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PoRVA and PEDV coinfections are extremely common in clinical practice. Although coinfections of PoRVA and PEDV are known to result in increased mortality, the underlying mechanism remains unknown. Here, we found that PoRVA infection promoted PEDV infection in vivo and in vitro and that PoRVA G9P[23] (RVA-HNNY strain) enhanced PEDV replication more significantly than did PoRVA G5P[7] (RVA-SXXA strain). Metabolomic analysis revealed that RVA-HNNY more efficiently induced an increase in the intracellular glutamine content in porcine small intestinal epithelial cells than did RVA-SXXA, which more markedly promoted ATP production to facilitate PEDV replication, whereas glutamine deprivation abrogated the effect of PoRVA infection on promoting PEDV replication. Further studies showed that PoRVA infection promoted glutamine uptake by upregulating the expression of the glutamine transporter protein SLC1A5. In SLC1A5 knockout cells, PoRVA infection neither elevated intracellular glutamine nor promoted PEDV replication. During PoRVA infection, the activity and protein expression levels of glutamine catabolism-related enzymes (GLS1 and GLUD1) were also significantly increased promoting ATP production through glutamine anaplerosis into the TCA cycle. Consistent with that, siRNAs or inhibitors of GLS1 and GLUD1 significantly inhibited the promotion of PEDV replication by PoRVA. Notably, RVA-HNNY infection more markedly promoted SLC1A5, GLS1 and GLUD1 expression to more significantly increase the uptake and catabolism of glutamine than RVA-SXXA infection. Collectively, our findings illuminate a novel mechanism by which PoRVA infection promotes PEDV infection and reveal that the modulation of glutamine uptake is key for the different efficiencies of PoRVA G9P[23] and PoRVA G5P[7] in promoting PEDV replication.

BackgroundGlioma, an aggressive brain tumor, poses a challenge in understanding the mechanisms of treatment resistance, despite promising results from immunotherapy.MethodsWe identified genes associated with immunotherapy resistance through an analysis of The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) databases. Subsequently, qRT-PCR and western blot analyses were conducted to measure the mRNA and protein levels of TBC1 Domain Family Member 1 (TBC1D1), respectively. Additionally, Gene Set Enrichment Analysis (GSEA) was employed to reveal relevant signaling pathways, and the expression of TBC1D1 in immune cells was analyzed using single-cell RNA sequencing (scRNA-seq) data from GEO database. Tumor Immune Dysfunction and Exclusion (TIDE) database was utilized to assess T-cell function, while Tumor Immunotherapy Gene Expression Resource (TIGER) database was employed to evaluate immunotherapy resistance in relation to TBC1D1. Furthermore, the predictive performance of molecules on prognosis was assessed using Kaplan-Meier plots, nomograms, and ROC curves.ResultsThe levels of TBC1D1 were significantly elevated in tumor tissue from glioma patients. Furthermore, high TBC1D1 expression was observed in macrophages compared to other cells, which negatively impacted T cell function, impaired immunotherapy response, promoted treatment tolerance, and led to poor prognosis. Inhibition of TBC1D1 was found to potentially synergistically enhance the efficacy of immunotherapy and prolong the survival of cancer patients with gliomas.ConclusionHeightened expression of TBC1D1 may facilitate an immunosuppressive microenvironment and predict a poor prognosis. Blocking TBC1D1 could minimize immunotherapy resistance in cancer patients with gliomas.

Abstract Background Contrast-enhanced ultrasound (CEUS) has been recently used for the assessment of cervical lymph node metastasis (LNM) to guide surgical operation in patients with papillary thyroid carcinoma (PTC). However, the specificity and sensitivity of CEUS reported from previous studies are not consistent. The objective of this study was to evaluate the diagnostic value of CEUS for the metastasis of cervical lymph nodes in PTC patients based on data from one regional central hospital. Methods The diagnostic value of CEUS in preoperative LNM of PTC patients was concluded by comparing the results of CEUS on lymph node status with postoperative pathology examination. In addition, this study conducted hierarchical analysis of PTC patients to explore whether tumor size, different lymph node regions, and Hashimoto’s thyroiditis influence the assessment of CEUS. Results This research study ultimately enrolled 965 PTC patients, including 266 males and 699 females with a mean age of 42.27 ± 11.34 years. A total of 527 patients were considered clinical-node negative, and 438 were clinical-node positive before surgery. The specificity, sensitivity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of CEUS in the assessment of LNM in PTC patients were 56.00%, 71.00%, 57.06%, 69.76% and 62.59%, respectively. For central and lateral lymph nodes, the accuracy of CEUS in PTC patients was 49.43% and 54.30%, respectively. In addition, it was shown that the accuracy of CEUS in PTC patients with Hashimoto’s thyroiditis (HT) slightly decreased to 58.44%, and the accuracy of CEUS in PTC patients with non-HT in turn increased to 64.17%. The accuracy of CEUS in non-papillary thyroid microcarcinoma (PTMC) and PTMC patients was 65.68% and 61.24%, respectively. The accuracy of CEUS in predicting central LNM was significantly different between PTC patients with or without HT (P

Sepsis is a multisystem disease characterized by dysregulation of the host immune response to infection. Immune response kinetics play a crucial role in the pathogenesis and progression of sepsis. Macrophages, which are known for their heterogeneity and plasticity, actively participate in the immune response during sepsis. These cells are influenced by the ever-changing immune microenvironment and exhibit two-sided immune regulation. Recently, the immunomodulatory function of mesenchymal stem cells (MSCs) in sepsis has garnered significant attention. The immune microenvironment can profoundly impact MSCs, prompting them to exhibit dual immunomodulatory functions akin to a double-edged sword. This discovery holds great importance for understanding sepsis progression and devising effective treatment strategies. Importantly, there is a close interrelationship between macrophages and MSCs, characterized by the fact that during sepsis, these two cell types interact and cooperate to regulate inflammatory processes. This review summarizes the plasticity of macrophages and MSCs within the immune microenvironment during sepsis, as well as the intricate crosstalk between them. This remains an important concern for the future use of these cells for immunomodulatory treatments in the clinic.

Background Aldehyde dehydrogenase 2 (ALDH2) is a crucial enzyme involved in endogenous aldehyde detoxification and has been implicated in tumor progression. However, its role in tumor immune evasion remains unclear.Methods Here, we analyzed the relationship between ALDH2 expression and antitumor immune features in multiple cancers. ALDH2 knockout tumor cells were then established using CRISPR/Cas9 system. In immunocompetent breast cancer EMT6 and melanoma B16-F10 mouse models, we investigated the impact of ALDH2 blockade on cytotoxic T lymphocyte function and tumor immune microenvironment by flow cytometry, mass cytometry, Luminex liquid suspension chip detection, and immunohistochemistry. Furthermore, RNA sequencing, flow cytometry, western blot, chromatin immunoprecipitation assay, and luciferase reporter assays were employed to explore the detailed mechanism of ALDH2 involved in tumor immune evasion. Lastly, the synergistic therapeutic efficacy of blocking ALDH2 by genetic depletion or its inhibitor disulfiram in combination with immune checkpoint blockade (ICB) was investigated in mouse models.Results In our study, we uncovered a positive correlation between the expression level of ALDH2 and T-cell dysfunction in multiple cancers. Furthermore, blocking ALDH2 significantly suppressed tumor growth by enhancing cytotoxic activity of CD8+ T cells and reshaping the immune landscape and cytokine milieu of tumors in vivo. Mechanistically, inhibiting ALDH2-mediated metabolism of aldehyde downregulated the expression of V-domain Ig suppressor of T-cell activation (VISTA) via inactivating the nucleotide oligomerization domain (NOD)/nuclear factor kappa-B (NF-κB) signaling pathway. As a result, the cytotoxic function of CD8+ T cells was revitalized. Importantly, ALDH2 blockade markedly reinforced the efficacy of ICB treatment.Conclusions Our data delineate that ALDH2-mediated aldehyde metabolism drives tumor immune evasion by activating the NOD/NF-κB/VISTA axis. Targeting ALDH2 provides an effective combinatorial therapeutic strategy for immunotherapy.

Dragon fruit peel, often discarded, is a valuable source of commercial pectin. This study investigates different extraction methods, including cold-water (CW), hot-water (HW), ultrasound (US), and novel enzyme extraction (xylanase: EZX), to extract pectins from dragon fruit peel and compare their characteristics. The pectin yield ranged from 10.93% to 20.22%, with significant variations in physicochemical properties across methods (p < 0.05). FTIR analysis revealed that extraction methods did not alter the primary structural configuration of the pectins. However, molecular weights (Mws) varied significantly, from 0.84 to 1.21 × 103 kDa, and the degree of esterification varied from 46.82% to 51.79% (p < 0.05). Monosaccharide analysis identified both homogalacturonan (HG) and rhamnogalacturonan-I (RG-I) pectic configurations in all pectins, predominantly comprising galacturonic acid (77.21–83.12 %mol) and rhamnose (8.11–9.51 %mol), alongside minor side-chain sugars. These properties significantly influenced pectin functionalities. In the aqueous state, a higher Mw impacted viscosity and emulsification performance, while a lower Mw enhanced antioxidant activities and promoted the prebiotic function of pectin (Lactis brevies growth). This study highlights the impact of extraction methods on dragon fruit peel pectin functionalities and their structure–function relationship, providing valuable insights into predicting dragon fruit peel’s potential as a food-grade ingredient in various products.

Abstract Background Breast cancer is a complex disease with a highly immunosuppressive tumor microenvironment, and has limited clinical response to immune checkpoint blockade (ICB) therapy. T-helper 2 (Th2) cells, an important component of the tumor microenvironment (TME), play an essential role in regulation of tumor immunity. However, the deep relationship between Th2-mediated immunity and immune evasion in breast cancer remains enigmatic. Methods Here, we first used bioinformatics analysis to explore the correlation between Th2 infiltration and immune landscape in breast cancer. Suplatast tosilate (IPD-1151 T, IPD), an inhibitor of Th2 function, was then employed to investigate the biological effects of Th2 blockade on tumor growth and immune microenvironment in immunocompetent murine breast cancer models. The tumor microenvironment was analyzed by flow cytometry, mass cytometry, and immunofluorescence staining. Furthermore, we examined the efficacy of IPD combination with ICB treatment by evaluating TME, tumor growth and mice survival. Results Our bioinformatics analysis suggested that higher infiltration of Th2 cells indicates a tumor immunosuppressive microenvironment in breast cancer. In three murine breast cancer models (EO771, 4T1 and EMT6), IPD significantly inhibited the IL-4 secretion by Th2 cells, promoted Th2 to Th1 switching, remodeled the immune landscape and inhibited tumor growth. Remarkably, CD8+ T cell infiltration and the cytotoxic activity of cytotoxic T lymphocyte (CTL) in tumor tissues were evidently enhanced after IPD treatment. Furthermore, increased effector CD4+ T cells and decreased myeloid-derived suppressor cells and M2-like macrophages were also demonstrated in IPD-treated tumors. Importantly, we found IPD reinforced the therapeutic response of ICB without increasing potential adverse effects. Conclusions Our findings demonstrate that pharmaceutical inhibition of Th2 cell function improves ICB response via remodeling immune landscape of TME, which illustrates a promising combinatorial immunotherapy.

Abstract Exploring an effective sepsis screening tool that can be widely implemented is important for improving the prognosis of sepsis worldwide. This study aimed to develop a new simple screening tool for sepsis (LIP scoring system) that includes the peripheral blood lymphocyte count, international normalized ratio, and procalcitonin level. In a single-center, prospective, observational study, 444 acute sepsis inpatients and 444 nonsepsis inpatients were ultimately included based on the Sepsis-3 and exclusion criteria. The differences in the Lym, INR, PCT level and other clinical biomarkers were compared between the two groups. Univariable and multivariable logistic regression analyses and receiver operating characteristic analysis were used to establish a LIP screening tool for sepsis with a combination of biomarkers. The Kappa and McNemar tests were used to evaluate the differences between the LIP screening results (LIP score ≥ 3) and Sepsis-3 criteria (SOFA score ≥ 2). Logistic regression analysis showed that the lymphocyte count, INR, PCT level, platelets, neutrophil/lymphocyte ratio (NLR) and prothrombin time (PT) were independent risk factors for the development of sepsis. The ROC analysis showed that the lymphocyte count, INR, and PCT level had high area under the ROC curve values (AUROC (95% CI): Lym 0.84 (0.810–0.860), INR 0.921 (0.902–0.938), PCT level 0.928 (0.909–0.944)). The LIP tool had satisfactory screening efficacy for sepsis (sensitivity, 92.8%; specificity, 94.1%), and a LIP score equal to or greater than 3 points had good agreement with Sepsis-3 criteria in the diagnosis of sepsis (Kappa = 0862 in the Kappa test and P = 0.512 in the McNemar test). The LIP tool has satisfactory sensitivity and specificity for sepsis screening, and it can be used for rapid screening of patients with sepsis in outpatient and emergency departments or in economically underdeveloped areas with limited resources.

Leakage detection technology is of vital importance to the safe operation and flow insurance of multiphase flow pipelines. This paper for the first time applies acoustic based leakage detection method to stratified flow pipelines and verifies the feasibility of this method in multiphase flow pipelines. Gas-liquid stratified flow pipeline leakage detection and localization experiment is conducted to investigate the effectiveness of different filtering methods when calculating the time difference (delay) between arrival times of leakage acoustic signals at different sensors using cross-correlation algorithm. Propagation characteristics of the leakage acoustic wave in stratified flow are also investigated. The results show that the 5-level Symlets wavelet filter can effectively improve the accuracy of time delay estimation. Moreover, the value of sound speed can be set as 346 m/s when carrying out leakage localization in stratified flow pipelines, which is nearly irrelevant with pressure, void fraction, superficial velocity of gas phase and the structure of pipe. The research in this paper lays a foundation for the application of acoustic based leakage detection technology in multiphase flow pipelines.

Astragalus variabilis is a locoweed of northwest China that can seriously impede livestock development. However, it also plays various ecological roles, such as wind protection and sand fixation. Here, we used an optimized MaxEnt model to predict the distribution of suitable habitat of A. variabilis under current (1970–2000) conditions and future (2021–2080) climate change scenarios based on recent occurrence records. The most important environmental variables (suitability ranges in parentheses) affecting the distribution of A. variabilis were average maximum temperature of February (–2.12–5.34°C), followed by total precipitation of June (2.06–37.33 mm), and topsoil organic carbon (0.36–0.69%). The habitat suitability of A. variabilis was significantly correlated with the frequency of livestock poisoning (p < 0.05). Under current climate conditions, the suitable environment of A. variabilis was distributed in central and western Inner Mongolia, Ningxia, central and northwestern Gansu, central and northwestern Qinghai, and the four basins around the Tianshan Mountains in Xinjiang. Under future climate conditions, the suitable habitat of A. variabilis shifted to higher latitudes and altitudes. No previous studies have used niche models to predict the suitable environment of this species nor analyzed the relationship between the habitat suitability of poisonous plants and the frequency of animal poisoning. Our findings provide new insights that will aid the prevention of livestock animal poisoning and the control of poisonous plants, promote the development of the livestock husbandry industry, and provide basic information that will facilitate the maintenance of the ecological balance of grassland ecosystems.

Abstract Background Klebsiella pneumoniae bloodstream infection (Kp-BSI) is a serious threat to pediatric patients. The objective of this study was to explore the risk factors, validate the prediction efficiency of pediatric Sequential Organ Failure Assessment (SOFA) and establish better early predictors of mortality in pediatric patients with Kp-BSI. Methods All children diagnosed with Kp-BSI were included in this retrospective cohort study from January 2009 to June 2019. Basic characteristics, symptoms and physical examinations, treatments, laboratory statistics, and SOFA at the onset of Kp-BSI were recorded. The Cox proportional hazard model and receiver operating characteristic curves were used to assess the association between the variables and the 90-day mortality and their predictive value. DeLong’s test of receiver operating characteristic curves and integrated discrimination improvement index were used to determine the improvement in predictive capacity of the modified SOFA models. A predictive score was developed using multivariate logistic regression. Results Of the 146 children enrolled, 33 (22.6%) patients died within 90 days. Hospitalization in the last 6 months, intra-abdominal source of infection, presence of organ failure, and altered levels of blood biomarkers, including C-reactive protein, albumin, and lactate were significant risk factors for 90-day mortality. The area under the curve (AUC) of SOFA for predicting 90-day mortality was 0.80 (95% CI 0.71–0.89). Moreover, we found that a prediction model combining SOFA with two other parameters, namely hospitalization in the last 6 months and intra-abdominal source of infection, was better at predicting mortality (AUC = 0.89, 95% CI 0.82–0.96; sensitivity = 0.86; specificity = 0.84). According to this novel risk model, we defined three statistically different groups: low-risk, medium-risk and high-risk groups, with an observed 90-day mortality of 5.4, 35.7, and 72.0%, respectively. With reference to the low-risk patients, the medium-risk and high-risk groups had a higher mortality, with hazard ratios of 8.36 (95% CI 3.60–27.83) and 20.27 (95% CI 7.47–54.95), respectively. Conclusions The modified SOFA may be better than the original score to predict 90-day mortality in pediatric patients with Kp-BSI. Future prospective studies are required to validate this novel scoring system in external cohorts.

Breast cancer (BC) is the most common tumor in women, and the molecular mechanism underlying its pathogenesis remains unclear. In this study, we aimed to investigate gene modules related to the phenotypes of BC, and identify representative candidate biomarkers for clinical prognosis of BC patients. Using weighted gene co-expression network analysis, we here identified NPY5R as a hub gene in BC. We further found that NPY5R was frequently downregulated in BC tissues compared with adjacent tumor-matched control tissues, due to its aberrant promoter CpG methylation which was confirmed by methylation analysis and treatment with demethylation agent. Higher expression of NPY5R was closely associated with better prognosis for BC patients. Gene set enrichment analysis showed that transcriptome signatures concerning apoptosis and cell cycle were critically enriched in specimens with elevated NPY5R. Ectopic expression of NPY5R significantly curbed breast tumor cell growth, induced cell apoptosis and G2/M arrest. Moreover, NPY5R also promoted the sensitivity of BC cells to doxorubicin. Mechanistically, we found that NPY5R restricted STAT3 signaling pathway activation through interacting with IL6, which may be responsible for the antitumor activity of NPY5R. Collectively, our findings indicate that NPY5R functions as a tumor suppressor but was frequently downregulated in BC.

The impairment of immunity characterized by T cell exhaustion is the main cause of death in patients with sepsis after the acute phase. Although PD-1 blockade is highly touted as a promising treatment for improving prognosis, the role of PD-1 plays in sepsis and particularly its different roles in different periods are still very limited. A recent study revealed LAG3 can resist the therapeutic effect of PD-1 blockade in tumor, which inspired us to understand their role in sepsis. We enrolled 26 patients with acute sepsis from 422 candidates using strict inclusion criteria. Follow-up analysis revealed that the expression levels of PD-1 were rapidly increased in the early stage of sepsis but did not change significantly as infection continued (P < 0.05). However, the expression of LAG3 was contrary to that of PD-1. Compared with LAG3 or PD-1 single-positive T cells, T cells coexpressing LAG3 and PD-1 were significantly exhausted (P < 0.05). The proportion of coexpressing T cells was negatively correlated with the total number of lymphocytes (r = −0.653, P = 0.0003) and positively correlated with the SOFA score (r = 0.712, P < 0.0001). In addition, the higher the proportion of coexpressing T cells was, the longer the hospital stay and the higher the mortality. These results showed that LAG3 and PD-1 had a potential synergistic effect in regulating the gradual exhaustion of T cells in sepsis, which seriously affected the clinical prognosis of patients. Therefore, LAG3 and PD-1 double-positive T cells are an important indicator for immunity detection and prognostic evaluation. In the future, precision therapy may pay more attention to the different expression patterns of these two molecules.

The existence of energy transfer channels from the self-trapped exciton (STE) emission to lanthanide (Ln3+) ions in double perovskites (DPs) opens up new possibilities for high security anti-counterfeiting applications. In the present investigation, we synthesized Sb3+/Ho3+/Er3+ doped Cs2NaGdCl6 rare-earthbased DPs using a simple solvothermal method, whose luminescence could be quenched by water and restored after drying. The efficient down-shifting (DS) red emission from the 4f-4f transition of Ho3+ was enhanced 8-fold due to the energy transfer of STEs - Ho3+ ions via Sb3+ sensitization. The DS and up-conversion (UC) dual-mode multicolor emissions were obtained by further introducing Er3+. Specifically, the DS luminescence of the tri-doped sample under the UV region and that under 448 nm irradiation were white and red, respectively; and the UC luminescence under 980 nm irradiation was green. In view of their stimulus response to water and dual-mode multicolor luminescence properties, advanced anti-counterfeiting materials based on the obtained samples were designed. [ABSTRACT FROM AUTHOR]

Yb2(MoO4)3:Ln3+ (Ln = Ho, Tm, Er) phosphors were synthesized by a hydrothermal method with further calcination. The crystal structure and morphology of the samples were characterized by X-ray diffraction and scanning electron microscopy. The effects of rare earth ion interaction in the Yb2(MoO4)3:Ln3+ phosphors on the upconversion (UC) luminescence properties and energy transfer process at different doping concentrations were discussed. It is concluded that by doping Ho3+, Tm3+, and Er3+ in the Yb2(MoO4)3 host, the phosphors emit orange-yellow, blue and green light, respectively, and the energy transfer from Yb3+ -- Ho3+/Er3+ and Yb3+ -- Tm3+ is a two and three photon process, respectively. Under the excitation of a 980 nm laser, by changing the Ho3+/Tm3+ ratio in doped Yb2(MoO4)3, we have realized the transition of phosphors from cold white light to warm white light. The temperature sensitivity of the ²H11/2 and 4S3/2 energy levels of Yb2(MoO4)3:Er3+ in the range of 323-573 K was studied by the FIR technology. The experimental results show that the maximum absolute sensitivity was 0.0081 K-1 at 573 K and the maximum relative sensitivity was 0.01 K-1 at 323 K. Compared with other materials, the Er3+ doped Yb2(MoO4)3 phosphor is an excellent optical temperature sensing material. [ABSTRACT FROM AUTHOR]

Traditional detect and count strategy cannot well handle the extremely crowded footage in computer vision- based counting task. In recent years, deep learning approaches have been widely explored to tackle this challenge. By regressing visual features to density map, the total crowd number can be predicted while avoids the detection of their actual positions. Efforts of improving performance distribute at various phases of the detecting pipeline, such as optimizing feature extraction and eliminating deviation of regressed density map etc. In this article, we conduct a thorough review on the most representative and state-of-the-art techniques. They are systematically categorized into three topics: the evolving of front-end network, the handling of unbalanced density map prediction, and the selection of loss function. After evaluating most significant techniques, innovations of the state-of-the-art are inspected in detail to analyze specific reasons of achieving high performances. As conclusion, possible directions of enhancement are discussed to provide insights of future research. [ABSTRACT FROM AUTHOR]

SRSF2 plays a dual role, functioning both as a transcriptional regulator and a key player in alternative splicing. The absence of Srsf2 in MyoD + progenitors resulted in perinatal mortality in mice, accompanied by severe skeletal muscle defects. SRSF2 deficiency disrupts the directional migration of MyoD progenitors, causing them to disperse into both muscle and non-muscle regions. Single-cell RNA-sequencing analysis revealed significant alterations in Srsf2-deficient myoblasts, including a reduction in extracellular matrix components, diminished expression of genes involved in ameboid-type cell migration and cytoskeleton organization, mitosis irregularities, and premature differentiation. Notably, one of the targets regulated by Srsf2 is the serine/threonine kinase Aurka. Knockdown of Aurka led to reduced cell proliferation, disrupted cytoskeleton, and impaired differentiation, reflecting the effects seen with Srsf2 knockdown. Crucially, the introduction of exogenous Aurka in Srsf2-knockdown cells markedly alleviated the differentiation defects caused by Srsf2 knockdown. Furthermore, our research unveiled the role of Srsf2 in controlling alternative splicing within genes associated with human skeletal muscle diseases, such as BIN1, DMPK, FHL1, and LDB3. Specifically, the precise knockdown of the Bin1 exon17-containing variant, which is excluded following Srsf2 depletion, profoundly disrupted C2C12 cell differentiation. In summary, our study offers valuable insights into the role of SRSF2 in governing MyoD progenitors to specific muscle regions, thereby controlling their differentiation through the regulation of targeted genes and alternative splicing during skeletal muscle development.