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Abstract Background Ubiquitin-specific protease 15 (USP15) exhibits amplifications in various tumors, including gastric cancer (GC), yet its biological function and mechanisms in GC progression remain elusive. Methods Here, we established stable USP15 knockdown or overexpression GC cell lines and explored the potential mechanism of USP15 in GC. Besides, we also identified interacting targets of USP15. Results USP15 knockdown significantly impeded cell proliferation, invasion, epithelial-mesenchymal transition, and distal colonization in xenograft models, while enhancing oxaliplatin's antitumor effect. USP15 was involved in ubiquitination modification of glycolytic regulators. Silencing of USP15 suppressed glycolytic activity and impaired mitochondrial functions. Interference with USP15 expression reversed tumor progression and distal colonization in vivo. HKDC1 and IGF2BP3 were found as core interacting targets of USP15, and HKDC1 was identified as a substrate for ubiquitination modification by USP15, whereby USP15 regulated glucose metabolism activity by inhibiting the ubiquitination degradation of HKDC1. Conclusions Our study unveiled aberrantly high expression of USP15 in GC tissues, correlating with malignant progression and nonresponse to neoadjuvant therapy. USP15 inhibitors, if developed, could be effective in promoting chemotherapy through glucose metabolism remodeling.

Abstract The prevalence of isolated systolic hypertension (ISH) has doubled between 2002−2005 and 2014 among the oldest‐old population in China. However, the prevalence and characteristics of ISH among the oldest‐old population in southwestern China remain less known. This study aimed to investigate the prevalence of ISH among the oldest‐old population in Chengdu and identify associated factors to provide valuable information for disease etiology and prevention. We recruited 1,312 participants aged over 80 years by using a stratified cluster sampling method between September 2015 and June 2016, from three districts (Jinjiang, Qingyang, and Longquanyi) of Chengdu, the largest city of southwest China. A structured questionnaire, anthropometric data, and blood pressure were collected according to the standard method. Blood pressure was measured three times by using a standardized mercury sphygmomanometer after a 10‐minute seated rest. Of 1312 participants, 53.0% (n = 695) had ISH. The prevalence of ISH in men and women was 54.7% and 51.3%, respectively, with no significant sex difference (P = .222). The prevalence of ISH increased with advanced age in men (P for trend = 0.029), 52.5% for the 80−84 years group, 55.2% for the 85−89 years group, and 70.4% for the 90–98 years group, respectively. Multivariable logistic regression analyses found that drinking (OR = 1.85, 95%CI = 1.26−2.71), being overweight (OR = 1.88, 95%CI = 1.19−2.96), and having a higher heart rate (OR = 0.66, 95%CI = 0.51−0.86) were associated with ISH. Stratified by sex, these three factors remained significant in men. Our work highlights that the burden of ISH is substantial among the oldest‐old population in southwestern China.

Abstract As an innovative technology for enhancing authenticity, security, and risk management, blockchain is being widely adopted in trade and finance systems. The unique capabilities of blockchain, such as immutability and transparency, enable new business models of distributed data storage, point‐to‐point transactions, and decentralized autonomous organizations. Here, the authors focus on blockchain‐based securities trading, in which blockchain technology plays a vital role in financial services as it ultimately lifts trust and frees the need for third‐party verification by using consensus‐based verification. The 12 most popular blockchain platforms are investigated and 6 platforms that are related to finance are elaborated on, seeking to provide a panorama of securities trading practices. Meanwhile, this survey provides a comprehensive summary of blockchain‐based securities trading applications. Numerous practical applications of blockchain‐based securities trading are gathered and they are categorized into four distinct categories. For each category, a typical example is introduced and how blockchain contributes to solving the key problems faced by FinTech companies and researchers explained. Finally, interesting observations are provided ranging from mainstream blockchain‐based financial institutions to security issues of decentralized finance applications, aiming to picture the current blockchain ecosystem in finance.

Abstract Background Studies has suggested that receiving social support improves the professional identity of health professional students. According to the two-way social support theory, social support includes receiving social support and giving social support. However, the effect of the two-way social support on health professional students’ professional identity has not been clarified yet. Methods To explore the mechanism of how two-way social support affects health professional students’ professional identity, an observational, cross-sectional study was conducted among a convenience and cluster sample of 1449 health professional students from two medical schools in western China. Measures included a short version of the two-way social support scale, a health professional students’ professional identity questionnaire, an achievement motivation scale, and a meaning in life scale. (Data were analyzed by use of SPSS26.0 software, Amos 28.0 software, and PROCESSv4.0 plug-in.). Results Receiving social support, giving social support, achievement motivation, meaning in life, and professional identity were positively correlated with each other. Receiving and giving social support not only directly predicted health professional students’ professional identity, but also indirectly predicted health professional students’ professional identity through the mediating roles of achievement motivation and meaning in life, and the chain mediating roles of achievement motivation and meaning in life, respectively. The effectiveness of predicting health professional students’ professional identity varied among different types of two-way social support, which could be depicted as two-way social support > mainly giving social support > mainly receiving social support > low two-way social support. Conclusion In the medical education, the awareness and ability of health professional students to receive and give social support should be strengthened. More attention should be drawn on the chain mediating effect of achievement motivation and meaning in life between two-way social support and professional identity. The current results shed new light on exploring effective ways of improving health professional students’ professional identity, which suggested that more attention should be paid to the positive effects of mainly giving social support and two-way social support rather than only on the effects of receiving social support.

Abstract Background This study aimed to assess the knowledge, attitudes and practices among medical workers toward outpatient diabetes information platform. Methods This web-based cross-sectional study was conducted between May 2023 and June 2023 at the First Hospital of Zhangjiakou, China. A self-designed questionnaire was developed to collect demographic information of medical workers, and assess their knowledge, attitudes and practices toward outpatient diabetes information platform. Results A total of 685 questionnaires were collected. Among the participants, 603 (88.03%) were female, 432 (63.07%) work in a tertiary hospital, 548 (80.00%) have a bachelor degree, 270 (39.42%) of them work in the department of internal medicine and 315 (45.99%) of them received previous training on outpatient diabetes information platform. The mean knowledge, attitudes and practices scores were 4.32 ± 1.27 (possible range: 0–6), 56.76 ± 5.72 (possible range: 14–70), and 32.22 ± 8.42 (possible range: 9–45), respectively. 350 (51.09%) of them have sufficient knowledge, 168 (24.53%) have positive attitudes and 395 (57.66%) have active practices. Pearson correlation analysis showed that knowledge was positively correlated with attitudes (r = 0.397, P

Abstract Sodium ion batteries (SIBs) are considered as the ideal candidates for the next generation of electrochemical energy storage devices. The major challenges of anode lie in poor cycling stability and the sluggish kinetics attributed to the inherent large Na+ size. In this work, Bi nanosphere encapsulated in N‐doped carbon nanowires (Bi@N‐C) is assembled by facile electrospinning and carbonization. N‐doped carbon mitigates the structure stress/strain during alloying/dealloying, optimizes the ionic/electronic diffusion, and provides fast electron transfer and structural stability. Due to the excellent structure, Bi@N‐C shows excellent Na storage performance in SIBs in terms of good cycling stability and rate capacity in half cells and full cells. The fundamental mechanism of the outstanding electrochemical performance of Bi@N‐C has been demonstrated through synchrotron in‐situ XRD, atomic force microscopy, ex‐situ scanning electron microscopy (SEM) and density functional theory (DFT) calculation. Importantly, a deeper understanding of the underlying reasons of the performance improvement is elucidated, which is vital for providing the theoretical basis for application of SIBs.

Abstract Background Rye (Secale cereale), one of the drought and cold-tolerant crops, is an important component of the Triticae Dumortier family of Gramineae plants. Basic helix-loop-helix (bHLH), an important family of transcription factors, has played pivotal roles in regulating numerous intriguing biological processes in plant development and abiotic stress responses. However, no systemic analysis of the bHLH transcription factor family has yet been reported in rye. Results In this study, 220 bHLH genes in S. cereale (ScbHLHs) were identified and named based on the chromosomal location. The evolutionary relationships, classifications, gene structures, motif compositions, chromosome localization, and gene replication events in these ScbHLH genes are systematically analyzed. These 220 ScbHLH members are divided into 21 subfamilies and one unclassified gene. Throughout evolution, the subfamilies 5, 9, and 18 may have experienced stronger expansion. The segmental duplications may have contributed significantly to the expansion of the bHLH family. To systematically analyze the evolutionary relationships of the bHLH family in different plants, we constructed six comparative genomic maps of homologous genes between rye and different representative monocotyledonous and dicotyledonous plants. Finally, the gene expression response characteristics of 22 ScbHLH genes in various biological processes and stress responses were analyzed. Some candidate genes, such as ScbHLH11, ScbHLH48, and ScbHLH172, related to tissue developments and environmental stresses were screened. Conclusions The results indicate that these ScbHLH genes exhibit characteristic expression in different tissues, grain development stages, and stress treatments. These findings provided a basis for a comprehensive understanding of the bHLH family in rye.

Abstract Silver/polymeric vesicle composite nanoparticles with good antibacterial properties were fabricated in this study. Silver nanoparticles (AgNPs) were prepared in situ on cross‐linked vesicle membranes through the reduction of silver nitrate (AgNO3) using polyvinylpyrrolidone (PVP) via coordination bonding between the Ag+ ions and the nitrogen atoms on the vesicles. X‐ray diffraction (XRD), ultraviolet‐visible spectroscopy (UV‐vis), and transmission electron microscopy (TEM) analyses confirmed the formation of AgNPs on the vesicles. The antibacterial test demonstrated good antibacterial activity against both Gram‐negative bacteria (Escherichia coli) and Gram‐positive bacteria (Staphylococcus aureus) for the produced AgNP‐decorated vesicles. The minimum inhibitory concentration (MIC) values of the AgNP‐decorated vesicles for E. coli and S. aureus were 8.4 and 9.6 μg/mL, respectively. Cell viability analysis on the A549 cells indicated that the toxicity was low when the AgNP concentrations did not exceed the MIC values, and the wound healing test confirmed the good antibacterial properties of the AgNP‐decorated vesicles.

Background: Pregnant women in the Shanghai Birth Cohort (SBC) of China faced dual threats of per- and polyfluoroalkyl substances (PFAS) exposure and vitamin D (VD) insufficiency, potentially impacting offspring neurodevelopment. However, little is known about whether maternal VD status modifies PFAS-related neurodevelopment effect. Objectives: To explore the modifying role of maternal VD status in the effect of prenatal PFAS exposure on childhood neurodevelopment. Methods: We included 746 mother–child pairs from the SBC. Ten PFAS congeners and VD levels were measured in maternal blood samples collected during the first and second trimester respectively. At 2 years of age, toddlers underwent neurodevelopment assessments using Bayley-III Scales. Multivariate linear, logistic regression, and weighted quantile sum approach were used to estimate associations of Bayley-III scores with individual and mixture PFAS. We stratified participants into VD sufficient and insufficient groups and further balanced PFAS differences between these groups by matching all PFAS levels. We fitted the same statistical models in each VD group before and after matching. Results: Nearly half (46.5 %) of pregnant women were VD insufficient (

Using meteorological analysis, composite analysis and water vapor trajectory analysis, the extreme value rainstorm process in northwest Hunan was analyzed. The results show that three types are summarized: the Southwest Vortex and Warm Shear Line Pattern (SVWSLP), the Subtropical High Edge Pattern (SHEP) and the Cold Trough and Shear Line Pattern (CTSLP). The main influence systems are upper trough, southwest vortex, shear line, low-level jet and subtropical high edge. For SVWSLP, the water vapor transport channels are only from the low-latitude ocean whether it is affected by long-distance typhoons. For SHEP, the main water vapor channel comes from the long-distance ocean and is finally transported to northwestern Hunan around 650 hPa in the form of warm and wet airflow, whether it is affected by long-distance typhoons. The CTSLP appears a significant water vapor confrontation between the north and the south and the baroclinicity of the atmosphere in the rainstorm area. The southern and western boundaries are the input boundary, while the eastern and northern boundaries are the outflow boundary. Therefore, one of the three types of weather systems appears in northwestern Hunan in May–August, with strong water vapor transport from the ocean surface, which is likely to cause extreme rainstorm. HIGHLIGHTS Climatic characteristics of extreme precipitation in northwest Hunan.; The terrain of northwest Hunan is complex, and the system extreme value is analyzed for the first time.; The influence of water vapor in northwest Hunan is analyzed by HYSPLT for the first time.; No one has ever studied the influence of long-distance typhoons in northwestern Hunan.; The results are of great significance to the prediction of extreme value rainstorms in northwest Hunan.;

Abstract Background Tumor regression grade (TRG) is a measure of histopathological response to neoadjuvant therapy (NAT). Post‐therapy lymph node (ypN) metastasis was reported as a prognostic factor. However, the evaluation of the treatment effectiveness of NAT has not been well studied. Here, we explored whether TRG combined with ypN status could be a prognostic factor for gastroesophageal junction (GEJ) and gastric cancer (GC). Besides, we aimed at making clear the association of different neoadjuvant regimens with different TRG and ypN status. Methods 376 patients with GEJ or GC accepting NAT in Peking University Cancer Hospital were retrospectively collected from January 1, 2003 to June 30, 2021. According to TRG and ypN status, patients were innovatively categorized into four groups: TRG0N0, TRG1‐3N0, TRG0‐1N+, and TRG2‐3N+. We applied Kaplan–Meier method and log‐rank test to testify the differences in disease free survival (DFS) and overall survival (OS) among four groups. Univariate and multivariate analyses were performed to examine the relationships between TRG combined with ypN status and prognosis. Results We observed significant survival differences among the four groups (p

Global warming is a significant challenge, and carbon stocks in terrestrial ecosystems are crucial for reducing the greenhouse effect and increasing sinks. A study was conducted in Zhengzhou City from 2000 to 2020 using Landsat image spectral reflectance to analyze changes in carbon stock. Environmental variables such as surface moisture, salinity, vegetation index, brightness, and soil texture were constructed. Multiple linear regression (MLR), support vector machine regression (SVR), random forest regression (RFR), and long short-term memory (LSTM) models were used to invert the carbon stock. The results showed that the NDCS index, constructed using Landsat's blue band and NIR band, was the best inversion variable for carbon stock, with the clay index (CI) playing a primary role. The LSTM algorithm had the best fitting effect on carbon stock, with an R2 of 0.84 and RMSE of 3.56. The carbon stock in Zhengzhou City decreased by 13.93% between 2000 and 2020, possibly due to the large-scale reduction of arable land. Future land-use planning should focus on protecting arable land, optimizing land-use patterns, and enhancing the ecosystem's carbon sequestration capacity.

Background: Early identification of fibrotic interstitial lung disease (F-ILD) patients with high risk of progression will help initiate early therapeutic intervention and potential improvement of outcomes. This study was designed to assess the predictors of progression in patients with F-ILD. Methods: Patients with F-ILD in Shanghai Pulmonary Hospital between January 1, 2019 and July 31, 2021 were retrospectively analyzed. The patients enrolled were divided into progressive group and non-progressive group according to the specified criteria. Baseline characteristics were collected and a multivariate regression was conducted to identify independent predictors of progression. Results: Of the 177 F-ILD cases, 87 were enrolled in the progressive group and 90 were in the non-progressive group. The cohort included 11 types of F-ILD, primarily were connective tissue disease-associated interstitial lung disease (CTD-ILD) (43, 24.3 %), idiopathic pulmonary fibrosis (IPF) (39, 22.0 %), interstitial pneumonia with autoimmune features (IPAF) (32, 18.1 %), and unclassifiable (23, 13.0 %). The highest proportion of progression was seen in nonspecific interstitial pneumonia (NSIP) subgroup (66.7 %), followed by IPF (59.0 %) and HP (57.1 %). After adjusting for gender and age, a course of disease longer than 9.5 months (OR: 2.633; 95 % CI: 1.190–5.826, P = 0.017), lymphocyte in peripheral blood more than 2.24 (109/L) (OR: 2.670; 95 % CI: 1.095–6.510, P = 0.031), and emphysema in high-resolution computed tomography (HRCT) (OR: 2.387; 95 % CI: 1.017–5.640, P = 0.046) were independent predictors of progression in F-ILD patients. Conclusions: This study suggested that in patients with F-ILD, long course of disease, elevated blood lymphocyte and emphysema on HRCT were independent predictors of progression, which may suggest utility in early therapeutic intervention.

AbstractPost-encapsulation and release of the anticancer drug doxorubicin hydrochloride (DOX·HCl) through cell-like transmission functions of polymeric vesicles were studied using cross-linked pH-responsive polymeric vesicles. The vesicles were fabricated for the first time via the redox-initiated reversible addition-fragmentation chain transfer dispersion polymerization in ethanol-water mixture, using 2-(diisopropylamino)ethyl methacrylate and glycidyl methacrylate, and the vesicle membrane was modified post-cross-linking by using ethylenediamine. A phase diagram was constructed for reproducible fabrication of the polymeric vesicles, and well-shaped vesicles were formed when the target degree of polymerization of the hydrophobic polymer chains was equal to or higher than 50 with solid content in the range of 10–30 wt%. The cross-linked vesicle membrane served as a gate enabling “open” and “closed” states in response to pH stimulation. Up to 50% drug loading efficiency and 39% drug loading content could be achieved, and in vitro release of the DOX-loaded vesicles in aqueous buffer solutions showed a much faster DOX release rate at pH 5.0 than at pH 6.5. The polymeric vesicles were of very low cytotoxicity to A549 cells up to the concentration of 2 mg/mL, and the IC50 of DOX-loaded vesicles were higher than that of the free DOX. The intracellular DOX release study indicated higher cellular uptake capability for DOX-loaded vesicles than that of free DOX.

This study presents two concepts for integrating a wave rotor combustor (WRC) into a baseline engine: the wave rotor pressure-gain cycle (WRPGC) and the wave rotor work cycle (WRWC). Performance parameters were calculated under different thermodynamic cycles, and a comparative analysis of the thermodynamic cycles was conducted, considering both the ideal- and actual-loss conditions. Furthermore, the impact of the WRC precompression ratio, turbine inlet temperature, and fixed peak cycle temperature on the thermodynamic-cycle performance was investigated. The results indicate that embedding a WRC into a baseline engine with a compressor pressure ratio higher than 24.0 does not lead to an improvement in the thermal efficiency. However, under a baseline engine pressure ratio of 3.6, the actual-loss WRC cycle achieves efficiency improvements of 40.5% and 49.5% in the WRPGC and WRWC, respectively, compared to the baseline engine cycle. Increasing the wave rotor precompression ratio or the turbine inlet temperature ratio results in greater performance improvements for the WRWC compared to the WRPGC. When the peak cycle temperature of the wave rotor is fixed, there exists a narrow pressure ratio range wherein the WRPGC outperforms the WRWC. Therefore, the WRPGC is more suitable for embedment in baseline engines with lower pressure ratios.

Dermal fibroblasts (dFBs) defend against deep bacterial skin infections by differentiating into preadipocytes (pAds) that produce the antimicrobial peptide cathelicidin; this differentiation is known as the dermal reactive adipogenesis response. However, the role of dFBs in fungal infection remains unknown. Here, we found that cathelicidin-producing pAds were present in high numbers in skin lesions from patients with cutaneous Candida granulomas. Second, we showed that dermal Candida albicans (C. albicans) infection in mice robustly triggered the dermal reactive adipogenesis response and induced cathelicidin expression, and inhibition of adipogenesis with pharmacological inhibitors of peroxisome proliferator-activated receptor γ (PPARγ) impaired skin resistance to C. albicans. In vitro, C. albicans products induced cathelicidin expression in pAds, and differentiating pAds markedly suppressed the growth of C. albicans by producing cathelicidin. Finally, we showed that C. albicans induced an antimicrobial response in pAds through the FGFR-MEK-ERK pathway. Together, our data reveal a previously unknown role of dFBs in the defense against skin infection caused by C. albicans.

ObjectivesWith reference to the definitions and requirements of intelligent engine rooms in the China Classification Society Rules for Intelligent Ships, this paper studies methods for predicting the remaining useful life (RUL) of bearings in order to explore prognostic and health management technologies.MethodsAddressing the poor prediction accuracy of conventional data-driven methods, this study uses the Stacking fusion strategy in integrated learning to construct an R-A-X (Ridge-ANN-XGBoost, with XGBoost and ANN as the base learner, and ridge regression as the meta learner) fusion model. It then designs a prediction performance comparison experiment using the life cycle data in the IEEE PHM 2012 Prognostic Challenge under the same working conditions, with MAE and R2 used as performance evaluation indicators to compare the R-A-X fusion model with the single algorithm and average.ResultsThe results show that the prediction performance of the R-A-X fusion model are better than those of the other methods involved in this article, with an improvement effect reaching up to 20%.ConclusionsThe proposed method can improve the accuracy of bearing RUL prediction and has certain reference value for the realization of the equipment health management of intelligent engine rooms.

Tree species transitioning between different developmental phases requires homeostatic adjustments in order to maintain the integrity of the tree hydraulic system. Hence, adjustments related to hydraulic traits (e.g., xylem conduit diameter) are of key functional significance. However, critical information on the differences between different developmental stages is rare. Using sapwood samples from 36 black locust trees with different growth stages (actively growing and declining stages) and a soil water gradient along a hillslope, xylem conduits at stem apexes and breast height (1.3 m above ground) stems were measured. The results showed marked differences in vascular traits between actively growing and declining trees. In contrast to actively growing trees, declining trees exhibited a reduction in conduit diameters accompanied by increased frequency with a positively skewed distribution and a subsequent decline in cumulative theoretical hydraulic conductivity. Across all sampled trees, the hydraulically weighted mean conduit diameter tapered acropetally from breast height to the stem apex. The extent of conduit tapering in actively growing trees (0.244, 95% CI 0.201–0.287) aligned with predictions from the hydraulic optimality model. Conversely, trees in a declining status displayed significantly reduced conduit tapering (0.175, 95% CI 0.146–0.198), indicating an elevation in hydraulic resistance with increasing tree height. Variations in hydraulic properties predominantly resulted from differences in tree height rather than variations in stem diameter or soil water content. The correlation between conduit diameter and soil water content in both actively growing and declining trees stemmed indirectly from variations in tree height rather than presenting a direct response to drought stress.

Acute upper respiratory tract infections (AURTIs) are common diseases of respiratory system, which are caused by adenoviruses and generate the mix of severe clinical presentation. Zukamu granules (ZKMG), a traditional Chinese medicine (TCM) prescription within Health Commission of Xinjiang Uygur Autonomous Region possesses anti-influenza virus, antibacterial and anti-inflammatory effects that exerts therapeutic effects in treatment of AURTIs. However, the main effective chemical components and their corresponding action mechanisms have not been clarified. Therefore, ultra-performance liquid chromatography coupled with quadrupole Exactive orbitrap tandem mass spectrometry (UHPLC-Q-Exactive Orbitrap MS) and network pharmacology were used to detect and identify potentially effective components in ZKMG as well as uncover their pharmacological mechanisms against AURTIs. As a result, a total of 265 components from all 12 composed herbal medicines were characterized based on self-built database and fragmentation patterns, of which 38 compounds were unambiguously confirmed using reference standards. Then, the compound-target-pathway network was constructed that implied potential therapeutic mechanisms of ZKMG on AURTIs. Compounds noscapine, cryptopine, steviol-19-O-glucoside, N-methylnarcotine, allocryptopine, naringenin, boldine, methyl rosmarinate with related targets EGFR, PTGS2, IL2, MMP9, TNF, AKT1, PIK3CA, F3 were considered as the key components and targets. Besides, the results also indicated that PI3K-Akt, AGE-RAGE, PD-L1, HIF-1 signaling pathways contributed significantly to the therapeutic effects of ZKMG on AURTIs. Overall, ZKMG could have an effect on AURTIs based on multicomponent, multitarget, and multichannel mechanisms of action as well as this method provides guiding significance for the further development of TCM treatment.

Summary: Dermal adipocyte lineage cells are highly plastic and can undergo reversible differentiation and dedifferentiation in response to various stimuli. Using single-cell RNA sequencing of developing or wounded mouse skin, we classify dermal fibroblasts (dFBs) into distinct non-adipogenic and adipogenic cell states. Cell differentiation trajectory analyses identify IL-1-NF-κB and WNT-β-catenin as top signaling pathways that positively and negatively associate with adipogenesis, respectively. Upon wounding, activation of adipocyte progenitors and wound-induced adipogenesis are mediated in part by neutrophils through the IL-1R-NF-κB-CREB signaling axis. In contrast, WNT activation, by WNT ligand and/or ablation of Gsk3, inhibits the adipogenic potential of dFBs but promotes lipolysis and dedifferentiation of mature adipocytes, contributing to myofibroblast formation. Finally, sustained WNT activation and inhibition of adipogenesis is seen in human keloids. These data reveal molecular mechanisms underlying the plasticity of dermal adipocyte lineage cells, defining potential therapeutic targets for defective wound healing and scar formation.

In December 2019, the novel coronavirus disease (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection broke. With the gradual deepening understanding of SARS-CoV-2 and COVID-19, researchers and clinicians noticed that this disease is closely related to the nervous system and has complex effects on the central nervous system (CNS) and peripheral nervous system (PNS). In this review, we summarize the effects and mechanisms of SARS-CoV-2 on the nervous system, including the pathways of invasion, direct and indirect effects, and associated neuropsychiatric diseases, to deepen our knowledge and understanding of the relationship between COVID-19 and the nervous system.

Neoadjuvant endocrine therapy (NET) instead of neoadjuvant chemotherapy (NCT) is an effective clinical strategy for estrogen receptor (ER)-positive breast cancer patients, which can reduce tumor stage, achieve breast-conserving surgery for breast cancer and reduce the need for adjuvant chemotherapy. This article aimed to review the latest research progress in several aeras: patient selection for NET, comparison of efficacy of NET, duration of NET, comparison and combined use of NET and NCT, NET combined with targeted therapy, window of opportunity trials, efficacy evaluation indicators and adjuvant therapy decision after neoadjuvant endocrine therapy.

The pulmonary function test (PFT) has been widely used in sarcoidosis. It may vary due to the severity, extent, and the presence of complications of the disease. Although the PFT of most sarcoidosis patients is normal, there are still 10–30% of cases who may experience a decrease in the PFT, with a progressive involvement of lungs. Restrictive ventilatory impairment due to parenchymal involvement has been commonly reported, and an obstructive pattern can also be present related to airway involvement. The PFT may influence treatment decisions. A diffusing capacity for carbon monoxide (DLCO) < 60% as well as a forced vital capacity (FVC) < 70% portends clinically significant pulmonary sarcoidosis pathology and warrants treatment. During follow-up, a 5% decline in FVC from baseline or a 10% decline in DLCO has been considered significant and reflects the disease progression. FVC has been recommended as the favored objective endpoint for monitoring the response to therapy, and an improvement in predicted FVC percentage of more than 5% is considered effective.

Abstract Background Once malignancy tumors were diagnosed, the determination of tissue origin and tumor type is critical for clinical management. Although the significant advance in imaging techniques and histopathological approaches, the diagnosis remains challenging in patients with metastatic and poorly differentiated or undifferentiated tumors. Gene expression profiling has been demonstrated the ability to classify multiple tumor types. The present study aims to assess the performance of a 90-gene expression test for tumor classification (i.e. the determination of tumor tissue of origin) in real clinical settings. Methods Formalin-fixed paraffin-embedded samples and associated clinicopathologic information were collected from three cancer centers between January 2016 and January 2021. A total of 1417 specimens that met quality control criteria (RNA quality, tumor cell content ≥ 60% and so on) were analyzed by the 90-gene expression test to identify the tumor tissue of origin. The performance was evaluated by comparing the test results with histopathological diagnosis. Results The 1417 samples represent 21 main tumor types classified by common tissue origins and anatomic sites. Overall, the 90-gene expression test reached an accuracy of 94.4% (1338/1417, 95% CI: 0.93 to 0.96). Among different tumor types, sensitivities were ranged from 74.2% (head&neck tumor) to 100% (adrenal carcinoma, mesothelioma, and prostate cancer). Sensitivities for the most prevalent cancers of lung, breast, colorectum, and gastroesophagus are 95.0%, 98.4%, 93.9%, and 90.6%, respectively. Moreover, specificities for all 21 tumor types are greater than 99%. Conclusions These findings showed robust performance of the 90-gene expression test for identifying the tumor tissue of origin and support the use of molecular testing as an adjunct to tumor classification, especially to those poorly differentiated or undifferentiated tumors in clinical practice.

Abstract Rapid proliferation and metastasis of gastric cancer (GC) resulted in a poor prognosis in the clinic. Previous studies elucidated that long non-coding RNA (LncRNA) LINC00205 was upregulated in various tumors and participated in tumor progression. The aim of our study was to investigate the regulating role of LINC00205 in tumorigenesis and metastasis of GC. Both public datasets and our data showed that the LINC00205 was highly expressed in GC tissues and several cell lines. Notably, GC patients with high level of LINC00205 had a poor prognosis in our cohort. Mechanistically, knockdown of LINC00205 by shRNAs suppressed GC cells proliferation, migration, invasion remarkably, and induced cell cycle arrest. Based on bioinformatics prediction, we found that LINC00205 might act as a competitive endogenous RNA (ceRNA) through targeting miR-26a. The level of miR-26a had negatively correlated with LINC00205 expression and was decreased among GC cell lines, tissues, and serum samples. Our results for the first time confirmed that miR-26a was a direct target of LINC00205 and might have the potential to become a plasma marker for clinical tumor diagnosis. Indeed, LINC00205 knockdown resulted in the dramatic promotion of miR-26a expression as well as inhibition of miR-26a potential downstream targets, such as HMGA2, EZH2, and USP15. These targets were essential for cell survival and epithelial-mesenchymal transition. Importantly, LINC00205 was able to remodel the miR-26a-mediated downstream silence, which identified a new mechanism of malignant transformation of GC cells. In conclusion, this study revealed the regulating role of the LINC00205/miR-26a axis in GC progression and provided a new potential therapeutic strategy for GC treatment.

Abstract Background To investigate characteristics of the acute angle-closure crisis (AACC) and fellow eyes using confocal microscopy. Methods Unilateral AACC patients hospitalized at the Xi’an People’s Hospital from October 2017 to October 2020 were recruited in this cross-sectional study. Age-matched participants scheduled for cataract surgery were enrolled as a healthy control group. Corneal epithelial cells, subepithelial nerve fiber plexus, stromal cells, and endothelial cells were examined by confocal and specular microscopy. Results This study enrolled 41 unilateral AACC patients (82 eyes) and 20 healthy controls (40 eyes). Confocal microscopy revealed that the corneal nerve fiber density, corneal nerve branch density and corneal nerve fiber length were reduced significantly in AACC eyes. The stromal cells were swollen and the size of the endothelial cells was uneven with the deposition of punctate high-reflective keratic precipitate on the surface. In severe cases, the cell volume was enlarged, deformed, and fused. The corneal subepithelial nerve fiber, stromal layer, and endothelial layer were unremarkable in the fellow eyes, and the density of the endothelial cells was 2601 ± 529 cells/mm2, which was higher than 1654 ± 999 cells/mm2 in AACC eyes (P

Abstract Background High serum Lipoprotein(a) (Lp(a)) level and Apolipoprotein B/Apolipoprotein AΙ (ApoB/ApoA-Ι) ratio are risk factors for cardiovascular disease and kidney disease and have been found to be correlated with the prevalence and prognosis of various kidney diseases. However, it is not clear whether the serum Lp(a) level and ApoB/ApoA-Ι ratio pre-PCI are correlated with the prevalence of contrast-induced acute kidney injury (CI-AKI). Methods A total of 931 participants undergoing emergency PCI from July 2018 to July 2020 were included. According to whether the serum creatinine concentration was higher than the baseline concentration (by ≥25% or ≥ 0.5 mg/dL) 48–72 h after contrast exposure, these participants were divided into a CI-AKI group (n = 174) and a non-CI-AKI group (n = 757). Serum Lp(a), ApoA-Ι and ApoB concentration were detected in the patients when they were admitted to hospital, and the ApoB/ApoA-Ι ratio was calculated. Logistic regression and restricted cubic spline analyses were used to explore the correlation between the Lp(a) concentration or the ApoB/ApoA-Ι ratio and the risk of CI-AKI. Results Among the 931 participants undergoing emergency PCI, 174 (18.69%) participants developed CI-AKI. Compared with the non-CI-AKI group, the Lp(a) level and ApoB/ApoA-Ι ratio pre-PCI in the CI-AKI group were significantly higher (P

ObjectiveThe objective of the study was to explore the CT and ultrasound features and clinical significance of perivascular epithelioid cell tumor (PEComa) of the liver.MethodsEleven hepatic PEComa patients treated in our hospital were retrospectively analyzed based on the characteristics of the imaging results of the patients, including conventional ultrasound, CDFI, contrast-enhanced ultrasound (CEUS), and contrast-enhanced CT (CECT).ResultsCT scans showed that all lesions were hypodense. Ultrasonography showed that lesions were either hyperechoic (4/11, 36.36%), hypoechoic (4/11, 36.36%), isoechoic (1/11, 9.09%), or heterogeneously echoic (2/11, 18.18%). CDFI showed that most of the lesions had an abundant blood supply (9/11, 81.82%). Whether on CT scan or ultrasonography, the margins of the lesions were dominated by clear margins. Ultrasonography revealed more features: hyperechoic patterns around lesions (3/11, 27.27%) and lateral shadow (5/11, 45.45%). The CDFI showed that large blood vessels were observed around the lesions (9/11, 81.82%). CECT shows two enhancement patterns: “fast in and fast out (FIFO)” (8/11, 72.72%) and “fast in and slow out (FISO)” (3/11, 27.27%). CEUS shows that all lesions had the enhancement pattern of “FISO,” which was different from CECT. All lesions displayed rapid enhancement during HAP in CEUS during 7–20 s. Four patients (36.36%) washed out at 60–180 s, another four (36.36%) washed out at 180–300 s, and the remaining three patients (27.27%) showed no signs of washout even at 360 s.ConclusionSome imaging features, such as clear margins, peripheral hyperechoic around the lesion, lateral shadow, the large blood vessels around lesions, and the “FISO” enhancement pattern, may indicate expansive growth of the tumor and be helpful in the diagnosis of PEComa. Ultrasound images may provide more details for clinical reference.

In December 2019, an outbreak emerged of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which leads to coronavirus disease 2019 (COVID-19). The World Health Organisation announced the outbreak a global health emergency on 30 January 2020 and by 11 March 2020 it was declared a pandemic. The spread and severity of the outbreak took a heavy toll and overburdening of the global health system, particularly since there were no available drugs against SARS-CoV-2. With an immediate worldwide effort, communication, and sharing of data, large amounts of funding, researchers and pharmaceutical companies immediately fast-tracked vaccine development in order to prevent severe disease, hospitalizations and death. A number of vaccines were quickly approved for emergency use, and worldwide vaccination rollouts were immediately put in place. However, due to several individuals being hesitant to vaccinations and many poorer countries not having access to vaccines, multiple SARS-CoV-2 variants quickly emerged that were distinct from the original variant. Uncertainties related to the effectiveness of the various vaccines against the new variants as well as vaccine specific-side effects have remained a concern. Despite these uncertainties, fast-track vaccine approval, manufacturing at large scale, and the effective distribution of COVID-19 vaccines remain the topmost priorities around the world. Unprecedented efforts made by vaccine developers/researchers as well as healthcare staff, played a major role in distributing vaccine shots that provided protection and/or reduced disease severity, and deaths, even with the delta and omicron variants. Fortunately, even for those who become infected, vaccination appears to protect against major disease, hospitalisation, and fatality from COVID-19. Herein, we analyse ongoing vaccination studies and vaccine platforms that have saved many deaths from the pandemic.

Vine tea (Ampelopsis grossedentata) is a plant resource with good nutritional and medicinal, and is widely consumed in China. This study aimed to develop a functional vine tea fermentation broth using microbial fermentation and cellulase degradation. First, the most suitable probiotics for vine tea fermentation were screened, and the fermentation conditions were optimized. Then, a new cellulase (Cel 906, MW076177) was added to evaluate the changes in the contents of effective substances and to study its efficacy. The results show that saccharomyces cerevisiae Y-401 was identified as the best strain, the optimal fermentation conditions were a time of 94.60 h, feeding concentration of 115.21 g/L, and temperature of about 34.97°C. The vine tea fermentation broth has a strong inhibitory ability on 2,2′-azinobis3-ethylbenzothiazoline-6-sulfonic acid (ABTS) (99.73%), peroxyl (53.15%), superoxide anion radicals (84.13%), and 1,1-Diphenyl-2-trinitrophenylhydrazine (DPPH) (92.48%). It has a decent inhibitory impact on the cell viability, tyrosinase activity (32.25%), and melanin synthesis (63.52%) of B16-F10 melanoma cells induced by α-MSH. Inflammatory cell recruitment was reduced in a zebrafish inflammation model. Therefore, this vine tea fermented broth has strong antioxidant, anti-melanoma, and anti-inflammatory effects, and has healthcare potential as a probiotic tea.

BackgroundAdenoid cystic carcinoma (ACC) is a rare type of triple-negative breast cancer that has an indolent clinical behavior. Given the substantial overlapping morphological, immunohistochemical, and molecular features with other basal-like triple-negative breast cancer (BL-TNBC), accurate diagnosis of ACC is crucial for effective clinical treatment. The integrative analysis of the proteome and clinicopathological characteristics may help to distinguish these two neoplasms and provide a deep understanding on biological behaviors and potential target therapy of ACC.MethodsWe applied mass spectrometry-based quantitative proteomics to analyze the protein expression in paired tumor and adjacent normal breast tissue of five ACC and five BL-TNBC. Bioinformatic analyses and the clinicopathological characteristics, including histological features, immunohistochemistry, and FISH results, were also collected to get comprehensive information.ResultsA total of 307 differentially expressed proteins (DEPs) were identified between ACC and BL-TNBC. Clustering analysis of DEPs clearly separated ACC from BL-TNBC. GSEA found downregulation of the immune response of ACC compared with BL-TNBC, which is consistent with the negative PD-L1 expression of ACC. Vesicle-mediated transport was also inhibited, while ECM organization was enriched in ACC. The top upregulated proteins in DEPs were ITGB4, VCAN, and DPT. Moreover, in comparison with normal breast tissue, ACC showed elevated ribosome biogenesis and RNA splicing activity.ConclusionThis study provides evidence that ACC presents a substantially different proteomic profile compared with BL-TNBC and promotes our understanding on the molecular mechanisms and biological processes of ACC, which might be useful for differential diagnosis and anticancer strategy.

Mycoplasma synoviae (MS) is an important avian pathogen that has brought substantial economic losses to the global poultry industry. Fast and accurate diagnosis is one of the critical factors for the control of MS infection. This study established a simple, rapid and visual detection method for MS using a recombinase-aided amplification (RAA) combined with a lateral flow dipstick (LFD). The reaction temperature and time of the RAA-LFD assay were optimized after selecting the primers and probe, and the specificity and sensitivity rates were analyzed. The results showed that RAA could amplify the target gene in 20 min at a constant temperature of 38°C, and the amplification products could be visualized by LFD within 5 min. There was no cross-reaction with Mycoplasma gallisepticum (MG), Pasteurella multocida (P. multocida), Escherichia coli (E. coli), Newcastle disease virus (NDV), infectious bursal disease virus (IBDV), infectious bronchitis virus (IBV), and avian reovirus (ARV). Furthermore, the RAA-LFD assay exhibited high sensitivity with a detection limit of 10 copies/μL. A total of 128 clinical samples with suspected infection of MS were tested by RAA-LFD, PCR, and real-time fluorescence quantitative PCR (RFQ-PCR). The coincidence rate of the detection results was 95.3% between RAA-LFD and PCR, and 98.4% between RAA-LFD and RFQ-PCR. These results suggested that the RAA-LFD method established in the present study was easy to use and was associated with strong specificity and high sensitivity. This method was very suitable for the rapid detection of MS in clinical practice.

Reinforcement learning has shown a great ability and has defeated human beings in the field of real-time strategy games. In recent years, reinforcement learning has been used in cyberspace to carry out automated and intelligent attacks. Traditional defense methods are not enough to deal with this problem, so it is necessary to design defense agents to counter intelligent attacks. The interaction between the attack agent and the defense agent can be modeled as a multi-agent Markov game. In this paper, an adversarial decision-making approach that combines the Bayesian Strong Stackelberg and the WoLF algorithms was proposed to obtain the equilibrium point of multi-agent Markov games. With this method, the defense agent can obtain the adversarial decision-making strategy as well as continuously adjust the strategy in cyberspace. As verified in experiments, the defense agent should attach importance to short-term rewards in the process of a real-time game between the attack agent and the defense agent. The proposed approach can obtain the largest rewards for defense agent compared with the classic Nash-Q and URS-Q algorithms. In addition, the proposed approach adjusts the action selection probability dynamically, so that the decision entropy of optimal action gradually decreases.

Abstract Background Cryptosporidium is an important zoonotic pathogen responsible for severe enteric diseases in humans and animals. However, the molecular mechanisms underlying host and Cryptosporidium interactions are still not clear. Methods To study the roles of circRNAs in host cells during Cryptosporidium infection, the expression profiles of circRNAs in HCT-8 cells infected with C. parvum were investigated using a microarray assay, and the regulatory role of a significantly upregulated circRNA, ciRS-7, was investigated during C. parvum infection. Results C. parvum infection caused notable alterations in the expression profiles of circRNAs in HCT-8 cells, and a total of 178 (including 128 up- and 50 downregulated) circRNAs were significantly differentially expressed following C. parvum infection. Among them, ciRS-7 was significantly upregulated and regulated the NF-κB signaling pathway by sponging miR-1270 during C. parvum infection. Furthermore, the ciRS-7/miR-1270/relA axis markedly affected the propagation of C. parvum in HCT-8 cells. Conclusions Our results revealed that ciRS-7 would promote C. parvum propagation by regulating the miR-1270/relA axis and affecting the NF-κB pathway. To the best of our knowledge, this is the first study to investigate the role of circRNA during Cryptosporidium infection, and the findings provide a novel view for implementing control strategies against Cryptosporidium infection. Graphic Abstract

Abstract Background Cervical cancer is one of the most frequent malignancies in women, particularly metastasis resulting in a poor prognosis. However, the clinical characteristics of cervical cancer patients with advanced liver metastasis have not been well investigated. We aimed to evaluate the incidence, clinical risk and prognostic factors for hepatic metastasis in cervical cancer patients. Materials and methods The clinical features of patients diagnosed with cervical cancer were collected from the Surveillance, Epidemiology and End Result (SEER) public cancer database between 2010 and 2015. Multivariate logistic and Cox regression models were performed to identify potential risk and prognostic factors for liver metastasis in patients with cervical cancer. Results A total of 431 patients (2.32%) developed liver metastasis in our analysis. The following characteristics were significantly associated with the development of liver metastasis: black ethnicity, uninsured status, higher tumor stage, poorer differentiated grade, non-squamous histology, non-surgery of primary site, patients with any additional lung, bone, and brain metastasis. Multivariate Cox regression showed that patients with additional lung metastasis, without radiotherapy, and without chemotherapy were negatively correlated with overall survival. Concurrent chemotherapy and radiotherapy was a favorable prognostic factor to improve overall survival, and chemotherapy showed to increase cause-specific survival. Additional lung metastasis was an independent characteristic for both risk and prognostic factors for hepatic metastasis in patients with cervical cancer. Conclusion Our results found several potential clinical features that may be used to assess the risk and prognosis of liver metastasis in patients with cervical cancer. These associated factors may provide clinical indications for the early identification and treatment of cervical cancer patients with hepatic metastasis.

Background: An increasing number of studies have reported neonicotinoid insecticides (NEOs), the emerging alternatives to conventional insecticides, may increase oxidative stress and cause adverse health effects, but limited is known about the prenatal NEOs exposures and their impact on birth outcomes. Objectives: We investigated the levels of prenatal exposure to NEOs/metabolites, to assess their associations with birth outcomes, and investigate whether these associations could be mediated by oxidative stress using 8-OHdG as the biomarker. Methods: We studied 296 mother-infant pairs recruited from Laizhou Wan Birth Cohort in 2010 – 2013. Two NEOs (IMI and ACE), three metabolites (6-CN, ND-ACE, and 2CTCA), and 8-OHdG were measured in maternal urine collected before delivery. Birth outcomes including birth weight, birth length, ponderal index (PI), head circumference, and gestational age, were acquired. We examined the associations between NEOs/metabolites and birth outcomes using multivariable linear regression. Mediation analysis was conducted to clarify the role of 8-OHdG on the association of NEOs/metabolites exposure and birth outcomes. Results: Highest detection rate was observed for ACE (100.0%), followed by IMI (98.3%) and 6-CN (98.0%), suggesting the common exposure of pregnant women. The highest median concentration was observed for 6-CN with creatinine-adjusted median levels of 9.58 μg/g creatinine. A decrease in newborns’ head circumference was observed with a 10-fold increase in IMI (β = -1.83; 95% CI = -3.04, −0.62) and ACE (β = -2.27; 95% CI = -3.56, −0.98). An increase in newborns’ PI was observed with a 10-fold increase in IMI (β = 0.40; 95% CI = 0.03, 0.75). Maternal 8-OHdG demonstrated 38.5–65.5% mediating effects in the negative association of IMI, ACE, 2-CTCA with head circumference. These associations might differ between boys and girls. Conclusions: Pregnant women were widely exposed to NEOs/metabolites in China. Results suggested the potential impacts of prenatal exposure to certain neonicotinoid insecticides on head circumference. Urinary 8-OHdG may partly mediate these associations.

Graphene/hexagonal boron nitride (h-BN) heterostructures have attracted a lot of research interests due to their superior electronic properties in field effect transistor devices and the novel physical properties such as fractional fractal quantum hall effect and massive Dirac fermions. Chemical vapor deposition (CVD) is the most common method to synthesize h-BN and graphene, however, the directly growth of graphene/h-BN heterostructures remains challenging. Here we report the crucial impact of hydrogen on the nucleation density, growth rate and etching rate in the h-BN CVD growth. It is found that the nucleation density increases monotonically, whereas the growth rate and etching rate first increases and then decreases with the increasing hydrogen partial pressure. Benefitting from the understanding of the crucial role of hydrogen, we successfully grow the graphene/h-BN vertical heterostructures by low pressure CVD in one-pot through the modulation of hydrogen partial pressure. The field effect transistor (FET) fabricated using graphene/h-BN heterostructure shows better performance with higher carrier mobility and lower level of doping than the one without h-BN. Our direct synthesis approach paves a new pathway for large-scale production of graphene/h-BN heterostructures and could be applied for the synthesis of other van der Waals heterostructures.

BackgroundThe recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak has caused millions of deaths and greatly influenced the timely diagnosis and treatment of other diseases. Throughout the pandemic, there was a dramatic reduction in the prevalence of several sexually transmitted infections. However, the impact of the ongoing pandemic on human papillomavirus (HPV) infection rates has not been investigated thus far.Materials and MethodsWe retrospectively collected data regarding HPV and cervical cancer screening results of outpatients from gynecological clinics of a tertiary hospital from 1 December 2018 to 31 December 2020 in Wuhan. Based on the timeline of the SARS-CoV-2 pandemic in Wuhan, we divided this period into four relatively independent stages to compare the HPV screening visit numbers and infection rates.ResultsThere was a 50% drop in HPV screening visits and a 10% drop in HPV infection rates throughout the pandemic when compared with the numbers collected before the pandemic. Strict lockdown measures greatly decreased the HPV infection rate (17.03 vs. 8.29, P = 0.003). During the pandemic, the most prevalent HPV genotypes were HPV 16, 52, 58, and 53. After the pandemic, the HPV infection rate recovered quickly, but it was still slightly lower than the infection rate found before the outbreak (23.3 vs. 21.2%).ConclusionDuring coronavirus disease 2019 (COVID-19) pandemic, cervical cancer screening visits and HPV infection rates have decreased dramatically. The HPV transmission has also decreased after strict lockdown. Effective HPV and cervical cancer screening programs should be strengthened immediately to reduce the transmission of HPV during and after the pandemic.

Drug-target interactions (DTIs) prediction plays a vital role in drug discovery and design. Current studies typically use only standard drug similarity and target similarity, but the influence of known interactions has not been taken into account. In this paper, we propose an ensembled computational approach called multi-similarity fusion and sparse dual-graph regularized matrix factorization (MSDGRMF) for DTIs prediction. Specifically, different similarities are integrated to mine more useful information from the known interactions. The dual-graph regularized matrix factorization is used to predict the DTIs, in which the manifold learning is used for the low-dimensional representation of the drugs and targets data. In addition, not all the information of drug pairs and target pairs is useful. Thus, the useless information is discarded by sparse process. The proposed MSDGRMF is evaluated and compared on some benchmark datasets. Comparison results show that the MSDGRMF is better than some state-of-the-art approaches. More importantly, the proposed method can contribute to predicting potential DTIs.

Cryptosporidium parvum is an important zoonotic protozoon that threatens the health of humans and animals, but the interaction mechanisms between C. parvum and hosts are poorly understood. Our previous study indicated that the expression levels of C3a and C3aR were up-regulated in mice during C. parvum infection, but the mechanisms of C3a/C3aR signaling during C. parvum infection have not been elucidated. In the present study, an optimized BALB/c suckling mouse model infected with C. parvum was used to explore the function of C3a/C3aR signaling during C. parvum infection. The expression levels of C3aR in the ileum tissues of mice infected with C. parvum were analyzed using real-time PCR, Western blot and immunohistochemistry. The mRNA levels of the Cryptosporidium 18S rRNA gene, tight junction proteins (zo-1, claudin 3, and occludin), intestinal stem cell marker lgr5, cell proliferation marker ki67, Th1 cell-related cytokine ifn-γ, and Treg cell-related cytokine tgf-β in mouse ileum tissues were analyzed by real-time PCR. The pathological injury of ileal mucosa was examined by histopathology analysis. The mRNA expression levels of Cryptosporidium 18S rRNA gene were significantly up-regulated in the ileum tissues of C3aR-inhibited mice during C. parvum infection. Meanwhile, histopathology analysis of ileal mucosa in mice showed that inhibition of C3aR significantly aggravated the changes in villus length, villus diameter, mucosal thickness and the ratio of villus length to crypt depth during C. parvum infection. Further studies found inhibition of C3aR aggravated the down-regulation of occludin at most time points during C. parvum infection. The mRNA levels of ki67 and lgr5 in the ileum tissues of mice infected with C. parvum were significantly down-regulated. Inhibition of C3aR significantly down-regulated the mRNA expression levels of lgr5 at most time points, but significantly up-regulated the mRNA expression levels of ki67 at most time points. The mRNA expression levels of ifn-γ and tgf-β were significantly up-regulated and down-regulated in the ileum tissues of mice infected with C. parvum, respectively. However, inhibition of C3aR significantly increased the mRNA expression levels of ifn-γ and tgf-β in the ileum tissues of mice infected with C. parvum. Taken together, C3a/C3aR signaling could possibly affect the propagation of C. parvum in mouse ileum tissues by regulating the gut barrier, cell proliferation and CD4+ T cell main effectors, which would contribute to our understanding of the interaction between Cryptosporidium and hosts.

The leaves of Engelhardia roxburghiana Wall (LERW) has been used as sweet tea in China throughout history. In this study, the ethanol extract of LERW (E-LERW) was prepared and the compositions were identified by HPLC-MS/MS. It indicates that astilbin was the predominant component in E-LERW. In addition, E-LERW was abundant in polyphenols. Compared to astilbin, E-LERW presented much more powerful antioxidant activity. The E-LERW also had stronger affinity with α-glucosidase and exerted more vigorous inhibitory effect on the enzyme. Alloxan-induced diabetic mice had significantly elevated glucose and lipid levels. Treatment with E-LERW at the medium dose (M) of 300 mg/kg could reduce the levels of glucose, TG, TC, and LDL by 16.64%, 12.87%, 32.70%, and 22.99%, respectively. In addition, E-LERW (M) decreased food intake, water intake, and excretion by 27.29%, 36.15%, and 30.93%, respectively. Moreover, E-LERW (M) therapy increased the mouse weight and insulin secretion by 25.30% and 494.52%. With respect to the astilbin control, E-LERW was more efficient in reducing the food and drink consumption and protecting pancreatic islet and body organs from alloxan-induced damage. The study demonstrates that E-LERW may be a promising functional ingredient for the adjuvant therapy of diabetes.

Accurate detection of HER2 expression through immunohistochemistry (IHC) is of great clinical significance in the treatment of breast cancer. However, manual interpretation of HER2 is challenging, due to the interobserver variability among pathologists. We sought to explore a deep learning method to predict HER2 expression level and gene status based on a Whole Slide Image (WSI) of the HER2 IHC section. When applied to 228 invasive breast carcinoma of no special type (IBC-NST) DAB-stained slides, our GrayMap+ convolutional neural network (CNN) model accurately classified HER2 IHC level with mean accuracy 0.952 ± 0.029 and predicted HER2 FISH status with mean accuracy 0.921 ± 0.029. Our result also demonstrated strong consistency in HER2 expression score between our system and experienced pathologists (intraclass correlation coefficient (ICC) = 0.903, Cohen’s κ = 0.875). The discordant cases were found to be largely caused by high intra-tumor staining heterogeneity in the HER2 IHC group and low copy number in the HER2 FISH group.

In estrogen receptor (ER)-positive breast cancer, changes in biomarker expression after neoadjuvant therapy indicate the therapeutic response and are prognostic. However, there is limited information about the biomarker alteration caused by neoadjuvant endocrine therapy in ER-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. We recruited ER-positive/HER2-negative breast cancer patients who received neoadjuvant chemotherapy (NCT), neoadjuvant endocrine therapy (NET), or sequential neoadjuvant endocrine-chemotherapy (NECT) at Peking University Cancer Hospital from 2015 to 2021. A total of 579 patients had paired immunohistochemistry information in both diagnostic biopsy samples and post-neoadjuvant therapy surgical samples. Through a paired comparison of the immunohistochemical information in pre-treatment and post-treatment samples, we found that progesterone receptor (PR) expression reductions were more frequent than ER expression reductions (70.8% vs. 35.2%) after neoadjuvant therapy. The percentage of patients who had a decreased Ki-67 index in the post-operative samples was similar in the three groups (79.8% vs. 79.7% vs. 78.4%). Moreover, PR losses caused by NET were related to low baseline PR expression (p = 0.001), while we did not find a significant association between PR losses and Ki-67 reductions (p = 0.428) or ER losses (p = 0.274). All three types of neoadjuvant therapies caused a reduction in ER, PR, and Ki-67 expression. In conclusion, we found that PR loss after NET was only significantly related to low baseline PR expression, and there is no significant difference in the extent of prognostic factor change including Ki-67 and ER between the PR loss and non-loss groups.

BackgroundIt is a critical challenge to diagnose leptomeningeal metastasis (LM), given its technical difficulty and the lack of typical symptoms. The existing gold standard of diagnosing LM is to use positive cerebrospinal fluid (CSF) cytology, which consumes significantly more time to classify cells under a microscope.ObjectiveThis study aims to establish a deep learning model to classify cancer cells in CSF, thus facilitating doctors to achieve an accurate and fast diagnosis of LM in an early stage.MethodThe cerebrospinal fluid laboratory of Xijing Hospital provides 53,255 cells from 90 LM patients in the research. We used two deep convolutional neural networks (CNN) models to classify cells in the CSF. A five-way cell classification model (CNN1) consists of lymphocytes, monocytes, neutrophils, erythrocytes, and cancer cells. A four-way cancer cell classification model (CNN2) consists of lung cancer cells, gastric cancer cells, breast cancer cells, and pancreatic cancer cells. Here, the CNN models were constructed by Resnet-inception-V2. We evaluated the performance of the proposed models on two external datasets and compared them with the results from 42 doctors of various levels of experience in the human-machine tests. Furthermore, we develop a computer-aided diagnosis (CAD) software to generate cytology diagnosis reports in the research rapidly.ResultsWith respect to the validation set, the mean average precision (mAP) of CNN1 is over 95% and that of CNN2 is close to 80%. Hence, the proposed deep learning model effectively classifies cells in CSF to facilitate the screening of cancer cells. In the human-machine tests, the accuracy of CNN1 is similar to the results from experts, with higher accuracy than doctors in other levels. Moreover, the overall accuracy of CNN2 is 10% higher than that of experts, with a time consumption of only one-third of that consumed by an expert. Using the CAD software saves 90% working time of cytologists.ConclusionA deep learning method has been developed to assist the LM diagnosis with high accuracy and low time consumption effectively. Thanks to labeled data and step-by-step training, our proposed method can successfully classify cancer cells in the CSF to assist LM diagnosis early. In addition, this unique research can predict cancer’s primary source of LM, which relies on cytomorphologic features without immunohistochemistry. Our results show that deep learning can be widely used in medical images to classify cerebrospinal fluid cells. For complex cancer classification tasks, the accuracy of the proposed method is significantly higher than that of specialist doctors, and its performance is better than that of junior doctors and interns. The application of CNNs and CAD software may ultimately aid in expediting the diagnosis and overcoming the shortage of experienced cytologists, thereby facilitating earlier treatment and improving the prognosis of LM.

Based on conventional observation data from the China Meteorological Administration (CMA) and reanalysis data from the American National Centers for Environmental Prediction and National Center for Atmospheric Research (NCEP/NCAR) between 2012 and 2021, combined with the meteorological analysis, composite synthesis, and water vapor trajectory analysis, the weather circulations of typical rainstorms during the 10 years can be divided into 4 categories: Static Front Pattern (SFP), Subtropical High Edge Pattern (SHEP), Northeast Cold Vortex Pattern (NCVP), and Low-Level Vortex and Shear Pattern (LLVSP). The SHEP and SFP rainstorms have the characteristics of long duration and wide range, while the NCVP rainstorms are characterized by mobility and disaster weather accompaniment. The daily precipitation of LLVSP cases has extremity feature. The occurrence and development of rainstorms are well coordinated with the systems on lower levels. The main water vapor channel in lower layers of the SFP cases is from the South China Sea, while it is from Bohai for the NCVP cases and the Bay of Bengal for the SHEP and LLVSP cases. The main water vapor channel in middle layers is from the Bay of Bengal because of the affection of the southwest air flow. The south boundary of the MLYRB is the most important water vapor input boundary, followed by the west boundary, while the East and North boundaries are the outflow boundaries. During the rainstorms, the low-level water vapor is exuberant with low-level water vapor convergence much stronger than the high-level divergence. Among the four types of rainstorms, the NCVP cases provide the most abundant low-level water vapor convergence, resulting in the strongest short-term precipitation among the four types. Combined with water vapor transportation and convergence, the refined spatial conceptual models of the four types of rainstorms can better judge the process intensity and falling area and provide reference for disastrous weather forecast and early warning.