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ABSTRACT The re-emerging human adenovirus (HAdV) types 3, 7, 14, and 55 of species B have caused severe or even fatal acute respiratory disease. Therefore, the development of multivalent vaccines against HAdV types 3, 7, 14, and 55 remains an important goal. In our previous study, we identified a cross-neutralizing epitope that induced broadly reactive monoclonal neutralizing antibodies against the knob proteins of HAdV types 7, 11, 14, and 55. To study the immunogenicity of HAdV species B knob proteins, we evaluated humoral immune responses to the knob proteins in vivo and in vitro. We found that the knob proteins elicited robust binding and neutralizing antibody responses after three immunizations of mice. In addition, mouse antisera raised against the knob proteins exhibited cross-neutralizing activity against original species B members. Furthermore, immunization with a mix of HAdV-3, 7, and 55 knob proteins protected Chinese tree shrews against an experimental HAdV challenge. Our results provide insight into the immunogenicity of HAdV species B knob proteins.IMPORTANCEHuman adenovirus (HAdV) species B are common pathogens causing severe pneumonia in children, and there is currently no vaccine available. Because there are many HAdV species B types, developing broad-spectrum vaccines against HAdV species B is an important research goal. Our study revealed that immunization with recombinant HAdV species B knob proteins effectively elicited cross-neutralizing antibody responses against original species B members with protective immunity. This study provides a novel insight into the immunogenicity of HAdV species B knob proteins.

Abstract To analyze the current status of "pseudo" unplanned endotracheal extubation in ICU patients in China's tertiary hospitals and to provide a reference for improving the quality of medical care. Through the National Nursing Quality Data Platform, unplanned endotracheal extubation data reported by ICUs in China's tertiary hospitals from 2019 to 2022 were analyzed. The situation of reported hospitals, causes, and the current status of "pseudo" unplanned endotracheal extubation in ICU patients was analyzed. The indicator of unplanned endotracheal extubation in ICUs of China’s tertiary hospitals is mainly from first-class tertiary hospitals (74.9%), most of which are self-extractions by patients (74.6%). The proportion of "pseudo" unplanned endotracheal extubation is 45.1%. "Pseudo" unplanned endotracheal extubation is common in the ICUs of China's tertiary hospitals. As such, management blind spots deserve attention from managers and clinical staff.

Pumpkin (Cucurbita moschata Duch.) is a versatile crop with strong stress resistance and promising growth potential. Widely cultivated in various regions of China, it ranks among the top crops globally in terms of both planting area and consumption. Known for its pleasant taste and high nutritional value, pumpkin pulp is rich in essential trace elements for the human body. Even after harvest, pumpkin fruit remains metabolically active, requiring its own nutrients to complete the postripening process. Failure to provide proper postharvest storage conditions can lead to excessive water loss and rapid nutrient depletion, resulting in rough, shriveled, and even rotten peel, ultimately diminishing the economic value of the pumpkin. This study aimed to investigate the changes in pumpkin quality and physiological indicators during storage to provide insights to determine optimal consumption and processing periods of pumpkins. The pumpkins were stored at a temperature of 16 ± 2 °C and 60% to 80% humidity during the experiment. The dynamic changes in fruit quality, hardness, respiration rate, malondialdehyde content, level of antioxidant enzymes, and other indicators of two pumpkin cultivars (BM5 and JQ) were assessed during storage, and the correlation among these indicators was evaluated. The results indicated a decrease in the vitamin C content and pulp hardness, whereas the superoxide dismutase and catalase contents initially increased and then decreased, and malondialdehyde and weight loss rates increased over the storage period. The weight loss rate exhibited significant positive and negative correlations with the malondialdehyde content (P < 0.01) of the two cultivars, whereas the vitamin C content showed a significant positive correlation with pulp hardness (P < 0.01). The findings indicate that optimal fruit quality was maintained within 40 days of postharvest storage. This study provides valuable insights into the selection of storable pumpkin cultivars.

Abstract In this work, we present a metastable helium lidar system for the measurements of metastable helium He(23S) density in the thermosphere and lower exosphere. This lidar system consists of a high power 1,083 nm pulsed laser, a 1 m aperture laser beam expander, six 1 m aperture receiving telescopes and a superconducting nanowire single‐photon detector (SNSPD). This system realizes metastable helium density detection up to 1,000 km. Daily rapid variation of metastable helium density within several hours was measured with a height resolution of 50 km for the first time. It demonstrates the capability of ground‐based lidar for continuous height‐resolved detection of the atmospheric metastable helium in the height range of 200–1,000 km. This is a promising tool to help study the coupling of neutral and ionized atmosphere in this height range and further providing observation basis for space weather prediction.

Human adenovirus (HAdV) type 40 in species F (HAdV-F40) and HAdV-F41 represent the third most prevalent causative agents of non-bacterial acute gastroenteritis in infants and young children, following norovirus and rotavirus. Despite their significant contribution to global child morbidity, vaccines to preemptively combat these viruses remain elusive. In this study, we investigate the potential for cross-neutralization between HAdV-F40 and HAdV-F41 using immune sera with the short fiber knob (SFK). We implemented a series of assays to evaluate the responses, including enzyme-linked immunosorbent, micro-neutralization, immunofluorescence, and quantitative polymerase chain reaction. Our results demonstrate that immune sera with HAdV-F40 SFK or HAdV-F41 SFK could effectively neutralize both HAdV-F40 and HAdV-F41, indicating a mutual cross-neutralizing effect. Notably, the immune sera with HAdV-F40 SFK demonstrated a stronger neutralization effect, suggesting the potential to develop a subunit vaccine that can simultaneously counteract both viruses. These findings underscore the potential of SFK immunization in evoking a cross-neutralizing antibody response between HAdV-F40 and HAdV-F41. This suggests a promising avenue for developing subunit vaccines against HAdV-F40 and HAdV-F41 and provides a novel perspective on the potential of neutralizing antibodies to protect against these two types of HAdV.

Melatonin regulates defense responses in plants under environmental stress. This study aimed to explore the impact of exogenous melatonin on the phenotype and physiology of ‘BM1’ pumpkin seedlings subjected to waterlogging stress. Waterlogging stress was induced following foliar spraying of melatonin at various concentrations (CK, 0, 10, 100, 200, and 300 μmol·L−1). The growth parameters, malondialdehyde (MDA) content, antioxidant enzyme activity, osmoregulatory substance levels, and other physiological indicators were assessed to elucidate the physiological mechanisms underlying the role of exogenous melatonin in mitigating waterlogging stress in pumpkin seedlings. The results indicate that pumpkin seedlings exhibit waterlogging symptoms, such as leaf wilting, water loss, edge chlorosis, and fading, under waterlogging stress conditions. Various growth indicators of the seedlings, including plant height, stem diameter, root length, fresh and dry weight, and leaf chlorophyll content, were significantly reduced. Moreover, the MDA content in leaves and roots increased significantly, along with elevated activities of superoxide dismutase, catalase, peroxidase, and soluble protein contents. When different concentrations of melatonin were sprayed on the leaves post waterlogging stress treatment, pumpkin seedlings showed varying degrees of recovery, with the 100 μmol·L−1 treatment displaying the best growth status and plant morphological phenotypes. There were no significant differences compared to the control group. Seedling growth indicators, chlorophyll content, root activity, antioxidant enzyme activities, soluble protein content, and osmotic adjustment substance content all increased to varying degrees with increasing melatonin concentration, peaking at 100 μmol·L−1. Melatonin also reduced membrane damage caused by oxidative stress and alleviated osmotic imbalance. Exogenous melatonin enhanced the activities of antioxidant enzymes and systems involved in scavenging reactive oxygen species, with 100 μmol·L−1 as the optimal concentration. These findings underscore the crucial role of exogenous melatonin in alleviating waterlogging stress in pumpkins. The findings of this study offer a theoretical framework and technical assistance for cultivating waterlogging-resistant pumpkins in practical settings. Additionally, it establishes a theoretical groundwork for the molecular breeding of pumpkins with increased tolerance to waterlogging.

To expand the channel capacity of a traditional single-polarization reconfigurable antenna, a design method for a dual-polarization reconfigurable microstrip antenna loaded with a passive metasurface was proposed. By utilizing the equivalent circuit method and characteristic modeling analysis, this method can provide guidance for designing an integrated antenna with adjustable dual-polarization. An antenna with an operating frequency of 3.5 GHz is designed, which is composed of four layers, from top to bottom: metasurface layer, radiation patch layer, feed layer, and reflector layer. By rotating the metasurface layer to adjust its relative position with other fixed layers, the designed antenna can achieve a mutual transformation between orthogonal dual-linear polarization (Horizontal polarization/Vertical polarization) and orthogonal dual-circular polarization (Left-handed circular polarization/Right-handed circular polarization), while ensuring antenna performance. The simulation and measurement results of the designed antenna demonstrate that it possesses competitive gain and polarization isolation performance, with a 3 dB axial ratio bandwidth reaching 17.4% in the dual-circular polarization state.

To evaluate the true load-bearing capacity and engineering reliability of a large span through a simply supported steel box arch bridge, a load test was conducted on the bridge. The example used in this test is the Jingchu Avenue Bridge located in Jingmen City, Hubei Province. Specifically, the static load test delineated six operational conditions, measuring parameters encompassing strain, hanger cable force, deflection, and potential cracks. The dynamic load test gauged the bridge’s dynamic response and various indicators, including pulse tests, vehicle tests, jump tests, and barrier-free vehicle tests. The findings indicated that the maximum measured strain values during the static load test surpassed the calculated values; nonetheless, the verification factors and relative residual strains adhered to the code requirements, and no cracks were detected. The dynamic load test unveiled that the measured frequency values exceeded the theoretical ones, the damping ratios were within the normal range, and the measured impact coefficients were lower than the values stipulated in the code, all of which were in conformance with the code requirements. The data obtained from this experiment can be utilized to refine the long-term maintenance plan for the bridge, especially as it holds considerable value for structural health monitoring and aging assessment.

The advancement of urbanization has led to a decline in the ecological function and environmental quality of cities, seriously reducing the services and sustainable development capacity of urban ecosystems. The construction of the National Forest Urban Agglomeration of China is conducive to alleviating the ecological and environmental problems brought about by rapid urbanization and promoting sustainable urban development. A time series analysis of ecological network changes can quickly and effectively explore the development and changes of ecological spatial patterns over time. Identifying ecological protection and restoration areas in urban agglomerations is an important way to promote ecosystem restoration and optimize ecological networks. This paper takes the Pearl River Delta forest urban agglomeration as the research area, uses multi-source remote sensing data from 2000 to 2020 (every 5 years), identifies ecological sources based on the morphological spatial pattern analysis (MSPA) method, generates ecological corridors based on the minimum cumulative resistance (MCR) model, constructs a time series ecological network pattern in the Pearl River Delta region, and analyzes the evolution process of the ecological network pattern over time. The results indicate that over time, the core green area in the ecological network pattern of the Pearl River Delta first decreased and then increased, and the complexity of ecological corridors first decreased and then increased. The main reason is that the urbanization process in the early 21st century led to severe ecological fragmentation. Under the promotion of the national forest urban agglomeration construction, the ecological network pattern of the Pearl River Delta was restored in 2015 and 2020. The time series analysis of the ecological network pattern in the Pearl River Delta region of this research confirms the effectiveness of the construction of forest urban agglomerations, providing a scientific reference for the identification of ecological networks and optimization of spatial patterns in forest urban agglomerations.

Abstract Bronchiolitis obliterans (BO) is a chronic airway disease that was often indicated by the pathological presentation of narrowed and irreversible airways. However, the molecular mechanisms of BO pathogenesis remain unknown. Although neutrophil extracellular traps (NETs) can contribute to inflammatory disorders, their involvement in BO is unclear. This study aims to identify potential signaling pathways in BO by exploring the correlations between NETs and BO. GSE52761 and GSE137169 datasets were downloaded from gene expression omnibus (GEO) database. A series of bioinformatics analyses such as differential expression analysis, gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), and gene set enrichment analysis (GSEA) were performed on GSE52761 and GSE137169 datasets to identify BO potential signaling pathways. Two different types of BO mouse models were constructed to verify NETs involvements in BO. Additional experiments and bioinformatics analysis using human small airway epithelial cells (SAECs) were also performed to further elucidate differential genes enrichment with their respective signaling pathways in BO. Our study identified 115 differentially expressed genes (DEGs) that were found up-regulated in BO. Pathway enrichment analysis revealed that these genes were primarily involved in inflammatory signaling processes. Besides, we found that neutrophil extracellular traps (NETs) were formed and activated during BO. Our western blot analysis on lung tissue from BO mice further confirmed NETs activation in BO, where neutrophil elastase (NE) and myeloperoxidase (MPO) expression were found significantly elevated. Transcriptomic and bioinformatics analysis of NETs treated-SAECs also revealed that NETs-DEGs were primarily associated through inflammatory and epithelial-to-mesenchymal transition (EMT) -related pathways. Our study provides novel clues towards the understanding of BO pathogenesis, in which NETs contribute to BO pathogenesis through the activation of inflammatory and EMT associated pathways. The completion of our study will provide the basis for potential novel therapeutic targets in BO treatment.

Water conservation is an essential parameter for maintaining the ecological balance. The Three-River Source Region (TRSR) cannot be an exception, since it is one of the most influential water conservation reserves in the Qinghai–Tibet Plateau in China. Therefore, the realization of its scientific significance can determine its future regional sustainable development and the optimal allocation of water resources. The study of the past is critical to predict the future temporal and spatial changes in the water conservation of the TRSR. The first task of this study was to obtain the optimal runoff simulations in the TRSR from 1981 to 2014 by calibrating the adjustable the parameters of the Soil and Water Assessment Tool (SWAT) model. Then, the water conservation of the TRSR from 1981 to 2014 was quantified. Finally, the future water conservation of the TRSR was also predicted using the optimal SWAT model. The predication took into consideration the three terms including the near-term (2015–2044), mid-term (2045–2074), and long-term (2075–2099) in three different climate scenarios of SSP1-1.9 (SSP119), SSP2-4.5 (SSP245), and SSP5-8.5 (SSP585). The main findings are as follows: (1) both the coefficient of determination (R2) and Nash–Sutcliffe efficiency coefficient (NSE) for runoff simulation on the three sub-basins reached above 0.78 during the calibration and validation periods, which indicates the reasonableness of the SWAT model in the TRSR. (2) From 1981 to 2014, the water conservation capacity of the TRSR showed an increasing trend (0.5135 mm/year), and its changes had significant positive correlations with precipitation and temperature. The Yellow River Source (YR) and the Yangtze River Source (YZ) had the strongest and weakest water conservation capacities, respectively. (3) From 2015 to 2099, the water conservation in the TRSR in the SSP119, SSP245, and SSP585 scenarios decreased first and then increased, increased first and then decreased, and increased steadily, respectively.

In this paper, molecular dynamics (MD) simulation was employed to systematically study the tensile deformation behaviors of nano-polycrystalline Cu, nano-polycrystalline Al, nano-polycrystalline Cu/Al, and nano-polycrystalline Cu/Al2Cu/Al models. The influence of interfacial compound Al2Cu on the deformation behavior of nano-polycrystalline Cu/Al2Cu/Al layered composite was analyzed in-depth. The results show that the grain boundary sliding dominates the tensile deformation of nano-polycrystalline Al. In contrast, the emergence of a significant number of deformed twins under the 1/6 Shockley dislocation dominates the tensile deformation of nano-polycrystalline Cu. The strength and toughness of the Cu/Al2Cu/Al model when Al2Cu was added as the interfacial layer are superior to those of nano-polycrystalline Cu/Al without Al2Cu. This is mainly because the Al2Cu interfacial layer could form gradient strain at the interface structure while narrowing the ductility consumption gap between the matrix Cu and Al in Cu/Al2Cu/Al model. Furthermore, Al2Cu is a distinctive interfacial layer that has the unique capacity to annihilate dislocations and prevent dislocation expansion in Cu/Al2Cu/Al. So, the interface layer Al2Cu plays a decisive role in effectively preventing microcrack propagation in the Cu/Al2Cu/Al model and promoting the co-deformation between the matrix Cu and Al. This work could provide a design criterion for fabricating Cu/Al layered composite with excellent strength-toughness synergy.

To enhance heat and fluid exchange between main flow and near-wall flow in microchannels, a twisted blade-like fin with an advantage in stimulating both spanwise and normalwise secondary flow is proposed. The cross sections of the fin are low-drag airfoils in different orientations. The flow and heat transfer performances of microchannels with fins are numerically investigated at Re = 50–700. The results show that the twisted blade-like fin improves heat transfer process significantly, especially wall temperature uniformity, and reduces the flow separation region behind the fin, resulting in an obvious small pressure penalty. At small inflow (Re = 50), the best heat transfer and lowest pressure penalty are obtained in the microchannel with a single fin. When Re > 150, better heat transfer is obtained in the microchannel with three fins, and the highest comprehensive thermal performance (TP) reaches 3.58. The twisted direction of fins has a significant effect on heat transfer but less on flow drag. Due to the twisted fins, left and right walls experience an overall decline in temperature, and the temperature uniformity of top and bottom walls is improved. Compared with a smooth microchannel, the average and maximum temperature of the investigated microchannels are reduced by 48.1 K and 49.0 K at most respectively.

The metal–organic framework (MOF) materials with significant steadiness and a large specific surface area have been popular with supercapacitor material in recent years. However, its application in supercapacitors is restricted due to the low specific capacitance and poor conductivity. Herein, sulfur compounds with a high theoretical specific capacitance and highly conductive titanium nitride (TiN) were introduced into Co-based metal–organic frameworks/nickel foam (Co-MOF/NF) through a two-step hydrothermal technique (nickel sulfide/titanium nitride@ Co-based metal–organic frameworks/nickel foam). In detail, the fabricated nickel sulfide/titanium nitride@Co-based metal–organic frameworks/nickel foam (Ni3S2/TiN@Co-MOF/NF) electrode material exhibits a markedly high specific capacitance (2648.8 F g−1) at 1 A g−1, compared with that (770 F g−1) of the precursor Co-MOF/NF. And its mass specific capacitance is retained 88.3% (8 A g−1) after 5000 cycles. Furthermore, a non-symmetrical supercapacitor (ASC) composed of Ni3S2/TiN@Co-MOF/NF and AC exhibits excellent power density (801.8 W kg−1) and energy density (97.8 W h kg−1). Therefore, Ni3S2/TiN@Co-MOF/NF with excellent electrochemical properties and stability provides new ideas for the development of excellent supercapacitor electrode materials.

Measurements of atmosphere density in the upper thermosphere and exosphere are of great significance for studying space–atmosphere interactions. However, the region from 200 km to 1000 km has been a blind area for traditional ground-based active remote sensing techniques due to the limitation of facilities and the paucity of neutral atmosphere. To fulfill this gap, the University of Science and Technology of China is developing a powerful metastable helium resonance fluorescent lidar incorporating a 2 m aperture telescope, a high-energy 1083 nm pulsed laser, as well as a superconducting nanowire single-photon detector (SNSPD) with high quantum efficiency and low dark noise. The system is described in detail in this work. To evaluate the performance of the lidar system, numerical simulation is implemented. The results show that metastable helium density measurements can be achieved with a relative error of less than 20% above 370 km in winter and less than 200% in 270–460 km in summer, demonstrating the feasibility of metastable helium lidar.

Background To satisfy the pharmaceutical care needs of a growing number of patients seeking healthcare in primary care, it is increasingly important to integrate family doctor teams as providers of such care services, while the way bringing the strength of the teams into full play needs to be further explored. Objective To understand the needs of pharmaceutical care services in the community of Shanghai, providing a reference for improving the way of integrating community pharmacists into a family doctor team for delivering such services. Methods This study was conducted from September to December in 2020. Multistage sampling was used to select 349 elderly patients with chronic diseases in the community and 855 main members of family doctor teams〔general practitioners (n=481) , nurses (n=234) , and public health doctors (n=140) 〕 for questionnaire survey. The questionnaire for the patients mainly includes demographics, chronic condition, use of medications, needs and utilization of community-based pharmaceutical care. And the questionnaire for family doctor team members mainly contains demographics, understanding of community-based pharmaceutical care, and pharmaceutical services preferred to be involved in as a provider. Results According to the survey results, the prevalence of three or more chronic diseases, and needing to take medications two or more times a day was 35.8% (125/349) , and 87.4% (305/349) , respectively. Among medication management services, "medication re-prescribing and follow-up" was the most needed〔14.9% (52/349) 〕, and "medication follow-up" was the most used〔14.0% (49/349) 〕. Among medication education services, "universal education on medication cautions for chronic conditions" was the most needed〔70.8% (247/349) 〕, and "healthy lifestyle promotion" was the most used〔9.4% (33/349) 〕. Among family doctor team members, 440 (91.5%) general practitioners, 202 (86.3%) nurses and 112 (80.0%) public health doctors expressed that they had an understanding of pharmaceutical care. In terms of the level of trust in pharmacists, the self-reported level of 302 (62.8%) general practitioners, 183 (78.2%) nurses, and 103 (73.6%) public health doctors was high. The number of general practitioners, nurses, and public health doctors wanting to be involved in "assisting physicians in providing medication selection and use services" was 359 (74.6%) , 112 (47.9%) , and 81 (57.8%) , respectively. The number of general practitioners, nurses, and public health doctors wanting to be involved in "providing nurses with guidance on medication use and management" was 190 (39.5%) , 153 (65.4%) and 57 (40.7%) , respectively. Conclusion Elderly patients with chronic diseases were in urgent need of medication management services, and more medication education services. However, the strength of pharmaceutical professional workforce in the community was weak, and family doctor team members had limited understanding of community-based pharmaceutical services. To efficiently provide residents with such services, it is suggested to train family doctor team members with relevant trainings by pharmaceutical professionals to improve their understanding level and service capability regarding pharmaceutical services at the individual and team levels.

Clarifying the spatio-temporal patterns of ecosystem services trade-off/synergy relationships (ESTSs) and their attribution in the Yellow River Basin is crucial to constructing ecological civilization in China. This study first analyzed the spatio-temporal change of ecosystem services (ESs) including the water yield, soil conservation, carbon sequestration, and habitat quality in the Yellow River Basin during 2000–2020 based on the InVEST and RUSLE models. Then, the spatial autocorrelation methods were used to quantify the spatio-temporal differentiation of ESTSs, and the Geo-detector method was employed to identify the contributions of driving factors associated with the natural, social-economic, and regional policy aspects of the ESTSs. Finally, the random forest and analysis of variance methods were used to validate the reasonability of major driving factors obtained by the Geo-detector. The main findings include: (1) In 2000–2020, water yield, soil conservation, and habitat quality increased, and carbon sequestration decreased. The ESs had a spatial pattern of high in the east and low in the west. (2) Overall, there were synergistic relationships between the four Ess. In the spatial distribution of ESTSs, the expansion of the synergy zone and trade-off zone occupied the majority. The synergy zones tended to be concentrated in the northwest and southeast of the study area. In contrast, the trade-off zones were more scattered than the synergy zone, mainly focused on the east-central and southwestern parts of the Yellow River Basin. (3) Geo-detector and random forest both showed that natural factors had a strong explanatory power on ESTSs, in which NDVI is a key driver. Both the results of Geo-detector and the analysis of variance showed that the interactions between natural factors exerted the most significant influence on ESTSs, followed by the interaction between natural factors and socio-economic factors.

The open-source software platform hosts a large number of software defects, and the task of relying on administrators to manually assign developers is often time consuming. Thus, it is crucial to determine how to assign software defects to appropriate developers. This paper presents DARIP, a method for assigning developers to address software defects. First, the correlation between software defects and issues is considered, predicting related issues for each defect and comprehensively calculating the textual characteristics of the defect using the BERT model. Second, a heterogeneous collaborative network is constructed based on the three development behaviors of developers: reporting, commenting, and fixing. The meta-paths are defined based on the four collaborative relationships between developers: report–comment, report–fix, comment–comment, and comment–fix. The graph-embedding algorithm metapath2vec extracts developer characteristics from the heterogeneous collaborative network. Then, a classifier based on a deep learning model calculates the probability assigned to each developer category. Finally, the assignment list is obtained according to the probability ranking. Experiments on a dataset of 20,280 defects from 9 popular projects show that the DARIP method improves the average of the Recall@5, the Recall@10, and the MRR by 31.13%, 21.40%, and 25.45%, respectively, compared to the state-of-the-art method.

In this work, the first-principles calculation was performed to investigate the effect mechanism of Zn, Ni and Mn solute elements on the WC/Cu-based filler metal interfacial properties, and the CuZnNiMn filler metal was designed, the diffusion behavior of interface elements was verified by experiments. Firstly, Zn, Ni and Mn element doping WC/Cu interface models were established respectively. The effect natures of alloying elements on the interfacial properties were explored by adhesive strength and interfacial electronic structure. The results show that Zn element slightly aggregate into the Cu matrix interior after full relaxation, which has little effect on the interface structure, but it can lower the melting point and optimize the properties of Cu-based filler metals. Ni, Mn elements tend to segregate toward the interface and form strong covalent bonds and metallic bonds with W atoms, which can significantly improve the interfacial bonding strength of WC/Cu. The Energy Dispersive Spectroscopy (EDS) analysis of the WC/CuZnNiMn interface region proves that the diffusion effect of Zn in the interface is not obvious, while the Ni and Mn elements strongly diffuse into the WC particle, which has a positive effect on the metallurgical bonding of the brazed joint.

Periodontitis is an inflammatory disease that is characterized by progressive destruction of the periodontium and causes tooth loss in adults. Periodontitis is known to be associated with dysbiosis of the oral microflora, which is often linked to various diseases. However, the complexity of plaque microbial communities of periodontitis, antibiotic resistance, and enhanced virulence make this disease difficult to treat. In this study, using metagenomic shotgun sequencing, we investigated the etiology, antibiotic resistance genes (ARGs), and virulence genes (VirGs) of periodontitis. We revealed a significant shift in the composition of oral microbiota as well as several functional pathways that were represented significantly more abundantly in periodontitis patients than in controls. In addition, we observed several positively selected ARGs and VirGs with the Ka/Ks ratio > 1 by analyzing our data and a previous periodontitis dataset, indicating that ARGs and VirGs in oral microbiota may be subjected to positive selection. Moreover, 5 of 12 positively selected ARGs and VirGs in periodontitis patients were found in the genomes of respiratory tract pathogens. Of note, 91.8% of the background VirGs with at least one non-synonymous single-nucleotide polymorphism for natural selection were also from respiratory tract pathogens. These observations suggest a potential association between periodontitis and respiratory infection at the gene level. Our study enriches the knowledge of pathogens and functional pathways as well as the positive selection of antibiotic resistance and pathogen virulence in periodontitis patients, and provides evidence at the gene level for an association between periodontitis and respiratory infection.

Waterlogging caused by short and severe, or prolonged precipitation can be attributed to global warming. Pumpkin plants are drought-tolerant but not tolerate to waterlogging stress. Under frequent rain and waterlogging conditions, the production of pumpkins is of lower quality, sometimes rotten, and harvest failure occurs in severe cases. Therefore, it is of great significance to assess the waterlogging tolerance mechanism of pumpkin plants. In this study, 10 novel pumpkin varieties from Baimi series were used. The waterlogging tolerance level of pumpkin plants was evaluated by measuring waterlogging tolerance coefficient of biomass and physiological indices using waterlogging stress simulation method. The criteria to evaluate the waterlogging tolerance capacities of pumpkin plants were also explored. Using principal component and membership function analysis, waterlogging tolerance levels of the pumpkin varieties were ranked as follows: Baimi No. 10>; Baimi No. 5>; Baimi No. 1>; Baimi No. 2>; Baimi No. 3>; Baimi No. 7>; Baimi No. 9>; Baimi No. 6>; Baimi No. 4>; Baimi No. 8. Based on the results, Baimi No. 10 was identified with strong waterlogging tolerance and Baimi No. 8 with weak waterlogging tolerance. The responses of malondialdehyde (MDA), proline, key enzymes responsible for anaerobic respiration, and antioxidant enzymes to waterlogging stress were studied in pumpkin plants. The relative expression levels of related genes were determined using real-time fluorescence quantitative PCR technique. The aim of our study was to assess the waterlogging tolerance mechanism of pumpkin plants, thus laying a theoretical foundation for breeding waterlogging-tolerant varieties in the future. After flooding stress treatment, the antioxidant enzyme activities, contents of proline and alcohol dehydrogenases of Baimi No. 10 and Baimi No. 8 displayed an increase followed by a decrease. All indices of Baimi No. 10 were higher than Baimi No. 8. MDA contents gradually increased, with the content being higher in Baimi No. 8 than Baimi No. 10. The activities of pyruvate decarboxylases (PDCs) in Baimi No. 8 and Baimi No. 10 exhibited a decrease initially, followed by an increase, and then a decrease again. The PDC activity in Baimi No. 8 was generally higher than Baimi No. 10. The relative expression levels of genes encoding superoxide dismutase, peroxidase, catalase, and ascorbate peroxidase were consistent with their corresponding enzyme activities. During the early stage of flooding stress, pumpkin plants waterlogging tolerance was improved by enhancing the expression levels of antioxidant enzyme encoding genes and increasing the antioxidant enzyme activities.

Transitioning to an asset-light strategy is a significant shift for tourism companies in light of the global COVID-19 outbreak. This study investigates the impact of asset-light strategy on corporate performance using a sample of 588 firm-year observations from China A-share publicly traded tourism companies from 2003 to 2021. Using two-way fixed effects models, our results indicate that adopting an asset-light strategy can significantly improve the performance of tourism enterprises. We further verify that this influence mechanism is supply chain management using path analysis. More interestingly, the positive impact of asset-light strategy on enterprise performance is particularly significant in non-state-owned enterprises. Robustness tests with the system GMM method, the variable substitution method and the two-stage instrumental variables method support our main findings. The findings have significant ramifications for assisting the tourism industry, managers, and investors to strategically cope with settings that are complex and dynamic.

Clay soil has poor engineering properties such as poor permeability and low shear strength. Waste steel slag is an industrial by-product formed in the furnace during the steelmaking process which has high quality, durability, anti-slip properties, gelling, high permeability and good particle interlocking properties. Therefore, in order to improve the engineering properties of clay and increase the utilization rate of waste steel slag, the steel slag was mixed into the clay. Steel slag clay mix was used for the straight shear test, cyclic shear test and post-cyclic straight shear test. To investigate the strength characteristics, damping ratio, shear stiffness variation and mixed soil displacement at the reinforcement-soil interface under different steel slag dosing, vertical stress, moisture content and shear amplitude conditions. The test results show that steel slag can significantly improve the shear strength of the clay tendon-soil interface, and the improvement effect is better than the conventional material sand improved clay. The steel slag mix has a large damping ratio and shear stiffness, suggesting that it has good damping and energy dissipation properties. In this case, the shear strength, damping ratio and shear stiffness of the soil mix at 40% steel slag admixture are better. The shear strength of the steel slag mix is increased after cyclic loading compared to straight shear before cyclic loading. In addition, the water content has a greater effect on the shear strength parameters, shear stiffness and damping ratio of the steel slag clay mix compared to the vertical stress and shear amplitude. The test results can provide a theoretical basis for the replacement of sand by steel slag in improving clay soils.

The potential of satellite precipitation products (SPPs) in monitoring and mitigating hydrometeorological disasters caused by extreme rainfall events has been extensively demonstrated. However, there is a lack of comprehensive assessment regarding the performance of SPPs over the Qinghai-Tibet Plateau (QTP). Therefore, this research aimed to evaluate the effectiveness of five SPPs, including CMORPH, IMERG-Final, PERSIANN-CDR, TRMM-3B42V7, and TRMM-3B42RT, in identifying variations in the occurrence and distribution of intense precipitation occurrences across the QTP during the period from 2001 to 2015. To evaluate the effectiveness of the SPPs, a reference dataset was generated by utilizing rainfall measurements collected from 104 rainfall stations distributed across the QTP. Ten standard extreme precipitation indices (SEPIs) were the main focus of the evaluation, which encompassed parameters such as precipitation duration, amount, frequency, and intensity. The findings revealed the following: (1) Geographically, the SPPs exhibited better retrieval capability in the eastern and southern areas over the QTP, while displaying lower detection accuracy in high-altitude and arid areas. Among the five SPPs, IMERG-Final outperformed the others, demonstrating the smallest inversion error and the highest correlation. (2) In terms of capturing annual and seasonal time series, IMERG-Final performs better than other products, followed by TRMM-3B42V7. All products performed better during summer and autumn compared to spring and winter. (3) The statistical analysis revealed that IMERG-Final demonstrates exceptional performance, especially concerning indices related to precipitation amount and precipitation intensity. Moreover, it demonstrates a slight advantage in detecting the daily rainfall occurrences and occurrences of intense precipitation. On the whole, IMERG-Final’s ability to accurately detect extreme precipitation events on annual, seasonal, and daily scales is superior to other products for the QTP. It was also noted that all products overestimate precipitation events to some extent, with TRMM-3B42RT being the most overestimated.

Background: Polypharmacy has become a major and growing public health issue, with significant implications for health outcomes and expenditure on healthcare resources. In this study, a risk prediction model of polypharmacy represented by a nomogram for community-dwelling elderly patients based on the Chinese population was constructed.Methods: A cross-sectional study was conducted in Shanghai, China. The variables data affecting polypharmacy were fetched from the information system database of health government departments in Shanghai. The Least Absolute Shrinkage Selection Operator (LASSO) regression analysis was used to select the predictor variables, and multivariate logistic regression was used to establish the prediction model. A visual tool of the nomogram was established for predicting the risk of polypharmacy in the elderly population. In addition, the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used to estimate the performance of the model.Results: A total of 80,012 elderly patients were included in this study. Eight variables, containing age, residential area, preferred medical institutions, number of visits to tertiary hospitals, number of visits to secondary hospitals, number of visits to community health centers, number of diagnoses, and main types of disease, were included in the risk prediction model of nomogram. The area under the curve (AUC) of the nomogram was 0.782 in both sets, demonstrating that the model has a good discriminant ability. The calibration chart shows that the prediction model fits well with the validation set. DCA results displayed that the threshold probabilities of the two sets in the prediction model reached up to 90%, implying that the model had a preferable application value.Conclusion: This study explored the risk factors for polypharmacy among the elderly in Shanghai, China, and applied the nomogram to establish a predictive model via eight variables, which provided an effective tool for early screening and timely prevention of polypharmacy. Family physicians or pharmacists could scientifically use the tool to closely observe community-dwelling elderly patients, decreasing the adverse health effects caused by medication for the elderly.

This paper aims to explore the impact of the purchase regret of consumers on dynamic closed-loop supply chains (CLSCs) under discrete-time conditions. Durable products are mostly traded under discrete-time conditions, and consumers tend to have different purchase regret psychologies during the trading process of different types of durable products (innovative or remanufactured). In addition, different purchase regret psychologies can affect the dynamic decision-making behaviour of the nodal enterprises in the supply chain, thus affecting the dynamic decision-making optimization sequence of the supply chain and nodal enterprises. Based on the traditional Bass model, this paper introduces the factor of consumer purchase regret psychology into the Bass model and constructs a model of a CLSC led by the manufacturer and followed by the retailer and recycler on the premise of heterogeneous characteristics of new products and remanufactured products. The optimal control theory of discrete systems is used to obtain the optimal decision sequence for each participant in the CLSC, when there is consumer regret psychology in the market. Then, the effects of consumer purchase regret psychology on the members of the CLSC at each stage are analysed. Finally, the conclusions are verified by using a numerical analysis. Compared to previous studies, the results further revealed the following: when the market share of brand new products is below 50%, the wholesale and retail prices are positively related to the regret psychology; while when they are above 50%, the wholesale and retail prices are negatively related to the regret psychology; the product sales and the manufacturers and retailers’ profits are negatively related to the regret psychology; purchase regret psychology does not affect the recyclers’ profits. To mitigate the negative consequences of the purchase regret psychology, manufacturers and merchants should completely grasp the market, enhance product quality, such that the price plan for the product is fairer.

BackgroundAs one of the countries with the most serious degree of aging, the incidence of potentially inappropriate drug use among the elderly is as high as 30. 4% in Chinese communities, and the lack of effective medication management and poor medication compliance at home are the main factors. Given these situations, we constructed a Rational Medication Management Mode based on family physician service, carried out an empirical research and evaluated the implementation effect.MethodsA prospective cohort study was conducted from September to December 2021 to analyze the implementation effect of the Rational Medication Management Mode by comparing the outcome indicators between the intervention group and control group. The primary outcome of this study was medication number and polypharmacy (taking 5 or more medications) at 90 days. The secondary outcomes included the situation for behavioral self-management and knowledge-belief-behavior of rational medication use.ResultsA total of 618 elderly patients (309 in the intervention group and 309 in the control group) with multimorbidity were included in this study, those were all available at follow-up at 90 days. At 90 days, the number of medications was achieved by 3.88 (1.48), and patients with polypharmacy were reduced by 59.55% in the intervention group, having a significant difference compared with the control group (P < 0.001). Patients with medication reminders, intermittent medication and adverse drug reactions were achieved in 294 (95.15%), 47 (15.21%), and 51 (16.51%) respectively in the intervention group (P < 0.001). The knowledge, belief, behavior security and behavior compliance of rational medication use of elderly patients were all greatly improved in the intervention group at 90 days (P < 0.0001).ConclusionThe Rational Medication Management Mode based family physician service, which provides the support of manuals and pillboxes, can decrease the elderly patients' number of drugs with multimorbidity, reduce the incidence of polypharmacy, enhance behavioral self-management, increase the knowledge and belief of rational medication use, and improve the security and compliance of medication usage behavior. In order to provide a practical basis for rational medication management of elderly patients with multimorbidity under the background of long-term prescriptions in China.

Abstract Background The purpose of this study was to assess the antioxidative activity of selenium-enriched Chrysomyia Megacephala (Fabricius) (C. megacephala) larvae powder (SCML) and its impact on the diversity and structure of intestinal microflora in a mouse model of D-galactose (D-gal)-induced oxidative damage. Methods Sixty male ICR mice were equally randomized to a normal control (NC) group, a model group, a positive group, a low-dose SCML (L-SCML) group, a mid-dose SCML (M-SCML) group, and a high-dose SCML (H-SCML) group. Animals in NC and model groups received water, animals in the positive group received 40 mg/Kg vitamin E (VE), and those in the three SCML groups received SCML which include 300, 1000 and 3000 μg/Kg selenium (Se) respectively. An oxidative damage model induced by subcutaneous injection of D-gal for 6 weeks via the neck was established. Serum oxidative stress levels and tissue appearance were evaluated. Tissues oxidative stress levels were detected by commercially available kit. Nuclear erythroid 2-related factor (Nrf2) and gut microbiota were determined by western blot and high throughput sequencing 16S rRNA gene respectively. Results An oxidative damage model was established successfully as represented by a significant elevation of malondialdehyde (MDA) and protein carbonylation, and inhibition of the antioxidants including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC) and glutathione (GSH). It was found that oxidative damage and histological alterations were attenuated, the expression of Kelch-like ECH-associated protein (Keap1) was decreased, and the expression of Nrf2 and hemeoxygenase-1 (HO-1) was increased after SCML treatment. In addition, significant changes were observed in the gut microbiota, including Proteobacteria and the ratio of Bacteroidetes to Firmicutes at the phylum level, as well as Helicobacter, Clostridium and Lactobacillus at the genus level. Conclusion SCML exerted an antioxidative effect in vivo, probably by increasing the antioxidant activity and reducing the production of oxidation products via the Nrf2 signaling pathway. SCML could also redress the intestinal flora imbalance induced by oxidative stress. All these findings suggest that SCML could serve as a functional food and natural drug additive to protect the human body against oxidative damage.

Abstract Background Pulmonary arterial hypertension (PAH) is a life-threatening condition. The aim of this study was to explore potential crucial genes and pathways associated with PAH based on integrative analyses of gene expression and to shed light on the identification of biomarker for PAH. Methods Gene expression profile of pulmonary tissues from 27 PAH patients and 22 normal controls were downloaded from public database (GSE53408 and GSE113439). After the identification of differentially expressed genes (DEGs), hub pathways and genes were identified based on the comprehensive evaluation of protein-protein interaction (PPI) network analysis, modular analysis and cytohubba’s analysis, and further validated in another PAH transcriptomic dataset (GSE33463). Potentially associated micro-RNAs (miRNAs) were also predicted. Results A total of 521 DEGs were found between PAH and normal controls, including 432 up-regulated DEGs and 89 down-regulated DEGs. Functional enrichment analysis showed that these DEGs were mainly enriched in mitotic cell cycle process, mitotic cell cycle and microtubule cytoskeleton organization. Moreover, five key genes (CDK1, SMC2, SMC4, KIF23, and CENPE) were identified and then further validated in another transcriptomic dataset associated with special phenotypes of PAH. Furthermore, these hub genes were mainly enriched in promoting mitotic cell cycle process, which may be closely associated with the pathogenesis of PAH. We also found that the predicted miRNAs targeting these hub genes were found to be enriched in TGF-β and Hippo signaling pathway. Conclusion These findings are expected to gain a further insight into the development of PAH and provide a promising index for the detection of PAH.

Satellite precipitation products have been applied to many research fields due to their high spatial and temporal resolution. However, satellite inversion of precipitation is indirect, and different inversion algorithms limit the accuracy of the measurement results, which leads to great uncertainty. Therefore, it is of great significance to quantify and record the error characteristics of different satellite precipitation products for their better application in hydrology and other research fields. In this study, based on CN05.1, which is a set of site–based interpolation data, we evaluated the accuracies of the six satellite precipitation datasets (IMERG–E, IMERG–L, IMERG–F, GSMaP, CMORPH, and PERSIANN–CDR) at different temporal scales (daily, monthly, and yearly) in mainland China for the period from 2001 to 2015. The results were as follows: (1) In terms of mean precipitation, IMERG–F was superior to other data in all areas. IMERG products and PERANN–CDR performed better than other products at all scales and were more suitable for precipitation research in mainland China. Site correction can effectively improve the accuracy of product inversion, so IMERG–F was significantly better than IMERG–E and IMERG–L. (2) Except PERSIANN–CDR, all precipitation products underestimated precipitation in the range of 1–4 mm/day and had a high coincidence with CN05.1 in the range of 4–128 mm/day. (3) The performance of six types of satellite precipitation products in summer was better than that in winter. However, the error was larger in seasons with more precipitation. (4) In the Qinghai–Tibet Plateau, where there are few stations, the inversion of precipitation by satellite products is closer to the actual situation, which is noteworthy. These results help users understand the characteristics of these products and improve algorithms for future algorithm developers.

Recent studies have highlighted observations regarding re-tested positivity (RP) of SARS-CoV-2 RNA in discharged COVID-19 patients, however, the immune mechanisms underlying SARS-CoV-2 RNA RP in immunocompetent patients remain elusive. Herein, we describe the case of an immunocompetent COVID-19 patient with moderate symptoms who was twice re-tested as positive for SARS-CoV-2 RNA, and the period between first and third viral RNA positivity was 95 days, longer than previously reported (18–25 days). The chest computed tomography findings, plasma anti-SARS-CoV-2 antibody, neutralizing antibodies (NAbs) titer, and whole blood transcriptic characteristics in the viral RNA RP patient and other COVID-19 patients were analyzed. During the SARS-CoV-2 RNA RP period, new lung lesions were observed. The COVID-19 patient with viral RNA RP had delayed seroconversion of anti-spike/receptor-binding domain (RBD) IgA antibody and NAbs and were accompanied with disappearance of the lung lesions. Further experimental data validated that NAbs titer was significantly associated with anti-RBD IgA and IgG, and anti-spike IgG. The RP patient had lower interferon-, T cells- and B cell-related genes expression than non-RP patients with mild-to-moderate symptoms, and displayed lower cytokines and chemokines gene expression than severe patients. Interestingly, the RP patient had low expression of antigen presentation-related genes and low B cell counts which might have contributed to the delayed anti-RBD specific antibody and low CD8+ cell response. Collectively, delayed antigen presentation-related gene expression was found related to delayed adaptive immune response and contributed to the SARS-CoV-2 RNA RP in this described immunocompetent patient.

This paper studies regulated state synchronization for homogeneous discrete-time multi-agent systems (MAS) in the presence of unknown nonuniform communication delays. We consider partial state coupling, i.e., agents are coupled through part of their states. A low gain-based protocol is designed which only requires rough knowledge of the communication network, such that the state synchronization for MAS is achieved where the required synchronized trajectory is only given to some of the agents.

Abstract The re-emerging human adenovirus types HAdV7, HAdV14, and HAdV55 of species B have caused severe lower respiratory tract diseases and even deaths during recent outbreaks. However, no adenovirus vaccine or therapeutic has been approved for general use. These adenoviruses attach to host cells via the knob domain of the fiber, using human desmoglein 2 as the primary cellular receptor. In this study, a recombinant HAdV11 fiber knob trimer (HAdV11FK) expressed in E. coli was shown to induce broadly neutralizing antibodies against HAdV11, -7, -14p1, and -55 in mice. Using HAdV11FK as an antigen, three monoclonal antibodies, 6A7, 3F11, and 3D8, with high neutralizing activity were generated. More importantly, the results of in vitro neutralization assays demonstrated that 3F11 and 3D8 cross-neutralized HAdV11, -7, and -55, but not HAdV14p1. The amino acids 251KE252 within the F-G loop may be the crucial amino acids in the conformational epitope recognized by 3F11, which is common to HAdV11, -7, -14p, and -55, but is not present in HAdV14p1 and HAdV3. A two-amino-acid deletion in the HAdV14p1 structure breaks the short alpha helix (248SREKE252) that is present in the HAdV7, -11, -55, and -14p fiber knob structures. Our findings add to the knowledge of adenovirus fiber structure and antibody responses and are important for the design of adenovirus vaccines and antiviral drugs with broad activity.

Aims: Present study was performed to examine whether ADH was implicated in psychological stress asthma and to explore the underlying molecular mechanism. Methods: We not only examined ADH levels in the cerebrospinal fluid (CSF) via radioimmunoassay, but also measured ADH receptor (ADHR) expression in airway-related vagal preganglionic neurons (AVPNs) through real-time PCR in all experimental mice. Western blotting was performed to evaluate the relationship between ADH and PKA/PKC in psychological stress asthma. Finally, the role of PKA/PKC in psychological stress asthma was analyzed. Results: Marked asthma exacerbations were noted owing to significantly elevated levels of ADH and ADHR after psychological stress induction as compared to OVA alone (asthma group). ADHR antagonists (SR-49095 or SR-121463A) dramatically lowered higher protein levels of PKAα and PKCα induced by psychological stress as compared to OVA alone, suggesting the correlation between ADH and PKA/PKC in psychological stress asthma. KT-5720 (PKA inhibitor) and Go-7874 (PKC inhibitor) further directly revealed the involvement of PKA/PKC in psychological stress asthma. Some notable changes were also noted after employing PKA and PKC inhibitors in psychological stress asthma, including reduced asthmatic inflammation (lower eosinophil peroxidase (EPO) activity, myeloperoxidase (MPO) activity, immunoglobulin E (IgE) level, and histamine release), substantial decrements in inflammatory cell counts (eosinophils and lymphocytes), and decreased cytokine secretion (IL-6, IL-10, and IFN-γ), indicating the involvement of PKA/PKC in asthma exacerbations induced by psychological stress. Conclusion: Our results strongly suggested that ADH participated in psychological stress-induced asthma exacerbations via PKA/PKC signal pathway in AVPNs.

Infantile spasm (IS) is an early-onset epileptic encephalopathy that usually presents with hypsarrhythmia on an electroencephalogram with developmental impairment or regression. In this study, whole-exome sequencing was performed to detect potential pathogenic de novo mutations, and finally we identified a novel damaging de novo mutation in SEMA5A and a compound heterozygous mutation in CLTCL1 in three sporadic trios with IS. The expression profiling of SEMA5A in the human brain showed that it was mainly highly expressed in the cerebral cortex, during the early brain development stage (8 to 9 post-conception weeks and 0 to 5 months after birth). In addition, we identified a close protein-protein interaction network between SEMA5A and candidate genes associated with epilepsy, autism spectrum disorder (ASD) or intellectual disability. Gene enrichment and function analysis demonstrated that genes interacting with SEMA5A were significantly enriched in several brain regions across early fetal development, including the cortex, cerebellum, striatum and thalamus (q < 0.05), and were involved in axonal, neuronal and synapse-associated processes. Furthermore, SEMA5A and its interacting genes were associated with ASD, epilepsy syndrome and developmental disorders of mental health. Our results provide insightful information indicating that SEMA5A may contribute to the development of the brain and is associated with IS. However, further genetic studies are still needed to evaluate the role of SEMA5A in IS to definitively establish the role of SEMA5A in this disorder.

Schimke immuno-osseous dysplasia (SIOD) is an extremely rare autosomal recessive pleiotropic disease. Although biallelic mutations in SMARCAL1 gene have been reported to be the genetic etiology of SIOD, its molecular diagnosis has been challenging in a relatively proportion of cases due to the extreme rarity. Here, we made a definitive SIOD diagnosis of a 5-year-old girl with an extremely mild phenotype by applying whole exome sequencing (WES). As a result, a novel maternal mutation (c.2141+5G > A) confirmed to create a novel splice donor site combined with a known paternal mutation (c.1933C > T; p.Arg645Cys) were detected. In addition, previous reported SIOD cases showed excessive enrichment for mutations in the helicase ATP-binding and C-terminal domains of SMARCAL1. Similarly, the novel mutation we identified caused a mutant protein truncated in the SMARCAL1 C-terminus. Interestingly, based on the phenotypic profile, compared to reported cases, the patient in our study exhibited milder symptoms with renal dysfunctions limited to asymptomatic proteinuria, but no neurological signs or recurrent infections. Moreover, we identified 73 SMARCAL1-interacting genes, which formed a significant interconnected interaction network with roles in disease-related pathways such as double-strand break repair via homologous recombination, DNA repair, and replication fork processing. Notably, the top 15 SMARCAL1-interacting genes all showed a similar renal temporal expression pattern. Altogether, to our knowledge, the case in this study is the first case diagnosed originally based on a genetic test via WES rather than a characteristic phenotype. The identification of the novel allelic mutation (c.2141+5G > A) extends the phenotypic spectrum of SMARCAL1 mutations and the following bioinformatics analysis presents additional genetic evidence to illustrate the role of SMARCAL1 in SIOD.

Primary Sjögren's syndrome (pSS) is a common chronic autoimmune disease characterized by a high prevalence of autoantibodies and lymphocyte-mediated exocrine gland damage. To enhance our understanding of the mechanisms underlying the progression of the disease and to discover potential biomarkers for the early diagnosis of pSS, we applied RNA sequencing to compare the gene expression patterns in minor salivary glands between pSS patients and non-pSS. A total of 293 differentially expressed genes (DEGs) were detected in pSS vs. non-pSS (FDR < 0.05, fold changes > 2). Of these DEGs, 285 (97.26%) were up-regulated, with most being involved in immune system activation, especially in the formation of the immunological synapse. Significantly elevated CCL19/CCR7 expression in the salivary gland was found to be related to anti-Sjögren's syndrome-related antigen A (SSA) antibody and IgG levels in pSS patients, which was further confirmed in a larger cohort. Up-regulated gene expression showed strong discriminatory accuracy in identifying pSS with area under the curve of 0.98 using receiver operating characteristic curve analysis. In conclusion, gene expression changes in pSS include strong markers of immunological activation and have good discriminatory power in identifying patients with pSS.

Abstract Epileptic encephalopathies (EE) are a group of severe childhood epilepsy disorders characterized by intractable seizures, cognitive impairment and neurological deficits. Recent whole-exome sequencing (WES) studies have implicated significant contribution of de novo mutations to EE. In this study, we utilized WES for identifying causal de novo mutations in 4 parent-offspring trios affected by West syndrome. As a result, we found two deleterious de novo mutations in DYNC1H1 and RTP1 in two trios. Expression profile analysis showed that DYNC1H1 and RTP1 are expressed in almost all brain regions and developmental stages. Interestingly, co-expression and genetic interaction network analyses suggested that DYNC1H1 and RTP1 are tightly associated with known epilepsy genes. Furthermore, we observed that the de novo mutations of DYNC1H1 were identified in several different neuropsychiatric disorders including EE, autism spectrum disorders and intellectual disabilities by previous studies, and these mutations primarily occurred in the functional domain of the protein. Taken together, these results demonstrate DYNC1H1 as a strong candidate and RTP1 as a potential candidate on the onset of EE. In addition, this work also proves WES as a powerful tool for the molecular genetic dissection of children affected by sporadic EE.

Detection of human adenoviruses (HAdVs) in nasopharyngeal swab samples by immunofluorescence assay (IFA) will be valuable for diagnosing HAdV infection, which is a leading cause of severe respiratory tract disease, and will help in curbing the spread of HAdV. Monoclonal antibodies employed in IFA for HAdV detection should ideally target highly conserved epitope types. Here, we describe the development of two antigen-binding fragments (Fabs) with specific reactivity to HAdV using phage antibody library technology. When tested with IFA, both Fabs recognized cells infected with several types of HAdV, some of which have been identified in epidemics globally, or associated with outbreaks of severe or fatal acute respiratory diseases. The specificity and cross-reactivity of both Fabs to HAdVs indicated that the generated Fabs could be applied in the development of IFAs to detect HAdVs. Both Fabs bound to the knob proteins, as shown by chemiluminescence enzyme immunoassay and western blot. In addition, epitope mapping showed that both Fabs recognized a conserved linear epitope among several types of HAdV. Two different Fabs recognized the same epitope, suggesting that the epitope triggered the production of at least two kinds of antibodies in the body. The generated Fabs exerted no neutralization against HAdVs. The results demonstrate that both Fabs bind to an epitope that plays no role in neutralization of HAdV.

Background: Respiratory infections pose a great challenge in global health, and the prevalence of viral infection in adult patients has been poorly understood in northeast China. Harbin is one of the major cities in northeast China, and more than half of any given year in Harbin is occupied by winter. To reveal the viral etiology and seasonality in adult patients from Harbin, a 4-year consecutive survey was conducted in Harbin, China.Methods: From January 2014 to December 2017, specimens were obtained from adult patients admitted to the Second Affiliated Hospital of Harbin Medical University with lower respiratory tract infections. Sputum samples were examined by direct immunofluorescence assays to detect seven common respiratory viruses, including influenza virus (type A and B), parainfluenza virus (type 1 to 3), respiratory syncytial virus and adenovirus. Adenovirus positive samples were seeded onto A549 cells to isolate viral strains. Phylogenetic analysis was conducted on the highly variable region of adenoviral hexon gene.Results: A total of 1,300 hospitalized adult patients with lower respiratory tract infections were enrolled, in which 189 patients (14.5%) were detected as having at least one viral infection. The co-infection rate in this study was 25.9% (49/189). The dominant viral pathogen from 2014 to 2017 was parainfluenza virus, with a detection rate of 7.2%, followed by influenza virus, respiratory syncytial virus and adenovirus. Based on the climate seasons determined by daily average temperature, the highest overall viral detection rate was detected in spring (22.0%, 52/236), followed by winter (13.4%, 109/813), autumn (11.4%, 13/114) and summer (10.9%, 15/137). Adenovirus type 3 strains with slight variations were isolated from positive cases, which were closely related to the GB strain from the United States, as well as the Harbin04B strain isolated locally.Conclusion: This study demonstrated that common respiratory viruses were partially responsible for hospitalized lower respiratory tract infections in adult patients from Harbin, China, with parainfluenza virus as the dominant viral pathogen. Climate seasons could be rational indicators for the seasonality analysis of airborne viral infections. Future surveillance on viral mutations would be necessary to reveal the evolutionary history of respiratory viruses.

Dissecting the genetic susceptibility to intellectual disability (ID) based on de novo mutations (DNMs) will aid our understanding of the neurobiological and genetic basis of ID. In this study, we identify 63 high-confidence ID genes with q-values < 0.1 based on four background DNM rates and coding DNM data sets from multiple sequencing cohorts. Bioinformatic annotations revealed a higher burden of these 63 ID genes in FMRP targets and CHD8 targets, and these genes show evolutionary constraint against functional genetic variation. Moreover, these ID risk genes were preferentially expressed in the cortical regions from the early fetal to late mid-fetal stages. In particular, a genome-wide weighted co-expression network analysis suggested that ID genes tightly converge onto two biological modules (M1 and M2) during human brain development. Functional annotations showed specific enrichment of chromatin modification and transcriptional regulation for M1 and synaptic function for M2, implying the divergent etiology of the two modules. In addition, we curated 12 additional strong ID risk genes whose molecular interconnectivity with known ID genes (q-values < 0.3) was greater than random. These findings further highlight the biological convergence of ID risk genes and help improve our understanding of the genetic architecture of ID.

The airway vagal preganglionic neurons (AVPNs) providing projections to intrinsic tracheobronchial ganglia are considered to be crucial to modulation of airway resistance in physiological and pathological states. AVPNs classified into inspiratory-activated AVPNs (IA-AVPNs) and inspiratory-inhibited AVPNs (II-AVPNs) are regulated by thyrotropin-releasing hormone (TRH)-containing terminals. TRH causes a direct excitatory current and attenuates the phasic inspiratory glycinergic inputs in II-AVPNs, however, whether and how TRH influences IA-AVPNs remains unknown. In current study, TRH regulation of IA-AVPNs and its mechanisms involved were investigated. Using retrogradely fluorescent labeling method and electrophysiology techniques to identify IA-AVPNs in brainstem slices with rhythmic inspiratory hypoglossal bursts recorded by a suction electrode, the modulation of TRH was observed with patch-clamp technique. The findings demonstrate that under voltage clamp configuration, TRH (100 nM) caused a slow excitatory inward current, augmented the excitatory synaptic inputs, progressively suppressed the inhibitory synaptic inputs and elicited a distinctive electrical oscillatory pattern (OP). Such a current and an OP was independent of presynaptic inputs. Carbenoxolone (100 μM), a widely used gap junction inhibitor, fully suppressed the OP with persistence of TRH-induced excitatory slow inward current and augment of the excitatory synaptic inputs. Both tetrodotoxin (1 μM) and riluzole (20 μM) functioned to block the majority of the slow excitatory inward current and prevent the OP, respectively. Under current clamp recording, TRH caused a slowly developing depolarization and continuously progressive oscillatory firing pattern sensitive to TTX. TRH increased the firing frequency in response to injection of a square-wave current. The results suggest that TRH excited IA-AVPNs via the following multiple mechanisms: (1) TRH enhances the excitatory and depresses the inhibitory inputs; (2) TRH induces an excitatory postsynaptic slow inward current; (3) TRH evokes a distinctive OP mediated by gap junction.

Background/Aims: Angiotensin converting enzyme 2 (ACE2) treatment suppresses the severity of acute lung injury (ALI), through antagonizing hydrolyzing angiotensin II (AngII) and the ALI-induced apoptosis of pulmonary endothelial cells. Nevertheless, the effects of ACE2 on vessel permeability and its relationship with vascular endothelial growth factor a (VEGFa) remain ill-defined. In the current study, we examined the relationship between ACE2 and VEGFa in ALI model in mice. Methods: Here, we used a previously published bleomycin method to induce ALI in mice, and treated the mice with ACE2. We analyzed the levels of VEGFa in these mice. The mouse lung vessel permeability was determined by a fluorescence pharmacokinetic assay following i.v. injection of 62.5µg/kg Visudyne. VEGFa pump or SU5416 pump was given to increase or decrease VEGFa effects, respectively. The long-term effects on lung function were determined by measurement of lung resistance using methacholine. Results: ACE2 treatment did not alter VEGFa levels in lung, but antagonized the effects of VEGFa on increases of lung vessel permeability. Ectogenic VEGFa abolished the antagonizing effects of ACE2 on the vessel permeability against VEGFa. On the other hand, suppression of VEGF signaling mimicked the effects of ACE2 on the vessel permeability against VEGFa. The suppression of vessel permeability resulted in improvement of lung function after ALI. Conclusion: ACE2 may antagonize the VEGFa-mediated increases in lung vessel permeability during ALI, resulting in improvement of lung function after ALI.

A novel microwave hydrothermal method was developed to prepare highly dispersed W/Al2O3 catalysts, in which WO3 was deposited on alumina via precipitation between tungstate and nitric acid under microwave hydrothermal environment and oxalic acid was used as an additive. Moreover, the role of oxalic acid was investigated by varying its amount and the addition method. It is found that the catalysts show higher WO3 dispersion and weaker W–Al interaction than that prepared by the conventional impregnation method. The hydrothermal period can be extremely reduced to a few minutes, and highly dispersed WO3 can be achieved even without oxalic acid. When oxalic acid was added after the formation of H2WO4, it mainly acts as a modifier for reacting with the hydroxyl groups on alumina and has little effect on WO3 dispersion. When oxalic acid was divided into two parts, one for pretreating alumina and the remains for preventing the aggregation of H2WO4, it may effectively act as both dispersant and modifier, leading to further increased WO3 dispersion and weakened W–Al interaction. The catalysts prepared by the microwave hydrothermal method show superior dibenzothiophene hydrodesulfurization activity. This method provides rapidity, convenience and cost effectiveness for preparing active hydrotreating catalysts.

Background/Aims: Angiotensin converting enzyme 2 (ACE2) treatment suppresses the severity of acute lung injury (ALI). The effects of ACE2 in ALI have been shown to not only result from its antagonizing hydrolyzing angiotensin II (AngII), which is responsible for reduction in the vascular tension and pulmonary accumulation of inflammatory cells, but also result from a role of ACE2 in suppressing the ALI-induced apoptosis of pulmonary endothelial cells (PECs). Nevertheless, the underlying mechanisms of the role of ACE2 on PEC apoptosis are not completely understood. Methods: Here, we used a bleomycin-induced mouse model for ALI that has been published in our previous studies. We analyzed the mRNA and protein levels of an anti-apoptotic protein Bcl-2 in the ALI-mice that have been treated w/o ACE2. We analyzed miR-4262 levels in the mouse lung in these mice. Bcl-2-targeting miRNAs were predicted using bioinformatics algorithms and a luciferase reporter assay was applied to examine the effects of miR-4262 on the Bcl-2 protein translation upon their binding to 3'-UTR of Bcl-2 mRNA. Adeno-associated viruses carrying either miR-4262 mimics or antisense were injected into ALI-mice without ACE2, and their effects on the apoptosis in mouse lung cells were analyzed by Western blot. Results: ACE2 inhibited the ALI-induced apoptosis of pulmonary cells in vivo partially through upregulation of Bcl-2 protein, but not Bcl-2 mRNA. ACE2 appeared to significantly suppress the upregulation of miR-4262 in mouse lung after ALI. MiR-4262 was found to target 3'-UTR of Bcl-2 mRNA to inhibit its protein translation in PECs. In vivo administration of antisense of miR-4262 decreased apoptosis of pulmonary cells and severity of the ALI in mice. Conclusion: ACE2-induced suppression of miR-4262 partially contribute to the inhibition of the PEC apoptosis after ALI through Bcl-2. MiR-4262 may be a novel promising treatment target for ALI and ARDS.

Background/Aims: Angiotensin converting enzyme 2 (ACE2) has an established role in suppressing the severity of acute lung injury (ALI), especially when it was applied together with transplantation of human umbilical cord mesenchymal stem cells (uMSCs). Although the effects of ACE2 in ALI are believed to mainly result from its role in hydrolyzing angiotensin II (AngII), which subsequently reduces the vascular tension and subsequent pulmonary accumulation of inflammatory cells, we and others have recently reported a possible role of ACE2 in suppressing the ALI-induced apoptosis of pulmonary endothelial cells. However, the underlying mechanisms remain undetermined. Methods: Here, we analyzed the alteration in lung injury severity in ALI after ACE2, by histology and inflammatory cytokine levels. We analyzed apoptosis-associated proteins in lung after ALI, as well as in cultured endothelial cells treated with nitric oxide (NO). We overexpressed SMAD7 to inhibit SMAD2 signaling in cultured endothelial cells and examined its effects on NO-induced cell apoptosis. Results: ACE2 alleviated severity of lung injury after ALI. ACE2 significantly decreased the ALI-induced apoptosis of pulmonary cells in vivo, and ACE2 protected endothelial cells against NO-induced apoptosis in vitro. NO induced phosphorylation of a key factor of transforming growth factor β (TGF β) receptor signaling, SMAD2, which could be dose-dependently inhibited by ACE2. Inhibition of SMAD2 phosphorylation through expression of its inhibitor SMAD7 significantly inhibited NO-induced cell apoptosis, without need for ACE2. Conclusion: Our data suggest that ACE2-mediated AngII degradation may inhibit AngII-mediated SMAD2-phophorylation, possibly through a TGFβ-independent manner, which subsequently suppresses the ALI-induced cell death. Our results thus reveal a novel molecular pathway that controls the pathogenesis of ALI.