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Abstract The global spread of H5 clade 2.3.4.4 highly pathogenic avian influenza (HPAI) viruses threatens poultry and public health. The continuous circulation of these viruses has led to their considerable genetic and antigenic evolution, resulting in the formation of eight subclades (2.3.4.4a–h). Here, we examined the antigenic sites that determine the antigenic differences between two H5 vaccine strains, H5-Re8 (clade 2.3.4.4g) and H5-Re11 (clade 2.3.4.4h). Epitope mapping data revealed that all eight identified antigenic sites were located within two classical antigenic regions, with five sites in region A (positions 115, 120, 124, 126, and 140) and three in region B (positions 151, 156, and 185). Through antigenic cartography analysis of mutants with varying numbers of substitutions, we confirmed that a combination of mutations in these eight sites reverses the antigenicity of H5-Re11 to that of H5-Re8, and vice versa. More importantly, our analyses identified H5-Re11_Q115L/R120S/A156T (H5-Re11 + 3) as a promising candidate for a broad-spectrum vaccine, positioned centrally in the antigenic map, and offering potential universal protection against all variants within the clade 2.3.4.4. H5-Re11 + 3 serum has better cross-reactivity than sera generated with other 2.3.4.4 vaccines, and H5-Re11 + 3 vaccine provided 100% protection of chickens against antigenically drifted H5 viruses from various 2.3.4.4 antigenic groups. Our findings suggest that antigenic regions A and B are immunodominant in H5 viruses, and that antigenic cartography-guided vaccine design is a promising strategy for selecting a broad-spectrum vaccine.

Abstract A new rapid dual detection method was established to distinguish Bupleurum scorzonerifolium Willd. (BS) and Bupleurum chinense DC. (BC) simultaneously using the proofreading enzyme-mediated probe cleavage coupled with ladder-shape melting temperature isothermal amplification (proofman–LMTIA). The internal transcribed spacer (ITS) sequences of BS and BC were selected as targets for designs of proofman–LMTIA primers and proofman fluorescence probes labeled with FAM or JOE. The reaction temperature optimization, repeatability and reliability assessment, specificity assessment and sensitivity assessment of the proofman–LMTIA performed for dual detection of BS and BC and its application. The results showed that the optimal reaction temperature of the proofman–LMTIA method was at 63℃, which had strongly specificity, repeatability and reliability, as well as sensitivity, and the detection was completed within 20 min with a detection sensitivity of 1 pg/μL. The proofman–LMTIA method realized dual rapid detection of BS and BC, which showed a strong practical value. The 4 kinds were BC, 1 kind was BS, and 2 kinds were counterfeit in the detection of 7 kinds of BS or BC samples from different habitats. Our study successfully established a new approach for dual rapid detection of BS and BC using the proofman–LMTIA, which will provide an effective technique or method for the authenticity detection of authentic Chinese medicinal materials and present a very important practical significance. Graphical Abstract

Abstract The Lys-Asp-Glu-Leu receptor (KDELR) family genes play critical roles in a variety of biological processes in different tumors. Our study aimed to provide a comprehensive analysis of the potential roles of KDELRs in lung adenocarcinoma (LUAD). Utilizing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, as well as clinical samples, we conducted a series of analyses and validations using R software tools and various online resources. The results showed that KDELR family genes and proteins were highly expressed and associated with a poor prognosis of LUAD. Promoter hypomethylation and the competing endogenous RNA (ceRNA) network of PCAT6/hsa-miR-326/KDELR1 might be potential causes of aberrant KDELR1 overexpression in LUAD. Three key Transcription factors (TFs) (SPI1, EP300, and MAZ) and a TFs-miRNAs-KDELRs network (involving 11 TFs) might be involved in modulating KDELRs expression abnormalities. Gene Set Enrichment Analysis (GSEA) indicated enrichment of genes highly expressing KDELR1, KDELR2, and KDELR3 in MTORC1_SIGNALING, P53_PATHWAY, and ANGIOGENESIS. Negative correlations between KDELRs expression and CD8 + T cell infiltration, as well as CTLA-4 expression. Our multiple analyses suggested that the KDELRs are important signaling molecules in LUAD. These results provided novel insights for developing prognostic markers and novel therapies of LUAD.

Abstract Cancer cachexia (CC) is a devastating metabolic syndrome characterized by skeletal muscle wasting and body weight loss, posing a significant burden on the health and survival of cancer patients. Despite ongoing efforts, effective treatments for CC are still lacking. Metabolomics, an advanced omics technique, offers a comprehensive analysis of small‐molecule metabolites involved in cellular metabolism. In CC research, metabolomics has emerged as a valuable tool for identifying diagnostic biomarkers, unravelling molecular mechanisms and discovering potential therapeutic targets. A comprehensive search strategy was implemented to retrieve relevant articles from primary databases, including Web of Science, Google Scholar, Scopus and PubMed, for CC and metabolomics. Recent advancements in metabolomics have deepened our understanding of CC by uncovering key metabolic signatures and elucidating underlying mechanisms. By targeting crucial metabolic pathways including glucose metabolism, amino acid metabolism, fatty acid metabolism, bile acid metabolism, ketone body metabolism, steroid metabolism and mitochondrial energy metabolism, it becomes possible to restore metabolic balance and alleviate CC symptoms. This review provides a comprehensive summary of metabolomics studies in CC, focusing on the discovery of potential therapeutic targets and the evaluation of modulating specific metabolic pathways for CC treatment. By harnessing the insights derived from metabolomics, novel interventions for CC can be developed, leading to improved patient outcomes and enhanced quality of life.

Accurate determination of gas content in deep coal mine is the premise for the prevention and control of gas disaster, as well as the efficient development and utilization of coalbed methane. Traditional coring technology of coal seam is generally open-ended and requires to obtain the amount of gas loss during the coring process by using estimation methods, making it difficult to ensure the accuracy and validity of the in-situ parameters of coalbed methane. Based on the academic idea of “in-site condition-maintaining coring”, the in-situ pressure- and gas-maintaining coring technology for deep coal seam was proposed, and the in-situ pressure- and gas-maintaining corer for deep coal seam was developed. The strength verification for corer outer tube, pressure-maintaining chamber and key weak parts were conducted based on three-dimensional numerical simulation. Meanwhile, the pressure-maintaining capacity of controller was measured and analysed relied on the self-developed pressure-maintaining coring laboratory simulation test platform, and the reliability of corer was verified through field tests in coal mine. The results shown that, the self-developed corer had the advantages of strong pressure-maintaining capacity, long pressure-maintaining time and stable anti-disturbance performance. The equivalent stress of the corer under internal fluid pressure of 20 MPa and torque of 1000 N·m was 121.1 MPa, which was much smaller than the yield strength of the material and met the strength design requirements. The equivalent stress of corer under the pressure of 20 MPa was 63.9 MPa, which met the strength design requirements. The corer can operate continuously and stably at the pressure of 19.4 MPa, which met the demand for gas testing in most of deep coal mines. The field test shown that, the pressure-maintaining controller of the pressure- and gas-maintaining corer closed well, with 100% of coring rate in the field. The research provides a theoretical, technical and equipment foundation for the accurate determination of gas content in deep coal seams, which is of great significance for the prevention and control of coal mine gas disasters and the exploration and development of coalbed methane.

Recently, an outbreak of highly pathogenic avian influenza A (H5N1), which carries the clade 2.3.4.4b hemagglutinin (HA) gene and has been prevalent among North American bird populations since the winter of 2021, was reported in dairy cows in the United States. As of 24 May 2024, the virus has affected 63 dairy herds across nine states and has resulted in two human infections. The virus causes unusual symptoms in dairy cows, including an unexpected drop in milk production, and thick colostrum-like milk. Notably, The US Food and Drug Administration reported that around 20% of tested retail milk samples contained H5N1 viruses, with a higher percentage of positive results from regions with infected cattle herds. Data are scant regarding how effectively pasteurization inactivates the H5N1 virus in milk. Therefore, in this study, we evaluated the thermal stability of the H5 clade 2.3.4.4b viruses, along with one human H3N2 virus and other influenza subtype viruses, including H1, H3, H7, H9, and H10 subtype viruses. We also assessed the effectiveness of pasteurization in inactivating these viruses. We found that the avian H3 virus exhibits the highest thermal stability, whereas the H5N1 viruses that belong to clade 2.3.4.4b display moderate thermal stability. Importantly, our data provide direct evidence that the standard pasteurization methods used by dairy companies are effective in inactivating all tested subtypes of influenza viruses in raw milk. Our findings indicate that thermally pasteurized milk products do not pose a safety risk to consumers.

ABSTRACTHuman infections with the H7N9 influenza virus have been eliminated in China through vaccination of poultry; however, the H7N9 virus has not yet been eradicated from poultry. Carefully analysis of H7N9 viruses in poultry that have sub-optimal immunity may provide a unique opportunity to witness the evolution of highly pathogenic avian influenza virus in the context of vaccination. Between January 2020 and June 2023, we isolated 16 H7N9 viruses from samples we collected during surveillance and samples that were sent to us for disease diagnosis. Genetic analysis indicated that these viruses belonged to a single genotype previously detected in poultry. Antigenic analysis indicated that 12 of the 16 viruses were antigenically close to the H7-Re4 vaccine virus that has been used since January 2022, and the other four viruses showed reduced reactivity with the vaccine. Animal studies indicated that all 16 viruses were nonlethal in mice, and four of six viruses showed reduced virulence in chickens upon intranasally inoculation. Importantly, the H7N9 viruses detected in this study exclusively bound to the avian-type receptors, having lost the capacity to bind to human-type receptors. Our study shows that vaccination slows the evolution of H7N9 virus by preventing its reassortment with other viruses and eliminates a harmful characteristic of H7N9 virus, namely its ability to bind to human-type receptors.

ABSTRACTH5N1 avian influenza viruses bearing the clade 2.3.2.1 hemagglutinin (HA) gene have been widely detected in birds and poultry in several countries. During our routine surveillance, we isolated 28 H5N1 viruses between January 2017 and October 2020. To investigate the genetic relationship of the globally circulating H5N1 viruses and the biological properties of those detected in China, we performed a detailed phylogenic analysis of 274 representative H5N1 strains and analyzed the antigenic properties, receptor-binding preference, and virulence in mice of the H5N1 viruses isolated in China. The phylogenic analysis indicated that the HA genes of the 274 viruses belonged to six subclades, namely clades 2.3.2.1a to 2.3.2.1f; these viruses acquired gene mutations and underwent complicated reassortment to form 58 genotypes, with G43 being the dominant genotype detected in eight Asian and African countries. The 28 H5N1 viruses detected in this study carried the HA of clade 2.3.2.1c (two strains), 2.3.2.1d (three strains), or 2.3.2.1f (23 strains), and formed eight genotypes. These viruses were antigenically well-matched with the H5-Re12 vaccine strain used in China. Animal studies showed that the pathogenicity of the H5N1 viruses ranged from non-lethal to highly lethal in mice. Moreover, the viruses exclusively bound to avian-type receptors and have not acquired the ability to bind to human-type receptors. Our study reveals the overall picture of the evolution of clade 2.3.2.1 H5N1 viruses and provides insights into the control of these viruses.

In order to determine the reasonable spacing of gas extraction holes under the increase permeability measures of hydraulic punching taking Jiuxin Coal Industry of Jincheng Mining Area as the engineering background, COMSOL Multiphysics numerical software was used to build a Three-Dimensional model of gas extraction holes and simulate the gas extraction process under the increase permeability measures of hydraulic punching with different spacing. The gas pressure evolution law of coal body is analyzed by gas pressure isosurface 3d stereograph, and the influence law of borehole spacing on gas extraction effect is quantitatively studied. The results show that with the increase of extraction time, the effective extraction radius and the influence radius of drilling continue to increase, but the growth rate decreases. At the same extraction time, different coal quantity has a significant effect on the effective influence radius, but has little effect on the extraction influence radius. Under the same extraction time, different coal outrush has a significant effect on the effective influence radius, but a small effect on the extraction influence radius. Extraction time and coal seam thickness are the main restricting factors of hydraulic punching drilling layout. The research results provide a reference for optimizing the spacing of hydraulic punching holes.

The purpose of this study was to assess the comparative efficacy of six programmed cell death-1 inhibitors (nivolumab, pembrolizumab, sintilimab, tislelizumab, toripalimab, and camrelizumab) that have been used as first-line therapy for Chinese patients with advanced non-small cell lung cancer (NSCLC), which remains unclear. We determined the differences in efficacy by observing patient survival data, with the goal of informing future treatment options. Retrospective data analysis from June 2015 to April 2023 included 913 patients across six groups: nivolumab (123%, 13.5%), pembrolizumab (421%, 46.1%), sintilimab (239%, 26.1%), tislelizumab (64%, 7.0%), toripalimab (39%, 4.3%), and camrelizumab (27%, 3.0%). The median progression-free survival (PFS) for each group was 16.0, 16.1, 18.4, 16.9, 23.7, and 12.8 months, and the median overall survival (OS) was 33.7, 36.1, 32.5, not reached, 30.9 and 46.0 months for the nivolumab, sintilimab, pembrolizumab, tislelizumab, toripalimab, and camrelizumab groups, respectively. While differences existed in the objective response rates among groups (p < 0.05), there were no significant differences (all p > 0.05) in PFS or OS. The findings suggest comparable efficacy among these PD-1 inhibitors for NSCLC treatment, underscoring their collective suitability and aiding treatment decisions.

Abstract Marine resources in unique marine environments provide abundant, cost-effective natural biomaterials with distinct structures, compositions, and biological activities compared to terrestrial species. These marine-derived raw materials, including polysaccharides, natural protein components, fatty acids, and marine minerals, etc., have shown great potential in preparing, stabilizing, or modifying multifunctional nano-/micro-systems and are widely applied in drug delivery, theragnostic, tissue engineering, etc. This review provides a comprehensive summary of the most current marine biomaterial-based nano-/micro-systems developed over the past three years, primarily focusing on therapeutic delivery studies and highlighting their potential to cure a variety of diseases. Specifically, we first provided a detailed introduction to the physicochemical characteristics and biological activities of natural marine biocomponents in their raw state. Furthermore, the assembly processes, potential functionalities of each building block, and a thorough evaluation of the pharmacokinetics and pharmacodynamics of advanced marine biomaterial-based systems and their effects on molecular pathophysiological processes were fully elucidated. Finally, a list of unresolved issues and pivotal challenges of marine-derived biomaterials applications, such as standardized distinction of raw materials, long-term biosafety in vivo, the feasibility of scale-up, etc., was presented. This review is expected to serve as a roadmap for fundamental research and facilitate the rational design of marine biomaterials for diverse emerging applications. Graphical Abstract

[This corrects the article DOI: 10.1371/journal.ppat.1006851.].

Premature ovarian insufficiency (POI) may lead to early menopause, fertility loss and birth defects without effective treatment. Here, we explored the efficacy and safety of gene therapy to rescue ovarian function in both natural ovarian aging and doxorubicin (Dox) induced POI mice. Sirt1 and Tgfbr2 were screened out and identified as key genes in both murine and human ovarian tissues. Then, adenovirus (AdV) was selected as a suited carrier for ovarian infection after comparison of multiple viral vectors. In both two models, murine fertility was significantly improved after AdV-Sirt1 and AdV-Tgfbr2 invention individually or in combination, without obvious side effects to themselves and their offspring. Compared with the control group, the successful pregnancy rate in the 9-month-old-AdV-Sirt1 group increased by 60 % (67 % vs 42 %). Meanwhile, the pregnancy rate in the AdV-Tgfbr2 + Dox group increased by 85 % (55.6 % vs 20 %). The biological process of ovarian follicle development and fibrosis was rescued. Our work demonstrated that AdV-Sirt1 and AdV-Tgfbr2 therapy alleviates natural ovarian aging and Dox-associated POI, which may be potentially applicable for female fertility protection.

Bacterial infections are a significant global health concern, particularly in the context of skin infections and chronic wounds, which was further exacerbated by the emerging of antibiotic resistance. Therefore, there are urgent needs to develop alternative antibacterial strategies without inducing significant resistance. Photothermal therapy (PTT) is a promising alternative approach but usually faces limitations such as the need for stable and environmental-friendly PTT agents and ensuring biocompatibility with living tissues, necessitating ongoing research for its clinical advancement. Herein, in this study, with the aim to develop a green synthesized PTT agent for photothermal enhanced antibacterial and wound healing, we proposed a facile one-pot method to prepare epigallocatechin gallate-ferric (EGCG-Fe) complex nanoparticles. The obtained nanoparticles showed improved good size distribution and stability with high reproducibility. More importantly, EGCG-Fe complex nanoparticles have additional photothermal conversion ability which can give photothermal enhanced antibacterial effect on various pathogens, including Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative Escherichia coli (E. coli) strains. EGCG-Fe complex nanoparticles also showed powerful biofilm prevention and destruction effects with promoted antibacterial and wound healing on mice model. In conclusion, EGCG-Fe complex nanoparticles can be a robust green material with effective and novel light controllable antibacterial properties for photothermal enhanced antibacterial and wound healing applications.

Fatal traffic crashes involving commercial vehicles exhibit distinct characteristics and mechanisms compared to general traffic crashes, influenced by numerous factors that impact the resulting fatalities. This study presents a comprehensive analysis of significant commercial vehicle crashes in China over a nine-year period (2014–2022), exploring an extensive range of factors including driver behavior, road conditions, vehicle characteristics, and environmental aspects. Utilizing a hierarchical Bayesian ordered probit model that incorporates both categorical and random effects, the research offers nuanced insights into the probabilistic outcomes of fatal traffic crashes. The model’s hierarchical structure enables the exploration of unobserved heterogeneities at individual and group levels. Key findings indicate that driver’s behaviors like speeding and overloading significantly escalate the likelihood of fatal traffic crashes, particularly those resulting in 10 or more fatalities. The study also highlights the role of road class in fatal crashes, with primary and secondary roads being associated with higher risks of more severe fatal crashes. The analysis extends to the impact of vehicle type, noting a distinct increase in the probabilities of fatal crashes with passenger vehicles, while freight vehicles exhibit a more complex relationship with fatal crashes severity. The insights from this study underscore the urgent need for enhanced enforcement of speed limit and vehicle weight regulations, particularly through the deployment of advanced monitoring technologies on highways frequented by commercial vehicles, and targeted infrastructure improvements on primary and secondary roads. This approach offers a novel analytical framework for evaluating commercial traffic crashes, assisting policymakers in devising targeted safety interventions to reduce the incidence of commercial vehicle crashes.

ABSTRACTThe continued evolution and emergence of novel influenza viruses in wild and domestic animals poses an increasing public health risk. Two human cases of H3N8 avian influenza virus infection in China in 2022 have caused public concern regarding the risk of transmission between birds and humans. However, the prevalence of H3N8 avian influenza viruses in their natural reservoirs and their biological characteristics are largely unknown. To elucidate the potential threat of H3N8 viruses, we analyzed five years of surveillance data obtained from an important wetland region in eastern China and evaluated the evolutionary and biological characteristics of 21 H3N8 viruses isolated from 15,899 migratory bird samples between 2017 and 2021. Genetic and phylogenetic analyses showed that the H3N8 viruses circulating in migratory birds and ducks have evolved into different branches and have undergone complicated reassortment with viruses in waterfowl. The 21 viruses belonged to 12 genotypes, and some strains induced body weight loss and pneumonia in mice. All the tested H3N8 viruses preferentially bind to avian-type receptors, although they have acquired the ability to bind human-type receptors. Infection studies in ducks, chickens and pigeons demonstrated that the currently circulating H3N8 viruses in migratory birds have a high possibility of infecting domestic waterfowl and a low possibility of infecting chickens and pigeons. Our findings imply that circulating H3N8 viruses in migratory birds continue to evolve and pose a high infection risk in domestic ducks. These results further emphasize the importance of avian influenza surveillance at the wild bird and poultry interface.

ABSTRACTAvian influenza viruses continue to present challenges to animal and human health. Viruses bearing the hemagglutinin (HA) gene of the H5 subtype and H7 subtype have caused 2634 human cases around the world, including more than 1000 deaths. These viruses have caused numerous disease outbreaks in wild birds and domestic poultry, and are responsible for the loss of at least 422 million domestic birds since 2005. The H5 influenza viruses are spread by migratory wild birds and have caused three waves of influenza outbreaks across multiple continents, and the third wave that started in 2020 is ongoing. Many countries in Europe and North America control highly pathogenic avian influenza by culling alone, whereas some countries, including China, have adopted a “cull plus vaccination” strategy. As the largest poultry-producing country in the world, China lost relatively few poultry during the three waves of global H5 avian influenza outbreaks, and nearly eliminated the pervasive H7N9 viruses that emerged in 2013. In this review, we briefly summarize the damages the H5 and H7 influenza viruses have caused to the global poultry industry and public health, analyze the origin, evolution, and spread of the H5 viruses that caused the waves, and discuss how and why the vaccination strategy in China has been a success. Given that the H5N1 viruses are widely circulating in wild birds and causing problems in domestic poultry around the world, we recommend that any unnecessary obstacles to vaccination strategies should be removed immediately and forever.

This research explores the synchronization issue of leader–follower systems with multiple nonlinear agents, which operate under input saturation constraints. Each follower operates under a spectrum of unknown dynamic nonlinear systems with non-strict feedback. Additionally, due to the fact that the agents may be geographically dispersed or have different communication capabilities, only a subset of followers has direct communication with the leader. Compared to linear systems, nonlinear systems can provide a more detailed description of real-world physical models. However, input saturation is present in most real systems, due to various factors such as limited system energy and the physical constraints of the actuators. An auxiliary system of Nth order is introduced to counteract the impact of input saturation, which is then employed to create a collaborative controller. Due to the powerful capability of fuzzy logic systems in simulating complex nonlinear relationships, they are deployed to approximate the enigmatic nonlinear functions intrinsic to the systems. A distributed adaptive fuzzy state feedback controller is designed by approximating the derivative of the virtual controller by filters. The proposed controller ensures the synchronization of all follower outputs with the leader output in the communication graph. It is shown that all signals in the closed-loop system are semi-globally uniformly ultimately bounded, and the tracking errors converge to a small neighborhood around the origin. Finally, a numerical example is given to demonstrate the effectiveness of the proposed approach.

Purpose: This study aimed to screen biomarkers to predict the efficacy of programmed cell death 1 (PD-1) blockade immunotherapy combined with chemotherapy as neoadjuvant therapy for esophageal squamous cell carcinoma (ESCC). Methods: In the first stage of the study, the baseline concentrations of 40 tumor-related chemokines in the serum samples of 50 patients were measured to screen for possible biomarkers. We investigated whether the baseline concentration of the selected chemokine was related to the therapeutic outcomes and tumor microenvironment states of patients treated with the therapy. In the second stage, the reliability of the selected biomarkers was retested in 34 patients. Results: The baseline concentration of macrophage migration inhibitory factor (MIF) was negatively correlated with disease-free survival (DFS) and overall survival (OS) in patients treated with the therapy. In addition, a low baseline expression level of MIF is related to a better tumor microenvironment for the treatment of ESCC. A secondary finding was that effective treatment decreased the serum concentration of MIF. Conclusion: Baseline MIF levels were negatively correlated with neoadjuvant therapy efficacy. Thus, MIF may serve as a predictive biomarker for this therapy. The accuracy of the prediction could be improved if the serum concentration of MIF is measured again after the patient received several weeks of treatment.

Abstract Background Patients with pulmonary large cell carcinoma (LCC) have a high incidence of synchronous brain metastases (SBM) and a poor prognosis. Our study was to evaluate the predictive and prognostic value of the clinical characteristics of pulmonary LCC patients with SBM at initial diagnosis by utilizing the Surveillance, Epidemiology, and End Results (SEER) database. Methods LCC patients, diagnosed from 2010 to 2019, were identified from the latest SEER database which was released in April 2022. Logistic regression and Cox regression were used to identify the predictive and prognostic factors for LCC patients with SBM. Propensity score matching (PSM) and Kaplan–Meier analyses were applied to assess different therapy modalities. Results A total of 1375 LCC patients were enrolled in this study and 216 (15.7%) of them had SBM at the initial diagnosis. The median overall survival (OS) of LCC patients with SBM was 4 months. Multivariate Cox regression identified age 60–79 (OR 0.57; 95% CI 0.41–0.78; p

H5N1 avian influenza viruses bearing the clade 2.3.4.4b hemagglutinin gene have been widely circulating in wild birds and are responsible for the loss of over 70 million domestic poultry in Europe, Africa, Asia, and North America since October 2020. During our routine surveillance, 13 H5N1 viruses were isolated from 26,767 wild bird and poultry samples that were collected between September 2021 and March 2022 in China. To investigate the origin of these Chinese isolates and understand their genetic relationship with the globally circulating H5N1 viruses, we performed a detailed phylogenic analysis of 233 representative H5N1 strains that were isolated from 28 countries. We found that, after they emerged in the Netherlands, the H5N1 viruses encountered complicated gene exchange with different viruses circulating in wild birds and formed 16 genotypes. Genotype one (G1) was predominant, being detected in 22 countries, whereas all other genotypes were only detected in one or two continents. H5N1 viruses of four genotypes (G1, G7, G9, and G10) were detected in China; three of these genotypes have been previously reported in other countries. The H5N1 viruses detected in China replicated in mice, with pathogenicity varying among strains; the G1 virus was highly lethal in mice. Moreover, we found that these viruses were antigenically similar to and well matched with the H5-Re14 vaccine strain currently used in China. Our study reveals the overall picture of H5N1 virus evolution and provides insights for the control of these viruses.

The globally circulating H5N8 avian influenza viruses bearing the clade 2.3.4.4b hemagglutinin (HA) gene are responsible for the loss of more than 33 million domestic poultry since January 2020. Moreover, the H5N8 viruses have reassorted with other avian influenza viruses and formed H5N1, H5N2, H5N3, H5N4, and H5N5 viruses in Europe, Africa, and North America. In this study, we analyzed 15 H5N6 viruses isolated from poultry and seven H5N6 viruses isolated from humans, and found these viruses formed seven different genotypes by deriving the clade 2.3.4.4b HA gene of H5N8 viruses, the neuraminidase of domestic duck H5N6 viruses, and internal genes of different viruses that previously circulated in domestic ducks and wild birds in China. Two of these genotypes (genotype 3 and genotype 6) have caused human infections in multiple provinces. The H5N6 viruses isolated from poultry have distinct pathotypes in mice; some of them replicate systemically and are highly lethal in mice. Although these viruses exclusively bind to avian-type receptors, it is worrisome that they may obtain key mutations that would increase their affinity for human-type receptors during replication in humans. Our study indicates that the novel H5N6 reassortants bearing the clade 2.3.4.4b HA gene of H5N8 viruses were generated through reassortment in domestic ducks and may have spread across a wide area of China, thereby posing a new challenge to the poultry industry and human health. Our findings emphasize the importance of careful monitoring, evaluation, and control of the H5N6 viruses circulating in nature.

Abstract Background Zishen Yutai (ZSYT) pill, a patent Chinese medicine, has been widely used in the treatment of infertility, abortion, and adjunctive treatment of in vitro fertilization (IVF) for decades. Recently, the results of clinical observations showed that premature ovarian failure (POF) patients exhibited improved expression of steroids and clinical symptoms associated with hormone disorders after treatment with Zishen Yutai pills. However, the pharmacological mechanism of action of these pills remains unclear. Methods The compounds of Zishen Yutai pills found in blood circulation were identified via ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) technique in the serum of POF mice after oral administration of Zishen Yutai pills. The potential targets of compounds were screened using Traditional Chinese Medicine Systems Pharmacology Database, Traditional Chinese Medicine Database@Taiwan, Drugbank Database, PubChem, HIT, Pharmapper, and Swiss Target Prediction. The target genes associated with POF were collected from Online Mendelian Inheritance in Man Database, PharmGkb, Genecards, Therapeutic Target Database, and Genetic Association Database. The overlapping genes between the potential targets of Zishen Yutai pills’ compounds and the target genes associated with POF were clarified via protein-protein interaction (PPI), pathway, and network analysis. Results Nineteen compounds in Zishen Yutai pills were detected in the serum of POF mice after oral administration. A total of 695 Zishen Yutai (ZSYT) pill-related targets were screened, and 344 POF-related targets were collected. From the results of Zishen Yutai (ZSYT) pill-POF PPI analysis, CYP19A1, AKR1C3, ESR1, AR, and SRD5A2 were identified as key targets via network analysis, indicating their core role in the treatment of POF with Zishen Yutai pills. Moreover, the pathway enrichment results suggested that Zishen Yutai pills treated POF primarily by regulating neuroactive ligand-receptor interaction, steroid hormone biosynthesis, and ovarian steroidogenesis. Conclusions Via virtual screening, we found that regulation of neuroactive ligand-receptor interaction, steroid hormone biosynthesis, and ovarian steroidogenesis was the potential therapeutic mechanism of Zishen Yutai pills in treating POF. Our study suggested that combining the analysis of Zishen Yutai pills’ compounds in blood in vivo in the POF model and network pharmacology prediction might offer a tool to characterize the mechanism of Zishen Yutai pills in the POF.

Backfill coal mining technology has drawn widespread attention due to its benefits of “controlling surface deformation and subsidence, reducing mining-induced disturbance in the stope, and recycling solid mine wastes”. However, the backfill coal mining technology is still progressing slowly in China. The geological environment of China’s mining areas is complex and highly diversified, and backfill coal mining is expected to fulfill different goals in a wide range of engineering scenarios. These facts explain the poor reproducibility of backfill coal mining projects. This study reviews the existing backfill coal mining systems in China. Based on findings from a survey of engineering cases, we summarize five types of new backfill coal mining methods classified by deployment style; namely, borehole grouting backfill, roadway backfill, borehole–roadway backfill, in situ backfill, and roadway-in-situ backfill. A total of 15 backfill coal mining methods falling into the above five categories are described. An engineering design workflow for backfill coal mining consisting of five steps is proposed; namely, identifying the targets of backfill, analyzing the feasibility of deploying the backfill system, comparing the engineering quantities of different engineering schemes, estimating the economic efficiency of backfill, and backfill performance tracking and monitoring. Real cases of backfill engineering design are analyzed to inform the fast and reasonable design of backfill strategy for specific working faces in certain coal mines.

Abstract Pyroptosis, systemic inflammation, and mitochondrial apoptosis are the three primary contributors to sepsis's multiple organ failure, the ultimate cause of high clinical mortality. Currently, the drugs under development only target a single pathogenesis, which is obviously insufficient. In this study, an acid‐responsive hollow mesoporous polydopamine (HMPDA) nanocarrier that is highly capable of carrying both the hydrophilic drug NAD+ and the hydrophobic drug BAPTA‐AM, with its outer layer being sealed by the inflammatory targeting peptide PEG‐LSA, is developed. Once targeted to the region of inflammation, HMPDA begins depolymerization, releasing the drugs NAD+ and BAPTA‐AM. Depletion of polydopamine on excessive reactive oxygen species production, promotion of ATP production and anti‐inflammation by NAD+ replenishment, and chelation of BAPTA (generated by BA‐AM hydrolysis) on overloaded Ca2+ can comprehensively block the three stages of sepsis, i.e., precisely inhibit the activation of pyroptosis pathway (NF‐κB‐NLRP3‐ASC‐Casp‐1), inflammation pathway (IL‐1β, IL‐6, and TNF‐α), and mitochondrial apoptosis pathway (Bcl‐2/Bax‐Cyt‐C‐Casp‐9‐Casp‐3), thereby restoring intracellular homeostasis, saving the cells in a state of “critical survival,” further reducing LPS‐induced systemic inflammation, finally restoring the organ functions. In conclusion, the synthesis of this agent provides a simple and effective synergistic drug delivery nanosystem, which demonstrates significant therapeutic potential in a model of LPS‐induced sepsis.

The H5 subtype highly pathogenic avian influenza viruses bearing the clade 2.3.4.4 HA gene have been pervasive among domestic poultry and wild birds worldwide since 2014, presenting substantial risks to human and animal health. Continued circulation of clade 2.3.4.4 viruses has resulted in the emergence of eight subclades (2.3.4.4a–h) and multiple distinct antigenic groups. However, the key antigenic substitutions responsible for the antigenic change of these viruses remain unknown. In this study, we analyzed the HA gene sequences of 5713 clade 2.3.4.4 viruses obtained from a public database and found that 23 amino acid residues were highly variable among these strains. We then generated a series of single-amino-acid mutants based on the H5-Re8 (a vaccine seed virus) background and tested their reactivity with a panel of eight monoclonal antibodies (mAbs). Six mutants bearing amino acid substitutions at positions 120, 126, 141, 156, 185, or 189 (H5 numbering) led to reduced or lost reactivity to these mAbs. Further antigenic cartography analysis revealed that the amino acid residues at positions 126, 156, and 189 acted as immunodominant epitopes of H5 viruses. Collectively, our findings offer valuable guidance for the surveillance and early detection of emerging antigenic variants.

Agrifood systems account for 31% of global greenhouse gas emissions. Substantial emissions reduction in agrifood systems is critical to achieving the temperature goal set by the Paris Agreement. A key challenge in reducing GHG emissions in the agrifood value chain is the imbalanced allocation of benefits and costs associated with emissions reduction among agrifood value chain participants. However, only a few studies have examined agrifood emissions reduction from a value chain perspective, especially using dynamic methods to investigate participants' long-term emissions reduction strategies. This paper helps fill this gap in the existing literature by examining the impact of collaborations among agrifood value chain participants on correcting those misallocations and reducing emissions in agrifood systems. We develop a dynamic differential game model to examine participants' long-term emissions reduction strategies in a three-stage agrifood value chain. We use the Hamilton-Jacobi-Bellman equation to derive the Nash equilibrium emissions reduction strategies under non-cooperative, cost-sharing, and cooperative mechanisms. We then conduct numerical analysis and sensitivity analysis to validate our model. Our results show that collaboration among value chain participants leads to higher emissions reduction efforts and profits for the entire value chain. Specifically, based on our numerical results, the cooperative mechanism results in the greatest emissions reduction effort by the three participants, which leads to a total that is nearly three times higher than that of the non-cooperative mechanism and close to two times higher than the cost-sharing mechanism. The cooperative mechanism also recorded the highest profits for the entire value chain, surpassing the non-cooperative and cost-sharing mechanisms by around 37% and 16%, respectively. Our results provide valuable insights for policymakers and agrifood industry stakeholders to develop strategies and policies encouraging emissions reduction collaborations in the agrifood value chain and reduce emissions in the agrifood systems.

Objective. To evaluate whether postoperative adjuvant treatment is beneficial for patient survival after surgery for early stage endometrial cancer (EC). We analyzed the outcomes of patients treated with radiotherapy, chemotherapy, or progestagen combined with other adjuvant treatments. Methods. We analyzed the outcomes of patients treated with radiotherapy alone, chemotherapy alone, or progestagen treatment with other adjuvant treatments. Women without any adjuvant treatment after operation were used as controls. We retrospectively examined disease-free survival (DFS), overall survival (OS), and high-risk factors that affected the survival status of all patients who received different postoperative adjuvant therapies. Results. In all 192 patients, the total relapse and mortality rates were 5.57% and 1.68%, respectively. Fourteen patients (7.29%) developed isolated local recurrence, and 2 patients died (1.04%) of recurrence during the follow-up period. The 5-year DFS and OS rates of all patients were 95.83% and 93.75%, respectively. No significant differences were observed in the 5-year DFS, 5-year OS, OS, or DFS among the four groups of patients with FIGO stage I endometrial cancer (P=0.9849, 0.7430, 0.9754, and 0.4534, respectively). The differences in the log-rank test results of the estimates of the 5-year DFS, 5-year OS, DFS, and OS of patients with different disease stages and different ages were all significant, but no differences were observed in these parameters among patients with varying degrees of differentiation. Histologic grade, CA125 level, ER and PR status, and adjuvant therapy had no significant effect on the DFS and OS of all patients according to univariate and multivariate regression analyses, but a significant effect on DFS and OS was found when the patients were stratified by age. Conclusion. This retrospective study showed that adjuvant therapy after surgery was not significantly associated with improved DFS or OS in patients with early stage endometrial cancer. However, FIGO stage and age affected the survival of patients with stage I endometrial cancer.

ABSTRACT H16 avian influenza viruses mainly circulate in wild migratory gulls worldwide, and the infection risks in poultry and mammals remain largely unknown. In this study, we isolated a novel H16N3 virus from migratory gulls in eastern China in 2021. Genetic analysis indicated that the H16N3 virus originated from the H16 and H13 viruses that circulated in wild birds. This H16N3 virus has not adapted to replicate in chickens, ducks, or mice, although it can be transmitted between inoculated and contacted birds. The circulation of H16Nx viruses in the Northern Hemisphere indicates that we should strengthen active surveillance to monitor their prevalence and evolution in migratory gulls and their introduction into other migratory and domestic waterfowl. IMPORTANCE Migratory wild birds are natural reservoirs of H16 viruses and play a key role in the global prevalence of these viruses. Here, we found that H16 viruses predominantly circulate in migratory gulls and that the gull H16N3 virus cannot replicate efficiently in chickens, ducks, or mice without prior adaptation. These findings contribute to our understanding of the ecology, evolution, and biological properties of H16 viruses and will guide avian influenza surveillance in birds.

BackgroundA systematic analysis of prognostic factors concerning endometrial clear cell carcinoma (ECCC) is lacking. The current study aimed to construct nomograms predicting the overall survival (OS) of ECCC patients.MethodsWe performed a retrospective study, and predicted nomograms for 3-, 5-, and 10-year OS were established. The nomograms were verified with the consistency index (C-index), calibration curve, and decision curve analysis (DCA).ResultsA total of 1778 ECCC patients, 991 from FIGO stage I/II and 787 from FIGO stage III/IV, were included in this study. The age at diagnosis, marital status, T stage, tumor size, and surgery-independent prognostic factors in FIGO stage I/II, and the age at diagnosis, T stage, lymph node involvement, distant metastasis, tumor size, surgery, radiotherapy, and chemotherapy in FIGO stage III/IV were independent prognostic factors. The C-indexes of the training and validation group were 0.766 and 0.697 for FIGO stage I/II and 0.721 and 0.708 for FIGO stage III/IV, respectively. The calibration curve revealed good agreement between nomogram-predicted and actual observation values. The DCA established that nomograms had better clinical benefits than the traditional FIGO stage.ConclusionsThe predicted nomograms showed good accuracy, excellent discrimination ability, and clinical benefits, depicting their usage in clinical practice.

Abstract Background Microparticles (MPs) are extracellular vesicles that are associated with cancer development and progression. Advanced non-small cell lung cancer (NSCLC) still shows disease progression after multiple lines of treatment. Therefore, the objective of this study was to explore the correlation between circulating MPs and disease progression in advanced NSCLC, and to find a new method for concise and rapid determination of disease progression. Methods Patients with advanced NSCLC admitted to hospital between October 2019 and October 2020 were included and divided into objective remission (OR) and progressive disease (PD) groups. The morphology of MPs was observed using transmission electron microscopy. The circulating total MPs, neutrophil MPs (NMPs), and platelet MPs (PMPs) before and after treatment were detected by flow cytometry, and a predictive model for disease progression in advanced NSCLC was developed. Results Eighty-six patients were included; 60 in the OR group and 26 in the PD group. There was no significant difference in total MPs, NMPs, or PMPs at baseline between the two groups. After treatment, total MPs, NMPs, and PMPs were significantly higher in the PD than those in the OR group. Multivariate regression analysis showed that post-treatment NMPs≥160 events/μL(OR,3.748;95%CI,1.147–12.253,p = 0.029), PMPs≥80 events/μL(OR,10.968;95%CI,2.973–40.462,p < 0.0001) and neutrophil/lymphocyte ratio (NLR) ≥3.3 (OR,4.929;95%CI,1.483–16.375,p = 0.009) were independently associated with progression of advanced NSCLC. Post-treatment NMPs and PMPs combined with NLR were used to build a predictive model for progression of advanced NSCLC. The area under the curve was 0.825 (95%CI,0.715–0.934, p < 0.0001), optimal cut-off value was 16, sensitivity was 80.8%, and specificity was 88.3%. Conclusion NMPs and PMPs are associated with progression of advanced NSCLC. The predictive model for progression of advanced NSCLC, established combining NMPs, PMPs, and NLR, can screen out 80.8% of patients with PD. This is helpful for real-time accurate, concise and rapid assessment of disease progression and timely adjustment of drug therapy. Trial registration Chinese Clinical Trial Registry, ChiCTR1800020223 . Registered 20 December 2018, http://www.chictr.org.cn/index.aspx .

Objectives: This study aimed to determine the genetic environment of antimicrobial resistance genes in Proteus mirabilis strain STP3 isolated from a diarrhoeic pig on a swine farm in Sichuan Province, China. Methods: Strain STP3 was subjected to antimicrobial susceptibility testing. Illumina MiSeq (200× coverage) and Nanopore PromethION (100× coverage) platforms were used for genome sequencing. A conjugation experiment was performed to determine the transferability and stability of antimicrobial resistance genes in this strain. Results: The assembled circular genome of P. mirabilis STP3 was 4 115 975 bp with a GC content of 39.58%; no plasmid sequence was detected. A novel genomic resistance island (PmGRI1-STP3) and an SXT/R391 integrative conjugative element (ICE) variant (ICEPmiChnSTP3) were characterised in P. mirabilis STP3. PmGRI1-STP3 of 52.7 kb was located at the 3′ end of tRNA-Sec and shared the greatest identity with PmGRI1-C55 (54% coverage, 99.99% identity). PmGRI1-STP3 carried 16 resistance genes, including the clinically important extended-spectrum β-lactamase (ESBL) gene blaCTX-M-3. ICEPmiChnSTP3 was inserted into the prfC gene. It carried 18 resistance genes, including the rRNA methyltransferase gene cfr and the fluoroquinolone resistance gene aac(6′)-Ib-cr. A class 2 integron (dfrA1–sat2–aadA1) was also identified on transposon Tn7. Mobilisation experiments indicated that ICEPmiChnSTP3 was conjugally mobilised to Escherichia coli. However, PmGRI1-STP3 appeared to lose its mobilisation ability. Conclusion: The identification of two genomic islands (GIs) in this study suggested that genetic elements might be key mediators for resistance gene acquisition in P. mirabilis and that IS26-mediated rearrangements promote the diversity of GIs.

BackgroundAntimicrobial resistance to metronidazole has emerged after several decades of worldwide use of the drug. The purpose of this study was to evaluate the effectiveness, safety and population pharmacokinetics of morinidazole plus levofloxacin in adult women with pelvic inflammatory disease (PID).MethodsPatients in 30 hospitals received a 14-day course of 500 mg intravenous morinidazole twice daily plus 500 mg of levofloxacin daily. A total of 474 patients were included in the safety analysis set (SS); 398 patients were included in the full analysis set (FAS); 377 patients were included in the per protocol set (PPS); 16 patients were included in the microbiologically valid (MBV) population.ResultsThe clinical resolution rates in the FAS and PPS populations at the test of cure (TOC, primary effectiveness end point, 7–30 days post-therapy) visit were 81.91 and 82.49% (311/377), respectively. There were 332 patients who did not receive antibiotics before treatment, and the clinical cure rate was 82.83%. Among 66 patients who received antibiotics before treatment, 51 patients were clinically cured 7–30 days after treatment, with a clinical cure rate of 77.27%. The bacteriological success rate in the MBV population at the TOC visit was 87.5%. The minimum inhibitory concentration (MIC) values of morinidazole for use against these anaerobes ranged from 1 to 8 μg/mL. The rate of drug-related adverse events (AEs) was 27.43%, and no serious AEs or deaths occurred during the study.ConclusionsThe study showed that treatment with a 14-day course of intravenous morinidazole, 500 mg twice daily, plus levofloxacin 500 mg daily, was effective and safe. The results of this study were consistent with the results of a phase III clinical trial, which verified the effectiveness and safety of morinidazole.

ObjectiveThe study was designed to explore the evolution of non-small cell lung cancer (NSCLC) management in the last 20 years.MethodsThe top 100 most-cited papers on NSCLC treatment were retrieved from the Web of Science Core Collection database. R and VOSviewer were used to extract bibliographic information, including the year of publication, countries/regions, institutions, authors, journals, keywords, impact factor, and total citations. The topic and type of papers were checked independently by authors. Bibliometric analysis was conducted and visualized with R, CiteSpace, Excel and VOSviewer to identify output dynamics, research forces, topics, hotspots, and frontiers in the field.ResultsThe average citation of each retrieved top 100 most-cited NSCLC management papers was 1,725 (range: 615-7,340). Fifty-seven corresponding authors were from the United States. This country contributed the most papers (n=76), followed by Germany (n=34), France (n=33), and South Korea (n=32). The top contributors were Paz-Ares L. (n=12) and Reck M. (n=12). The Memorial Sloan Kettering Cancer Center published the largest number of papers (n=20). There were two significant citation paths, indicating publications in medicine/medical/clinical journals primarily cited journals in molecular/biology/genetics fields, partly cited health/nursing/medicine fields. Top-cited papers mainly came from the New England Journal of Medicine (n=33, citations=80,427), followed closely by the Journal of Clinical Oncology (n=28, citations=32,408). “Chemotherapy” (n=36) was the keyword with the greatest frequency of co-occurrence. “Open-label” was the keyword with the strongest burst strength (=4.01), followed by “nivolumab” (=3.85), “blockade” (=2.86), and “efficacy” (=2.85).ConclusionsThe United States as a nation and the Memorial Sloan Kettering Cancer Center as an institute contributed the most to this field. The New England Journal of Medicine is the most eye-catching journal. Hotspots of NSCLC management have almost undergone an evolution from chemotherapy and radiotherapy to targeted therapy to immunotherapy. Molecular/biological/genetic fields become the main research base for NSCLC treatment. Immunotherapy and combination therapy are research frontiers.

ObjectiveIn order to solve the remotely operated vehicle (ROV) motion control being easily influenced by the environment and model uncertainty factors, as it is difficult to achieve the desired control effect, a sliding mode control method of ROV based on a parameter disturbance model is proposed. MethodsOn the base of standard ROV model, taking the external environmental disturbance, and the uncertainty parameter of the model as the model disturbance parameters, the ROV model with parameter disturbance is established, and the depth direction control model is obtained by decoupling the model. Under the new model, the sliding mode controller is designed for the depth determination motion of ROV. The sliding mode controller is designed based on the new model.ResultsThe simulation results show that the sliding mode controller based on the ROV model can control the ROV depth stabily, effectively and efficiently, and the control method can improve the influence of external disturbance and model parameter uncertainty.ConclusionThe design method of the controller can provide a solution to the problem of disturbance and model uncertainty in the ROV control process.

Abstract Background Avian infectious bronchitis virus (IBV) is a gamma coronavirus that severely affects the poultry industry worldwide. Long non-coding RNAs (lncRNAs), a subset of non-coding RNAs with a length of more than 200 nucleotides, have been recently recognized as pivotal factors in the pathogenesis of viral infections. However, little is known about the function of lncRNAs in host cultured cells in response to IBV infection. Results We used next-generation high throughput sequencing to reveal the expression profiles of mRNAs and lncRNAs in IBV-infected HD11 cells. Compared with the uninfected cells, we identified 153 differentially expressed (DE) mRNAs (106 up-regulated mRNAs, 47 down-regulated mRNAs) and 181 DE lncRNAs (59 up-regulated lncRNAs, 122 down-regulated lncRNAs) in IBV-infected HD11 cells. Moreover, gene ontology (GO) and pathway enrichment analyses indicated that DE mRNAs and lncRNAs were mainly involved in cellular innate immunity, amino acid metabolism, and nucleic acid metabolism. In addition, 2640 novel chicken lncRNAs were identified, and a competing endogenous RNA (ceRNAs) network centered on gga-miR-30d and miR-146a-5p was established. Conclusions We identified expression profiles of mRNAs and lncRNAs during IBV infection that provided new insights into the pathogenesis of IBV.

Continuous cuff-less blood pressure (BP) monitoring has become a research hotspot in recent years. Researches have studied the impact of pulse transit time (PTT) and ballistocardiogram (BCG) signals on BP. However, the accuracy of these methods are not high enough to put them into practice on a large scale. In this paper, we propose a new BP estimation model which combines features extracted from electrocardiogram (ECG), BCG and photoplethysmogram (PPG). We calculate several features containing amplitude, time and energy from these three signals and use stepwise regression to select key ones for this combination model. The combination model was examined in 20 young healthy subjects and it presents good results: a correlation coefficient (R) of 0.84 (systolic blood pressure, SBP) and 0.7 (diastolic blood pressure, DBP), a root-mean-squared error (RMSE) of 8.16 mmHg (SBP) and 6.63 mmHg (DBP), and a mean absolute error (MAE) of 6.84 mmHg (SBP) and 5.46 mmHg (SBP). Besides, The PTT-based BP estimation model and BCG-based estimation model are also established in this paper. The comparison of these three models shows that the PPG-ECG-BCG-based model has better performance.

H9N2 avian influenza viruses are widely prevalent in birds and pose an increasing threat to humans because of their enhanced virulence and transmissibility in mammals. Active surveillance on the prevalence and evolution of H9N2 viruses in different avian hosts will help develop eradication measures. We isolated 16 H9N2 viruses from chickens, green peafowls, and wild birds in eastern China from 2017 to 2019 and characterized their comparative genetic evolution, receptor-binding specificity, antigenic diversity, replication, and transmission in chickens and mice. The phylogenetic analysis indicated that the green peafowl viruses and swan reassortant shared the same ancestor with the poultry H9N2 viruses prevalent in eastern China, while the seven wild bird viruses belonged to wild bird lineage. The chicken, peafowl, and swan H9N2 viruses that belonged to the poultry lineage preferentially recognized α-2, 6-linked sialic acids (human-like receptor), but the wild bird lineage viruses can bind both α-2, 3 (avian-like receptor) and human-like receptor similarly. Interestingly, the H9N2 viruses of poultry lineage replicated well and transmitted efficiently, but the viruses of wild bird lineage replicated and transmitted with low efficiency. Importantly, the H9N2 viruses of poultry lineage replicated in higher titer in mammal cells and mice than the viruses of wild birds lineage. Altogether, our study indicates that co-circulation of the H9N2 viruses in poultry, wild birds, and ornamental birds increased their cross-transmission risk in different birds because of their widespread dissemination.

The concept of neurotrophic factor tyrosine kinase receptor (NTRK) fusion tumor has emerged in recent years. Moreover, NTRK fusion is unusual in common tumors but can often be identified in rare tumors. The NTRK fusion cervical or uterine tumors are mainly recognized through case reports due to their extremely low incidence. In this study, we reported a new case of EML4–NTRK3 fusion cervical sarcoma to enhance its recognition. To the best of our knowledge, this is the first case from a Chinese institution. We also conducted a literature review, in which a total of 19 cases of NTRK fusion cervical tumors and 4 cases of uterine tumors were retrieved. We summarized the clinicopathological features, treatment methods, and prognosis of these cases. Based on available information, we observed that surgery and complete excision, if possible, are still the primary modes of therapy. In addition, an increasing number of studies have shown that tropomyosin receptor kinases (TRK) inhibitors can improve the prognosis of cancer patients with NTRK gene fusion, which gives a silver lining for patients with metastatic lesions. We found that age and mitotic rate may be associated with recurrence or metastasis by univariate survival analysis. To draw more convincing conclusions, there is a need to establish an international database of rare cases and aggregate these sporadic cases.

ABSTRACT H10Nx influenza viruses have caused increasing public concern due to their occasional infection of humans. However, the genesis and biological characteristics of H10 viruses in migratory wild birds are largely unknown. In this study, we conducted active surveillance to monitor circulation of avian influenza viruses in eastern China and isolated five H10N4 and two H10N8 viruses from migratory birds in 2020. Genetic analysis indicated that the hemagglutinin (HA) genes of the seven H10 viruses were clustered into the North American lineage and established as a novel Eurasian branch in wild birds in South Korea, Bangladesh, and China. The neuraminidase (NA) genes of the H10N4 and H10N8 viruses originated from the circulating HxN4 and H5N8 viruses in migratory birds in Eurasia. We further revealed that some of the novel H10N4 and H10N8 viruses acquired the ability to bind human-like receptors. Animal studies indicated that these H10 viruses can replicate in mice, chickens, and ducks. Importantly, we found that the H10N4 and H10N8 viruses can transmit efficiently among chickens and ducks but induce lower HA inhibition (HI) antibody titers in ducks. These findings emphasized that annual surveillance in migratory waterfowl should be strengthened to monitor the introduction of wild-bird H10N4 and H10N8 reassortants into poultry. IMPORTANCE The emerging avian influenza reassortants and mutants in birds pose an increasing threat to poultry and public health. H10 avian influenza viruses are widely prevalent in wild birds, poultry, seals, and minks and pose an increasing threat to human health. The occasional human infections with H10N8 and H10N3 viruses in China have significantly increased public concern about the potential pandemic risk posed by H10 viruses. In this study, we found that the North American H10 viruses have been successfully introduced to Asia by migratory birds and further reassorted with other subtypes to generate novel H10N4 and H10N8 viruses in eastern China. These emerging H10 reassortants have a high potential to threaten the poultry industry and human health due to their efficient replication and transmission in chickens, ducks, and mice.

ABSTRACTLethal infection of wild birds with different subtypes of H5 viruses continuously occur. To investigate the genetic evolution and pathogenicity of H5 viruses in wild birds, we performed a detailed genetic and biologic analysis of 27 viruses, including H5N1, H5N2, H5N6, and H5N8 subtypes, that were responsible for avian influenza outbreaks in wild birds in China over the past decade. We found that these 27 viruses, bearing different clades/subclades of HA, were complicated reassortants and formed 12 different genotypes. Ten of the viruses tested were highly pathogenic in chickens, but showed distinct pathotypes in ducks and mice. Five of these 10 viruses, which were all from clade2.3.4.4, could bind human-type receptors. Our findings reveal the diversity of the genetic and biologic properties of H5 viruses circulating in wild birds and highlight the need to carefully monitor and evaluate the risks these viruses pose to animal and public health.

Cancer cachexia (CC) is a complicated metabolic derangement and muscle wasting syndrome, affecting 50–80% cancer patients. So far, molecular mechanisms underlying CC remain elusive. Metabolomics techniques have been used to study metabolic shifts including changes of metabolite concentrations and disturbed metabolic pathways in the progression of CC, and expand further fundamental understanding of muscle loss. In this article, we aim to review the research progress and applications of metabolomics on CC in the past decade, and provide a theoretical basis for the study of prediction, early diagnosis, and therapy of CC.

Butorphanol, a partial agonist of opioid receptor κ 1 receptor, can and is widely used as an analgesic drug to relieve moderate and severe pain in clinic. Osteosarcoma is one of the most common malignant bone tumor in adolescents under the age of 20. To our knowledge no study has investigated the effect of butorphanol on the proliferation of osteosarcoma cells. In this study, The proliferation of osteosarcoma cells was measured by CCK-8 and colony formation assays, and the migration of osteosarcoma cells were detected by scratch and transwell assays. The expression of piRNA was detected by RNA sequencing and real-time PCR. PiRNA mimics or inhibitors have been used to upregulate or inhibit piRNA expression in osteosarcoma cells, respectively. We found that butorphanol, at the concentration of 10ug/ml or higher, could significantly inhibit the proliferation and migration of osteosarcoma cells. Our resuslts indicated that butorphanol promoted the expression of piRNA hsa_piR_006613 and overexpression of piRNA hsa_piR_006613 inhibited the proliferation and migration of osteosarcoma cells. our study also showed that inhibition of the expression of piRNA hsa_piR_006613 could promote the proliferation and migration of osteosarcoma cells. Butorphanol played the regulatory role on osteosarcoma cells in dependent of piRNA hsa_piR_006613. Butorphanol was found to inhibit the proliferation and migration of osteosarcoma cells by promoting piRNA hsa_piR_006613 expression. Bioinformatics analysis showed that hsa_piR_006613 downregulated FN1 protein expression by binding with 3’-UTR of FN1 mRNA. In all, the present research indicated that butorphanol suppresses the proliferation of osteosarcoma by promoting the expression of piRNA hsa_piR_006613, which downregulated the expression of FN1. Has_piR_006613 may become a new therapeutic target for osteosarcoma.

In order to extract gas accurately in Yue Nan coal mine and prevent gas over limit and gas accidents, a combination of theoretical analysis and numerical simulation was used to investigate the height of the overburden caving zone and fracture zone in the working face, using 215102 working face as the engineering background. The results show three key strata in the 215102 working face, namely siltstone, sandy mudstone, and sandy mudstone. The empirical formula’s calculation results are in good accord with the findings of the theoretical analysis, which indicates that the height of the water-conducting fracture zone created by mining in 215102’s working face is 87.35 m. The plastic zone, stress distribution and displacement variation of the model overburden of the working face were analyzed separately in the numerical simulation. The results of the plastic zone simulation show that the caving zone’s maximum height is about 15.96 m, and the fracture zone’s maximum height is approximately 82.39 m. The stress distribution shows that the caving zone’s greatest height is around 13.65 m, while the fracture zone’s maximum height is roughly 77.24 m. The amount of overburden subsidence proves that the caving zone’s maximum height of about 10.08 m, and the fracture zone’s maximum height of approximately 82.69 m. The height of the overburden caving zone and fracture zone of 215102 working face are ultimately found to be 14.02 m and 76.42 m, respectively, based on theoretical analysis, empirical formula calculation, and numerical simulation findings.

The widespread nature and economic importance of Infectious bronchitis virus (IBV) and interactions between IBV and the host immune response remain poorly understood. Understanding the mechanism of virus recognition via innate immunity can help resist IBV invasion. Retinoic acid-induced gene I-like receptor (RLRs) recognize virus RNA in virus infection, and LGP2 is a member of RLRs. According to the current studies, LGP2 exhibited certain inhibition in the virus, and there is a lack of investigation for chicken’s LGP2. It is important to figure out the role of chLGP2 in host immune recognition of IBV. Our results showed that chLGP2 inhibited the proliferation of IBV Beaudette in cells. Also, chLGP2 can identify and combine with IBV RNA. The domains of chLGP2 were separately expressed and inspired by related literature, and the chLGP2 K30A mutant was constructed. Our results suggested its structural integrity and the adenosine triphosphatase (ATPase) activity are critical for IBV inhibiting activity. chTRBP was selected after CO-IP and Mass spectrometry test. We found chTRBP and chLGP2 are the interacting partners and promote mutual expression. Our study showed that chTRBP could also suppress IBV infections via chLGP2, which provided a basis for future innate immunity research for IBV.

Traditional onefold data-driven methods for fault detection in complex process industrial systems with high-dimensional, linear, nonlinear, Gaussian, and non-Gaussian coexistence often have less than satisfactory monitoring performance because only a single distribution of process variables is considered. To address this problem, a hybrid fault detection model based on PCA-KPCA-ICA-KICA-BI (Bayesian inference) is proposed, taking into account the advantages of principal component analysis (PCA), kernel principal component analysis (KPCA), independent component analysis (ICA), and kernel independent component analysis (KICA) in terms of dimensionality reduction and feature extraction. Foremost, this paper proposed a nonlinear evaluation method and divided the feature variables into Gaussian linear blocks, Gaussian nonlinear blocks, non-Gaussian linear blocks, and non-Gaussian nonlinear blocks by using the Jarque–Bera (JB) test and nonlinear discrimination method. Each division was monitored by the PCA-KPCA-ICA-KICA model, and finally the Bayesian fusion strategy proposed in this study is used to synthesize the detection results for each block. The hybrid model helps in evaluating variable features and bettering detection performance. Ultimately, the superiority of this hybrid model was verified through the Tennessee Eastman (TE) process and the Continuous Stirred Tank Reactor (CSTR) process, and the fault monitoring results showed an average accuracy of 85.91% for this hybrid model.

Currently, nucleic acid preparations have gained much attention due to their unique working principle and application value. However, as macromolecular drugs, nucleic acid preparations have complex construction and poor stability. The current methods to promote stability face problems such as high cost and inconvenient operatios. In this study, the hydrophilic pharmaceutical excipient PEG was used to gelate nucleic acid preparations to avoid the random movements of liquid particles. The results showed that PEG gelation significantly improved the stability of PEI25K−based and liposome−based nucleic acid preparations, compared with nucleic acid preparations without PEG gelation. After being stored at 4 °C for 3 days, non−PEG gelled nucleic acid preparations almost lost transfection activity, while PEGylated preparations still maintained high transfection efficiency. Fluorescence experiments showed that this effect was caused by inhibiting particle aggregation. The method described in this study was simple and effective, and the materials used had good biocompatibility. It is believed that this study will contribute to the better development of gene therapy drugs.

Oxidative stress initiated by reactive oxygen species (ROS) is the cause of many acquired or congenital skin diseases. Oral antioxidants or using topical antioxidants preparations may bring the nonspecific distribution of drugs or anaphylaxis due to repeated use. In this study, a biocompatible gene vector by cross-linking of chitosan-oligosaccharide (CSO) and N,N’-cystamine-bis-acrylamide (CBA) was synthesized (CSO-CBA), which could carry therapeutic genes into the skin, express functional proteins in epidermal cells, and play an efficient antioxidant effect. Infrared and 1H NMR spectrum data showed that CSO-CBA was successfully synthesized. Gel electrophoresis results showed that the gene could be successfully compressed by the carrier and can be released in a reducing environment. Hemolysis experiments showed that the carrier had good biocompatibility. Transdermal gene delivery experiments proved that the vector can bring genes into the skin, express functional proteins, and protect the skin from reactive oxygen species damage after 7 days of administration. Skin compatibility experiments show that our therapy is biocompatible. Our study provides a minimally invasive and painless, high-biocompatibility, and long-term effective treatment for skin damage caused by reactive oxygen species, which has a potential application.

With the increasing number of drug-resistant bacteria, there is an urgent need for new antimicrobial agents, and antimicrobial peptides (AMPs), which exist in the human non-specific immune system, are one of the most promising candidates. It is an effective optimization strategy to modify antimicrobial peptides (AMPs) according to the distribution of amino acids and hydrophobic characteristics. The addition of bacterial pheromones to the N short peptide can increase the ability to recognize bacteria. In this study, we designed and synthesized AMP1–6 by amino acid substitution of mBjAMP1. Additionally, P-6, S-6, and L-6 were designed and synthesized by adding bacterial pheromones based on 1–6. Functional tests showed that the four AMPs had the ability to kill Gram-negative Vibrio anguillarum, Pseudomonas mendocina, and Vibrio parahaemolyticus, and Gram-positive Micrococcus luteus and Listeria monocytogenes. Additionally, all four AMPs induced permeabilization and depolarization of bacterial cell membranes and increased intracellular reactive oxygen species (ROS) levels. Importantly, they had little or no mammalian cytotoxicity. At the same time, 1–6 and L-6 protected the stability of intestinal flora in Sebastes schlegelii and increased the relative abundance of Lactobacillaceae. In summary, our results indicate that the designed AMPs have broad application prospects as a new type of polypeptide antimicrobial agent.