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Abstract To prevent sexually-acquired HIV-1 infection by immunoprophylaxis, effective concentrations of broadly neutralizing antibodies are likely needed at mucosal sites of exposure. Here, we examine the biodistribution of monoclonal antibody VRC01 and its extended half-life variant, VRC01LS, in colorectal and genitourinary tracts of healthy adults 1-52 weeks after intravenous infusion. At 1-2 weeks, VRC01LS levels are ~3-4 times higher than VRC01 in serum (p = 0.048), rectal (p = 0.067), vaginal (p = 0.003) and cervical tissues (p = 0.003); these differences increase over time. Both antibodies primarily localize within rectal lamina propria and cervicovaginal stroma, with limited and variable epithelial distribution. Although 8-28% of serum mAb levels reach mucosal tissues,

Abstract Assessment of immune correlates of severe COVID-19 has been hampered by the low numbers of severe cases in COVID-19 vaccine efficacy (VE) trials. We assess neutralizing and binding antibody levels at 4 weeks post-Ad26.COV2.S vaccination as correlates of risk and of protection against severe-critical COVID-19 through 220 days post-vaccination in the ENSEMBLE trial (NCT04505722), constituting ~4.5 months longer follow-up than our previous correlates analysis and enabling inclusion of 42 severe-critical vaccine-breakthrough cases. Neutralizing antibody titer is a strong inverse correlate of severe-critical COVID-19, with estimated hazard ratio (HR) per 10-fold increase 0.35 (95% CI: 0.13, 0.90). In a multivariable model, HRs are 0.31 (0.11, 0.89) for neutralizing antibody titer and 1.22 (0.49, 3.02) for anti-Spike binding antibody concentration. VE against severe-critical COVID-19 rises with neutralizing antibody titer: 63.1% (95% CI: 40.0%, 77.3%) at unquantifiable [

Abstract In the phase 3 Coronavirus Efficacy (COVE) trial (NCT04470427), post-dose two Ancestral Spike-specific binding (bAb) and neutralizing (nAb) antibodies were shown to be correlates of risk (CoR) and of protection against Ancestral-lineage COVID-19 in SARS-CoV-2 naive participants. In the SARS-CoV-2 Omicron era, Omicron subvariants with varying degrees of immune escape now dominate, seropositivity rates are high, and booster doses are administered, raising questions on whether and how these developments affect the bAb and nAb correlates. To address these questions, we assess post-boost BA.1 Spike-specific bAbs and nAbs as CoRs and as correlates of booster efficacy in COVE. For naive individuals, bAbs and nAbs inversely correlate with Omicron COVID-19: hazard ratios (HR) per 10-fold marker increase (95% confidence interval) are 0.16 (0.03, 0.79) and 0.31 (0.10, 0.96), respectively. In non-naive individuals the analogous results are similar: 0.15 (0.04, 0.63) and 0.28 (0.07, 1.08). For naive individuals, three vs two-dose booster efficacy correlates with predicted nAb titer at exposure, with estimates -8% (-126%, 48%), 50% (25%, 67%), and 74% (49%, 87%), at 56, 251, and 891 Arbitrary Units/ml. These results support the continued use of antibody as a surrogate endpoint.

Abstract Angiogenesis is extensively involved in embryonic development and requires complex regulation networks, whose defects can cause a variety of vascular abnormalities. Cis-regulatory elements control gene expression at all developmental stages, but they have not been studied or profiled in angiogenesis yet. In this study, we exploited public DNase-seq and RNA-seq datasets from a VEGFA-stimulated in vitro angiogenic model, and carried out an integrated analysis of the transcriptome and chromatin accessibility across the entire process. Totally, we generated a bank of 47,125 angiogenic cis-regulatory elements with promoter (marker by H3K4me3) and/or enhancer (marker by H3K27ac) activities. Motif enrichment analysis revealed that these angiogenic cis-regulatory elements interacted preferentially with ETS family TFs. With this tool, we performed an association study using our WES data of TAPVC and identified rs199530718 as a cis-regulatory SNP associated with disease risk. Altogether, this study generated a genome-wide bank of angiogenic cis-regulatory elements and illustrated its utility in identifying novel cis-regulatory SNPs for TAPVC, expanding new horizons of angiogenesis as well as vascular abnormality genetics.

Summary: Standard flow cytometry-based assays can determine the cytotoxicity of immune effector cells, but it is challenging to monitor the dynamic processes of cytotoxicity. Here, we present a protocol for continuous observation of natural killer (NK) cell-mediated cytotoxicity with microwell arrays using an automated microscope. We describe steps for isolating and labeling primary NK cells, loading cells onto microwell arrays, monitoring target wells, and image analysis. This protocol facilitates observation of the dynamics of immune-target cell interactions at the single-cell level.For complete details on the use and execution of this protocol, please refer to Li et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Heat-induced stress has a significant impact on the health of broilers. It induces panting behavior and elevates oxygen consumption, leading to considerable strain on the broiler lungs. However, the precise effects of heat stress on lung injury, along with changes in the lung and gut microbiota, are not yet fully understood. In our study, Arbor Acres (AA) broilers were employed as a model to assess the efficacy of sodium butyrate (SB) in mitigating heat stress-induced lung injury, while concurrently exploring the potential role of lung and gut microbiota in this phenomenon. Heat stress negatively affected broilers, particularly leading to lung injury, which was alleviated by dietary supplementation with SB. However, antibiotic-induced dysbiosis of the microbiota diminished the protective effects of SB, highlighting the critical importance of gut microbiota homeostasis. Heat stress resulted in a reduction in lung microbial diversity and altered its composition, primarily due to the depletion of g_Clostridia and the proliferation of g_Staphylococcus. SB supplementation helped restore beneficial microbes and improved their adaptation to heat stress. Heat stress induced comparable effects on the gut microbiota, resulting in a decline in p_Firmicutes and an elevation in p_Bacteroidetes. However, SB supplementation effectively modulated these alterations in the gut microbiota, promoting a more beneficial microbial profile. Our findings highlighted the significant contributions of both lung and gut microbiota in maintaining homeostasis during heat stress. Moreover, SB administration demonstrated its efficacy in mitigating heat stress-induced lung injury in broilers. This study provides critical insights for developing dietary strategies to reduce heat stress and promote broiler health.

Key Clinical Message Abscess at a previous surgical site induced by an insect bite has rarely been reported. Here we report a case of abscess at the breast surgical site, which occurred 7 years after mastectomy following an ant bite. Abstract Surgical site abscess generally occurs following operation within 30 days. However, surgical site abscess induced by an insect bite, which occurs several years after surgery, has rarely been reported. Here, we report a 65‐year‐old female patient with a history of breast cancer presenting with an abscess at the site of her mastectomy and ipsilateral arm lymphedema. Her left foot was bitten by an ant 25 days earlier and itchy red bumps with whiteheads were raised. After antibiotic treatment and abscess incision and drainage, the abscess healed, but the ipsilateral arm lymphedema persisted. This unique case demonstrates that surgical procedures can alter the susceptibility of tissues to allergic or infectious cues long after the operation.

Introduction: Rhubarb is a frequently used and beneficial traditional Chinese medicine. Wild resources of these plants are constantly being depleted, meaning that rhubarb products have been subjected to an unparalleled level of adulteration. Consequentially, reliable technology is urgently required to verify the authenticity of rhubarb raw materials and commercial botanical drugs.Methods: In this study, the barcode-DNA high-resolution melting (Bar-HRM) method was applied to characterize 63 rhubarb samples (five Polygonaceae species: Rheum tanguticum, Rh. palmatum, Rh. officinale, Rumex japonicus and Ru. sp.) and distinguish the rhubarb contents of 24 traditional Chinese patent medicine (TCPM) samples. Three markers, namely ITS2, rbcL and psbA-trnH, were tested to assess the candidate DNA barcodes for their effectiveness in distinguishing rhubarb from its adulterants. A segment from ITS2 was selected as the most suitable mini-barcode to identify the botanical drug rhubarb in TCPMs. Then, rhubarbs and TCPM samples were subjected to HRM analysis based on the ITS2barcode.Results: Among the tested barcoding loci, ITS2 displayed abundant sites of variation and was effective in identifying Polygonaceae species and their botanical origins. HRM analysis based on the ITS2 mini-barcode region successfully distinguished the authenticity of five Polygonaceae species and eight batches of TCPMs. Of the 18 TCPM samples, 66.7 % (12 samples) were identified as containing Rh. tanguticum or Rh. officinale. However, 33.3 % were shown to consist of adulterants.Conclusions: These results demonstrated that DNA barcoding combined with HRM is a specific, suitable and powerful approach for identifying rhubarb species and TCPMs, which is crucial to guaranteeing the security of medicinal plants being traded internationally.

This study was designed to develop a 30 m resolution land cover dataset to improve the performance of regional weather forecasting models in East China. A 10-class land cover mapping scheme was established, reflecting East China’s diverse landscape characteristics and incorporating a new category for plastic greenhouses. Plastic greenhouses are key to understanding surface heterogeneity in agricultural regions, as they can significantly impact local climate conditions, such as heat flux and evapotranspiration, yet they are often not represented in conventional land cover classifications. This is mainly due to the lack of high-resolution datasets capable of detecting these small yet impactful features. For the six-province study area, we selected and processed Landsat 8 imagery from 2015–2018, filtering for cloud cover. Complementary datasets, such as digital elevation models (DEM) and nighttime lighting data, were integrated to enrich the inputs for the Random Forest classification. A comprehensive training dataset was compiled to support Random Forest training and classification accuracy. We developed an automated workflow to manage the data processing, including satellite image selection, preprocessing, classification, and image mosaicking, thereby ensuring the system’s practicality and facilitating future updates. We included three Weather Research and Forecasting (WRF) model experiments in this study to highlight the impact of our land cover maps on daytime and nighttime temperature predictions. The resulting regional land cover dataset achieved an overall accuracy of 83.2% and a Kappa coefficient of 0.81. These accuracy statistics are higher than existing national and global datasets. The model results suggest that the newly developed land cover, combined with a mosaic option in the Unified Noah scheme in WRF, provided the best overall performance for both daytime and nighttime temperature predictions. In addition to supporting the WRF model, our land cover map products, with a planned 3–5-year update schedule, could serve as a valuable data source for ecological assessments in the East China region, informing environmental policy and promoting sustainability.

Rhubarb is a significant medicinal herb in China. Its adulteration or fabrication is common in the market. Consequently, it is necessary to establish a comprehensive identification method to accurately identify genuine rhubarb and its adulterants. In this study, the sequences of chloroplast genes rps3-rpl22 and rpl16 from three genuine rhubarbs (Rheum tanguticum, Rh. palmatum and Rh. officinale) and their adulterants (Rumex japonicus and Rumex spp.) were amplified, sequenced and subjected to genetic analyses. The genetic distances for rps3-rpl22 and rpl16 between genuine rhubarbs and their adulterants showed that there was an evident barcoding gap, which allowed the adulterants to be distinguished from the genuine rhubarbs, as demonstrated by a neighbor joining tree. Additionally, Rh. officinale could be distinguished from the other two genuine rhubarbs. The anthraquinone, sennoside, polysaccharide and protein contents were analyzed in seven rhubarbs using high-performance liquid chromatography and ultraviolet spectrophotometry. Cluster and principal component analyses results showed that Rh. tanguticum and Rh. palmatum could be effectively distinguished. The study suggests that DNA barcoding based on rps3-rpl22 and rpl16 sequences coupled with multiple-indicator quantification can be successfully applied to identify rhubarb species and distinguish among the three genuine rhubarbs, and this can provide a scientific foundation for rhubarb quality assurance.

ObjectivesIn order to reduce the influence of ship service life extension uncertainty and fatigue risk during future service life extension, a dynamic maintenance sequence decision based on the real option analysis method is adopted. MethodsThe local fatigue of a high-speed ship is taken as an example. This strategy strengthens the maintenance in the early stages of the ship's service and determines the adaptive maintenance decision according to the requirements of service life extension in the later stages, thereby adapting to the various possibilities of service life extension in the future. ResultsCompared with the traditional maintenance strategy, the flexible decision under real option analysis can reduce the influence of service life extension uncertainty and effectively reduce failure risk during service life extension. ConclusionsThe sequential decision made via the real option analysis method has strong adaptability to the uncertainty of service life extension in the future and provides a new idea for maintenance decisions.

Hypoxanthine phosphoribosyl transferase 1 (HPRT1), once considered a housekeeping gene, has been identified as playing an important role in several tumors. Its role in pan-cancer, however, has not been systematically studied. This study evaluates the relationship between HPRT1 and clinical parameters, survival prognosis, and tumor immunity based on multi omics data from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Drug sensitivity analysis screened 16 effective drugs against HPRT1, exploring the interactions with chemicals and genes. The significance of HPRT1 in tumor immunotherapy has also been investigated. Immunohistochemistry confirmed significant differences in the expression of HPRT1 between five tumor types (colon adenocarcinoma [COAD], head-neck squamous cell carcinoma [HNSC], lung adenocarcinoma [LUAD], thyroid carcinoma [THCA], and uterine corpus endometrial carcinoma [UCEC]) and adjacent normal tissues (P < 0.05). HPRT1 competitive endogenous RNA network was constructed in HNSC. Through cytological experiments, it was verified that HPRT1 plays a carcinogenic role in HNSC and is associated with tumor cell proliferation, migration, invasion, and apoptosis. In addition, there was a significant positive correlation between HPRT1 and programmed cell death-1 (PD-1) expression in HNSC (P < 0.05). These findings suggest that HPRT1 may be a potential biomarker for predicting and treating cancer.

Abstract In the phase 3 trial of the AZD1222 (ChAdOx1 nCoV-19) vaccine conducted in the U.S., Chile, and Peru, anti-spike binding IgG concentration (spike IgG) and pseudovirus 50% neutralizing antibody titer (nAb ID50) measured four weeks after two doses were assessed as correlates of risk and protection against PCR-confirmed symptomatic SARS-CoV-2 infection (COVID-19). These analyses of SARS-CoV-2 negative participants were based on case-cohort sampling of vaccine recipients (33 COVID-19 cases by 4 months post dose two, 463 non-cases). The adjusted hazard ratio of COVID-19 was 0.32 (95% CI: 0.14, 0.76) per 10-fold increase in spike IgG concentration and 0.28 (0.10, 0.77) per 10-fold increase in nAb ID50 titer. At nAb ID50 below the limit of detection (< 2.612 IU50/ml), 10, 100, and 270 IU50/ml, vaccine efficacy was −5.8% (−651%, 75.6%), 64.9% (56.4%, 86.9%), 90.0% (55.8%, 97.6%) and 94.2% (69.4%, 99.1%). These findings provide further evidence towards defining an immune marker correlate of protection to help guide regulatory/approval decisions for COVID-19 vaccines.

Authors have previously reported on the efficacy and safety of the recombinant spike protein nanoparticle vaccine, NVX-CoV2373, in healthy adults. In this work, they assess anti-spike binding IgG, anti-RBD binding IgG and neutralising antibody titer as correlates of risk and protection against COVID-19.

Abstract Background and aims Effective traction is an important prerequisite for successful endoscopic submucosal dissection (ESD). The combined orthodontic rubber band (ORB) and clip method was effective in colorectal cancer ESD. To date, the method was not reported in gastric ESD. This study aimed to investigate its efficacy and safety for gastric neoplasms ESD. Methods We retrospectively analyzed data of 118 patients with gastric neoplasms treated by ESD from November 2020 to April 2022, 43 by ORB-ESD and 75 by the conventional ESD. The primary outcome measure was the ESD procedure time. Clinical data on efficacy and safety were also collected and analyzed. Propensity score matching (PSM) matched the patients in both groups. Results PSM successfully matched 31 pairs of patients. The ORB-ESD operation time was shorter (median [interquartile range], 35 [30–48] vs. 49 [40–70] min, P 0.05). Conclusions Compared to the conventional ESD, ORB-ESD significantly reduced the procedure time and increased the dissection speed, proving beneficial to gastric ESD.

Common vetch (Vicia sativa L.) is an important annual diploid leguminous forage. In the present study, transcriptomic profiling in common vetch in response to salt stress was conducted using a salt-tolerant line (460) and a salt-sensitive line (429). The common responses in common vetch and the specific responses associated with salt tolerance in 460 were analyzed. Several KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, including plant hormone and MAPK (mitogen-activated protein kinase) signaling, galactose metabolism, and phenylpropanoid phenylpropane biosynthesis, were enriched in both lines, though some differentially expressed genes (DEGs) showed distinct expression patterns. The roots in 460 showed higher levels of lignin than in 429. α-linolenic acid metabolism, carotenoid biosynthesis, the photosynthesis-antenna pathway, and starch and sucrose metabolism pathways were specifically enriched in salt-tolerant line 460, with higher levels of accumulated soluble sugars in the leaves. In addition, higher transcript levels of genes involved in ion homeostasis and reactive oxygen species (ROS) scavenging were observed in 460 than in 429 in response to salt stress. The transcriptomic analysis in common vetch in response to salt stress provides useful clues for further investigations on salt tolerance mechanism in the future.

Background: Perfluoroheptanoic acid (PFHpA), a persistent organic pollutant widespread in the environment, is suspected as an environmental endocrine disruptor for its disturbance effect on hormone homeostasis and reproductive development. Whereas the effect of intrauterine PFHpA exposure during gestation on spermatogenesis of male offspring mice is still unknown. Objective: This study aimed to explore the effect of prenatal PFHpA exposure on the reproductive development of male offspring mice and the role of N6-methyladenosine (m6A) during the process. Methods: Fifty-six C57BL/6 pregnant mice were randomly divided into 4 groups. During the gestation period, the pregnant mice were exposed to 0, 0.0015, 0.015, and 0.15 mg/kg bw/d PFHpA from gestational day 1 (GD1) to GD16 by oral gavage. The male offspring mice were sacrificed by spinal dislocation at 7 weeks old. The body weight, testicular weight, and brain weight were weighed, and the intra-testicular testosterone was detected. The sperm qualities were analyzed with computer-aided sperm analysis (CASA). The testicular tissues were taken to analyze the pathological changes and examine the global m6A RNA methylation levels. Quantitative real-time PCR (qRT-PCR) was adopted to figure out the mRNA expression levels of m6A-related enzymes in testicular tissues of different PFHpA treated groups. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) was applied to further explore the m6A RNA methylation at a whole-genome scale. Results: Compared with the control group, no significant differences were observed in body weight, testicular weight, testicular coefficient, and the visceral-brain ratio of testicular tissue in the PFHpA treated groups. And no significant change was observed in intra-testicular testosterone among the four groups. CASA results showed a decrease of sperm count, sperm concentration, and total cell count, as well as an increase of sperm progressive cells’ head area after prenatal PFHpA exposure (P

Multi cooperative satellites can provide multi spectral, multi temporal, multi factor, multi scale and multi-level remote sensing data, which is rich in valuable information for numerical weather prediction (NWP).In order to support earth system seamless fine gridded forecasting service in the future, the application status of satellite observation big data was discussed for numerical weather prediction from the aspects of detection variables, time density, spatial coverage, horizontal and vertical resolution, as well as accuracy and timeliness.At the same time, in order to make satellite big data be highly tolerant with NWP, the challenges and prospects were summarized, such as multi-satellite integrated and consistent processing, all-weather, coupled data assimilation methods, deep integration with artificial intelligence, and interaction between satellite observation and prediction.

Abstract Targeting CD96 that originates in immune cells has shown potential for cancer therapy. However, the role of intrinsic CD96 in solid tumor cells remains unknown. Here, it is found that CD96 is frequently expressed in tumor cells from clinical breast cancer samples and is correlated with poor long‐term prognosis in these patients. The CD96+ cancer cell subpopulations exhibit features of both breast cancer stem cells and chemoresistance. In vivo inhibition of cancer cell‐intrinsic CD96 enhances the chemotherapeutic response in a patient‐derived tumor xenograft model. Mechanistically, CD96 enhances mitochondrial fatty acid β‐oxidation via the CD155‐CD96‐Src‐Stat3‐Opa1 pathway, which subsequently promotes chemoresistance in breast cancer stem cells. A previously unknown role is identified for tumor cell‐intrinsic CD96 and an attractive target in improving the chemotherapeutic response.

BackgroundGrowing evidence has indicated that epigenetic factors might be associated with the pathophysiology of idiopathic nonobstructive azoospermia (iNOA). As the most common RNA modification, N6-methyladenosine (m6A) methylation has recently attracted more attention in the regulation of spermatogenesis; however, its role in the mechanisms of iNOA is still unclear.ObjectiveTo determine the differential expression of mRNA and m6A methylation status in the testes of iNOA patients.MethodsTestes tissues from diagnosed iNOA and controlled obstructive azoospermia (OA) patients were collected and grouped according to the histological examinations. Total RNA was isolated and quantified by an m6A RNA Methylation Quantification Kit. The expression level of mRNAs was detected by qRT-PCR analysis. Differentially expressed m6A genes were analyzed using the human ArrayStar m6A epitranscriptomic microarray, and bioinformatics analyses were applied.ResultsA total of 36 iNOA and 8 controlled patients were included. The global expression of m6A in the iNOA group was significantly decreased. A dosage relationship was observed between the m6A decline and the degree of impaired spermatogenesis, with the successive process of normal spermatogeneis, hypospermatogenesis (HP), maturation arrest (MA), and Sertoli cell-only syndrome (SO). Four down-expressed genes (BDNF, TMEM38B, RPL3L, and C22orf42) displayed significantly lower expression of m6A methylation. Additionally, they also showed a gradually down-expressed tendency in the three groups (OA, HP, SO/MA groups). Moreover, m6A reader EIF3A was approved to have differential expression through microarrays analysis, which was consistent with the result from the qRT-PCR test.ConclusionsThe m6A expression was gradually downregulated in the testes tissue from iNOA patients in accordance with the degree of spermatogenic dysfunction. The determined differential expression of mRNA and m6A methylation status may represent potentially novel molecular targets for the mechanism study of iNOA in the epigenetic level, which could benefit the understanding of the pathophysiology of iNOA.

The COVE trial randomized participants to receive two doses of mRNA-1273 vaccine or placebo on Days 1 and 29 (D1, D29). Anti-SARS-CoV-2 Spike IgG binding antibodies (bAbs), anti-receptor binding domain IgG bAbs, 50% inhibitory dilution neutralizing antibody (nAb) titers, and 80% inhibitory dilution nAb titers were measured at D29 and D57. We assessed these markers as correlates of protection (CoPs) against COVID-19 using stochastic interventional vaccine efficacy (SVE) analysis and principal surrogate (PS) analysis, frameworks not used in our previous COVE immune correlates analyses. By SVE analysis, hypothetical shifts of the D57 Spike IgG distribution from a geometric mean concentration (GMC) of 2737 binding antibody units (BAU)/mL (estimated vaccine efficacy (VE): 92.9% (95% CI: 91.7%, 93.9%)) to 274 BAU/mL or to 27,368 BAU/mL resulted in an overall estimated VE of 84.2% (79.0%, 88.1%) and 97.6% (97.4%, 97.7%), respectively. By binary marker PS analysis of Low and High subgroups (cut-point: 2094 BAU/mL), the ignorance interval (IGI) and estimated uncertainty interval (EUI) for VE were [85%, 90%] and (78%, 93%) for Low compared to [95%, 96%] and (92%, 97%) for High. By continuous marker PS analysis, the IGI and 95% EUI for VE at the 2.5th percentile (519.4 BAU/mL) vs. at the 97.5th percentile (9262.9 BAU/mL) of D57 Spike IgG concentration were [92.6%, 93.4%] and (89.2%, 95.7%) vs. [94.3%, 94.6%] and (89.7%, 97.0%). Results were similar for other D29 and D57 markers. Thus, the SVE and PS analyses additionally support all four markers at both time points as CoPs.

Dynamic and continuous land use and cover change (LUCC) is one of the external forcing factors affecting regional climate in China. Based on the annual dynamic global land cover dataset derived from the Global Land Surface Satellite (GLASS-GLC), this paper modelled and investigated the effects of annual transient LUCC on precipitation over China using the regional climate model RegCM4.8.2. Analysis of the GLASS-GLC data revealed that considerable conversions of cropland to forest, grassland to cropland and bare ground to grassland had occurred during the last 3 decades (1984–2013) in southern, northeastern and northwestern China respectively. By comparing the differences between the two sets of experiments under the fixed LUCC and dynamic LUCC scenarios, the results showed that reforestation in southern China during the past 3 decades significantly enhanced local convective afternoon rainfall (CAR; ∼2 mm/day) during the post-flood season (POF; July-August-September). This reforestation effect on CAR also increased with the intensity of LUCC. However, the realistic LUCC effects were weak and negligible for other periods, regions and large-scale precipitation. Furthermore, we have identified two possible reasons that favored the occurrence of POFCAR, namely that the moisture and instability conditions required to trigger convections were both enhanced by reforestation. This was evidenced by increases (decreases) in convective available potential energy (lifting condensation level), increases in atmospheric water vapor content and declining tendencies of equivalent potential temperature with height. Overall, this study highlights the importance of reforestation impacts on the diurnal variations of the precipitation.

Alfalfa is one of the most important legume forages in the world. Root rot caused by soil-borne pathogens severely restricts the production of alfalfa. The knowledge of the interaction between alfalfa and root rot-pathogens is still lacking in China. Phytophthora cactorum was isolated from symptomatic seedlings of an alfalfa field in Nanjing with high levels of damping-off. We observed the different infection stages of P. cactorum on alfalfa, and found that the purified P. cactorum strain was aggressive in causing alfalfa seed and root rot. The infecting hyphae penetrated the epidermal cells and wrapped around the alfalfa roots within 48 h. By evaluating the resistance of 37 alfalfa cultivars from different countries to P. cactorum, we found Weston is a resistant variety, while Longdong is a susceptible variety. We further compared the activities of various enzymes in the plant antioxidant enzyme system between Weston and Longdong during P. cactorum infection, as well as gene expression associated with plant hormone biosynthesis and response pathways. The results showed that the disease-resistant variety Weston has stronger antioxidant enzyme activity and high levels of SA-responsive PR genes, when compared to the susceptible variety Longdong. These findings highlighted the process of interaction between P. cactorum and alfalfa, as well as the mechanism of alfalfa resistance to P. cactorum, which provides an important foundation for breeding resistant alfalfa varieties, as well as managing Phytophthora-caused alfalfa root rot.

Abstract Carcinoma‐associated fibroblasts (CAFs) consist of heterogeneous subpopulations that play a critical role in the dynamics of the tumor microenvironment. The extracellular signals of CAFs have been attributed to the extracellular matrix, cytokines, cell surface checkpoints, and exosomes. In the present study, it is demonstrated that the CD10 transmembrane hydrolase expressed on a subset of CAFs supports tumor stemness and induces chemoresistance. Mechanistically, CD10 degenerates an antitumoral peptide termed osteogenic growth peptide (OGP). OGP restrains the expression of rate‐limiting desaturase SCD1 and inhibits lipid desaturation, which is required for cancer stem cells (CSCs). Targeting CD10 significantly improves the efficacy of chemotherapy in vivo. Clinically, CD10‐OGP signals are associated with the response to neoadjuvant chemotherapy in patients with breast cancer. The collective data suggest that a nexus between the niche and lipid metabolism in CSCs is a promising therapeutic target for breast cancer.

No Abstract

Single-cell RNA sequencing(scRNA-seq) technology has boomed in the past decade which makes it possible to study biological problems at the resolution of cellular-level. Currently, the research mainly focuses on exploring the cellular heterogeneity, involving studies about identifying cell type identification, cell lineage tracing, spatial model reconstruction of complex organizations, etc. Clustering analysis is always the most effective way in grouping single cells in previous studies. However, existing scRNA-seq clustering methods separate pre-processing and clustering tasks that complicated the problem. In addition, the emergence of big data further limits the traditional clustering algorithms' application on scRNA-seq data. Therefore, developing novel clustering methods and improving clustering accuracy for growing scRNA-seq data is a continuous task. In this paper, we propose a highly integrated Deep Subspace Clustering Denoise Network named DSCD, which integrates denoise, dimension reduction and clustering in a unified framework. Based on the neural network architecture of autoencoder, DSCD discovers the low dimensional latent structure within scRNA-seq data from the compressed representation. Furthermore, we add a novel self-expressive denoise layer to learning the global relationships between single cells, which is the main innovation of DSCD. Experimental results on the synthetic data demonstrate the effectiveness of the novel denoise layer. From the clustering results on 5 real scRNA-seq datasets, we find that DSCD outperforms the related subspace clustering algorithms and state of the art methods. In conclusion, DSCD responds well to the rapidly increasing scRNA-seq data scale, greatly reduces human interference in dimension reduction and handles the noisy scRNA-seq data in proper way thus obtain a higher clustering accuracy.

The study of human dietary structures is an effective means of elucidating the subsistence patterns of our prehistoric ancestors and can highlight the processes through which humans interacted with the environment. We conducted stable isotope and archeobotanical analyses of human, animal, and plant remains at the Jiangxifen site, dated to ~900–400 BC, to explore human paleodiets and determine the environmental adaptation strategies adopted by humans in the middle valley of the Jinshajiang River in Yunnan Province. Humans predominantly consumed C4 foods (e.g., millet) and C4 food-fed animal protein sources, with smaller contributions from C3 food plants (e.g., rice) and C3 food-fed animal protein sources. We argued that the local dry-hot environment was the reason for the accessibility of C4 plants in the studied area. A comparison of our results with previously published archeobotanical data and isotopic evidence from human bones in other Bronze Age sites in Yunnan Province revealed high spatial variability in diets of human and subsistence strategies during this period. These differences were caused by the highly varying living environment of each region, which was related to fragmentation resulting from the geomorphological features of Yunnan Province.

Epilepsy is a prevalent neurological disorder that threatens human health in the world. The most commonly used method to detect epilepsy is using the electroencephalogram (EEG). However, epilepsy detection from the EEG is time-consuming and error-prone work because of the varying levels of experience we find in physicians. To tackle this challenge, in this paper, we propose a multi-scale non-local (MNL) network to achieve automatic EEG signal detection. Our MNL-Network is based on 1D convolution neural network involving two specific layers to improve the classification performance. One layer is named the signal pooling layer which incorporates three different sizes of 1D max-pooling layers to learn the multi-scale features from the EEG signal. The other one is called a multi-scale non-local layer, which calculates the correlation of different multi-scale extracted features and outputs the correlative encoded features to further enhance the classification performance. To evaluate the effectiveness of our model, we conduct experiments on the Bonn dataset. The experimental results demonstrate that our MNL-Network could achieve competitive results in the EEG classification task.

SUMMARY: Single-cell analysis of tumor-infiltrating lymphocytes obtained before and after preoperative therapy reflects the dynamic interplay of the tumor and immune system during treatment. Here, we present a protocol to implement single-cell analysis of tumor-infiltrating B cells, which were isolated from paired human breast cancers before and after neo-adjuvant chemotherapy. This protocol also facilitates isolation and single-cell analysis of other tumor-infiltrating lymphocytes.For complete information on the generation and use of this protocol, please refer to Lu et al. (2020).

The mid-late Holocene witnessed the rapid development of Neolithic and Bronze cultures in the Yellow River Valley (YRV) of northern China. Spatio-temporal patterns of plant utilization during this period and its influencing factors have been intensively discussed, whereas the variation in animal exploitation in relation to climate change and human activities has not been adequately studied. In this paper, we reviewed zooarchaeological data obtained from 38 Neolithic and Bronze sites in YRV, and compared them with paleoclimate and archaeological records, to reconstruct the trajectory of animal utilization in this area between 7500 and 2000 BP and discern the influencing factors driving it. The results revealed that animal exploitation was mainly sourced from wildlife between 7500 and 6000 BP, shifting to omnivorous livestock sources in the period of 6000–4000 BP except in the northeast Tibetan Plateau. During 4000–2000 BP, however, omnivorous and herbivorous livestock had come to dominate humans' subsistence on animals, which nonetheless showed substantial spatio-temporal variation in the YRV. Further analysis suggests that animal exploitation in the Neolithic and Bronze YRV were both directly affected by human activities, while climate change might have influenced the environment surrounding human settlements and, indirectly, their choice of animals to exploit. This work provides new perspectives for exploring the changing patterns of human-environment interactions in the YRV during the mid-late Holocene.

Three-dimensional convolutional neural networks (3DCNNs), a rapidly evolving modality of deep learning, has gained popularity in many fields. For oral cancers, CT images are traditionally processed using two-dimensional input, without considering information between lesion slices. In this paper, we established a 3DCNNs-based image processing algorithm for the early diagnosis of oral cancers, which was compared with a 2DCNNs-based algorithm. The 3D and 2D CNNs were constructed using the same hierarchical structure to profile oral tumors as benign or malignant. Our results showed that 3DCNNs with dynamic characteristics of the enhancement rate image performed better than 2DCNNS with single enhancement sequence for the discrimination of oral cancer lesions. Our data indicate that spatial features and spatial dynamics extracted from 3DCNNs may inform future design of CT-assisted diagnosis system.

Coronary artery disease has emerged as one of the major diseases causing death worldwide. Coronary stent has great effect to improve blood flow to the myocardium subtended by that artery, in which bioresorbable vascular scaffolds are new-generation stents used by people. However, Coronary stents implantation has a risk of restenosis, which is relative to hemodynamic parameters. Most of existing literatures studied in this issue have not taken into account such important factors as the strut thickness and lumen profile, and has yet to analyze the time effects among hemodynamic parameters over a certain period of time based on individual models. In this research, we proposed a framework to assess the chronic impact of hemodynamic on coronary stent implantation. In the framework, the optical coherence tomography (OCT) is combined with angiography to reconstruct patient-specific models of bioresorbable vascular scaffolds. Then, the hemodynamics parameters are extracted through the simulated 3D models, obtaining the distribution of wall shear stress (WSS), relative residence time (RRT) and oscillatory shear index (OSI). Finally, the changes of these parameters representing the effectiveness of hemodynamics exerted on the implanted stent can be assessed to estimate the chronic impacts. By a 9-month follow-up case study, it is observed that the difference of hemodynamic parameters are not significance. Both at baseline and 9-month follow-up experiments show that the hemodynamic parameters remain normal and similar, proving that the coronary stent implantation nowadays appears to have a robust and everlasting curative effect.

Spatial and temporal variation of aerosol optical depth (AOD) and optical depth of different aerosol types derived from the second Modern-Era Retrospective analysis for Research and Applications (MERRA-2) over the South China Sea (SCS) between 1980 and 2020 were studied. AOD distribution showed different characteristics throughout the entire SCS. Sulfate Aerosol Optical Depth (SO4AOD) and Sea Salt Aerosol Optical Depth (SSAOD) mainly contributed to the spatial and temporal variation of AOD over the SCS. A significant increasing trend followed by a decreasing trend of AOD could be observed in the north of the SCS from 1980 to 2020. Mean MERRA-2 AOD between 1980 and 2020 showed that AOD was high in the north and low in the south and that AOD gradually decreased from north to south over the SCS. AOD after 2000 was obviously higher than that of the 1980s and 1990s. Higher AOD appeared in the spring and winter, and low AOD appeared in the summer. The spatial distribution of scattering aerosol optical depth (SAOD) was similar to AOD distribution over the SCS. SO4AOD and SSAOD were obviously higher than black carbon aerosol optical depth (BCAOD), organic carbon aerosol optical depth (OCAOD), and dust aerosol optical depth (DUAOD) over the SCS. SO4AOD accounted for over 50% of total AOD (TAOD) over the north of the SCS, while BCAOD and DUAOD accounted for less than 10% of TAOD over the entire SCS. An obvious annual mean TAOD increase between 1980 and 2007 could be observed over the northern part of the SCS (NSCS), while a TAOD decrease happened from 2008 to 2020 in this region. The correlation coefficient between TAOD and SO4AOD over NSCS from 1980 to 2020 was about 0.93, indicating SO4AOD was the driving factor of TAOD variation in this area. Different AOD variation trends over the different areas of the SCS could be observed during the two periods including 1980–2007 and 2008–2020. AOD increase appeared over most of the SCS during the period from 1980 to 2007, while AOD decrease could be observed over most of the SCS from 2008 to 2020.

Abstract Background Male infertility is a complex disease caused by a combination of genetic, environmental, and lifestyle factors. Abnormal epigenetic programming has been proposed as a possible mechanism compromising male fertility. Recent studies suggest that aberrant imprinting in spermatozoa in a subset of infertile men is a risk factor for congenital diseases in children conceived via assisted reproduction techniques. In this study, we examined the DNA methylation status of CpG sites within the differentially methylated regions (DMRs) of three imprinted genes, H19, GNAS, and DIRAS3, using combined bisulfite PCR restriction analysis and bisulfite sequencing in sperm obtained from 135 men with idiopathic male infertility, including normozoospermia (n = 39), moderate oligozoospermia (n = 45), and severe oligozoospermia (n = 51), and fertile controls (n = 59). The percentage of global methylation was compared between fertile controls and infertile patients displaying abnormal DNA methylation status of imprinted loci. Moreover, we also analyzed whether the DNA methyltransferases (DNMTs) polymorphisms impact upon the methylation patterns of imprinted genes in idiopathic infertile males. Results Aberrant methylation patterns of imprinted genes were more prevalent in idiopathic infertile males, especially in patients with oligozoospermia. Infertile males with aberrant methylation patterns of imprinted genes displayed a tendency of lower global methylation levels, although not reaching statistical significance (P = 0.13). In the genotype-epigenotype correlation analysis, no significant association was observed between aberrant methylation patterns of the three imprinted genes and genotypes of the four DNA methyltransferase (DNMT) genes. Conclusion We conclude that abnormalities of DMR within imprinted genes may be associated with idiopathic male infertility. Disruption in methylation pattern of the three imprinted genes does not occur in high-risk genotypes of DNMTs.

Nowadays, modern data centers are seeking for importing renewable energy together with conventional energy in order to be more environment-friendly and to reduce operation expenditures. Meanwhile, considering the fact that electricity prices and renewable energy generations are diverse in time and geography, a task scheduling strategy should be designed to ensure the efficient and economic operations of data centers. In this paper, an optimal task placement strategy is presented for geo-distributed data centers powered by mixed renewable and conventional energies with dynamic voltage and frequency scaling technique. We aim at minimizing the total electricity cost and making full use of the renewable energy so as to construct green and economic data centers. The optimal task placement problem is formulated as a mixed integer nonlinear problem (MINLP), in which the quality-of-service constraint is restricted by an M/G/1 queuing model. To tackle the complexity of the MINLP, we first transform it into a tractable form, and then develop an optimal sever activation configuration and task placement algorithm to solve it. The proposed algorithm can obtain the global optimal solution of the electricity minimization problem and meanwhile dramatically reduce the complexity of the problem solving. Finally, evaluations based on real-world traces exhibit impacts of different system parameters on the electricity cost and sever activation configurations, which prove the superiority of our proposed algorithm and provide us some illuminations on how to build cost-effective and eco-friendly data centers.

Abstract To better understand the biological function of long noncoding RNAs, it is critical to determine their spatiotemporal expression patterns. We generated transgenic reporter strains for 149 out of the 170 annotated C. elegans long intervening noncoding RNAs (lincRNAs) and profiled their temporal activity. For the 68 lincRNAs with integrated reporter lines, we profiled their expression at the resolution of single cells in L1 larvae, and revealed that the expression of lincRNAs is more specific, heterogeneous and at lower level than transcription factors (TFs). These expression patterns can be largely attributed to transcriptional regulation because they were observed in assays using reporters of promoter activity. The spatial expression patterns of the 68 lincRNAs were further examined in 18 tissue categories throughout eight developmental stages. We compared the expression dynamics of lincRNAs, miRNAs and TFs during development. lincRNA and miRNA promoters are less active at embryo stage than those of TFs, but become comparable to TFs after embryogenesis. Finally, the lincRNA gene set shows a similar tissue distribution to that of miRNAs and TFs. We also generated a database, CELE, for the storage and retrieval of lincRNA reporter expression patterns and other relevant information. The data and strains described here will provide a valuable guide and resource for future functional exploration of C. elegans lincRNAs.

Background: Several techniques are under investigation to improve the immunogenicity of HIV-1 DNA vaccine candidates. DNA vaccines are advantageous due to their ease of design, expression of multiple antigens, and safety. Methods: The HVTN 098 trial assessed the PENNVAX®-GP DNA vaccine (encoding HIV env, gag, pol) administered with or without plasmid IL-12 at 0-, 1-, 3-, and 6-month timepoints via intradermal (ID) or intramuscular (IM) electroporation (EP) in healthy, adult participants. We report on safety, tolerability, and acceptability. Results: HVTN 098 enrolled 94 participants: 85 received PENNVAX®-GP and nine received placebo. Visual analog scale (VAS) pain scores immediately after each vaccination were lower in the ID/EP than in the IM/EP group (medians 4.1–4.6 vs. 6–6.5, p < 0.01). IM/EP participants reported greater pain and/or tenderness at the injection site. Most ID/EP participants had skin lesions such as scabs/eschars, scars, and pigmentation changes, which resolved within 6 months in 51% of participants (24/55). Eighty-two percent of IM/EP and 92% of ID/EP participant survey responses showed acceptable levels of discomfort. Conclusions: ID/EP and IM/EP are distinct experiences; however, HIV-1 DNA vaccination by either route was safe, tolerable and acceptable by most study participants.

Background:. We examined the associations of surgeon and hospital volume with total cost, length of stay (LOS), and cost per day for free tissue transfer (FTT) surgeries. Evidence demonstrates a higher likelihood of success for FTT in higher volume hospitals. Little, however, is known about volume-outcome associations for surgical costs and LOS. We hypothesized that higher provider volume is associated with lower cost and shorter LOS. Methods:. Using Taiwan’s national data (2001–2012), we conducted a retrospective cohort study of all adults 18–64 years of age who underwent FTT during the study period. We used hierarchical regression modeling for our analyses. Our 3 outcome variables were total cost of FTT surgery, LOS in hospital, and cost per day. Results:. Except for functional muscle flap, in which LOS was 12 days shorter in high-volume compared with low-volume hospitals (P = 0.017), no association between hospital volume and LOS was found. Contrary to our hypothesis, our results for all FTT cases demonstrate positive associations of medium-volume hospitals (OR = 1.31; CI, 1.11–1.55) and high-volume surgeons (OR = 1.16; CI,1.03–1.32) with total cost and cost per day, respectively. The interactions of hospital volume and surgeon volume show that in medium- and high-volume hospitals, surgeons with the highest volume had the lowest predicted cost per day among hospitals in that category; but all differences in cost were small. Conclusions:. There were no substantial variations based on different hospital or surgeon volume in LOS, total cost, or cost per day for FTT operations performed in Taiwan.