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Abstract Type I interferons have been well recognized for their roles in various types of immune cells during tumor immunotherapy. However, their direct effects on tumor cells are less understood. Oxidative phosphorylation is typically latent in tumor cells. Whether oxidative phosphorylation can be targeted for immunotherapy remains unclear. Here, we find that tumor cell responsiveness to type I, but not type II interferons, is essential for CD47-SIRPα blockade immunotherapy in female mice. Mechanistically, type I interferons directly reprogram tumor cell metabolism by activating oxidative phosphorylation for ATP production in an ISG15-dependent manner. ATP extracellular release is also promoted by type I interferons due to enhanced secretory autophagy. Functionally, tumor cells with genetic deficiency in oxidative phosphorylation or autophagy are resistant to CD47-SIRPα blockade. ATP released upon CD47-SIRPα blockade is required for antitumor T cell response induction via P2X7 receptor-mediated dendritic cell activation. Based on this mechanism, combinations with inhibitors of ATP-degrading ectoenzymes, CD39 and CD73, are designed and show synergistic antitumor effects with CD47-SIRPα blockade. Together, these data reveal an important role of type I interferons on tumor cell metabolic reprograming for tumor immunotherapy and provide rational strategies harnessing this mechanism for enhanced efficacy of CD47-SIRPα blockade.

Abstract Immune checkpoint blockade (ICB) therapies function by alleviating immunosuppression on tumor-infiltrating lymphocytes (TILs) but are often insufficient to fully reactivate these dysfunctional TILs. Although interleukin 12 (IL-12) has been used in combination with ICB to improve efficacy, this remains limited by severe toxicity associated with systemic administration of this cytokine. Here, we engineer a fusion protein composed of an anti-PD-1 antibody and a mouse low-affinity IL-12 mutant-2 (αPD1-mIL12mut2). Systemic administration of αPD1-mIL12mut2 displays robust antitumor activities with undetectable toxicity. Mechanistically, αPD1-mIL12mut2 preferentially activates tumor-infiltrating PD-1+CD8+T cells via high-affinity αPD-1 mediated cis-binding of low-affinity IL-12. Additionally, αPD1-mIL12mut2 treatment exerts an abscopal effect to suppress distal tumors, as well as metastasis. Collectively, αPD1-mIL12mut2 treatment induces robust systemic antitumor responses with reduced side effects.

Abstract Background Acute type A aortic dissection (ATAAD) complicated by mesenteric malperfusion is a critical and complicated condition. The optimal treatment strategy remains controversial, debate exists as to whether aortic dissection or mesenteric malperfusion should be addressed first, and the exact time window for mesenteric ischemia intervention is still unclear. To solve this problem, we developed a new concept based on the pathophysiological mechanism of mesenteric ischemia, using a 6-hour time window to divide newly admitted patients by the time from onset to admission, applying different treatment protocols to improve the clinical outcomes of patients with ATAAD complicated by mesenteric malperfusion. Methods This was a retrospective study that covered a five-year period. From July 2018 to December 2020(phase I), all patients underwent emergency open surgery. From January 2021 to June 2023(phase II), patients with an onset within 6 h all underwent open surgical repair, followed by immediately postoperative examination if the malperfusion is suspected, while the restoration of mesenteric perfusion and visceral organ function was performed first, followed by open repair, in patients with an onset beyond 6 h. Results There were no significant differences in baseline and surgical data. In phase I, eleven patients with mesenteric malperfusion underwent open surgery, while in phase II, our novel strategy was applied, with sixteen patients with an onset greater than 6 h and eleven patients with an onset less than 6 h. During the waiting period, none died of aortic rupture, but four patients died of organ failure, twelve patients had organ function improvement and underwent surgery successfully survived. The overall mortality rate decreased with the use of this novel strategy (54.55% vs. 18.52%, p = 0.047). Furthermore, the surgical mortality rate between the two periods showed even stronger statistical significance (54.55% vs. 4.35%, p = 0.022). Moreover, the proportions of patients with sepsis and multiorgan failure also showed differences. Conclusions Our novel strategy for patients with ATAAD complicated by mesenteric malperfusion not only improves the surgical success rate but also reduces the overall mortality rate.

Abstract Aim To elaborate the underlying mechanisms by which IL-1β promote progression of Dry eye disease(DED) through effect on pyroptosis and apoptosis of corneal epithelial cells(CECs). Methods 400 mOsM solutions were used to establish the DED model (hCECs- DED). RT-qPCR was performed to measure IL-1β mRNA and miR-146a-5p in CECs. Western blotting was performed to measure STAT3, GSDMD, NLRP3, and Caspase-1 levels. Cell counting kit-8 assay was adopted to check cell viability. Apoptosis was detected by flow cytometry. ELISAs were performed to determine IL-18, IL-33 and LDH. The luciferase test detects targeting relationships. Results After treatment with 400 mOsM solution, cell viability decreased and apoptosis increased. Compared with hCECs, IL-1β was increased and miR-146a-5p was decreased in hCECs-DED. At the same time, GSDMD, NLRP3, Caspase-1, IL-18, IL-33 and LDH were significantly higher in hCECs-DED than in hCECs, while IL-1β silencing reversed this effect. In addition, IL-1β negatively regulated miR-146a-5p. MiR-146a-5p mimics eliminated the inhibition of hCECs-DED pyroptosis and apoptosis caused by IL-1β silencing. At the same time, miR-146a-5p reduced STAT3 levels in hCECs. Conclusion Highly expressed IL-1β promoted pyroptosis and apoptosis of hCECs- DED through downregulated miR-146a-5p and inhibited STAT3.

Abstract Background The era of high throughput sequencing offers new paths to identifying species boundaries that are complementary to traditional morphology-based delimitations. De novo species delimitation using traditional or DNA super-barcodes serve as efficient approaches to recognizing putative species (molecular operational taxonomic units, MOTUs). Tea plants (Camellia sect. Thea) form a group of morphologically similar species with significant economic value, providing the raw material for tea, which is the most popular nonalcoholic caffeine-containing beverage in the world. Taxonomic challenges have arisen from vague species boundaries in this group. Results Based on the most comprehensive sampling of C. sect. Thea by far (165 individuals of 39 morphospecies), we applied three de novo species delimitation methods (ASAP, PTP, and mPTP) using plastome data to provide an independent evaluation of morphology-based species boundaries in tea plants. Comparing MOTU partitions with morphospecies, we particularly tested the congruence of MOTUs resulting from different methods. We recognized 28 consensus MOTUs within C. sect. Thea, while tentatively suggesting that 11 morphospecies be discarded. Ten of the 28 consensus MOTUs were uncovered as morphospecies complexes in need of further study integrating other evidence. Our results also showed a strong imbalance among the analyzed MOTUs in terms of the number of molecular diagnostic characters. Conclusion This study serves as a solid step forward for recognizing the underlying species boundaries of tea plants, providing a needed evidence-based framework for the utilization and conservation of this economically important plant group.

Abstract Objective To explore the application of magnetic resonance imaging (MRI) in the evaluation of radiation-induced sinusitis (RIS), MRI-based scoring system was used to evaluate the development regularity, characteristics and influencing factors of RIS in nasopharyngeal carcinoma (NPC) patients. Patients and methods A retrospective analysis was performed by collecting the clinical and MRI data of 346 NPC patients to analyze the characteristics and prognosis of RIS. The predictive model was constructed according to the influencing factors of RIS. Results (1) In the 2-year follow-up after radiotherapy (RT), there was significant change in L-M score in both groups of NPC patients (sinusitis before RT group: p = 0.000 vs. non-sinusitis before RT group: p = 0.000). After 6 months of RT, the L-M scores of the two groups tended to plateau (sinusitis before RT group: p = 0.311 vs. non-sinusitis before RT group: p = 0.469). (2) The prevalence of sinusitis in two groups of NPC patients (without or with sinusitis before RT) was 83% vs. 93%, 91% vs. 99%, 94% vs. 98% at 1, 6 and 24 months after RT, respectively. (3) In the patients without sinusitis before RT, the incidence of sinusitis in maxillary and anterior/posterior ethmoid, sphenoid and frontal sinuses was 87.1%, 90.0%/87.1%, 49.5%, 11.8% respectively, 1 month after RT. (4) A regression model was established according to the univariate and multivariate analysis of the factors related to RIS (smoking history: p = 0.000, time after RT: p = 0.008 and TNM staging: p = 0.040). Conclusion (1) RIS is a common complication in NPC patients after RT. This disorder progressed within 6 months after RT, stabilized and persisted within 6 months to 2 years. There is a high incidence of maxillary sinus and ethmoid sinus inflammation in NPC patients after RT. (2) Smoking history, time after RT and TNM staging were significant independent risk factors for RIS. (3) The intervention of the risk factors in the model may prevent or reduce the occurrence of RIS in NPC patients.

Tuberculosis, caused by Mycobacterium tuberculosis (M. tuberculosis), remains a formidable global health challenge, affecting a substantial portion of the world’s population. The current tuberculosis vaccine, bacille Calmette–Guérin (BCG), offers limited protection against pulmonary tuberculosis in adults, underscoring the critical need for innovative vaccination strategies. Cytokines are pivotal in modulating immune responses and have been explored as potential adjuvants to enhance vaccine efficacy. The strategic inclusion of cytokines as adjuvants in tuberculosis vaccines holds significant promise for augmenting vaccine-induced immune responses and strengthening protection against M. tuberculosis. This review delves into promising cytokines, such as Type I interferons (IFNs), Type II IFN, interleukins such as IL-2, IL-7, IL-15, IL-12, and IL-21, alongside the use of a granulocyte–macrophage colony-stimulating factor (GM-CSF) as an adjuvant, which has shown effectiveness in boosting immune responses and enhancing vaccine efficacy in tuberculosis models.

In the exploration of sustainable construction materials, the application of ferronickel slag (FNS) in creating pervious concrete has been investigated, considering its potential to meet the dual requirements of mechanical strength and fluid permeability. To elucidate the statistical properties and models for predicting the performance of FNS-composited pervious concrete with different sizes of aggregates and mixtures, a series of experiments, including 54 kinds of mixtures and three kinds of aggregate, were conducted. The focus was on measuring the compressive strength and the permeability coefficient. The results indicate that the compressive strength of pervious concrete decreases with the increase in aggregate size, while the permeability coefficient increases with the increase in aggregate size. Through normalization, the variability of these properties was quantitatively analyzed, revealing coefficients of variation for the concrete’s overall compressive strength and the permeability coefficient at 0.166, 0.132, and 0.150, respectively. Predictive models were developed using machine learning techniques, such as Linear Regression, Support Vector Machines, Regression Trees, and Gaussian Process Regression. These models demonstrated proficiency in forecasting the concrete’s compressive strength and permeability coefficient.

It is unknown whether Ferronickel slag (FNS)-ordinary Portland cement (OPC)-based pervious concrete (FOPC) is feasible. To this end, a feasibility study was conducted on FOPC. Firstly, a detailed microscopic examination of the FNS powder was conducted, encompassing analyses of its particle size distribution, SEM, EDS, and chemical composition. These analyses aimed to establish the suitability of a composite of FNS and OPC as a composite cementitious material. Subsequent experimentation focused on evaluating the compressive strength of the composite paste material with varying mixed proportions, revealing a slight reduction in strength as the FNS substitution rate increased. Furthermore, the study designed eighteen different mix proportions of FOPC to investigate the key physical properties, including porosity, density, compressive strength, and the coefficient of permeability. Findings indicated that increases in the cementitious material proportion correlate with enhanced concrete strength, where the ratio of cementitious to aggregate increased by 6.7% and 16.5%, and the strength of FOPC increased by 10–13% and 30–50%, respectively. Conversely, a rise in the FNS substitution rate led to a reduction in compressive strength across different mix ratios. Additionally, the ratio of paste material to aggregate was found to significantly influence the permeability coefficient. These comprehensive performance evaluations suggest that incorporating FNS into OPC for pervious concrete applications is a feasible approach, offering valuable insights for the promotion of waste reuse and the advancement of energy conservation and emissions reduction efforts.

Abstract Background Lifestyle changes are important for the prevention and management of metabolic syndrome (MetS), but studies that focus on gender differences in the lifestyle risk factors of MetS are limited in China. This research aimed to generate a healthy lifestyle index (HLI) to assess the behavioral risk factors of MetS and its components, and to explore the gender differences in HLI score and other influencing factors of MetS. Methods A convenience sample of 532 outpatients were recruited from a general hospital in Changsha, China. The general information and HLI scores [including physical activity (PA), diet, smoking, alcohol use, and body mass index (BMI)] of the subjects were collected through questionnaires, and each patient’s height, weight, waist circumference, and other physical signs were measured. Logistic regression analysis was used to analyze the risk factors of MetS and its components. Results The prevalence of MetS was 33.3% for the whole sample (46.3% in males and 23.3% in females). The risk of MetS increased with age, smoking, unhealthy diet, and BMI in males and with age and BMI in females. Our logistic regression analysis showed that lower HLI (male: OR = 0.838,95%CI = 0.757–0.929; female: OR = 0.752, 95%CI = 0.645–0.876) and older age (male: OR = 2.899, 95%CI = 1.446–5.812; female: OR = 4.430, 95%CI = 1.640–11.969) were independent risk factors of MetS, for both sexes. Conclusion Low levels of HLI and older ages were independent risk factors of MetS in both males and females. The association between aging and MetS risk was stronger in females, while the association between unhealthy lifestyles and MetS risk was stronger in males. Our findings reinforced the expected gender differences in MetS prevalence and its risk factors, which has implications for the future development of gender-specific MetS prevention and intervention programs.

BackgroundThere are discrepancies of olfactory impairment between Alzheimer’s disease (AD) and other neurodegenerative disorders. Olfactory deficits may be a potential marker for early and differential diagnosis of AD. We aimed to assess olfactory functions in patients with AD and other neurodegenerative disorders, to further evaluate the smell tests using subgroup analysis, and to explore moderating factors affecting olfactory performance.MethodsCross-sectional studies relating to olfactory assessment for both AD and other neurodegenerative disorders published before 27 July 2022 in English, were searched on PubMed, Embase and Cochrane. After literature screening and quality assessment, meta-analyses were conducted using stata14.0 software.ResultsForty-two articles involving 12 smell tests that evaluated 2,569 AD patients were included. It was revealed that smell tests could distinguish AD from mild cognitive impairment (MCI), Lewy body disease (LBD), depression, and vascular dementia (VaD), but not from diseases such as frontotemporal dementia (FTD). Our finding indicated that in discriminating AD from MCI, the University of Pennsylvania Smell Identification Test (UPSIT) was most frequently used (95%CI: −1.12 to −0.89), while the Brief Smell Identification Test (B-SIT), was the most widely used method in AD vs. LBD group. Further subgroup analyses indicated that the methods of smell test used contributed to the heterogeneity in olfactory threshold and discrimination scores in group AD vs. MCI. While the moderating variables including age, MMSE scores, education years in AD vs. LBD, were account for heterogeneity across studies.ConclusionOur finding suggests smell tests have potential value in early differential diagnosis of AD. UPSIT and its simplified variant, B-SIT, are widely used methods in the analyses.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php? RecordID = 357970 (PROSPERO, registration number CRD42022357970).

The atmospheric weighted mean temperature (Tm) is an important parameter in calculating the precipitable water vapor from Global Navigation Satellite System (GNSS) signals. As both GNSS positioning and GNSS precipitable water vapor detection require high spatial and temporal resolutions for calculating Tm, high-precision modeling of Tm has gained widespread attention in recent years. The previous models for calculating Tm have the limitation of too many model parameters or single-grid data. Therefore, this study presents a global high-precision Tm model (GGTm-H model) developed from the latest Modern-Era Retrospective Analysis for Research and Applications, version-2 (MERRA-2) atmospheric reanalysis data provided by the United States National Aeronautics and Space Administration. The accuracy of the GGTm-H model was verified by combining the MERRA-2 surface Tm data and 319 radiosonde data. The results highlighted that 1) When the MERRA-2 Tm data were used as a reference value, the mean annual RMSE of the GGTm-H model was observed to be 2.72 K. When compared with the Bevis model, GPT2w-5 model, and GPT2w-1 model, the GGTm-H model showed an improvement of 1.5, 0.33, and 0.21 K, respectively. 2) When the radiosonde data were used as a reference value, the mean bias and RMSE of the GGTm-H model were −0.41 K and 3.82 K, respectively. Compared with the other models, the GGTm-H model had the lowest mean annual bias and RMSE. The developed model does not consider any meteorological parameters while calculating Tm. Therefore, it has important applications in the real-time and high-precision monitoring of precipitable water vapor from GNSS signals.

A new orchid species, Hemipilia avisoides, is described from Songpan County and Maoxian County, Sichuan Province, China. Morphologically, H. avisoides is most similar to H. hui, but can be distinguished by the combination of its involute middle lip lobe that is smaller than the lateral lobes, floral bracts that are 5 mm long and are always shorter than the ovary, a leaf that is appressed to the substrate and is adaxially green with white lines along 7–9 principal veins and the subterranean stem with a solitary sheath at its base. The floral morphology of H. avisoides is presented by utilising in vivo micro-CT scanning and 3D visualisation.

The study analyses the theoretical mechanism through which environmental regulation affects the dairy industry's technological progress, with a particular focus on how the effect is conditional on farm size. Using the input–output data of dairy farms of different sizes from 2009 to 2019 in 10 Chinese provinces/autonomous regions in China and the quantitative measurement index of environmental regulation, the study estimates environmental regulation's heterogeneous influences on the dairy industry's technological progress by dynamic panel data models. The empirical results suggest that, first, environmental regulation has a U-type influence on the technological progress of dairy farming. The U-type influence means moving from pollution control's high cost and low technology progress to the high profit and high innovation input generated by optimizing the breeding structure. Second, the promotion of dairy farming technology depends on farm size. The effect of environmental regulation on technological progress in moderately large-farms showed a U-type relationship. In contrast, the effect in free-range and large-size dairy farms showed a linear and positive relationship. The government should further strengthen environmental regulation based on advancing moderately large-farms in compliance with market mechanisms in the long run. Particular attention should be paid to the forms of environmental regulation so that dairy cattle breeding technology can break through the inflection point of the “U” curve as soon as possible and ensure the significance of the rising stage. Along the way, technical support should be provided for realizing environmental protection and economic growth.

IntroductionMalonyl coenzyme A decarboxylase deficiency is caused by an abnormality in the MLYCD gene. The clinical manifestations of the disease involve multisystem and multiorgan.MethodsWe collected and analyzed a patient's clinical characteristics, genetic chain of evidence and RNA-seq. We use the search term “Malonyl-CoA Decarboxylase Deficiency” on Pubmed to collect cases reported.ResultsWe report a 3-year-old girl who is presented with developmental retardation, myocardial damage and elevated C3DC. High-throughput sequencing identified heterozygous mutation (c.798G>A, p.Q266?) in the patient inherited from her father. The other heterozygous mutation (c.641+5G>C) was found in the patient inherited from her mother. RNA-seq showed that there were 254 differential genes in this child, among which 153 genes were up-regulated and 101 genes were down-regulated. Exon jumping events occurred in exons encoding PRMT2 on the positive chain of chromosome 21, which led to abnormal splicing of PRMT2. (P

Abstract Background Aortic dissection in pregnancy is a life-threatening event that is associated with high maternal and foetal mortality. Most cases occur during the third trimester of pregnancy, Herein, we describe a case of a pregnant woman with acute type A aortic dissection at 28 weeks of gestation. Case presentation A previously healthy, 24-year-old gravida 2 para 1 woman was brought to the emergency department during at the 28 weeks of gestation and diagnosed with acute type A aortic dissection. Cesarean section was performed with the cardiac surgical team on standby for cardiopulmonary bypass and the patient delivered a baby weighing 1000 g. After the operation, we performed the Beatall procedure and total arch replacement with FET using the deep hypothermic circulatory arrest technique. Both the mother and child survived and recovered well. A review of the literature on antepartum acute aortic dissection during pregnancy is also presented. Conclusion Women should have a comprehensive, systematic physical examination before getting pregnant. Women at high risks of aortic dissection must undergo multidisciplinary evaluation and be counseled before pregnancy, once they become pregnant, their consistent aortic root diameter should be consistently monitored, and their blood pressure strictly controlled.

Primula longipilosa from SW Yunnan, China, is described as a species new to science and illustrated. The systematic placement of this new species is also discussed based on an nrITS molecular tree. It is morphologically most similar to P. mollis, but differs from the latter in its racemose inflorescence, green calyx tube, pink to pink rose corolla, stamens at 1/3 length above the base of the corolla tube and applanate globose capsule.

To address the problems of wind power abandonment and the stoppage of electricity transmission caused by a short circuit in a power line of a doubly-fed induction generator (DFIG) based wind farm, this paper proposes an intelligent location method for a single-phase grounding fault based on a multiple random forests (multi-RF) algorithm. First, the simulation model is built, and the fundamental amplitudes of the zero-sequence currents are extracted by a fast Fourier transform (FFT) to construct the feature set. Then, the random forest classification algorithm is applied to establish the fault section locator. The model is resampled on the basis of the bootstrap method to generate multiple sample subsets, which are used to establish multiple classification and regression tree (CART) classifiers. The CART classifiers use the mean decrease in the node impurity as the feature importance, which is used to mine the relationship between features and fault sections. Subsequently, a fault section is identified by voting on the test results for each classifier. Finally, a multi-RF regression fault locator is built to output the predicted fault distance. Experimental results with PSCAD/EMTDC software show that the proposed method can overcome the shortcomings of a single RF and has the advantage of locating a short hybrid overhead/cable line with multiple branches. Compared with support vector machines (SVMs) and previously reported methods, the proposed method can meet the location accuracy and efficiency requirements of a DFIG-based wind farm better.

Carex malipoensis, a new species from southeast Yunnan, China, is here described and illustrated. It is morphologically similar to C. trichophylla in sect. Euprepes, but differs from it by its longer inflorescences and peduncles, pendulous spikes, hispidulous female glumes, densely hispidulous utricles, and longer nutlets.

Abstract The current COVID-19 pandemic caused by constantly emerging SARS-CoV-2 variants still poses a threat to public health worldwide. Effective next-generation vaccines and optimized booster vaccination strategies are urgently needed. Here, we sequentially immunized mice with a SARS-CoV-2 wild-type inactivated vaccine and a heterologous mutant RBD vaccine, and then evaluated their neutralizing antibody responses against variants including Beta, Delta, Alpha, Iota, Kappa, and A.23.1. These data showed that a third booster dose of heterologous RBD vaccine especially after two doses of inactivated vaccines significantly enhanced the GMTs of nAbs against all SARS-CoV-2 variants we tested. In addition, the WT and variants all displayed good cross-immunogenicity and might be applied in the design of booster vaccines to induce broadly neutralizing antibodies.

A single small population of chasmophytic plants is described as Mojiangia oreophila, a monotypic genus in the subtribe Crepidinae, characterised by a unique combination of morphological features, in particular densely long-papillose homomorphic achenes with five main ribs each accompanied by two secondary ribs, coarse brownish pappus bristles, moderately many-flowered capitula, a small involucre with numerous outer phyllaries, perennial rosette herb growth and brown-woolly caudex and leaf axils. Molecular phylogenetic analysis detected that in the nrITS phylogeny M. oreophila forms a clade of its own in the Crepidinae; in the plastid DNA phylogeny it is nested in the clade formed by the hybridogenous genus Faberia, the maternal ancestor of which comes from the Crepidinae and the paternal ancestor from the Lactucinae, where Faberia is placed in nrITS phylogenies. M. oreophila shares several morphological features with Faberia and also shares the expected chromosome number of 2n = 16 with its hitherto unknown maternal ancestor. M. oreophila may therefore be a successor of the maternal ancestor of Faberia. Alternatively, cytonuclear discordance is to be assumed in Mojiangia, caused by chloroplast capture as a result of hybridisation and introgression with Faberia.

The superstructure of the metro depot is not only convenient for traffic but also solves the land-use problem. However, the construction of the superstructure comes after the metro depot has been put into normal operation. The foundation of the depot is bound to produce secondary settlement. Based on the calculation method of the friction-end bearing pile of Mindlin’s solution in the specification, the superstructure construction project above the Beijing Guogongzhuang metro depot is taken as the basis. Under certain conditions, the settlement of the pile foundation under the action of secondary load and the influence on the track structure are calculated. Moreover, the finite element analysis software ANSYS 18.0 is used to establish the analysis model of the construction of the superstructure of the applied depot. The results show that the influence of the pile foundation settlement produces a certain additional influence on the surrounding tracks, and the maximum value locates at the center of the bearing platform and gradually decreases outward. Under the conditions of informative construction, uniform loading of the structure and control of the construction process, local bias loads and uneven settlements are avoided. The impact of the construction on the track can be effectively controlled, and the impact on the structure can be kept within the allowable limits. By comparing this instance with a number of similar superstructure projects in Beijing, this study shows that the overall risk of this type of project can be controlled and can provide a technical reference for similar superstructure projects on top of a metro depot construction in the future.

Taking a double-line underground excavation subway tunnel underneath the medium-low-speed Maglev bridge section of the Beijing S1 Metro line as a project reference, the deformation control index of the Maglev metro bridge and track panel was studied using numerical simulation and data monitoring, under the conditions of deep-hole grouting measures for the soil layer around the excavation tunnel and active lifting for the superstructure of the viaduct. The results of the numerical simulation show that the maximum deformation value of the pier is −1.73 mm and the maximum vertical deformation value of the Maglev rail track is −1.56 mm. Monitoring shows that the maximum vertical deformation value of the magnetic levitation rail is −1.25 mm and the deformation is within the allowable range. Both numerical simulation and field monitoring results reflect the deformation trend of existing structures; the deep-hole grouting measures taken to strengthen the soil layer around the tunnel and the upper structure of the active roof elevation frame can effectively control the deformation of the existing structure. The study can provide guidance and reference for similar projects.

Abstract. Background:. Innovative coronavirus disease 2019 (COVID-19) vaccines, with elevated global manufacturing capacity, enhanced safety and efficacy, simplified dosing regimens, and distribution that is less cold chain-dependent, are still global imperatives for tackling the ongoing pandemic. A previous phase I trial indicated that the recombinant COVID-19 vaccine (V-01), which contains a fusion protein (IFN-PADRE-RBD-Fc dimer) as its antigen, is safe and well tolerated, capable of inducing rapid and robust immune responses, and warranted further testing in additional clinical trials. Herein, we aimed to assess the immunogenicity and safety of V-01, providing rationales of appropriate dose regimen for further efficacy study. Methods:. A randomized, double-blind, placebo-controlled phase II clinical trial was initiated at the Gaozhou Municipal Centre for Disease Control and Prevention (Guangdong, China) in March 2021. Both younger (n = 440; 18–59 years of age) and older (n = 440; ≥60 years of age) adult participants in this trial were sequentially recruited into two distinct groups: two-dose regimen group in which participants were randomized either to follow a 10 or 25 μg of V-01 or placebo given intramuscularly 21 days apart (allocation ratio, 3:3:1, n = 120, 120, 40 for each regimen, respectively), or one-dose regimen groups in which participants were randomized either to receive a single injection of 50 μg of V-01 or placebo (allocation ratio, 3:1, n = 120, 40, respectively). The primary immunogenicity endpoints were the geometric mean titers of neutralizing antibodies against live severe acute respiratory syndrome coronavirus 2, and specific binding antibodies to the receptor binding domain (RBD). The primary safety endpoint evaluation was the frequencies and percentages of overall adverse events (AEs) within 30 days after full immunization. Results:. V-01 provoked substantial immune responses in the two-dose group, achieving encouragingly high titers of neutralizing antibody and anti-RBD immunoglobulin, which peaked at day 35 (161.9 [95% confidence interval [CI]: 133.3–196.7] and 149.3 [95%CI: 123.9–179.9] in 10 and 25 μg V-01 group of younger adults, respectively; 111.6 [95%CI: 89.6–139.1] and 111.1 [95%CI: 89.2–138.4] in 10 and 25 μg V-01 group of older adults, respectively), and remained high at day 49 after a day-21 second dose; these levels significantly exceed those in convalescent serum from symptomatic COVID-19 patients (53.6, 95%CI: 31.3–91.7). Our preliminary data show that V-01 is safe and well tolerated, with reactogenicity predominantly being absent or mild in severity and only one vaccine-related grade 3 or worse AE being observed within 30 days. The older adult participants demonstrated a more favorable safety profile compared with those in the younger adult group: with AEs percentages of 19.2%, 25.8%, 17.5% in older adults vs. 34.2%, 23.3%, 26.7% in younger adults at the 10, 25 μg V-01 two-dose group, and 50 μg V-01 one-dose group, respectively. Conclusions:. The vaccine candidate V-01 appears to be safe and immunogenic. The preliminary findings support the advancement of the two-dose, 10 μg V-01 regimen to a phase III trial for a large-scale population-based evaluation of safety and efficacy. Trial Registration:. http://www.chictr.org.cn/index.aspx (No. ChiCTR2100045107, http://www.chictr.org.cn/showproj.aspx?proj=124702).

Abstract Background Memantine, a low- to moderate-affinity uncompetitive N-methyl-D-aspartate receptor antagonist, has been shown to improve cognitive functions in animal models of Alzheimer’s disease (AD). Here we treated APP/PS1 AD mice with a therapeutic dose of memantine (20 mg/kg/day) and examined its underlying mechanisms in ameliorating cognitive defects. Methods Using behavioral, electrophysiological, optogenetic and morphology approaches to explore how memantine delay the pathogenesis of AD. Results Memantine significantly improved the acquisition in Morris water maze (MWM) in APP/PS1 mice without affecting the speed of swimming. Furthermore, memantine enhanced EC to CA1 synaptic neurotransmission and promoted dendritic spine regeneration of EC neurons that projected to CA1. Conclusions Our study reveals the underlying mechanism of memantine in the treatment of AD mice.

A taxonomic revision of Sageretia lucida, S. thea var. cordiformis and S. yunlongensis in China is presented. Sageretia lucida is revised in terms of morphological characters (habit, branchlet color, phyllotaxis and rachis length), distribution, habitat, and phenology; S. thea var. cordiformis is raised to S. cordiformis; and S. yunlongensis is excluded from the genus Sageretia and reduced to the synonym of Rhamnus nigricans. Furthermore, a new species, S. ellipsoidea, is erected based on the paratype collections of S. lucida. The new species morphologically differs from S. lucida in having reddish brown branchlets, opposite or subopposite phyllotaxis, shorter rachises, and flowering in spring or early summer. S. ellipsoidea is factually closest to S. hamosa as they share similar woody-vine habit and larger fruit size, and fruiting in winter, whereas the former can be easily recognized based on its smaller leaf blades, fewer lateral veins, shorter rachises, and ellipsoidal or elliptic-ovoid fruits.

According to the previous reports, hypothyroidism has been shown to be strongly correlated with increased circulating concentrations of total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). Notably, thyroid hormones are confirmed to modulate the production, clearance, and transformation process of cholesterol within circulation of mammals. Moreover, emerging evidence suggests that the thyroid-stimulating hormone could also participate in modulating serum lipid metabolism independently of thyroid hormones, which further induces the pathological development of dyslipidemia. However, the underlying mechanism is still not fully elucidated. Recently, several research studies have demonstrated that the pathogenic progression of hypothyroidism-related dyslipidemia might be correlated with the decreased serum concentrations of thyroid hormones and the increased serum concentrations of thyroid-stimulating hormones. Thus, this indicates that hypothyroidism could induce dyslipidemia and its related cardio-metabolic disorder diseases. In addition, several newly identified modulatory biomarkers, such as proprotein convertase subtilisin/kexin type 9 (PCSK9), angiopoietin-like protein (ANGPTLs), and fibroblast growth factors (FGFs), might play an important role in the regulation of dyslipidemia induced by hypothyroidism. Furthermore, under the status of hypothyroidism, significantly dysfunctional HDL particles could also be observed. In the current review, we summarized the recent knowledge of the relationship between the development of hypothyroidism with dyslipidemia. We also discussed the updated understanding of the mechanisms whereby hypothyroidism induces the risk and the development of dyslipidemia and cardio-metabolic diseases.

Background Although many young Chinese women migrate to urban regions for better opportunities, little is known about the prevalence and awareness of having high blood pressure (HBP) in this population. This study investigated the prevalence, awareness, and factors associated with HBP among young female migrant workers in Central South China. Methods We conducted a cross-sectional study to identify HBP (2017 ACC/AHA guidelines) among female migrant workers aged 18–45 years in Central South China. Demographics, anthropometric measurements, hypertension-related lifestyle, awareness of HBP, and blood pressure were recorded. Logistic regression analysis was used to identify the factors associated with HBP (blood pressure ≥ 130/80 mmHg). Results Overall, 232 female migrants participated in the study (mean age 34.4; standard deviation: 6.4 years). The prevalence of HBP was 27.2% (95% CI [21.6–33.2]), and 88.9% of the participants were unaware of their HBP status. Having rural medical insurance (odds ratio [OR] = 20.7; 95% confidence interval 95% CI [2.1–204.8]), awareness of having HBP (OR = 5.1; 95% CI [1.4–18.5]), physical inactivity (OR = 2.9; 95% CI [1.1–7.9]), and being overweight/obese (OR = 2.7; 95% CI [1.3–6.1]) were independently associated with HBP. Conclusions This study revealed a high prevalence of HBP among young Chinese female migrant workers, as well as a high frequency of being unaware of their condition and some associated factors (rural medical insurance, awareness of having HBP, physical inactivity, and overweight/obesity). The uncontrolled HBP among young Chinese female migrant workers suggested that health education needs further promotion in such a population.

China’s raw milk production is confronted with problems such as high production costs, stringent environmental constraints, weak industrial interest linkages, etc. The extensive and inefficient operation mode seriously restricts the further development of China’s dairy industry. How to increase the production efficiency of raw milk and realize the transition from “a country with high milk production” to “a country with high-efficiency milk production” has become the key to further developing China’s dairy industry. In order to explore the upgrading path of the raw milk industry in China, this study used the DEA-Malmquist model to estimate the production efficiency of raw milk in China and analyze its spatial and temporal distribution characteristics based on raw milk production input and output data at four scales (i.e., free-range, small-scale, medium-scale, and large-scale) from 2004 to 2020. It then adopted the SFA model to explore the relationship between raw milk input and output factors and the driving factors of production efficiency. Finally, robustness was discussed according to the existing research differences. The study draws several valuable conclusions. First, the production efficiency of raw milk in China from 2004 to 2020 fluctuated upward and showed specific regular regional distribution characteristics, but the spatial–temporal differences were minor. Second, raw milk production efficiency is significantly influenced by various factors, including the proportion of concentrate to roughage consumption, medical and epidemic prevention investment, the price of raw milk, the wage level, and fixed assets. Third, the spatial–temporal distribution and driving factors of raw milk production efficiency are less robust, so efficiency analysis and improvement measures should fully consider analytical methods, scale heterogeneity, indicator systems, and temporal heterogeneity.

N6-methyladenosine (m6A) RNA modification regulates RNA metabolism, and has been implicated in immune regulation. Here, the authors show that the m6A methyltransferase, METTL3, translocates into the cytoplasm to increase viral RNA m6A modification, decreases viral ds RNA content, and thereby dampens the RIG/MDA5-induced anti-viral immunity.

AimClinical utility of doxorubicin (DOX) is limited by its cardiotoxic side effect, and the underlying mechanism still needs to be fully elucidated. This research aimed to examine the role of (pro)renin receptor (PRR) in DOX-induced heart failure (HF) and its underlying mechanism.Main MethodsSprague Dawley (SD) rats were injected with an accumulative dosage of DOX (15 mg/kg) to induce HF. Cardiac functions were detected by transthoracic echocardiography examination. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK) in serum were detected, and oxidative stress related injuries were evaluated. Furthermore, the mRNA expression of PRR gene and its related genes were detected by real-time PCR (RT-PCR), and protein levels of PRR, RAC1, NOX4 and NOX2 were determined by Western blot. Reactive oxygen species (ROS) were determined in DOX-treated rats or cells. Additionally, PRR and RAC1 were silenced with their respective siRNAs to validate the in vitro impacts of PRR/RAC1 on DOX-induced cardiotoxicity. Moreover, inhibitors of PRR and RAC1 were used to validate their effects in vivo.Key FindingsPRR and RAC1 expressions increased in DOX-induced HF. The levels of CK and LDH as well as oxidative stress indicators increased significantly after DOX treatment. Oxidative injury and apoptosis of cardiomyocytes were attenuated both in vivo and in vitro upon suppression of PRR or RAC1. Furthermore, the inhibition of PRR could significantly down-regulate the expressions of RAC1 and NOX4 but not that of NOX2, while the inhibition of RAC1 did not affect PRR.SignificanceOur findings showed that PRR inhibition could weaken RAC1-NOX4 pathway and alleviate DOX-induced HF via decreasing ROS production, thereby suggesting a promising target for the treatment of DOX-induced HF.

Abstract Background A robust molecular phylogeny is fundamental for developing a stable classification and providing a solid framework to understand patterns of diversification, historical biogeography, and character evolution. As the sixth largest angiosperm family, Lamiaceae, or the mint family, consitutes a major source of aromatic oil, wood, ornamentals, and culinary and medicinal herbs, making it an exceptionally important group ecologically, ethnobotanically, and floristically. The lack of a reliable phylogenetic framework for this family has thus far hindered broad-scale biogeographic studies and our comprehension of diversification. Although significant progress has been made towards clarifying Lamiaceae relationships during the past three decades, the resolution of a phylogenetic backbone at the tribal level has remained one of the greatest challenges due to limited availability of genetic data. Results We performed phylogenetic analyses of Lamiaceae to infer relationships at the tribal level using 79 protein-coding plastid genes from 175 accessions representing 170 taxa, 79 genera, and all 12 subfamilies. Both maximum likelihood and Bayesian analyses yielded a more robust phylogenetic hypothesis relative to previous studies and supported the monophyly of all 12 subfamilies, and a classification for 22 tribes, three of which are newly recognized in this study. As a consequence, we propose an updated phylogenetically informed tribal classification for Lamiaceae that is supplemented with a detailed summary of taxonomic history, generic and species diversity, morphology, synapomorphies, and distribution for each subfamily and tribe. Conclusions Increased taxon sampling conjoined with phylogenetic analyses based on plastome sequences has provided robust support at both deep and shallow nodes and offers new insights into the phylogenetic relationships among tribes and subfamilies of Lamiaceae. This robust phylogenetic backbone of Lamiaceae will serve as a framework for future studies on mint classification, biogeography, character evolution, and diversification. Graphical abstract

Safe and effective vaccines are still urgently needed to cope with the ongoing COVID-19 pandemic. Recently, we developed a recombinant COVID-19 vaccine (V-01) containing fusion protein (IFN-PADRE-RBD-Fc dimer) as antigen verified to induce protective immunity against SARS-CoV-2 challenge in pre-clinical study, which supported progression to Phase I clinical trials in humans. A Randomized, double-blind, placebo-controlled Phase I clinical trial was initiated at the Guangdong Provincial Center for Disease Control and Prevention (Gaozhou, China) in February 2021. Healthy adults aged between 18 and 59 years and over 60 years were sequentially enrolled and randomly allocated into three subgroups (1:1:1) either to receive the vaccine (10, 25, and 50 μg) or placebo (V-01: Placebo = 4:1) intramuscularly with a 21-day interval by a sentinel and dose escalation design. The data showed a promising safety profile with approximately 25% vaccine-related overall adverse events (AEs) within 30 days and no grade 3 or worse AEs. Besides, V-01 provoked rapid and strong immune responses, elicited substantially high-titre neutralizing antibodies and anti-RBD IgG peaked at day 35 or 49 after first dose, presented with encouraging immunogenicity at low dose (10 μg) subgroup and elderly participants, which showed great promise to be used as all-aged (18 and above) vaccine against COVID-19. Taken together, our preliminary findings indicate that V-01 is safe and well tolerated, capable of inducing rapid and strong immune responses, and warrants further testing in Phase II/III clinical trials.

A fourth dose of a COVID-19 vaccine has been recommended by a number of authorities due to waning immunity over time and the emergence of immune-escaping variants. Here, we evaluated the safety and immunogenicity of the bivalent BV-01-B5 or V-01D-351 or the prototype V-01 for heterologous boosting in three-dose inactivated COVID-19 vaccine (ICV) recipients, in comparison with ICV homologous boosting. One pilot study (NCT05583357) included 20 participants randomized at 1:1, either receiving V-01D-351 or CoronaVac. The other one (NCT05585567) recruited 36 participants randomized at 2:1, either receiving BV-01-B5 or V-01, respectively. BV-01-B5, V-01D-351, and V-01 were safe and well-tolerated as heterologous booster shots after three doses of ICV, with adverse reactions predominantly being mild and moderate in severity, similar to the safety profile of ICV boosters. The bivalent V-01D-351 and BV-01-B5 and prototype V-01 booster demonstrated remarkable cross-reactive immunogenicity against the prototype and multiple emerging variants of concern (VOCs), with the geometric mean ratio (versus CoronaVac) in particular being 31.3 (500 vs. 16), 12.0 (192 vs. 16) and 8.5 (136 vs.16) against BA.4/5 14 days after the booster, respectively. Taken together, the modified bivalent-formulation V-01 boosters induced robust neutralizing responses against multiple Omicron sublineages, better than V-01 and remarkably superior to ICV booster, without compromising the safety and tolerability.

The role of PD-L1 expression on tumor-infiltrating immune cells in promoting tumor immune escape is not fully understood. Here, the authors show that PD-L1 expression by dendritic cells plays a crucial role in hindering anti-tumor T cell responses and is essential for the therapeutic efficacy of PD-L1 blockade.

With the economic and social development and the improvement of people’s living standards, consumers have put forward higher requirements for clothing from quantity to quality. The clothing industry has ushered in vigorous vitality and broad development space. China’s clothing industry has achieved great results after long-term development. With the gradual abolition of world textile and apparel trade quotas, China’s apparel and textile industry is facing greater opportunities and challenges. In today’s increasingly developing market economy, many production companies are making marketing forecasts. A good forecast result can be used to guide the company’s decision-making. The results of the model help decision-makers to reasonably arrange production and formulate marketing strategies. With the development of genetic neural network technology, this technology has been more and more widely used in signal processing, pattern recognition and other application fields. This article discusses a marketing forecasting model based on genetic neural network, predicting model parameters based on historical data of actual sales, and then carrying out experimental analysis. First of all, a series of analysis and preprocessing must be performed on the collected data. In the process of estimating and calculating the parameters of the prediction model, an error criterion is selected to determine a set of relatively optimal prediction parameters, and finally the model results A verification analysis was carried out. The experimental results show that the genetic neural network method can be used to establish a marketing forecasting model, and the established forecasting model has certain practical application value.

Silicon (Si) plays a pivotal role in mitigating phytotoxicity caused by cadmium (Cd). However, few former reports focused on the internal mechanism how Si assisted in alleviating Cd stress in rice under different durations of Cd exposure. Herein, the effects of Si on subcellular distribution of Cd in rice roots under short-term (12 h) and long-term (20 d) Cd exposure were explored. Results showed that Si decreased shoot Cd concentration but had little impact on root Cd levels. Under short-term Cd exposure, subcellular distribution analysis showed that Si increased the ratio of Cd in root cell wall by 23.2~24.0%, and decreased the ratio of Cd in root soluble fraction by 20.6~21.5%. This suggested that Si supply improved root retention of Cd by fixing it on the cell wall and thus restricted intracellular transportation of Cd. Further analysis unraveled that pectin (especially ionic-soluble pectin) of the cell wall was the main binding component, and Si supply induced more Cd accumulation in covalent-soluble pectin and hemicellulose. Moreover, the overexpression of germin-like proteins (GLPs) proved the role of cell wall in moderating Cd toxicity. Under long-term Cd exposure, Si promoted phytochelatin 2 (PC2) and phytochelatin 3 (PC3) synthesis in cytosol, at the same time, Si down-regulated the expression of the Cd efflux-related protein multidrug resistance-associated protein-like ATP-binding cassette transporters (MRP-like ABC transporters) and limited Cd transportation from vacuole to cytosol. Taken together, Si rather predominates in limiting Cd translocation by the cell wall of root under short-term Cd exposure and promoting vacuole compartmentalization to mitigate the Cd toxicity under long-term exposure, instead of reducing the absorption of Cd in rice roots, thereby decreasing Cd delivery into shoots.

Organic-inorganic hybrid perovskite materials possess advantages over other candidate classes for chemo-sensory materials because of their structural tunability and stability. In this work, we prepared highly qualitied MAPbBr3 perovskite crystals to provide a high carrier mobility to enhance the sensing on gas, where the response time of sensing below 0.1 s is obtained. Because the perovskite field effect transistor provides a large surface to adsorb gas, the sensitivity of detection can reach 0.2 ppm. Furthermore, combining with theoretical simulation, we analyzed the binding energy, electronic structure, and charge transfer density between perovskite surface (including PbBr2-terminated surface and CH3NH3Br-terminated surface) and gas molecules to study the mechanism behind the phenomena. It is obtained that enhancing the interfacial charge transfer density and then suppressing the recombination of transferred charges will effectively increase the sensitivity of the sensor.

BackgroundConcurrent chemoradiotherapy (CRT) is the preferred treatment strategy for inoperable esophageal cancer (EC). However, the effect of CRT needs to be improved.MethodsThis study comprehensively analyzed targeted agents combined with CRT for the treatment of EC by a network meta-analysis. The search was performed in public databases from incipient to 5 August 2021. Randomized controlled trials comparing the effect of targeted agents combined with CRT and CRT alone on EC patients were included.ResultsTen studies were included. For progression-free survival (PFS), nivolumab (67.4%) and erlotinib (64.6%) had advantages based on Cox analysis. Regarding the frequency of PFS, cetuximab (OR: 1.39; 95% CI: 1.01, 1.91; p=0.042) and nivolumab (OR: 1.81; 95% CI: 1.34, 2.44; p

Abstract The novel coronavirus (2019‐nCoV) was first detected in patients with pneumonia of an unknown cause in Wuhan, China in December 2019. It has since been confirmed as the pathogen for the new coronavirus pneumonia, recently named “coronavirus disease 2019” (COVID‐19) by the World Health Organization. Although the general population is commonly susceptible to the disease, infected elderly people show fast progression and severe manifestations with a high proportion in critical condition as a result of compromised immunity and underlying diseases. In order to improve the quality of nursing, reduce complications, and decrease mortality of critically ill elderly patients, we assembled a national expert group with expertise in critical nursing to write this consensus, based on a literature review and a subsequent panel discussion. The consensus covers the assessment, clinical nursing, discharge care, and other aspects of care for critically ill elderly patients with COVID‐19, aiming to share insights and provide guidance for clinical practice.

Abstract Background As a new generation antihistamine, fexofenadine has been widely used in allergic diseases. However, there is still a lack of collective evidence regarding the antihistamine effects and safety profiles of fexofenadine relative to other antihistamine drugs and placebo. Therefore, we aimed to systematically evaluate the antihistamine effects and safety of fexofenadine. Methods An electronic literature search of randomized controlled trials (RCTs) was performed using Embase, Cochrane and PubMed from establishment to January 1st, 2018. RCTs comparing the antihistamine effects or safety (adverse events, sedative effects, and cognitive/psychomotor function) of fexofenadine with either other antihistamines or placebo for healthy subjects and patients with allergy were selected. Results Fifty-one studies of 14,551 participants met the inclusion criteria. When compared with the first-generation antihistamines, fexofenadine produced significantly lower adverse events frequency (OR = 0.446; 95% CI: 0.214 to 0.929, P = 0.031), significantly lower sedative effects frequency (OR = 0.265; 95% CI: 0.072 to 0.976, P = 0.046) and significantly less change of all cognitive/psychomotor function. When compared with the second-generation antihistamines, fexofenadine produced significantly marginal sedative effects (OR = 0.59; 95% CI, 0.38 to 0.93; P = 0.02) and significantly less change of most of the cognitive/psychomotor function. When compared with placebo, fexofenadine produced more significant antihistamine effects. Conclusions Fexofenadine has a positive antihistamine effect, which is probably no worse than the second-generation antihistamines. Fexofenadine probably has a favorable safety profile, which is more likely better than that of the first-generation antihistamines. There is lack of data to support that fexofenadine has a better overall safety profile compared to the second-generation antihistamines, however, some presently available evidence on sedative effects and certain aspects of cognitive/psychomotor function favors fexofenadine. Therefore, fexofenadine may be worthy of recommendation for safety related workers.

Abstract Histamine H1 receptor (H1R) and histamine H4 receptor (H4R) are essential in allergic inflammation. The roles of H4R have been characterized in T cell subsets, whereas the functional properties of H4R in monocytes remain unclear. In the current study, the responses of H4R in peripheral monocytes from patients with allergic rhinitis (AR) were investigated. The results confirmed that H4R has the functional effects of mediating cytokine production (i.e., down-regulating IFN-γ and up-regulating IL-6) in cells from a monocyte cell line following challenge with histamine. We demonstrated that when monocytes from AR patients were stimulated with allergen extracts of house dust mite (HDM), IFN-γ secretion was dependent on H4R activity, but IL-6 secretion was based on H1R activity. Furthermore, a combination of H1R and H4R antagonists was more effective at blocking the inflammatory response in monocytes than treatment with either type of antagonist alone.

Interleukin-2 (IL-2) based cancer therapy is limited by severe toxicity and strong Treg amplification at the therapeutic dosage. Here, the authors develop a recombinant IL-2 immunocytokine which is comprised of a tumor-targeting antibody fused to a super mutant IL-2 and show in mouse models that this next-generation IL2 has reduced toxicity and enhanced antitumor activity.

Abstract Global Navigation Satellite System (GNSS) has become a powerful tool for sensing precipitable water vapor (PWV), which is important in investigating long‐term climate or nowcasting. Zenith hydrostatic delay (ZHD) and weighted mean temperature (Tm) are the two key parameters for retrieving PWV GNSS observations. ZHD is generally derived from the Saastamoinen model by using surface pressure or numerical weather model (NWM). However, the lack of meteorological observations located at or near the GNSS sites is a big challenge for the calculation of accurate ZHD, leading to inconvenience in GNSS‐derived PWV. In this study, a method for GNSS retrieval in China by using ZHD from the NWM and Tm derived from IGPT2w is proposed. First, a new grid model, namely CGZHD model, is developed for the vertical adjustment of ZHD in China. Then, two types of ZHD products derived from NWM data, that is, postprocessing and forecast ones, namely ZHD and ZHDFC, respectively. Finally, the performance of GNSS PWV estimation for 18 GNSS sites is evaluated with PWVs from collocated radiosonde sites for China. Results show that the CGZHD model has excellent performance against the GPT2w model and previous studies. ZHD and ZHDFC from NWM present high precision after vertical adjustment. In terms of GNSS PWV retrieval, two modes of GNSS PWV estimation results, that is, ZHD and ZHDFC obtained from postprocessing and forecast ones, respectively, show excellent performance in China. The proposed method does not require any in situ meteorological information as input and thus has potential applications for high‐precision and real‐time GNSS PWV retrieval in China.