-positive population of South Africa, and women aged 45-55 years of Russia. China had little progress in its HIV-positive population with worsening period risks from 2010 to 2019, and higher risks in the younger cohorts born after 1980. Interpretation: BRICS’ actions on controlling tuberculosis achieved positive results, but the overall improvements were less than those in high-income Asia Pacific countries. BRICS and other high-burden countries should strengthen specified public health approaches and policies targeted at different priority groups in each country. Funding: National Natural Science Foundation of China (82073573; 72074009), Peking University Global Health and Infectious Diseases Group.

The possibility to record proteomes in high throughput and at high quality has opened new avenues for biomedical research, drug discovery, systems biology, and clinical translation. However, high-throughput proteomic experiments often require high sample amounts and can be less sensitive compared to conventional proteomic experiments. Here, we introduce and benchmark Zeno SWATH MS, a data-independent acquisition technique that employs a linear ion trap pulsing (Zeno trap pulsing) to increase the sensitivity in high-throughput proteomic experiments. We demonstrate that when combined with fast micro- or analytical flow-rate chromatography, Zeno SWATH MS increases protein identification with low sample amounts. For instance, using 20 min micro-flow-rate chromatography, Zeno SWATH MS identified more than 5000 proteins consistently, and with a coefficient of variation of 6%, from a 62.5 ng load of human cell line tryptic digest. Using 5 min analytical flow-rate chromatography (800 µl/min), Zeno SWATH MS identified 4907 proteins from a triplicate injection of 2 µg of a human cell lysate, or more than 3000 proteins from a 250 ng tryptic digest. Zeno SWATH MS hence facilitates sensitive high-throughput proteomic experiments with low sample amounts, mitigating the current bottlenecks of high-throughput proteomics.

The sesquiterpene lactone, artemisinin, is a primary component of the medicinal plant Artemisia annua L., which has anti-inflammatory, antibacterial and antioxidant activities. However, the potential effects of artemisinin on the mammary gland of dairy cows and the underlying molecular mechanisms remain unclear. Here, we utilized systematic network pharmacology and proteomics to elucidate the mechanism by which artemisinin affects milk production and the proliferation of bovine mammary epithelial cells (BMECs). Nineteen bioactive compounds and 56 key targets were identified through database mining. To delineate the mechanism of artemisia’s activity, a protein-protein interaction network and integrated visual display were generated from bioinformatics assays to explore the relationships and interactions among the bioactive molecules and their targets. The gene ontology (GO) terms and kyoto encyclopedia of genes and genomes annotation suggested that the apoptotic process, cell division, p53 pathway, prolactin and PI3K-Akt pathways played vital roles in mammary gland development. Using proteomics analysis, we identified 122 up-regulated and 96 down-regulated differentially significant expressed proteins (DSEPs). The differentially significant expressed proteins had multiple biological functions associated with cell division, apoptosis, differentiation, and migration. Gene ontology enrichment analysis suggested that differentially significant expressed proteins may promote cell proliferation and regulate apoptosis in bovine mammary epithelial cells. Kyoto encyclopedia of genes and genomes pathway analysis indicated that several biological pathways, such as those involved in antigen processing and presentation, cell adhesion molecules and ribosomes, played significant roles in the effects of artemisinin on bovine mammary epithelial cells. These findings contribute to a comprehensive understanding of the mechanism by which artemisinin affects bovine mammary epithelial cells to improve mammary gland turnover by inducing cell proliferation and mammary gland development.

BackgroundBovine metabolism undergoes significant changes during subclinical mastitis, but the relevant molecular mechanisms have not been elucidated. In this study we investigated the changes in milk microbiota and metabolites after intramammary infusion of matrine-chitosan hydrogels (MCHs) in cows with subclinical mastitis.MethodsInfusions were continued for 7 days, and milk samples were collected on days 1 and 7 for microbiome analysis by 16S rRNA gene sequencing and metabolite profiling by liquid chromatography-mass spectrometry.ResultsMCHs significantly decreased the somatic cell count on day 7 compared to day 1, and the Simpson index indicated that microbial diversity was significantly lower on day 7. The relative abundance of Aerococcus, Corynebacterium_1, Staphylococcus and Firmicutes was significantly decreased on day 7, while Proteobacteria increased. In the milk samples, we identified 74 differentially expressed metabolites. The MCHs infusion group had the most significantly upregulated metabolites including sphingolipids, glycerophospholipids, flavonoids and fatty acyls. The mammary gland metabolic pathways identified after MCHs treatment were consistent with the known antimicrobial and anti-inflammatory properties of matrine that are associated with glycerophospholipid metabolism and the sphingolipid metabolic signaling pathways.ConclusionThese insights into the immunoregulatory mechanisms and the corresponding biological responses to matrine demonstrate its potential activity in mitigating the harmful effects of bovine mastitis.

Abstract Background Colony-stimulating factor 1 (CSF1) expression in the central nervous system (CNS) increases in response to a variety of stimuli, and CSF1 is overexpressed in many CNS diseases. In young adult mice, we previously showed that CSF1 overexpression in the CNS caused the proliferation of IBA1+ microglia without promoting the expression of M2 polarization markers. Methods Immunohistochemical and molecular analyses were performed to further examine the impact of CSF1 overexpression on glia in both young and aged mice. Results As CSF1 overexpressing mice age, IBA1+ cell numbers are constrained by a decline in proliferation rate. Compared to controls, there were no differences in expression of the M2 markers ARG1 and MRC1 (CD206) in CSF1 overexpressing mice of any age, indicating that even prolonged exposure to increased CSF1 does not impact M2 polarization status in vivo. Moreover, RNA-sequencing confirmed the lack of increased expression of markers of M2 polarization in microglia exposed to CSF1 overexpression but did reveal changes in expression of other immune-related genes. Although treatment with inhibitors of the CSF1 receptor, CSF1R, has been shown to impact other glia, no increased expression of oligodendrocyte lineage or astrocyte markers was observed in CSF1 overexpressing mice. Conclusions Our study indicates that microglia are the primary glial lineage impacted by CSF1 overexpression in the CNS and that microglia ultimately adapt to the presence of the CSF1 mitogenic signal.

Surfactants have been widely used as effective additives to increase the solubility and dissolution rates of amorphous solid dispersions (ASDs). However, they may also generate adverse effects on the physical stability of ASDs. In this study, we systematically investigated the impacts of poloxamer, a frequently used surfactant, on the crystallization of amorphous clotrimazole (CMZ). The added poloxamer significantly decreased the glass transition temperature (Tg) of CMZ and accelerated the growth of Form 1 and Form 2 crystals. It was found that the poloxamer had an accelerating effect on Form 1 and Form 2 but showed a larger accelerating effect on Form 1, which resulted from a combined effect of increased mobility and local phase separation at the crystal–liquid interface. Additionally, the added poloxamer exhibited different effects on nucleation of the CMZ polymorphs, which was more complicated than crystal growth. The nucleation rate of Form 1 was significantly increased by the added poloxamer, and the effect increased with increasing P407 content. However, for Form 2, nucleation was slightly decreased or unchanged. The nucleation of Form 2 may have been influenced by the Form 1 crystallization, and Form 2 converted to Form 1 during nucleation. This study increases our understanding of poloxamer and its impacts on the melt crystallization of drugs.

Abstract Background Clear cell renal cell carcinoma (ccRCC) has been the commonest renal cell carcinoma (RCC). Although the disease classification, diagnosis and targeted therapy of RCC has been increasingly evolving attributing to the rapid development of current molecular pathology, the current clinical treatment situation is still challenging considering the comprehensive and progressively developing nature of malignant cancer. The study is to identify more potential responsible genes during the development of ccRCC using bioinformatic analysis, thus aiding more precise interpretation of the disease Methods Firstly, different cDNA expression profiles from Gene Expression Omnibus (GEO) online database were used to screen the abnormal differently expressed genes (DEGs) between ccRCC and normal renal tissues. Then, based on the protein–protein interaction network (PPI) of all DEGs, the module analysis was performed to scale down the potential genes, and further survival analysis assisted our proceeding to the next step for selecting a credible key gene. Thirdly, immunohistochemistry (IHC) and quantitative real-time PCR (QPCR) were conducted to validate the expression change of the key gene in ccRCC comparing to normal tissues, meanwhile the prognostic value was verified using TCGA clinical data. Lastly, the potential biological function of the gene and signaling mechanism of gene regulating ccRCC development was preliminary explored. Results Four cDNA expression profiles were picked from GEO database based on the number of containing sample cases, and a total of 192 DEGs, including 39 up-regulated and 153 down-regulated genes were shared in four profiles. Based on the DEGs PPI network, four function modules were identified highlighting a FGF1 gene involving PI3K-AKT signaling pathway which was shared in 3/4 modules. Further, both the IHC performed with ccRCC tissue microarray which contained 104 local samples and QPCR conducted using 30 different samples confirmed that FGF1 was aberrant lost in ccRCC. And Kaplan–Meier overall survival analysis revealed that FGF1 gene loss was related to worse ccRCC patients survival. Lastly, the pathological clinical features of FGF1 gene and the probable biological functions and signaling pathways it involved were analyzed using TCGA clinical data. Conclusions Using bioinformatic analysis, we revealed that FGF1 expression was aberrant lost in ccRCC which statistical significantly correlated with patients overall survival, and the gene’s clinical features and potential biological functions were also explored. However, more detailed experiments and clinical trials are needed to support its potential drug-target role in clinical medical use.

Introduction Oral epithelial cells were recently shown to be able to differentiate into corneal epithelium, and the efficacy of cultured autologous oral mucosal epithelial cells (CAOMEC) has been suggested by the presence of epithelium replacement. Therefore, the aim of this study was to evaluate the treatment outcome in limbal stem cell deficiency (LSCD) by adding CAOMEC to regular amniotic membrane (AM) treatment. Material and methods Eyes with LSCD were randomized to two groups to undergo either autologous oral mucosal epithelial cell sheet (CAOMECS) combined with AM transplantation (A group) or AM transplantation alone (B group). Clinical outcome measures were corneal epithelium healing, best corrected visual acuity, symblepharon, corneal transparency, corneal neovascularization and ocular surface inflammation. Results The normal corneal epithelialization rate in group A (73.33%) was higher than that in group B (35.48%), and the average healing time was shorter (3.45 ±2.12 weeks vs. 4.64 ±1.63 weeks). The symblepharon in the above two groups was improved in the first 3 months after surgery, but after 6 months, part of the B group had recurrence. In improving corneal transparency, group A has obvious advantages. Corneal neovascularization (CNV) was improved to some extent in the first 3 months after surgery, but group A (1.47 ±0.64) was better than group B (1.94 ±0.85) after 6 months. Both groups can improve the inflammatory state to some extent. Conclusions The transplantation of CAOMECS offers a viable and safe alternative in the reconstruction of a stable ocular surface. The effect is better than that of traditional AM transplantation, mainly in promoting corneal epithelialization, improving ocular surface structure, and reducing fiber and vascular infiltration.

Summary: Background: Global healthcare systems continue to be challenged by the COVID-19 pandemic, and there is a need for clinical assays that can help optimise resource allocation, support treatment decisions, and accelerate the development and evaluation of new therapies. Methods: We developed a multiplexed proteomics assay for determining disease severity and prognosis in COVID-19. The assay quantifies up to 50 peptides, derived from 30 known and newly introduced COVID-19-related protein markers, in a single measurement using routine-lab compatible analytical flow rate liquid chromatography and multiple reaction monitoring (LC-MRM). We conducted two observational studies in patients with COVID-19 hospitalised at Charité – Universitätsmedizin Berlin, Germany before (from March 1 to 26, 2020, n=30) and after (from April 4 to November 19, 2020, n=164) dexamethasone became standard of care. The study is registered in the German and the WHO International Clinical Trials Registry (DRKS00021688). Findings: The assay produces reproducible (median inter-batch CV of 10.9%) absolute quantification of 47 peptides with high sensitivity (median LLOQ of 143 ng/ml) and accuracy (median 96.8%). In both studies, the assay reproducibly captured hallmarks of COVID-19 infection and severity, as it distinguished healthy individuals, mild, moderate, and severe COVID-19. In the post-dexamethasone cohort, the assay predicted survival with an accuracy of 0.83 (108/130), and death with an accuracy of 0.76 (26/34) in the median 2.5 weeks before the outcome, thereby outperforming compound clinical risk assessments such as SOFA, APACHE II, and ABCS scores. Interpretation: Disease severity and clinical outcomes of patients with COVID-19 can be stratified and predicted by the routine-applicable panel assay that combines known and novel COVID-19 biomarkers. The prognostic value of this assay should be prospectively assessed in larger patient cohorts for future support of clinical decisions, including evaluation of sample flow in routine setting. The possibility to objectively classify COVID-19 severity can be helpful for monitoring of novel therapies, especially in early clinical trials. Funding: This research was funded in part by the European Research Council (ERC) under grant agreement ERC-SyG-2020 951475 (to M.R) and by the Wellcome Trust (IA 200829/Z/16/Z to M.R.). The work was further supported by the Ministry of Education and Research (BMBF) as part of the National Research Node ‘Mass Spectrometry in Systems Medicine (MSCoresys)', under grant agreements 031L0220 and 161L0221. J.H. was supported by a Swiss National Science Foundation (SNSF) Postdoc Mobility fellowship (project number 191052). This study was further supported by the BMBF grant NaFoUniMedCOVID-19 – NUM-NAPKON, FKZ: 01KX2021. The study was co-funded by the UK's innovation agency, Innovate UK, under project numbers 75594 and 56328.

Background: Geriatric conditions (eg, cognitive impairment, frailty) are increasingly recognized for their impact on clinical and quality-of-life outcomes in older patients with cardiovascular disease, but are not systematically assessed in the context of clinical visits owing to time constraints. Objective: To examine feasibility of remote monitoring of the physical, cognitive, and psychosocial status of older adults with atrial fibrillation (AF) via a novel smartphone app over 6 months. Methods: Forty participants with AF and eligible for anticoagulation therapy (CHA2DS2VASc ≥2) enrolled in an ongoing cohort study participated in a mobile health pilot study. A 6-component geriatric assessment, including validated measures of frailty, cognitive function, social support, depressive symptoms, vision, and hearing, was deployed via a smartphone app and 6-minute walk test was completed using a Fitbit. Adherence to mobile assessments was examined over 6 months. Results: Participants were an average of 71 years old (range 65–86 years) and 38% were women. At 1 month, 75% (30/40) of participants completed the app-based geriatric assessment and 63% (25/40) completed the 6-minute walk test. At 6 months, 52% (15/29) completed the geriatric assessment and 28% (8/29) completed the walk test. There were no differences in demographic, clinical, or psychosocial factors between participants who completed the surveys at 6 months and those who did not. Participants, on average, required less than 10 minutes of telephone support over the 6-month period. Conclusion: It is feasible, among smartphone users, to use a mobile health app and wearable activity monitor to conduct serial geriatric assessments in older patients with AF for up to 6 months.

Abstract Background Lung cancer has been the leading cause of tumor related death, and 80% ~ 85% of it is non-small cell lung cancer (NSCLC). Even with the rising molecular targeted therapies, for example EGFR, ROS1 and ALK, the treatment is still challenging. The study is to identify credible responsible genes during the development of NSCLC using bioinformatic analysis, developing new prognostic biomarkers and potential gene targets to the disease. Methods Firstly, three genes expression profiles GSE44077, GSE18842 and GSE33532 were picked from Gene Expression Omnibus (GEO) to analyze the genes with different expression level (GDEs) between NSCLC and normal lung samples, and the cellular location, molecular function and the biology pathways the GDEs enriched in were analyzed. Then, gene function modules of GDEs were explored based on the protein-protein interaction network (PPI), and the top module which contains most genes was identified, followed by containing genes annotation and survival analysis. Moreover, multivariate cox regression analysis was performed in addition to the Kaplan meier survival to narrow down the key genes scale. Further, the clinical pathological features of the picked key genes were explored using TCGA data. Results Three GEO profiles shared a total of 664 GDEs, including 232 up-regulated and 432 down-regulated genes. Based on the GDEs PPI network, the top function module containing a total of 69 genes was identified, and 31 of 69 genes were mitotic cell cycle regulation related. And survival analysis of the 31 genes revealed that 17/31 genes statistical significantly related to NSCLC overall survival, including 4 spindle assembly checkpoints, namely NDC80, BUB1B, MAD2L1 and AURKA. Further, multivariate cox regression analysis identified NDC80 and MAD2L1 as independent prognostic indicators in lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) respectively. Interestingly, pearson correlation analysis indicated strong connection between the four genes NDC80, BUB1B, MAD2L1 and AURKA, and their clinical pathological features were addressed. Conclusions Using bioinformatic analysis of GEO combined with TCGA data, we revealed two independent prognostic indicators in LUAD and LUSC respectively and analyzed their clinical features. However, more detailed experiments and clinical trials are needed to verify their drug targets role in clinical medical use.

Abstract Purposes to study the effect of titanium particles on MLO-Y4 and the effects of osteocytes alterations on osteoblasts. Methods cultured MLO-Y4 osteocytes were exposed to different concentrations of titanium (Ti) particles, cell viability was measured using the Cell Counting Kit-8 (CCK-8) assay, apoptosis of MLO-Y4 cells was evaluated by flow cytometry, Real-time PCR quantification of mRNA expression of SOST, at the same time with Western Blot detection sclerosteosis protein expression levels.MC3T3-E1 cells culture with MLO-Y4 cells exposed to different concentrations of titanium (Ti) particles in vitro, in order to detection of osteoblast osteogenetic activity. Results Our results showed that Ti particles inhibited cell viability of MLO-Y4 osteocytes in a dose-dependent manner. Incubation with Ti particles caused apoptosis of MLO-Y4cells.Treatment with Ti particles significantly increased expression of the osteocytic marker SOST/sclerostin. Furthermore, treatment of MLO-Y4 cells with Ti particles produced a dose-dependent decrease in ALP activity and decreased mineralization of MC3T3-E1 cells through direct cell-cell contact. Conclusions Titanium particles damage osteocytes and inhibit osteoblast differentiation.

Insulin secretion from pancreatic β cells is essential for glucose homeostasis. An insufficient response to the demand for insulin results in diabetes. We previously showed that β cell–specific deletion of Zfp148 (β-Zfp148KO) improves glucose tolerance and insulin secretion in mice. Here, we performed Ca2+ imaging of islets from β‑Zfp148KO and control mice fed both a chow and a Western-style diet. β-Zfp148KO islets demonstrated improved sensitivity and sustained Ca2+ oscillations in response to elevated glucose levels. β-Zfp148KO islets also exhibited elevated sensitivity to amino acid–induced Ca2+ influx under low glucose conditions, suggesting enhanced mitochondrial phosphoenolpyruvate-dependent (PEP-dependent), ATP-sensitive K+ channel closure, independent of glycolysis. RNA-Seq and proteomics of β-Zfp148KO islets revealed altered levels of enzymes involved in amino acid metabolism (specifically, SLC3A2, SLC7A8, GLS, GLS2, PSPH, PHGDH, and PSAT1) and intermediary metabolism (namely, GOT1 and PCK2), consistent with altered PEP cycling. In agreement with this, β-Zfp148KO islets displayed enhanced insulin secretion in response to l-glutamine and activation of glutamate dehydrogenase. Understanding pathways controlled by ZFP148 may provide promising strategies for improving β cell function that are robust to the metabolic challenge imposed by a Western diet.

The aim of this work was to investigate the microbial diversity characteristics and driving factors in a high elevation drop river and to analyze the potential risks of river microorganisms to human health. In March 2019, we analyzed the microbial diversity characteristics in surface water and sludge from the Huotong River using high-throughput sequencing. The Huotong River is of great importance to the production and life of the people living along this river. The sampling points were set at the estuary of the river, on a downstream section of the river, on an upstream section of the main river, at one tributary flowing through a town, at one tributary with a barrage, and at the source of one tributary. The results showed significant differences in bacterial diversity in different areas of the river. For example, actinomycetes were less abundant in water samples from the headwaters of tributaries and more abundant upriver. The results revealed that different intensities of human activities had significant different effects on functional flora. Anthropogenic disturbance and human activities reduced the abundance of probiotic bacteria and increased the abundance of pathogenic bacteria in the river. The changes in functional floral diversity may pose potential threats to human health.

With the recurrence of high-impact extreme events and the growing public demands to understand the causes of the events, event attribution has emerged as a frontier of climate change research. Typically, an event attribution study focuses on one individual extreme event that has just occurred. Studies rarely examine human influence on multiple extreme events in different times of the past. Here we conduct a comprehensive attribution analysis on the four heaviest precipitation events in the Yangtze River Valley during the past 100 years. We start by defining extreme precipitation events as the heaviest precipitation over a fixed size area that is of direct relevance to flood preparedness and management. When examining the events over the historical time, we allow the precise location of the area to change in different years. By definition, four extremely strong events are identified, and they happened in the summer of 1931, 1954, 1998 and 2020. We find that the impacts of greenhouse gases (GHGs) and anthropogenic aerosols (AAs) on these events show clear difference in different time period. The impacts were negligible in the early period and became more and more discernible since the late 20th century. The GHGs have gradually increased the occurrence probability of extreme precipitaiton while the AAs have decreased the occurrence of extrem precipitation. These competing effects from the GHGs and AAs have led to a slight and then gradually increasing human influence on extreme precipitation over time. GHGs have exerted a larger influence on short-duration precipitation events while AAs have had a larger influence on monthly mean precipitation. The more extreme the precipitation event, the clearer the anthropogenic influence.

Background Atrial fibrillation (AF) commonly occurs in the setting of acute conditions. We aimed to identify the acute conditions associated with secondary AF (AF precipitants) including pneumonia/sepsis, pneumothorax, respiratory failure, myocarditis, pericarditis, alcohol intoxication, thyrotoxicosis, cardiothoracic surgery, other surgery in patients with newly diagnosed AF and determine their association with subsequent oral anticoagulant use. Methods and Results We assembled a cohort of patients in the UMass Memorial Healthcare system with a new diagnosis of AF with and without AF precipitants. We used combinations of International Classification of Diseases, Tenth Revision (ICD‐10) codes, Current Procedural Terminology codes, laboratory values, imaging reports, and physician notes including discharge summary texts to identify AF precipitants. We then manually reviewed the individual charts to validate presence of AF precipitants. The study sample consisted of 185 patients with and 172 patients without AF precipitants. Pneumonia/sepsis, myocardial infarction, respiratory failure, and cardiothoracic surgery were the most common precipitants identified. In multivariable analyses adjusting for age, sex, patient comorbidities, left atrial enlargement, left ventricular ejection fraction, and antiplatelet use, patients with AF precipitants were less likely to receive subsequent anticoagulation therapy at 30 days after the initial AF diagnosis (odds ratio, 0.31; 95% CI, 0.19–0.52). The association was persistent after excluding men with CHA2DS2‐VASc score

ABSTRACT Alteromonas is a ubiquitous, abundant, copiotrophic and phytoplankton-associated marine member of the Gammaproteobacteria with a range extending from tropical waters to polar regions and including hadal zones. Here, we describe a novel Alteromonas phage, ZP6, that was isolated from surface coastal waters of Qingdao, China. ZP6 contains a linear, double-stranded, 38,080-bp DNA molecule with 50.1% G+C content and 47 putative open reading frames (ORFs). Three auxiliary metabolic genes were identified, encoding metal-dependent phosphohydrolase, diaminopurine synthetase, and nucleotide pyrophosphohydrolase. The first two ORFs facilitate the replacement of adenine (A) by diaminopurine (Z) in phage genomes and help phages to evade attack from host restriction enzymes. The nucleotide pyrophosphohydrolase enables the host cells to stop programmed cell death and improves the survival rate of the host in a nutrient-depleted environment. Phylogenetic analysis based on the amino acid sequences of whole genomes and comparative genomic analysis revealed that ZP6 is most closely related to Enhodamvirus but with low similarity (shared genes,

Background Little research has evaluated patient bleeding risk perceptions in comparison with calculated bleeding risk among oral anticoagulant users with atrial fibrillation. Our objective was to investigate underestimation of bleeding risk and to describe the characteristics and patient‐reported outcomes associated with underestimation of bleeding risk. Methods and Results In the SAGE‐AF (Systematic Assessment of Geriatric Elements in Atrial Fibrillation) study, a prospective cohort study of patients ≥65 years with atrial fibrillation, a CHA2DS2‐VASc risk score ≥2 and who were on oral anticoagulant therapy, we compared patients’ self‐reported bleeding risk with their predicted bleeding risk from their HAS‐BLED score. Among the 754 participants (mean age 74.8 years, 48.3% women), 68.0% underestimated their bleeding risk. Participants who were Asian or Pacific Islander, Black, Native American or Alaskan Native, Mixed Race or Hispanic (non‐White) (adjusted OR [AOR], 0.45; 95% CI, 0.24–0.82) and women (AOR, 0.62; 95% CI, 0.40–0.95) had significantly lower odds of underestimating their bleeding risk than respective comparison groups. Participants with a history of bleeding (AOR, 3.07; 95% CI, 1.73–5.44) and prior hypertension (AOR, 4.33; 95% CI, 2.43–7.72), stroke (AOR, 5.18; 95% CI, 1.87–14.40), or renal disease (AOR, 5.05; 95% CI, 2.98–8.57) had significantly higher odds of underestimating their bleeding risk. Conclusions We found that more than two‐thirds of patients with atrial fibrillation on oral anticoagulant therapy underestimated their bleeding risk and that participants with a history of bleeding and several comorbid conditions were more likely to underestimate their bleeding risk whereas non‐Whites and women were less likely to underestimate their bleeding risk. Clinicians should ensure that patients prescribed oral anticoagulant therapy have a thorough understanding of bleeding risk.

Knowledge Graphs (KGs) are graph-structured knowledge bases storing factual information about real-world entities. Understanding the uniqueness of each entity is crucial to the analyzing, sharing, and reusing of KGs. Traditional profiling technologies encompass a vast array of methods to find distinctive features in various applications, which can help to differentiate entities in the process of human understanding of KGs. In this work, we present a novel profiling approach to identify distinctive entity features. The distinctiveness of features is carefully measured by a HAS model, which is a scalable representation learning model to produce a multi-pattern entity embedding. We fully evaluate the quality of entity profiless generated from real KGs. The results show that our approach facilitates human understanding of entities in KGs.

Abstract Background Triatomines are natural vectors of Chagas disease and are mainly prevalent in the Americas. In China, previous data from decades ago showed that there were two species of triatomine bugs, Triatoma rubrofasciata and T. sinica. However, the distribution, genetic characteristics and public health implications of triatomines in China are still relatively unknown. In order to gain knowledge on the distribution, genetic characteristics and public health implications of the triatomines in Guangxi, China, an entomological-epidemiological study and genetic research was conducted. Methods Different methods were used to elucidate the distribution of triatomines in Guangxi including consultations with county-level Center for Disease Prevention and Control staff and village doctors, the distribution of educational material on triatomines though the internet and social media apps such as Wechat and QQ, and conducting manual inspections and light trapping to collect triatomines. The morphological characteristics of the collected triatomines were identified under light microscopy. The mitochondrial 16S rRNA, cytochrome b (cytb) genes and nuclear 28S rRNA gene were amplified, sequenced and used in phylogenetic analyses. Results A total of 305 triatomines were captured from 54 different sites in 13 cities in Guangxi. All collected bugs were identified as T. rubrofasciata based on morphology. Most triatomine collection sites were around or inside houses. Four triatomines bite cases were observed during the investigation indicating that triatomine bites are common, the bites can cause serious anaphylaxis and skin papules and urticaria, suggesting a systemic skin response. The 16S rRNA, 28S rRNA and cytb sequence analyses of T. rubrofasciata from Guangxi and other countries showed that T. rubrofasciata sequences from different regions exhibit a high similarity, with no geographical differences. The phylogenetic tree based on the 16S rRNA and cytb genes showed that T. rubrofasciata sequences from different regions and continents were in the same cluster, indicating no differentiation among different geographical populations. Conclusions Our study showed that T. rubrofasciata is widely distributed in Guangxi and that people are commonly bitten by this insect in some regions. This highlights the need to enhance surveillance for and control of T. rubrofasciata and to strengthen the monitoring of imported Trypanosoma cruzi in China. The 16S rRNA, 28S rRNA and cytb sequence analyses of T. rubrofasciata from different regions and continents suggested that T. rubrofasciata populations exhibit high similarity, and the clustering in the phylogenetic analyses indicates that T. rubrofasciata has a close ancestor originating in the Americas.

We propose a robust task learning method based on nonlinear regression model with mixtures of t-distributions. The model can adaptively reduce the effects of complex noises and accurately learn the nonlinear structure of targets. By introducing latent variables, the model is expressed into a hierarchical structure, which helps explain the advantage of flexibility compared to the traditional Gaussian based learning model. We develop a two-stage efficient estimation procedure to obtain penalized likelihood estimator of the parameters combined an expectation-maximization algorithm with Lagrange multiplier method. The learning performances of the model are investigated through experiments on both synthetic and real data sets.

Abstract Background China’s TB control system has been transforming its service delivery model from CDC (Centers for Disease Control and Prevention)-led model to the designated hospital-led model to combat the high disease burden of TB. The implications of the new service model on TB health workforce development remained unclear. This study aims to identify implications of the new service model on TB health workforce development and to analyze whether the new service model has been well equipped with appropriate health workforce. Methods The study applied mixed methods in Zhejiang, Jilin, and Ningxia provinces of China. Institutional survey on designated hospitals and CDC was conducted to measure the number of TB health workers. Individual questionnaire survey was conducted to measure the composition, income, and knowledge of health workers. Key informant interviews and focus group discussions were organized to explore policies in terms of recruitment, training, and motivation. Results Zhejiang, Jilin, and Ningxia provinces had 0.33, 0.95, and 0.47 TB health professionals per 10 000 population respectively. They met the national staffing standard at the provincial level but with great variety at the county level. County-designated hospitals recruited TB health professionals from other departments of the same hospital, existing TB health professionals who used to work in CDC, and from township health centers. County-designated hospitals recruited new TB health professionals from three different sources: other departments of the same hospital, CDC, and township health centers. Most newly recruited professionals had limited competence and put on fixed posts to only provide outpatient services. TB doctors got 67/100 scores from a TB knowledge test, while public health doctors got 77/100. TB professionals had an average monthly income of 4587 RMB (667 USD). Although the designated hospital had special financial incentives to support, they still had lower income than other health professionals due to their limited capacity to generate revenue through service provision. Conclusions The financing mechanism in designated hospitals and the job design need to be improved to provide sufficient incentive to attract qualified health professionals and motivate them to provide high-quality TB services.

Abstract Background Lung cancer has been a common malignant tumor with a leading cause of morbidity and mortality, current molecular targets are woefully lacking comparing to the highly progressive cancer. The study is designed to identify new prognostic predictors and potential gene targets based on bioinformatic analysis of Gene Expression Omnibus (GEO) database. Methods Four cDNA expression profiles GSE19188, GSE101929, GSE18842 and GSE33532 were chosen from GEO database to analyze the differently expressed genes (DEGs) between non-small cell lung cancer (NSCLC) and normal lung tissues. After the DEGs functions were analyzed, the protein–protein interaction network (PPI) of DEGs were constructed, and the core gene in the network which has high connectivity degree with other genes was identified. We analyzed the association of the gene with the development of NSCLC as well as its prognosis. Lastly we explored the conceivable signaling mechanism of the gene regulation during the development of NSCLC. Results A total of 92 up regulated and 214 down regulated DEGs were shared in four cDNA expression profiles. Based on their PPI network, TOP2A was connected with most of other genes and was selected for further analysis. Kaplan–Meier overall survival analysis (OS) revealed that TOP2A was associated with worse NSCLC patients survival. And both GEPIA analysis and immunohistochemistry experiment (IHC) confirmed that TOP2A was aberrant gain of expression in cancer comparing to normal tissues. The clinical significance of TOP2A and probable signaling pathways it involved in were further explored, and a positive correlation between TOP2A and TPX2 expression was found in lung cancer tissues. Conclusion Using bioinformatic analysis, we revealed that TOP2A could be adopted as a prognostic indicator of NSCLC and it potentially regulate cancer development through co-work with TPX2. However, more detailed experiments are needed to clarify its drug target role in clinical medical use.

There is a lack of human models to study vocal fold epithelia making it difficult to provide therapies for vocal fold disease. Here, the authors generate a human-based model of vocal fold mucosa that mimics in utero development and shows inflammation on exposure to cigarette smoke abstract.

Abstract Background Echinococcosis has led to considerable social and economic losses in China, particularly in the endemic communities of the eastern Tibetan Plateau. In China, human cases of Echinococcus granulosus (sensu stricto), E. canadensis and E. multilocularis infections have been described, but no E. ortleppi (G5) infections in humans or animals have been reported. Results A case of E. ortleppi infection in a human from Guangxi, which is a non-endemic echinococcosis area in China, is described. A 17 × 12 × 20 cm (diameter) cyst was observed in the liver of the patient, and Echinococcus larvae were collected from the cyst. A morphological examination indicated that the larvae were E. ortleppi, and amplification and analysis of the nicotinamide adenine dinucleotide hydrogenase dehydrogenase subunit 1 (nad1) and cytochrome c oxidase subunit 1 (cox1) genes showed that the larvae had 99–100% homology with the corresponding E. ortleppi sequences on GenBank. Conclusions To our knowledge, this report describes the first identification of a human E. ortleppi infection in China. Our data broaden the geographical distribution of this rarely reported species of Echinococcus.

Abstract Background The chemotherapy-resistance of triple-negative breast cancer (TNBC) remains a major challenge. The Nek2B kinase and β-catenin serve as crucial regulators of mitotic processes. The aim of this study was to test the correlation between Nek2B and TNBC chemotherapy sensitivity, and to determine the regulation of Nek2B on β-catenin and wnt/β-catenin signal pathway. Methods Gene Expression Omnibus(GEO) databases were used to gather gene exprsssion data of TNBC patients who undergoing chemotherapy. The co-expression of Nek2B and β-catenin in TNBC surgical sections and cells were analysed by immunohistochemistry, Q-RT-PCR, Western-blot and immunofluorescent staining. The impact of the expression of Nek2B and β-catenin in prognosis was also assessed using the Kaplan-Meier curves. CCK8 assay was used to detect the IC50 value of TNBC cell line. The endogenous binding capacity of Nek2B and β-catenin and phosphorylation of β-catenin by Nek2B were detected using co-immunoprecipitation (CO-IP). Chromatin immune-precipitation (ChIP) analysis and Luciferase Assays were used to evaluate the binding ability of the Nek2B, β-catenin and TCF4 complex with LEF-1 promoter. Nek2B-siRNA and Nek2B plasmid were injected into nude mice, and tumorigenesis was monitored. Results We found that overexpression of Nek2B and β-catenin in TNBC samples, was associated with patients poor prognosis. Patients with positive Nek2B expression were less sensitive to paclitaxel-containing neoadjuvant chemotherapy. Interestingly, in a panel of established TNBC cell line, Nek2B and β-catenin were highly expressed in cells exhibiting paclitaxel resistance. Our data also suggest that β-catenin binded to and was phosphorylated by Nek2B, and was in a complex with TCF4. Nek2B mainly regulates the expression of β-catenin in TNBC nucleus. Nek2B, β-catenin and TCF4 can be binded with the WRE functional area of LEF-1 promoter. Nek2B can activite wnt signaling pathway and wnt downstream target genes. The tumors treated by Nek2B siRNA associated with paclitaxel were the smallest in nude mouse, and Nek2B can regulate the expression of β-catenin and wnt downstream target genes in vivo. Conclusion Our study suggested that Nek2B can bind to β-catenin and the co-expression correlated with TNBC patients poor prognosis. It appears that Nek2B and β-catenin might synergize to promote chemotherapy resistance.

Abstract Background Physical forces, such as mechanical stress, are essential for tissue homeostasis and influence gene expression of cells. In particular, the fibroblast has demonstrated sensitivity to extracellular matrices with assumed adaptation upon various mechanical loads. The purpose of this study was to compare the vocal fold fibroblast genotype, known for its unique mechanically stressful tissue environment, with cellular counterparts at various other anatomic locales to identify differences in functional gene expression profiles. Results By using RNA-seq technology, we identified differentially expressed gene programs (DEseq2) among seven normal human fibroblast primary cell lines from healthy cadavers, which included: vocal fold, trachea, lung, abdomen, scalp, upper gingiva, and soft palate. Unsupervised gene expression analysis yielded 6216 genes differentially expressed across all anatomic sites. Hierarchical cluster analysis revealed grouping based on anatomic site origin rather than donor, suggesting global fibroblast phenotype heterogeneity. Sex and age-related effects were negligible. Functional enrichment analyses based on separate post-hoc 2-group comparisons revealed several functional themes within the vocal fold fibroblast related to transcription factors for signaling pathways regulating pluripotency of stem cells and extracellular matrix components such as cell signaling, migration, proliferation, and differentiation potential. Conclusions Human fibroblasts display a phenomenon of global topographic differentiation, which is maintained in isolation via in vitro assays. Epigenetic mechanical influences on vocal fold tissue may play a role in uniquely modelling and maintaining the local environmental cellular niche during homeostasis with vocal fold fibroblasts distinctly specialized related to their anatomic positional and developmental origins established during embryogenesis.

BackgroundCardiac rehabilitation programs, consisting of exercise training and disease management interventions, reduce morbidity and mortality after acute myocardial infarction. ObjectiveIn this pilot study, we aimed to developed and assess the feasibility of delivering a health watch–informed 12-week cardiac telerehabilitation program to acute myocardial infarction survivors who declined to participate in center-based cardiac rehabilitation. MethodsWe enrolled patients hospitalized after acute myocardial infarction at an academic medical center who were eligible for but declined to participate in center-based cardiac rehabilitation. Each participant underwent a baseline exercise stress test. Participants received a health watch, which monitored heart rate and physical activity, and a tablet computer with an app that displayed progress toward accomplishing weekly walking and exercise goals. Results were transmitted to a cardiac rehabilitation nurse via a secure connection. For 12 weeks, participants exercised at home and also participated in weekly phone counseling sessions with the nurse, who provided personalized cardiac rehabilitation solutions and standard cardiac rehabilitation education. We assessed usability of the system, adherence to weekly exercise and walking goals, counseling session attendance, and disease-specific quality of life. ResultsOf 18 participants (age: mean 59 years, SD 7) who completed the 12-week telerehabilitation program, 6 (33%) were women, and 6 (33%) had ST-elevation myocardial infarction. Participants wore the health watch for a median of 12.7 hours (IQR 11.1, 13.8) per day and completed a median of 86% of exercise goals. Participants, on average, walked 121 minutes per week (SD 175) and spent 189 minutes per week (SD 210) in their target exercise heart rate zone. Overall, participants found the system to be highly usable (System Usability Scale score: median 83, IQR 65, 100). ConclusionsThis pilot study established the feasibility of delivering cardiac telerehabilitation at home to acute myocardial infarction survivors via a health watch–based program and telephone counseling sessions. Usability and adherence to health watch use, exercise recommendations, and counseling sessions were high. Further studies are warranted to compare patient outcomes and health care resource utilization between center-based rehabilitation and telerehabilitation.

Abstract The interdecadal variability of intensity of the Madden–Julian oscillation (MJO) during boreal winter was investigated based on two reanalysis datasets (NOAA 20CR and ERA‐20C). Both the reanalysis datasets reveal statistically significant power spectrum peaks at 12–20‐year periods. A composite analysis shows that during the active interdecadal phase, eastward propagating MJO activity was strengthened over the equatorial warm pool expanded from the Indian Ocean (IO) to the western Pacific (WP). The cause of the enhanced MJO variability was attributed to the interdecadal change of background mean precipitation in situ. A further diagnosis shows that the increase of the background precipitation over the Maritime Continent and the WP was attributed to interdecadal warm sea surface temperature (SST) anomalies in situ, whereas the increase of the precipitation over the IO resulted from the local convective instability due to the increase of wind induced surface evaporation and moisture. The strengthened background precipitation impacted the MJO strength through the increase of the interdecadal background moisture in the lower and middle troposphere induced by anomalous vertical moisture advection.

Salicylic acid (SA) is a plant growth regulator that can enhance the abiotic stress tolerance of plants; however, the physiological mechanisms are not yet fully understood. The objective of this study was to examine whether exogenous SA could enhance the salt tolerance of perennial ryegrass (Loliumperenne L.; PRG) and investigate the physiological underlying mechanisms. SA was applied to the foliage of PRG at five concentrations (0, 0.25, 0.5, and 1 mM). The SA-treated grass was grown under either control (0 mM NaCl) or salt stress (250 mM NaCl) conditions for 24 d. The SA treatments reduced the leaf electrolyte leakage (EL), malonaldehyde (MDA), and hydrogen peroxide (H2O2) content by 36%, 41%, and 40%, respectively, relative to the control under salt stress as measured at 24 d. The SA treatments also alleviated the decline in the leaf photosynthetic rate (Pn), stomatal conductance (gs), nitrate activity (NR), turfgrass quality (TQ) ratings, and chlorophyll (Chl) content under salt stress. In addition, exogenous SA increased the activity of superoxide dismutase (SOD), ascorbate peroxidase (APX), and peroxidase (POD) as well as the expression levels of the Cyt Cu/ZnSOD, FeSOD, APX, CAT, and POD genes under salt stress. The results of this study suggested that the foliar application of SA at 0.25 and 0.5 mM may enhance photosynthesis and antioxidant defense systems and thus improve tolerance to salt stress in perennial ryegrass.

Glaesserella parasuis (GPS), a causative agent of Glässer’s disease, is thought to be the main fatal cause of peritonitis in swine, thus resulting in high mortality and morbidity and significant economic losses to the swine industry. However, the mechanisms of GPS infection-induced apoptosis and possible therapeutic pathway for GPS infection in peritonitis remain unclear. Baicalin has important biological functions during disease treatment, such as antiviral, bacterial inhibition, anti-apoptosis, and anti-inflammatory. However, whether baicalin has anti-apoptotic effects during the process of GPS infection in peritonitis is unclear. In the present study, the anti-apoptotic effect and mechanisms of baicalin in GPS infection-induced apoptosis were investigated in porcine peritoneal mesothelial cells (PPMC). The results showed that baicalin could inhibit the apoptosis rate occurrence of PPMC induced by GPS to various degrees and inhibit the expression of apoptosis-related genes and cleaved caspase-3. Meanwhile, baicalin significantly antagonized the expression of p-JNK, p-p38, and p-ERK induced by GPS in PPMC. These findings for the first time demonstrate that baicalin exerted the effect of antagonizing GPS induced apoptosis in PPMC by inhibiting the activation of the PKC-MAPK pathway and could be a therapeutic option in the management of GPS infection.

In order to better implement maintenance strategies according to equipment levels, this paper proposes a method based on the grey correlation interval Analytic hierarchy process(AHP)-Entropy method to divide the importance of production system equipment. First, a three-level importance evaluation index system for the production system equipment is established considering the characteristics of the production system in five aspects of operating rate, reliability, maintainability, economy and detectability. Next, the interval number is combined with the AHP and the Entropy method to obtain the interval AHP and the interval Entropy method, and the two methods are combined into an interval AHP-Entropy method to determine the combined weight of each evaluation index. Combined with the evaluated equipment, the grey correlation comprehensive evaluation analysis is performed, the grey correlation degree is calculated and ranked, and the equipment is finally divided by the ABC classification method. Finally, the method is applied to the equipment division of the actual production system. Compared with the interval AHP and interval Entropy method, the evaluation difference rates are reduced by 20% and 15%, respectively, which verifies the effectiveness of the method and provides an accurate and scientific method for equipment division.

Background Direct‐acting oral anticoagulant (DOAC) dosing guidelines for atrial fibrillation recommend dose alteration based on age, renal function, body weight, and drug‐drug interactions. There is paucity of data describing the frequency and factors associated with prescription of potentially inappropriate doses. Methods and Results In the ongoing SAGE‐AF (Systematic Assessment of Geriatric Elements in Atrial Fibrillation) study, we performed geriatric assessments (frailty, cognitive impairment, sensory impairments, social isolation, and depression) for participants with atrial fibrillation (age ≥65 years, CHA2DS2VASc ≥2, no anticoagulant contraindications). We developed an algorithm to analyze DOAC dose appropriateness accounting for drug‐drug interactions, age, renal function, and body weight. We also examined whether geriatric impairments were related to inappropriate dosing. Of 1064 patients prescribed anticoagulants, 460 received a DOAC. Participants were aged 74±7 years, 49% were women, and 82% were white. A quarter (23%; n=105) of participants received inappropriate DOAC dose, of whom 82 (78%) were underdosed and 23 (22%) were overdosed. Among participants receiving an inappropriate dose, 12 (11%) were identified using the drug‐drug interactions criteria and would have otherwise been misclassified. In multivariable regression analyses, older age, higher CHA2DS2VASc score, and history of renal failure were associated with inappropriate DOAC dosing (P

Robot automatic assembly of weak stiffness parts is difficult due to potential deformation during assembly. The robot manipulation cannot adapt to the dynamic contact changes during the assembly process. A robot assembly skill learning system is designed by combining the compliance control and deep reinforcement, which could acquire a better robot assembly strategy. In this paper, a robot assembly strategy learning method based on variable impedance control is proposed to solve the robot assembly contact tasks. During the assembly process, the quality evaluation is designed based on fuzzy logic, and the impedance parameters in the assembly process are studied with a deep deterministic policy gradient. Finally, the effectiveness of the method is verified using the KUKA iiwa robot in the weak stiffness peg-in-hole assembly. Experimental results show that the robot obtains the robot assembly strategy with variable compliant in the process of weak stiffness peg-in-hole assembly. Compared with the previous methods, the assembly success rate of the proposed method reaches 100%.