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Abstract Gliomas represent a highly aggressive class of tumors located in the brain. Despite the availability of multiple treatment modalities, the prognosis for patients diagnosed with glioma remains unfavorable. Therefore, further exploration of new biomarkers is crucial to enhance the prognostic assessment of glioma and to investigate more effective treatment options. In this research, we utilized multiple machine learning techniques to assess the significance of genes related to angiogenesis and epithelial-mesenchymal transition (EMT) in the context of prognosis and treatment for glioma patients. The random forest algorithm highlighted the significance of CALU, and further analysis indicated that the effect of CALU on glioma progression may be regulated by MYC. Different machine learning approaches were employed in our investigation to uncover crucial genes associated with angiogenesis and EMT in glioma. Our findings verify the connection between these genes and the prognosis of patients with glioma, as well as the results of immunotherapeutic interventions. Notably, through experimental verification, we identified CALU as a new prognostic marker for glioma, and inhibiting the expression of CALU can impede the progression of glioma.

A new species from China, Elymus multiramosus Y.C. Zhang, sp. nov. is described and illustrated herein, based on morphological characters and molecular phylogenetic analysis. The taxonomic descriptions of E. multiramosus and the comparison with related species are presented. The taxonomic distinctiveness of this new species was inferred by Maximum Likelihood (ML) analysis and Bayesian phylogenetic analysis, based on the complete chloroplast genome sequence. It is assigned to the Elymus section and bears similarity to Elymus nutans Griseb. However, it can be easily distinguished from other species by its compound spike, in contrast to the simple spike inflorescence typical of those species. The compound spike is characterised by rhachillas that are extended at the base of the main axis, giving rise to 3–6 mini-spike-like branches. Notably, these branches significantly increase in length from the top towards the bottom of the compound spike. In the molecular phylogeny, Elymus multiramosus from Qinghai, north-western China, is phylogenetically positioned as a distinct lineage. The lineage comprising Elymus sinosubmuticus from Sichuan, east of the Tibetan Plateau and Elymus nutans from the Himalayas forms a sister group to Elymus multiramosus, suggesting that these three species share a common ancestor that is distinct from the lineage leading to Elymus atratus from Gansu, north of the Tibetan Plateau.

Abstract Background Abiotic stress seriously affects the growth and yield of crops. It is necessary to search and utilize novel abiotic stress resistant genes for 2.0 breeding programme in quinoa. In this study, the impact of drought stress on glucose metabolism were investigated through transcriptomic and metabolomic analyses in quinoa seeds. Candidate drought tolerance genes on glucose metabolism pathway were verified by qRT-PCR combined with yeast expression system. Results From 70 quinoa germplasms, drought tolerant material M059 and drought sensitive material M024 were selected by comprehensive evaluation of drought resistance. 7042 differentially expressed genes (DEGs) were indentified through transcriptomic analyses. Gene Ontology (GO) analysis revealed that these DEGs were closely related to carbohydrate metabolic process, phosphorus-containing groups, and intracellular membrane-bounded organelles. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis detected that DEGs were related to pathways involving carbohydrate metabolisms, glycolysis and gluconeogenesis. Twelve key differentially accumulated metabolites (DAMs), (D-galactose, UDP-glucose, succinate, inositol, D-galactose, D-fructose-6-phosphate, D-glucose-6-phosphate, D-glucose-1-phosphate, dihydroxyacetone phosphate, ribulose-5-phosphate, citric acid and L-malate), and ten key candidate DEGs (CqAGAL2, CqINV, CqFrK7, CqCELB, Cqbg1x, CqFBP, CqALDO, CqPGM, CqIDH3, and CqSDH) involved in drought response were identified. CqSDH, CqAGAL2, and Cqβ-GAL13 were candidate genes that have been validated in both transcriptomics and yeast expression screen system. Conclusion These findings provide a foundation for elucidating the molecular regulatory mechanisms governing glucose metabolism in quinoa seeds under drought stress, providing insights for future research exploring responses to drought stress in quinoa.

Abstract Background Cysticercosis is a zoonotic parasitic disease that poses a serious threat to public health. It is widely distributed and has a high incidence rate in China. Reports of disseminated cysticercosis worldwide are rare. This article presents a case of disseminated cysticercosis in the Guangxi Zhuang Autonomous Region of southwestern China. Case presentation The patient, a 46-year-old male belonging to the Miao ethnic group, hailed from a region in Guangxi Zhuang Autonomous Region known for its high incidence of cysticercosis. He had a habit of consuming raw pork and beef. With a history of recurrent consciousness disturbances and limb convulsions for five years, he presented with headaches and dizziness nine days prior. Comprehensive examinations were conducted on the patient. Ultimately, based on epidemiological history, imaging findings, pathogen testing, and pathological results, he was diagnosed with disseminated cysticercosis. Following anthelmintic treatment, the patient was discharged with clear consciousness, free from headaches, dizziness, nausea, vomiting, and seizures. The patient is currently under follow-up care. Conclusion It is crucial to enhance public awareness, promote health education, and cultivate good hygiene habits, as these are essential measures in reducing the incidence of cysticercosis.

Abstract Background Given the significant role of immune-related genes in uterine corpus endometrial carcinoma (UCEC) and the long-term outcomes of patients, our objective was to develop a prognostic risk prediction model using immune-related genes to improve the accuracy of UCEC prognosis prediction. Methods The Limma, ESTIMATE, and CIBERSORT methods were used for cluster analysis, immune score calculation, and estimation of immune cell proportions. Univariate and multivariate analyses were utilized to develop a prognostic risk model for UCEC. Risk model scores and nomograms were used to evaluate the models. String constructs a protein-protein interaction (PPI) network of genes. The qRT-PCR, immunofluorescence, and immunohistochemistry (IHC) all confirmed the genes. Results Cluster analysis divided the immune-related genes into four subtypes. 33 immune-related genes were used to independently predict the prognosis of UCEC and construct the prognosis model and risk score. The analysis of the survival nomogram indicated that the model has excellent predictive ability and strong reliability for predicting the survival of patients with UCEC. The protein-protein interaction network analysis of key genes indicates that four genes play a pivotal role in interactions: GZMK, IL7, GIMAP, and UBD. The quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence, and immunohistochemistry (IHC) all confirmed the expression of the aforementioned genes and their correlation with immune cell levels. This further revealed that GZMK, IL7, GIMAP, and UBD could potentially serve as biomarkers associated with immune levels in endometrial cancer. Conclusion The study identified genes related to immune response in UCEC, including GZMK, IL7, GIMAP, and UBD, which may serve as new biomarkers and therapeutic targets for evaluating immune levels in the future.

Abstract Background Canine circovirus (CanineCV), a non-enveloped virus with a circular DNA genome, has been identified in various avian and mammalian species, including domestic and wild canids. This study aimed to comprehensively analyze the prevalence of CanineCV across diverse animal species in 11 provinces of China. Results A total of 1,666 serum samples were collected, revealing a 5.82% prevalence of CanineCV in dogs, with the highest rates being observed in southern and eastern China. Phylogenetic analysis of 266 global CanineCV genomes sourced from the NCBI identified six distinct genotypes, elucidating the complex dynamics of their evolution. Evidence suggested a potential bat origin for CanineCV, with positive selection and high rates of evolution being observed. Recombination analysis revealed dynamic genetic exchange, highlighting the intricate nature of CanineCV evolution. Mutational analysis identified key amino acid substitutions likely to influence the virus’s adaptation. Additionally, glycosylation, palmitoylation, and SUMOylation sites were predicted, shedding light on crucial functional properties of the virus. Conclusions This study provides a global perspective on the origin, genetic diversity, and evolutionary dynamics of CanineCV. Understanding these factors is crucial for elucidating its epidemiology and potential health risks.

Objective Lipoprotein glomerulopathy (LPG) is a rare disorder characterized by the development of glomerular lipoprotein thrombosis. LPG exhibits familial aggregation, with mutations in the apolipoprotein E (APOE) gene identified as the leading cause of this disease. This study aimed to investigate APOE gene mutations and the clinicopathological features in eleven LPG patients.Methods Clinicopathological and follow-up data were obtained by extracting DNA, followed by APOE coding region sequencing analysis. This study analyzed clinical and pathological manifestations, gene mutations, treatment and prognosis.Results The mean age of the eleven patients was 33.82 years. Among them, five had a positive family history for LPG, ten presented with proteinuria, four exhibited nephrotic syndrome, and six presented with microscopic hematuria. Dyslipidemia was identified in ten patients. In all renal specimens, there was evident dilation of glomerular capillary lumens containing lipoprotein thrombi, and positive oil red O staining was observed in frozen sections of all samples. APOE gene testing revealed that one patient had no mutations, while the remaining ten patients exhibited mutations in the APOE gene, with three patients presenting with multiple mutations simultaneously. Following the confirmation of LPG diagnosis, treatment with angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) was initiated, and the disease progressed slowly.Conclusion LPG is histologically characterized by lamellated lipoprotein thrombi in glomeruli, and kidney biopsy is essential for diagnosis. Mutations in the APOE gene are the leading cause of LPG. This study revealed clinicopathological characteristics and APOE gene mutations in patients with LPG, which helps us better understand the disease.

ABSTRACTCombinatorial strategies, such as targeting different immune checkpoint receptors, hold promise to increase the breadth and duration of the response to cancer therapy. Here we describe the preclinical evaluation of CTX-8371, a protein construct which combines PD-1 and PD-L1 targeting in one bispecific, tetravalent antibody. CTX-8371 matched or surpassed the activity of anti-PD-1 and PD-L1 benchmark antibodies in several in vitro T cell activation assays and outperformed clinically approved benchmarks in the subcutaneous MC38 colon and the B16F10 lung metastasis mouse tumor models. Investigation into the mechanism of action revealed that CTX-8371 co-engagement of PD-1 and PD-L1 induced the proteolytic cleavage and loss of cell surface PD-1, which is a novel and non-redundant mechanism that adds to the PD-1/PD-L1 signaling axis blockade. The combination of CTX-8371 and an agonistic anti-CD137 antibody further increased the anti-tumor efficacy with long-lasting curative therapeutic effect. In summary, CTX-8371 is a novel checkpoint inhibitor that might provide greater clinical benefit compared to current anti-PD-1 and PD-L1 antibodies, especially when combined with agents with orthogonal mechanisms of action, such as agonistic anti-CD137 antibodies.

Introduction Renal involvement of primary biliary cholangitis (PBC) usually presents as distal renal tubular acidosis. Proximal tubular (PT) dysfunctions in PBC were rarely reported with unclear clinicopathological characteristics and renal prognosis.Methods We identified 11 cases of PBC with PT dysfunctions (PBC-PT). Their medical document, kidney pathology, and follow-up data were retrospectively reviewed and analyzed.Results The 11 PBC-PT patients were mainly middle-aged (57.8 ± 5.2 years) females (81.8%). Most of them were asymptomatic PBC (7, 63.6%) with a high prevalence of elevated serum immunoglobulin M (IgM, 81.8%) and G (IgG, 54.5%) levels. In the kidney, they had a mean estimated glomerular filtration rate (eGFR) level of 46.54 ± 23.03 ml/min/1.73m2, and 81.8% of them had eGFR below 60 ml/min/1.73m2. They showed different degrees of PT dysfunctions, including hyperuricosuria, hypouricemia, normoglycemic glycosuria, generalized aminoaciduria, hyperphosphaturia, and hypophosphatemia. Their kidney pathology showed tubulointerstitial nephritis with lymphoplasmacytic infiltrates, brush border defects, and proximal tubulitis. After glucocorticoids treatment, the PT dysfunctions manifesting as hypophosphatemia, hypouricemia, and renal glycosuria all recovered, and the eGFR levels were improved from 43.24 ± 19.60 ml/min/1.73m2 to 55.02 ± 21.14 ml/min/1.73m2 (p = 0.028), accompanied by significant improvements of serum IgM levels (from 5.97 ± 4.55 g/L to 2.09 ± 1.48 g/L, p = 0.019).Conclusions The PT dysfunctions were rare in PBC patients, and glucocorticoids treatment could benefit the improvements of eGFR and tubular functions.

BackgroundLung metastasis has garnered significant attention due to its prevalent occurrence. Pre-metastatic niche (PMN) establishment is a critical prerequisite for the onset of lung metastasis. Emerging evidence indicates that long noncoding RNAs (lncRNAs) play pivotal roles in the metastatic cascade to the lungs. However, the relationship between lncRNA expression profiles and the formation of PMN remains uncharacterized. This study aims to explore the expression profiles and potential roles of lncRNAs in the context of pre-metastatic lung microenvironment.MethodsRNA sequencing was utilized to elucidate the lncRNA landscape in pre-metastatic lung of murine models. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to infer the prospective functions of the differentially expressed lncRNAs. Among these, lncRNA Gm5144-202 in alveolar macrophages (AMs) was further scrutinized for its role in driving M2 macrophage polarization, facilitating the formation of PMN, and orchestrating the apoptosis, proliferation, and migration of tumor cells in vitro.ResultsA total of 232 lncRNAs exhibited differential expression in pre-metastatic murine lungs compared to normal controls, predominantly enriching pathways such as PI3K-Akt signaling, calcium signaling, neuroactive ligand-receptor interaction, and NF-κB signaling. Notably, lncRNA Gm5144-202 exhibited the most pronounced difference, with elevated level in alveolar macrophages (AMs) during the pre-metastatic phase. Silencing of lncRNA Gm5144-202 impeded the polarization of M2-like macrophages, suppressed the expression of factors critical for the formation of the PMN, and inhibited tumor cell invasion.ConclusionsOur research delineated the lncRNA expression profiles in pre-metastatic pulmonary tissues and identified, for the first time, the pivotal role of lncRNA Gm5144-202 in modulating M2 macrophage polarization and tumor cell invasiveness. Consequently, targeting lncRNA Gm5144-202 holds substantial promise for translational applications aimed at mitigating pulmonary metastasis.

ObjectivePoly (ADP-ribose) polymerase inhibitors (PARPis) are emerging targeted therapeutic agents in oncology, primarily indicated for ovarian and metastatic breast cancer. Acute kidney injury (AKI) has been observed in patients undergoing PARPi treatment, while there is still a lack of comprehensive comparisons of AKI associated with different PARPis. Our study aimed to extensively characterize the renal adverse effects (RAEs) of PARPi using real-world data.MethodsDisproportionality analysis and Bayesian analysis were employed for data mining to identify suspected RAE cases after different PARPis use within the Food and Drug Administration’s Adverse Event Reporting System from January 2004 to September 2023. The time to onset, fatality, and hospitalization rates of PARPi-related RAEs were also investigated.ResultsWe identified 1,696 PARPi-related RAEs, predominantly affecting patients over 85 (56.31%). Veliparib exhibited a more pronounced association with RAEs compared to others, as indicated by the highest reporting odds ratio (ROR = 29.20, 95% CI = 8.79–96.97), proportional reporting ratio (PRR = 19.80, χ2 = 72.62), and empirical Bayes geometric mean (EBGM = 19.80, the lower 90% one-sided CI = 7.25). The median time to RAEs onset was 15 (interquartile range: 6–55.75) days following the initiation of PARPi therapy. PARPi-related RAEs generally led to a 28.15% hospitalization rate and a 4.34% fatality rate.ConclusionAlthough the majority present with reversible creatinine elevation, PARPi-related RAEs merits broader attention, given its potential for clinical consequences. We should strive to early identify those individuals who may have irreversible kidney damage. The focus should be directed toward monitoring renal function in individuals receiving PARPi, especially in senile people and those with a predisposition to AKI.

Chronic graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (HSCT). Chronic GVHD may have atypical manifestations affecting non-classical organs. The diagnosis in patients with atypical manifestations of chronic GVHD is particullarly challenging, and there is a lack of knowledge regarding their pathogenesis and treatment. We reported a case who developed post-HSCT nephrotic syndrome and portal hypertensive ascites, which are both rare and atypical manifestations of chronic GVHD. Kidney biopsy revealed membranous nephropathy and renal thrombotic microangiopathy with glomerular immune deposits, suggesting antibody-mediated kidney injury. Treatment with ruxolitinib resulted in remission of both nephrotic syndrome and ascites, suggesting a role of cytokines in the pathogenesis. This case highlighted the awareness of nephrotic syndrome and portal hypertensive ascites as atypical manifestations of chronic GVHD, and the efficacy of ruxolitinib for the two manifestations.

Abstract Background Venous thromboembolism (VTE), is a noteworthy complication in individuals with gastric cancer, but the current diagnosis and treatment methods lack accuracy. In this study, we developed a t-PAIC chemiluminescence kit and employed chemiluminescence to detect the tissue plasminogen activator inhibitor complex (t-PAIC), thrombin-antithrombin III complex (TAT), plasmin-α2-plasmin inhibitor complex (PIC) and thrombomodulin (TM), combined with D-dimer and fibrin degradation products (FDP), to investigate their diagnostic potential for venous thrombosis in gastric cancer patients. The study assessed variations in six indicators among gastric cancer patients at different stages. Results The t-PAIC reagent showed LOD is 1.2 ng/mL and a linear factor R greater than 0.99. The reagents demonstrated accurate results, with all accuracy deviations being within 5%. The intra-batch and inter-batch CVs for the t-PAIC reagent were both within 8%. The correlation coefficient R between this method and Sysmex was 0.979. Gastric cancer patients exhibited elevated levels of TAT, PIC, TM, D-D, FDP compared to the healthy population, while no significant difference was observed in t-PAIC. In the staging of gastric cancer, patients in III-IV stages exhibit higher levels of the six markers compared to those in I-II stages. The ROC curve indicates an enhancement in sensitivity and specificity of the combined diagnosis of four or six indicators. Conclusion Our chemiluminescence assay performs comparably to Sysmex’s method and at a reduced cost. The use of multiple markers, including t-PAIC, TM, TAT, PIC, D-D, and FDP, is superior to the use of single markers for diagnosing VTE in patients with malignant tumors. Gastric cancer patients should be screened for the six markers to facilitate proactive prophylaxis, determine the most appropriate treatment timing, ameliorate their prognosis, decrease the occurrence of venous thrombosis and mortality, and extend their survival.

Grouting can effectively reduce residual deformation of coal mine goafs, but fly ash grouting materials suffer from poor flowability and slow early strength development. Microbially -induced calcite precipitation (MICP), with its high environmental compatibility and minimal disturbance to geotechnical bodies, effectively improves the injectability of grouting slurry in goafs. This study combined Castellaniella denitrificans and Sporosarcina pasteurii to induce calcite precipitation, preparing cement–fly ash slurry with varying water–solid ratios, solid ratios and denitrifying bacteria concentrations. The physical properties of the slurry and the mechanical properties of the grouted stone bodies under sealed curing conditions were measured. Results show that the dual-bacteria MICP improves stone body performance by enhancing cohesive, frictional and interlocking forces, so that the strength of the stone bodies cured by MICP increased rapidly within 7 days, and the strength reached the standard 2.03 MPa at 28 days under conditions of low solid ratio and high water–solid ratio, with the best compressive strength at a denitrifying bacteria concentration with an optical density of 0.8 at 600 nm wavelength. At a water–solid ratio of 1 : 1.2 and a solid ratio of 15%, initial and final setting times were 67.2 and 96 h, respectively, which prolonged the initial setting time and final setting time by nearly 70% and 110% compared with that of the slurry without MICP treatment, indicating that MICP enhances slurry fluidity, providing more time for grouting construction in goafs.

IntroductionPrevious studies on hemodialysis adequacy primarily focused on the association between Kt/V and survival, and low Kt/V is associated with increased mortality. There is a paucity of research on the correlation between Kt/V and chronic kidney disease (CKD) complications.MethodsThe retrospective study was conducted in the blood purification center of a tertiary hospital in China from July 2020 to September 2022. It aimed to analyze the association between latent Kt/V trajectory categories and CKD complications (hypertension, anemia, mineral and bone disorder) and inflammatory markers. The latent class trajectory model was established to describe the different patterns of Kt/V changes over the observation period.ResultsDuring the 2-year study period, 93 patients on thrice-weekly hemodialysis with residual kidney function 1.6 to

With the outbreak of the coronavirus disease 2019 (COVID-19), reductions in T-cell function and exhaustion have been observed in patients post-infection of COVID-19. T cells are key mediators of anti-infection and antitumor, and their exhaustion increases the risk of compromised immune function and elevated susceptibility to cancer. Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer with high incidence and mortality. Although the survival rate after standard treatment such as surgical treatment and chemotherapy has improved, the therapeutic effect is still limited due to drug resistance, side effects, and recurrence. Recent advances in molecular biology and immunology enable the development of highly targeted therapy and immunotherapy for cancer, which has driven cancer therapies into individualized treatments and gradually entered clinicians’ views for treating NSCLC. Currently, with the development of photosensitizer materials, phototherapy has been gradually applied to the treatment of NSCLC. This review provides an overview of recent advancements and limitations in different treatment strategies for NSCLC under the background of COVID-19. We discuss the latest advances in phototherapy as a promising treatment method for NSCLC. After critically examining the successes, challenges, and prospects associated with these treatment modalities, their profound prospects were portrayed.

The successful pulmonary metastasis of malignant cancer cells depends on the survival of circulating tumor cells in a distant and hostile microenvironment. The formation of a pre-metastatic niche (PMN) creates a supportive environment for subsequent metastasis. Circular RNAs (circRNAs) are increasingly acknowledged as crucial elements in the mechanisms of metastasis due to their stable structures and functions, making them promising early metastasis detection markers. However, the specific expression patterns and roles of circRNAs in the lungs before metastasis remain largely unexplored. Our research aims to chart the circRNA expression profile and assess their impact on the lung PMN. We developed a lung PMN model and employed comprehensive RNA sequencing to analyze the differences in circRNA expression between normal and pre-metastatic lungs. We identified 38 significantly different circRNAs, primarily involved in metabolism, apoptosis, and inflammation pathways. We then focused on one specific circRNA, circ:chr4:150406196 – 150406664 (circRERE-PMN), which exhibited a significant change in expression and was prevalent in myeloid-derived suppressor cells (MDSCs), alveolar epithelial cells, and macrophages within the pre-metastatic lung environment. CircRERE-PMN was found to potentially regulate apoptosis and the expression of cytokines and chemokines through its interaction with the downstream target HUR in alveolar epithelial cells. Overall, our study highlights the crucial role of circRNAs in the formation of lung PMNs, supporting their potential as diagnostic or therapeutic targets for lung metastasis.

Artificial grasslands of F. kryloviana in the region surrounding Qinghai Lake have been observed to a decline in productivity following three years of establishment. Traditional fertilization practices, aimed at maintaining ecological balance, have predominantly focused on the application of phosphorus. However, it remains unclear whether phosphorus fertilizers offer a superior advantage over nitrogen fertilizers in sustaining productivity. Consequently, from 2017 to 2019, we conducted an experimental to assess the impact of nitrogen and phosphorus fertilization on forage yield and quality. We designed with four levels of phosphorus and two levels of nitrogen, resulting in eight distinct fertilizer combinations. Our experimental findings indicate that the degradation of artificial grasslands leads to a shift in the allocation pattern of aboveground biomass. There was a respective decrease of 68.2 % and 62.5 % in the biomass proportions of stems and ears, contrasted by a greater than 200 % increase in the biomass proportion of leaves. The application of nitrogen not only elevated the total aboveground biomass but also promoted a preferential allocation of biomass to stems and leaves, consequently enhancing the forage's crude protein content. Nitrogen fertilization significantly increased aboveground biomass, and crude protein content by 63.21 %, and 6 %, respectively. Phosphorus fertilization's impact varied annually but favored the distribution of biomass to stems and ears. The net photosynthetic rate improved by over 53.12 % with fertilizer application, although the differences among treatments were not statistically significant. The balanced application of nitrogen and phosphorus fertilizers significantly bolstered the aboveground biomass, ear biomass, stem biomass, leaf biomass, and crude protein content in varying years by 17.25 %–209.83 %, 34.7 %–438.9 %, 25.5 %–250.2 %, 18.4 %–133.3 %, and 10.21 %–25.62 %, respectively. Our analysis revealed that nitrogen-only fertilization exhibited the most optimal fertilizer use efficiency and economic returns. In conclusion, nitrogen fertilization is crucial for sustaining the productivity and quality of F. kryloviana artificial grasslands. The local practice of 75 kg ha−1 phosphorus fertilizer is detrimental to the maintenance of productivity in F. kryloviana artificial grasslands. This study offers valuable insights into the optimization of fertilization strategies for sustainable forage production within alpine regions.

Summary: Background: MIL62, a novel glycoengineered type Ⅱ anti-CD20 monoclonal antibody, with a nearly completely afucosylated N-glycans in Fc region, has demonstrated superior activity compared with rituximab and obinutuzumab in vitro and in vivo, respectively. Methods: This multicentre, single-arm, phase 1b/2 trial aimed to explore the efficacy, pharmacokinetics, and safety of MIL62 combined with lenalidomide in patients with relapsed/refractory (R/R) follicular lymphoma (FL) or marginal zone lymphoma (MZL). Eligible patients included those who had histopathologically confirmed CD20 positive FL (grade 1–3a) or MZL and failed to be treated with rituximab. Patients received intravenously infused MIL62 1000 mg (cycle 1: day 1, 15; cycles 2–8: day 1, cycles 10 and 12: day 1) combined with oral lenalidomide (once a day, days 2–22, the initial dose was 10 mg, and the maximum dose was 20 mg) for 12 cycles, 28 days as a cycle. The primary endpoint was objective response rate (ORR) assessed by investigator per Lugano 2014 criteria every 3 cycles. This study was registered in ClinicalTrials.gov (NCT04110301). Findings: Between November 22, 2019 and December 22, 2020, 54 patients were enrolled from 11 hospitals in China and received study treatment. Fifty patients were included in the efficacy analysis set, and 43 patients (86%, 95% CI: 73, 94) achieved objective response, meeting the pre-specified primary endpoint. Disease control rate was 96% (48/50, 95% CI: 86, 100), proportion of patients with duration of response (DoR) > 6 months was 77% (33/43). The median follow-up for survival was 12.3 months (IQR 12.0–12.6). The 1-year progression-free survival rate was 72% (95% CI: 57, 83), 9-month DoR rate was 74% (95% CI: 58, 85), and 1-year overall survival rate was 98% (95% CI: 85, 100). Most common TRAEs were neutropenia (93%, 50/54), leukopenia (85% 46/54), thrombocytopenia (61% 33/54), lymphopenia (32% 17/54), and alanine aminotransferase increased (20% 11/54). Interpretation: MIL62 combined with lenalidomide showed promising efficacy in patients with R/R FL and MZL. A multicentre, randomized, open-label, phase Ⅲ trial of MIL62 combined with lenalidomide versus lenalidomide in anti-CD20 monoclonal antibody refractory FL patients is ongoing (NCT04834024). Funding: Beijing Mabworks Biotech Co. Ltd, Beijing China and the National Science and Technology Major Project for Key New Drug Development (2017ZX09304015).

Abstract Introduction Thrombosis in ANCA-associated vasculitis (AAV) was prevalent and has been neglected in Chinese patients. This study tried to describe the clinical characteristics, identify the risk factors, and investigate the causal relationship between AAV and venous thromboembolism (VTE) by two-sample Mendelian randomization (MR) analysis. Methods In this retrospective, observational study, we included all hospitalized AAV patients from Jan 2013 to Apr 2022 in Peking Union Medical College Hospital. We collected their clinical data for multivariate regression analysis to determine the risk factors for thrombosis. The nomogram was constructed by applying these risk factors to predict thrombosis in AAV patients. As for MR analysis, we selected single nucleotide polymorphisms (SNPs) related to AAV from published genome-wide association studies and extracted the outcome data containing deep vein thrombosis (DVT) and pulmonary embolism (PE) from the UK biobank. Results 1203 primary AAV patients were enrolled, and thrombosis occurred in 11.3%. Multivariate regression suggested that older than 65 years, EGPA, neurological involvement, lung involvement, significantly elevated serum creatinine (> 500µmol/L), and elevated D-dimer were associated with thrombosis in AAV patients. The model demonstrated satisfied discrimination with an AUC of 0.769 (95% CI, 0.726–0.812). MR analysis showed that EGPA could increase the risk of developing DVT and PE (OR = 1.0038, 95%CI = 1.0035–1.0041, P = 0.009). Conclusion Thrombosis was not rare in Chinese patients with AAV. Renal damage and old age emerged as critical risk factors for thrombosis. EGPA might have a potential causal relationship with DVT and PE.

Abstract Optimizing the spatial layout of the national territory is crucial for realizing the transformation and development of resource-oriented cities in the context of high-quality development in the new period. This paper takes Tongling City as a case study, based on the analysis of the historical development foundation, then uses the SD-FLUS comprehensive model to carry out a systematic analysis of the transformation in five dimensions of economy, society, population, science and technology, resources and environment, and discusses the optimization of spatial pattern under the contextual simulation. The conclusions are as follows: ① The hierarchical framework of “system-indicator-element” is not only internally interconnected, but also inextricably linked with the relationship between the various categories of the land use system. ② Decrease of cropland, forest, water, grassland, and barren decreases from the economic development, social progress, and comprehensive development, and there is a small increase in the area under the scenario of resource and environmental protection, and the direction of the change of the impervious is in the opposite direction. ③ Cultivated land is retained in situ and concentrated to a small extent, forested land is reduced to a small extent while the status quo is maintained, and the Yangtze River water system will be retained and protected to a large extent, but part of the waters of Zongyang County will give way to the expansion of construction land under the development objectives of the new county. Building land will be expanded and extended to the northeast in the original site area, while the southwest corner of the original county center will be expanded to some extent in Zongyang County to promote the county’s economic development.

Abstract Hard carbon has been widely used in anode of lithium/sodium ion battery, electrode of supercapacitor, and carbon molecular sieve for CO2 capture and hydrogen storage. In this study the lignin derived hard carbon products are investigated, and the conclusions are abstracted as follows. (1) The lignin derived hard carbon products consist of microcrystal units of sp 2 graphene fragments, jointed by sp 3 carbon atoms and forming sp 2–sp 3 hybrid hard carbon family. (2) From the lignin precursors to the sp 2–sp 3 hybrid hard carbon products, most carbon atoms retain their original electron configurations (sp 2 or sp 3) and keep their composition in lignin. (3) The architectures of lignin-derived hard carbon materials are closely dependent on the forms of their lignin precursors, and could be preformed by different pretreatment techniques. (4) The carbonization of lignin precursors follows the mechanism “carbonization in situ and recombination nearby”. (5) Due to the high carbon ratio and abundant active functional groups in lignin, new activation techniques could be developed for control of pore size and pore volume. In general lignin is an excellent raw material for sp 2–sp 3 hybrid hard carbon products, a green and sustainable alternative resource for phenolic resin, and industrial production for lignin derived hard carbon products would be feasible.

Abstract Therapeutic targeting of KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) has remained a significant challenge in clinical oncology. Direct targeting of KRAS has proven difficult, and inhibition of the KRAS effectors have shown limited success due to compensatory activation of survival pathways. Being a core downstream effector of the KRAS-driven p44/42 MAPK and PI3K/AKT pathways governing intrinsic apoptosis, BAD phosphorylation emerges as a promising therapeutic target. Herein, a positive association of the pBADS99/BAD ratio with higher disease stage and worse overall survival of PDAC was observed. Homology-directed repair of BAD to BADS99A or small molecule inhibition of BADS99 phosphorylation by NCK significantly reduced PDAC cell viability by promoting cell cycle arrest and apoptosis. NCK also abrogated the growth of preformed colonies of PDAC cells in 3D culture. Furthermore, high-throughput screening with an oncology drug library to identify potential combinations revealed a strong synergistic effect between NCK and MEK inhibitors in PDAC cells harboring either wild-type or mutant-KRAS. Mechanistically, both mutant-KRAS and MEK inhibition increased the phosphorylation of BADS99 in PDAC cells, an effect abrogated by NCK. Combined pBADS99-MEK inhibition demonstrated strong synergy in reducing cell viability, enhancing apoptosis, and achieving xenograft stasis in KRAS-mutant PDAC. In conclusion, the inhibition of BADS99 phosphorylation enhances the efficacy of MEK inhibition, and their combined inhibition represents a mechanistically based and potentially effective therapeutic strategy for the treatment of KRAS-mutant PDAC.

ObjectiveTo explore the risk of different levels of pre-pregnancy obesity on trimester-specific thyroid dysfunction.MethodsQuestionnaire information， blood samples， and urine samples from a 2017 pregnancy cohort study in Shanghai， China were collected. A total of 2 455 pregnant women were included in the analysis. Pre-pregnancy BMI was calculated based on the height and self-reported pre-pregnancy weight. Serum TSH， total thyroxine （TT4）， free thyroxine （FT4）， total triiodothyronine （TT3）， free triiodothyronine （FT3）， thyroid globulin antibody（TgAb）， and Thyroid peroxidase antibody （TPOAb） were measured using the electrochemiluminescence method. Urine iodine levels were measured using the acid digestion method. Levels of thyroid function indexes of pregnant women with different degrees of obesity during pre-pregnancy were compared， and trimester-specific thyroid dysfunction was evaluated according to the reference range of trimester-specific thyroid hormone established by this cohort. Multivariate logistic regressions analysis was used to assess the correlation between pre-pregnancy obesity and trimester-specific thyroid dysfunction.ResultsAs the degree of obesity increased， maternal levels of FT3 and TT3 gradually increased during pregnancy （P

Abstract HLX01 (HanliKang®) is a rituximab biosimilar that showed bioequivalence to reference rituximab in untreated CD20-positive diffuse large B-cell lymphoma (DLBCL) in the phase 3 HLX01-NHL03 study. Here, we report the 5-year follow-up results from the open-label extension part. Patients were randomised to either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or HLX01 plus CHOP (H-CHOP) every 21 days for up to six cycles. The primary efficacy endpoint was overall survival (OS), and secondary efficacy endpoint was progression-free survival (PFS). Of the 407 patients enrolled in HLX01-NHL03, 316 patients (H-CHOP = 157; R-CHOP = 159) were included in the 5-year follow-up for a median duration of 65.1 (range, 2.2–76.5) months. 96.5% of the patients had an International Prognostic Index (IPI) of 1 or 2, and 17.7% had bone marrow involvement. The 5-year OS rates were 81.0% (95% CI: 74.9–87.5%) and 75.4% (95% CI: 68.9–82.6%)( HR: 0.75, 95% CI 0.47–1.20; p = 0.23) while 5-year PFS rates were 77.7% (95% CI: 71.4–84.6%) and 73.0% (95% CI: 66.3–80.3%) (HR: 0.84, 95% CI 0.54–1.30; p = 0.43) in the H-CHOP and R-CHOP groups, respectively. Treatment outcomes did not differ between groups regardless of IPI score and were consistent with the primary analysis. H-CHOP and R-CHOP provided no significant difference in 5-year OS or PFS in previously untreated patients with low or low-intermediate risk DLBCL.

Abstract Objective To explore the relative sensitivity of different methods for detecting cervical glandular lesions. Methods A total of 225 patients with cervical glandular lesions diagnosed from January 2018 to February 2023 were retrieved from the pathology database of Guangdong Maternal and Child Health Hospital, and their clinicopathological features were reviewed. Results Four human papillomavirus (HPV) genotypes: HPV18, 16, 45, and 52, dominated all glandular lesions, and accounting for 74.10% of HPV-positive tumors. Furthermore, 36.89% of abnormal squamous cells were diagnosed as abnormal based on cytological examinations leading to the detection of cervical glandular lesions; only 16.89% were diagnosed based on the initial detection of abnormal glandular cytology. The most common abnormal cervical screening result was ASC-US on cytology (14.22%), followed by HSIL (11.56%). Only few number of patients were diagnosed with or suspected of having cervical adenopathy via a Pap test (18.22%). Nearly one-third of cervical glandular lesions cases were not detected on the Pap test; but were diagnosed upon cervical biopsy or based on the histological examination of ECC, LEEP, or CKC specimens. The LEEP or CKC biopsy specimens had negative margins in 49 cases (40.83%), while the margins were positive in the other 71 cases (59.17%). Five cases (10.20%) with negative margins still had residual lesions following total hysterectomy, and 19 (26.76%) with positive margins had no residual lesions after total hysterectomy. Conclusion The ability to detect cervical glandular lesions varies for routine HPV genotyping, Pap test, or biopsy/ECC, with different sensitivities and advantages and disadvantages for each method.

Abstract Alphaviruses are arboviruses transmitted by mosquitoes and are pathogenic to humans and livestock, causing a substantial public health burden. So far, several receptors have been identified for alphavirus entry; however, they cannot explain the broad host range and tissue tropism of certain alphaviruses, such as Getah virus (GETV), indicating the existence of additional receptors. Here we identify the evolutionarily conserved low-density lipoprotein receptor (LDLR) as a new cell entry factor for GETV, Semliki Forest virus (SFV), Ross River virus (RRV) and Bebaru virus (BEBV). Ectopic expression of LDLR facilitates cellular binding and internalization of GETV, which is mediated by the interaction between the E2-E1 spike of GETV and the ligand-binding domain (LBD) of LDLR. Antibodies against LBD block GETV infection in cultured cells. In addition, the GST-LBD fusion protein inhibits GETV infection both in vitro and in vivo. Notably, we identify the key amino acids in LDLR-LBD that played a crucial role in viral entry; specific mutations in the CR4 and CR5 domain of LDLR-LBD reduce viral entry to cells by more than 20-fold. These findings suggest that targeting the LDLR-LBD could be a potential strategy for the development of antivirals against multiple alphaviruses.

Abstract Aberrant activation of the PI3K/AKT signaling axis along with the sustained phosphorylation of downstream BAD is associated with a poor outcome of TNBC. Herein, the phosphorylated to non-phosphorylated ratio of BAD, an effector of PI3K/AKT promoting cell survival, was observed to be correlated with worse clinicopathologic indicators of outcome, including higher grade, higher proliferative index and lymph node metastasis. The structural optimization of a previously reported inhibitor of BAD-Ser99 phosphorylation was therefore achieved to generate a small molecule inhibiting the phosphorylation of BAD at Ser99 with enhanced potency and improved oral bioavailability. The molecule 2-((4-(2,3-dichlorophenyl)piperazin-1-yl)(pyridin-3-yl)methyl) phenol (NCK) displayed no toxicity at supra-therapeutic doses and was therefore assessed for utility in TNBC. NCK promoted apoptosis and G0/G1 cell cycle arrest of TNBC cell lines in vitro, concordant with gene expression analyses, and reduced in vivo xenograft growth and metastatic burden, demonstrating efficacy as a single agent. Additionally, combinatorial oncology compound library screening demonstrated that NCK synergized with tyrosine kinase inhibitors (TKIs), specifically OSI-930 or Crizotinib in reducing cell viability and promoting apoptosis of TNBC cells. The synergistic effects of NCK and TKIs were also observed in vivo with complete regression of a percentage of TNBC cell line derived xenografts and prevention of metastatic spread. In patient-derived TNBC xenograft models, NCK prolonged survival times of host animals, and in combination with TKIs generated superior survival outcomes to single agent treatment. Hence, this study provides proof of concept to further develop rational and mechanistic based therapeutic strategies to ameliorate the outcome of TNBC.

Coal mining-induced ground subsidence is a severe hazard that can damage property, infrastructure, and the environment in the vicinity when the deformation is not negligible. The boundary of a mining-induced subsidence-affected zone refers to the area beyond which the ground subsidence is less concerned. Accurately measuring mining-induced ground deformation is essential for delineating the irregular boundary of the impacted area. This study employs multitemporal interferometric synthetic aperture radar (MT-InSAR) techniques, including differential InSAR (DInSAR), InSAR stacking, and interferometric point target analysis (IPTA), to analyze coal mine subsidence and delineate the boundaries of the mining-impacted zones. DInSAR accurately reconstructs, locates, and detects the trend in mining-induced subsidence and correlates well with documented mining operations. The InSAR stacking method maps the spatial variation of the ground’s average line-of-sight (LOS) velocity over the mining area, delineating the boundary of the impacted zone. IPTA analysis combining multilook and single-pixel phases achieves millimeter-level surface measurement above tunnel alignments and measures unevenly distributed deformation fields. This study considers an average of 4 cm per year of surface deformation in the LOS direction as the subsidence threshold value for delineating the boundary of the mining-induced subsidence-affected (MISA) zone during the active coal mining stage. Interestingly, there are twin transportation tunnels near the mining area. The twin tunnels completed before the coal mining activities started were functioning well, but damage was observed after the mining began. Our study reveals the tunnels are located within the InSAR-derived MISA zone, although the tunnels approach the MISA boundary. As direct signs of subsidence, ground fissures have been identified near the tunnels via field investigations and UAV photogrammetry. Furthermore, the derived distribution of ground fissures validates and verifies InSAR measurements. The integrated approach of MT-InSAR, UVA photogrammetry, and field investigation developed in this study can be applied to delineate the irregular boundary of the MISA zone and study the accumulating effects of mining-induced subsidence on the performance of infrastructure in areas proximate to coal mining activities.

Abstract West Africa continues to host a growing number of low and intermediate‐magnitude earthquakes (M2‐5) along its passive margins, and its continental interior. Earthquake activity in these regions raises the need to comprehend the causes and the tectonic controls of the seismicity. Unfortunately, such studies are rare. Here, we apply single‐station inversion techniques to constrain fourteen focal mechanisms, computed after compiling a set of high‐quality waveforms. We describe the connection between seismicity, the contemporary stress field, anthropogenic activity and Holocene fault scarps in the region. Our results indicate transpressive stresses acting on the inherited brittle structures in the passive margins. We also observe a compressive regime in the intracontinental failed rifts. We attribute the seismicity to the reactivation of “weak” faults in the Neoproterozoic and Mesozoic failed rifts, the passive transform structures, and the intracratonic Precambrian brittle shear zones.

IntroductionStaphylococcus aureus bacteremia (SAB) is a life-threatening infection particularly involving methicillin-resistant S. aureus (MRSA). In contrast to resolving MRSA bacteremia (RB), persistent MRSA bacteremia (PB) blood cultures remain positive despite appropriate antibiotic treatment. Host immune responses distinguishing PB vs. RB outcomes are poorly understood. Here, integrated transcriptomic, IL-10 cytokine levels, and genomic analyses sought to identify signatures differentiating PB vs. RB outcomes.MethodsWhole-blood transcriptomes of propensity-matched PB (n=28) versus RB (n=30) patients treated with vancomycin were compared in one independent training patient cohort. Gene expression (GE) modules were analyzed and prioritized relative to host IL-10 cytokine levels and DNA methyltransferase-3A (DNMT3A) genotype.ResultsDifferential expression of T and B lymphocyte gene expression early in MRSA bacteremia discriminated RB from PB outcomes. Significant increases in effector T and B cell signaling pathways correlated with RB, lower IL-10 cytokine levels and DNMT3A heterozygous A/C genotype. Importantly, a second PB and RB patient cohort analyzed in a masked manner demonstrated high predictive accuracy of differential signatures.DiscussionCollectively, the present findings indicate that human PB involves dysregulated immunity characterized by impaired T and B cell responses associated with excessive IL-10 expression in context of the DNMT3A A/A genotype. These findings reveal distinct immunologic programs in PB vs. RB outcomes, enable future studies to define mechanisms by which host and/or pathogen drive differential signatures and may accelerate prediction of PB outcomes. Such prognostic assessment of host risk could significantly enhance early anti-infective interventions to avert PB and improve patient outcomes.

Over-expression of glutathione S-transferase (GST) can promote Cisplatin resistance in hepatocellular carcinoma (HCC) treatment. Hence, inhibiting GST is an attractive strategy to improve Cisplatin sensitivity in HCC therapy. Although several synthesized GST inhibitors have been developed, the side effects and narrow spectrum for anticancer seriously limit their clinical application. Considering the abundance of natural compounds with anticancer activity, this study developed a rapid fluorescence technique to screen “green” natural GST inhibitors with high specificity. The fluorescence assay demonstrated that schisanlactone B (hereafter abbreviated as C1) isolated from Xue tong significantly down-regulated GST levels in Cisplatin-resistant HCC cells in vitro and in vivo. Importantly, C1 can selectively kill HCC cells from normal liver cells, effectively improving the therapeutic effect of Cisplatin on HCC mice by down-regulating GST expression. Considering the high GST levels in HCC patients, this compound demonstrated the high potential for sensitizing HCC therapy in clinical practice by down-regulating GST levels.

Canine circovirus (CanineCV), which is a new mammalian circovirus first reported in the United States in 2012, mainly causes diarrhea and vomiting in dogs. As CanineCV evolves and new subtypes emerge, there is an urgent need for new detection technologies to improve the sensitivity and detection rates of viruses in complex scenarios. A chip digital PCR(cdPCR) assay was established for the detection of CanineCV in this study. The results showed good reproducibility, specificity and a linear relationship; the minimum detection limit of CanineCV by cdPCR was 6.62 copies/μL, which is 10 times more sensitive than quantitative real-time PCR (qPCR). The qPCR-positive detection rate was 1 %, while CanineCV cdPCR (2.1 %) exhibited a greater positive detection rate. Fifteen complete genomes were sequenced and subdivided into CanineCV-1 and CanineCV-3. In conclusion, we developed a rapid, reliable, and specific cdPCR method for screening and monitoring canine CV.

Objective: Human endogenous retrovirus-H long terminal repeat associating 2 (HHLA2) is a new immune checkpoint in the B7 family, and the value of HHLA2 in small cell lung cancer (SCLC) is unknown. Methods: We retrospectively detected HHLA2 expression by immunohistochemistry in SCLC patients. Moreover, plasma biomarkers of SCLC were detected retrospectively. Results: Seventy-four percent of SCLC patients exhibited HHLA2 expression. HHLA2 staining was localised within the nucleus of SCLC cells, while no staining was detected in normal lung tissue specimens. The correlation between HHLA2 expression and clinical factors was also analysed. Limited stage (LS) SCLC was more common than extensive stage (ES) SCLC among patients with HHLA2 staining. SCLC patients without metastasis had higher HHLA2 expression than SCLC patients with metastasis. HHLA2 expression was more frequently detected in the group with a tumour size greater than 5 cm than in the group with a tumour size less than 5 cm. The proportion of patients with HHLA2-positive staining was greater in the stage III and IV SCLC groups than in the stage I and II SCLC groups. A high proportion of SCLC patients with HHLA2-positive staining had a survival time

Introduction: The aim of this study is to understand nephrology medical staff’s awareness of, basic knowledge of, practical ability of, and the barriers to palliative kidney care to patients on maintenance hemodialysis (HD) in mainland China. Methods: This cross-sectional descriptive study employed convenience sampling of medical staff (physicians and nurses) working in nephrology departments in mainland China. Independent predictors of self-assessment ability for palliative care (PC) were determined using multivariate binary logistic regression. Results: Responses were received from medical staff in 28 provinces and 657 questionnaires were analyzed. Among the participants, 53.1% (349/657) were doctors, and only 4.3% claimed to be confident in providing PC to patients on HD. The average score of self-assessing ability for PC was 2.65 ± 1.15 (range 1–5). Among the 580 participants who experienced patient withdrawal from dialysis, only 16.0% reported that their patients had well-planned withdrawal from dialysis. Male (odds ratio [OR] [95% confidence interval [CI], 0.585 [0.34–0.99], P = 0.048), nurse (OR [95% CI], 1.81 [1.01–3.27], P = 0.047), more experience in dealing with deceased cases (OR [95% CI], 1.28 [1.02–1.61], P = 0.034), less experience of medical disputes before/after withdrawal from dialysis (OR [95% CI], 0.62 [0.40–0.98], P = 0.041), and PC training experiences (OR [95% CI], 2.33 [1.86–2.91], P < 0.001) were independently correlated with significant better self-assessing ability for PC. Conclusion: This study demonstrates that the nephrology medical staff had a positive attitude but lacked relative knowledge and training in PC. Institutionalized education, training models, practice guidelines for kidney PC, and guidelines for well-planned withdrawal from dialysis according to cultural background are urgently needed in mainland China.

ABSTRACT: Objectives: Several linezolid population pharmacokinetic (popPK) models have been established to facilitate optimal therapy; however, their extrapolated predictive performance to other clinical sites is unknown. This study aimed to externally evaluate the predictive performance of published pharmacokinetic models of linezolid in adult patients. Methods: For the evaluation dataset, 150 samples were collected from 70 adult patients (72.9% of which were critically ill) treated with linezolid at our center. Twenty-five published popPK models were identified from PubMed and Embase. Model predictability was evaluated using prediction-based, simulation-based, and Bayesian forecasting-based approaches to assess model predictability. Results: Prediction-based diagnostics found that the prediction error within ±30% (F30) was less than 40% in all models, indicating unsatisfactory predictability. The simulation-based prediction- and variability-corrected visual predictive check and normalized prediction distribution error test indicated large discrepancies between the observations and simulations in most of the models. Bayesian forecasting with one or two prior observations significantly improved the models’ predictive performance. Conclusion: The published linezolid popPK models showed insufficient predictive ability. Therefore, their sole use is not recommended, and incorporating therapeutic drug monitoring of linezolid in clinical applications is necessary.

Abstract Objectives ICIs have become the standard treatment for advanced NSCLC patients. Currently, PD-L1 is the most widely useful biomarker to predict ICI efficacy, but the sensitivity and specificity are limited. Therefore, the useful predictive biomarkers of ICI efficacy is urgently needed. BMI is an internationally used measure of body health. Obesity may affect ICI efficacy by changing T cell functions. This meta-analysis aimed to clarify the relationship between BMI and survival outcomes of NSCLC patients treated with ICIs. Methods A systematic review was conducted to identify studies that assessed the association between BMI and survival outcomes in patients treated with ICIs. OS was the primary endpoint, and PFS was the secondary endpoint. Random-effect models or fixed-effect models were utilized to combine study effects according to the Cochran Q and I 2 tests. Results Nine studies, including 4602 NSCLC patients treated with ICIs, that met the inclusion criteria were selected for this meta-analysis. There was no significant difference in PFS (HR 0.885; 95% CI 0.777–1.009, p = 0.068) or OS (HR 0.947; 95% CI 0.789–1.137, p = 0.560) between the low BMI group and the high BMI group. However, in the subgroup analysis, compared with normal-weight patients, overweight and obese patients achieved prolonged PFS (HR 0.862; 95% CI 0.760–0.978, p = 0.021) and OS (HR 0.818; 95% CI 0.741–0.902, p

In order to raise yields and reduce production costs, the fermentation medium of succinic acid production by Actinobacillus succinogenes from sweet potato powder. First, the effects of sweet potato powder concentration, MgCO3 concentration, liquefaction enzyme dose, saccharifying enzyme dose, nitrogen source concentration and fermentation time on succinic acid production were investigated by single factor experiments in this study. Then, the optimum values of the parameters were obtained by orthogonal experiment design. Finally，the optimal fermentation conditions were amplified by 2 L stirred bioreactor. The results showed that mixed nitrogen source (yeast powder:corn steep liquor=1:2) was used as a proper nutrient in the succinic acid production from sweet potato powder. The formula optimization results showed that the important parameters were sweet potato powder, MgCO3, liquifying enzyme dose, glucoamylase dose and mixed nitrogen source. The optimum condition was as follows: Sweet potato powder 115 g/L, MgCO3 60 g/L, liquifying enzyme dose 0.008 KUN-S/g substrate, glucoamylase dose 3.09 AGU/g substrate, mixed nitrogen source 33 g/L. Succinic acid yield reached 69.89 g/L at the optimal condition, which was increased by 64.60% compared to that before optimization (42.46 g/L). Approximately 71.42 g/L of succinic acid content with a yield of 79.87% and a productivity of 0.99 g/(L·h) was obtained after 72 h in a 2 L bioreactor. Therefore, sweet potato powder could be a promising feedstock for the economical and efficient production of succinic acid through fermentation by A. succinogenes.

Accurate electrical load forecasting is crucial for the stable operation of power systems. However, existing forecasting models face limitations when handling multidimensional features and feature interactions. Additionally, traditional metaheuristic algorithms tend to become trapped in local optima during the optimization process, negatively impacting model performance and prediction accuracy. To address these challenges, this paper proposes a short-term electrical load forecasting method based on a parallel Temporal Convolutional Network–Gated Recurrent Unit (PTCN-GRU) model, optimized by an improved Dung Beetle Optimization algorithm (IDBO). This method employs a parallel TCN structure, using TCNs with different kernel sizes to extract and integrate multi-scale temporal features, thereby overcoming the limitations of traditional TCNs in processing multidimensional input data. Furthermore, this paper enhances the optimization performance and global search capability of the traditional Dung Beetle Optimization algorithm through several key improvements. Firstly, Latin hypercube sampling is introduced to increase the diversity of the initial population. Next, the Golden Sine Algorithm is integrated to refine the search behavior. Finally, a Cauchy–Gaussian mutation strategy is incorporated in the later stages of iteration to further strengthen the global search capability. Extensive experimental results demonstrate that the proposed IDBO-PTCN-GRU model significantly outperforms comparison models across all evaluation metrics. Specifically, the mean absolute error (MAE), mean absolute percentage error (MAPE), and root mean square error (RMSE) were reduced by 15.01%, 14.44%, and 14.42%, respectively, while the coefficient of determination (R2) increased by 2.13%. This research provides a novel approach to enhancing the accuracy of electrical load forecasting.

Dextransucrases play a crucial role in the production of dextran from economical sucrose; therefore, there is a pressing demand to explore novel dextransucrases with better performance. This study characterized a dextransucrase enzyme, LmDexA, which was identified from the Leuconostoc mesenteroides NN710. This bacterium was isolated from the soil of growing dragon fruit in Guangxi province, China. We successfully constructed six different N-terminal truncated variants through sequential analysis. Additionally, a truncated variant, ΔN190LmDexA, was constructed by removing the 190 amino acids fragment from the N-terminal. This truncated variant was then successfully expressed heterologously in Escherichia coli and purified. The purified ΔN190LmDexA demonstrated optimal hydrolysis activity at a pH of 5.6 and a temperature of 30 °C. Its maximum specific activity was measured to be 126.13 U/mg, with a Km of 13.7 mM. Results demonstrated a significant improvement in the heterologous expression level and total enzyme activity of ΔN190LmDexA. ΔN190LmDexA exhibited both hydrolytic and transsaccharolytic enzymatic activities. When sucrose was used as the substrate, it primarily produced high-molecular-weight dextran (>400 kDa). However, upon the addition of maltose as a receptor, it resulted in the production of a significant amount of oligosaccharides. Our results can provide valuable information for enhancing the characteristics of recombinant dextransucrase and potentially converting sucrose into high-value-added dextran and oligosaccharides.

Abstract Background This study aimed to compare the efficacy and safety of high-dose methotrexate (HD-MTX) versus teniposide (TEN) in patients with newly diagnosed immunocompetent primary central nervous system lymphomas (PCNSLs). Methods The study included immunocompetent, adult patients with newly diagnosed PCNSL at 22 centers in China from 2007 to 2016. The patients received HD-MTX or TEN as first-line induction therapy. The objective response rate, progression-free survival, and overall survival were analyzed for each patient cohort. Results A total of 96 patients were eligible: 62 received HD-MTX, while 34 received teniposide. The overall response rate was 73.2% and 72.7% in the MTX and the TEN cohorts, respectively (P = 0.627). The median progression-free survival was 28.4 months [95% confidence interval (CI): 13.7–51.2] in the MTX cohort and 24.3 months (95% CI: 16.6–32.1) in the TEN cohort (P = 0.75). The median overall survival was 31 months (95% CI: 26.8–35.2) in the MTX cohort and 32 months (95% CI: 27.6–36.4) in the TEN cohort (P = 0.77). The incidence of any grade of coagulopathy/deep-vein thrombosis and gastrointestinal disorders was significantly higher in the MTX cohort than in the TEN cohort; no significant difference was found in the incidence of other adverse events between the two cohorts. Conclusions This was the first multicenter study using TEN as the main agent compared with HD-MTX in newly diagnosed primary CNS lymphoma. The TEN-based regimen was non-inferior to the HD-MTX-based regimen with similar overall responses. Classification of evidence This study provided Class III evidence that the teniposide-based regimen was non-inferior to high-dose methotrexate − based regimen with similar overall responses and long-time survival in immunocompetent patients with PCNSL.

BackgroundThe burden of metabolic syndrome (MetS) continues to rise globally and is associated with complications of multiple organ systems. We aimed to identify the association between changes in MetS status and accelerated renal function progression through a regional epidemiological survey in China, thus discovering influence factors with treatable potential.MethodsThis study was a population-based survey conducted in 2008 and 2014, assessing a representative sample of 5,225 individuals from rural areas of China. They were divided into four subgroups according to their MetS status in 2008 and 2014 (Never, Previously abnormal, New-onset, and Consistent). Multivariate logistic regression and stratification analysis evaluated the relationship between clinical factors and renal function decline under different MetS statuses. Smooth curve fitting further addressed the role of serum uric acid, illustrating the vital turning point of uric acid levels in the background of renal function deterioration.ResultsOf all groups of MetS states, the new-onset MetS showed the most significant eGFR decline, with a 6.66 ± 8.21 mL/min/1.73 m2 decrease over 6 years. The population with newly-onset MetS showed a considerable risk increase in delta eGFR with a beta coefficient of 1.66 (95%CI=1.09-2.23) after necessary correction. In searching for the drivers, the strength of the association was significantly reduced after additional adjustment for uric acid levels (β=0.91, 95%CI=0.35-1.45). Regarding the turning point, uric acid levels exceeding 426 μmol/L were more significantly associated with the stepped-up deterioration of kidney function for those with new-onset MetS.ConclusionMetabolic syndrome demonstrated a solid correlation with the progression of renal function, particularly in those with newly-onset MetS status. In addition to the diagnostic components of MetS, hyperuricemia could be used as a marker to identify the high risk of accelerating eGFR decline early. Furthermore, we suggested a potential renal benefit for the newly-onset MetS population when maintaining their serum uric acid level below the criteria for asymptomatic hyperuricemia.

To ensure the continuous high-efficiency operation of fuel cell systems, it is essential to perform real-time estimation of the maximum efficiency point and maximum power point for multi-stack fuel cell systems. The region between these two power points is commonly referred to as the "high-efficiency operating region." Initially, a transformation of the general expression for hydrogen consumption in multi-stack fuel cell systems is conducted to obtain an algebraic expression for the efficiency curve of multi-stack fuel cells. Utilizing a polynomial differentiation approach, the parameter equation for the maximum system efficiency is computed. Subsequently, a reverse deduction is carried out using the maximum efficiency and its corresponding power of underperforming subsystems to enhance the maximum efficiency of multi-stack fuel cell systems.Furthermore, an equivalent hydrogen consumption minimization method is introduced for real-time optimization of hybrid energy systems. The state machine control method serves as an auxiliary strategy, imposing the high-efficiency operating region as a boundary constraint for the equivalent hydrogen consumption minimization strategy's results. This ensures that the multi-stack fuel cell system operates as much as possible within the high-efficiency operating region.Through simulation validation using MATLAB/Simulink, the proposed approach comprehensively leverages the advantages of the state machine and equivalent hydrogen consumption. This approach enables effective identification of the high-efficiency operating region of fuel cells, while concurrently enhancing the operational range efficiency of the system, reducing hydrogen consumption, and elevating system stability.

Coix lacryma-jobi L. belongs to family Poaceae, is widely cultivated in tropical Asian countries for its nutritional and medicinal values. Coix is often threatened by lepidopteran such as Mythimna separata during its life cycle, resulting in severe yield reduction. Insect feeding can trigger defense signaling and increased defense responses in many other crops, yet little is known about whether simulated armyworm feeding on Coix leaves could induce anti-herbivory responses and whether armyworm feeding could activate priming in systemic leaves. In this study, Mythimna separata simulated herbivory elicited increased jasmonic acid (JA) level, JA-Ile (JA-isoleucine conjugate) and altered transcriptome in the Coix leaves. Meanwhile, M. separata simulated herbivory in local leaves primed the systemic leaves for increased accumulation of jasmonic acid and enhanced resistance to M. separata. Consistently, transcriptome analysis showed the systemic leaves were primed, which were up- or down-regulated comparing with the non-primed systemic leaves. In this study, we first reported Mythimna separata simulated herbivory induced increased defense response in leaves of Coix, also Mythimna separata herbivory primed Coix resistance in systemic leaves. This study provides new insight into the regulation of defense responses of Coix against M. separata and the ecological function of priming in Coix.

ABSTRACT: Ustekinumab is a first-line drug for Crohn's disease. However, little is known about its potential adverse effects on renal function. We present the case of a 42-year-old man with Crohn's disease who developed chronic renal dysfunction during ustekinumab treatment, which resolved after discontinuing ustekinumab. The findings underscore the importance of close monitoring of renal function in patients receiving ustekinumab, particularly those with preexisting kidney disease or risk factors for renal dysfunction.

Nitrogen (N) addition is a simple and effective field management approach to enhancing plant productivity. Nonetheless, the regulatory mechanisms governing nitrogen concentrations and their effect on soil enzyme activity, nutrient levels, and seed yield in the Festuca kirilowii seed field have yet to be elucidated. Therefore, this study sought to investigate the effect of N fertilizer application on soil enzyme activities, soil nutrients, and seed yield of F. kirilowii Steud cv. Huanhu, the only domesticated variety in the Festuca genus of the Poaceae family, was investigated based on two-year field experiments in the Qinghai–Tibet Plateau (QTP). Results showed that N input significantly affected soil nutrients (potential of hydrogen, total nitrogen, organic matter, and total phosphorus). In addition, soil enzyme activities (urease, catalase, sucrase, and nitrate reductase) significantly increased in response to varying N concentrations, inducing changes in soil nutrient contents. Introducing N improved both seed yield and yield components (number of tillers and number of fertile tillers). These findings suggest that the introduction of different concentrations of N fertilizers can stimulate soil enzyme activity, thus hastening nutrient conversion and increasing seed yield. The exhaustive evaluation of the membership function showed that the optimal N fertilizer treatment was N4 (75 kg·hm−2) for both 2022 and 2023. This finding provides a practical recommendation for improving the seed production of F. kirilowii in QTP.

The titanium alloy brake shell is an important component used in aviation, but its surface polishing is mostly done manually, making it difficult to ensure surface quality and consistency. As a result, an industrial robot polishing system based on digital twin is proposed, which can realize the interaction between physical and virtual platforms by using digital twin technology, acquire various parameters in real time, and monitor the polishing process. Based on this system, a removal depth model was established, and the polishing parameters to be analyzed were determined by combining the removal depth model. On this basis, the influence law of polishing parameters on surface roughness is analyzed through physical tests, and orthogonal experiments are used to optimize the polishing parameters. The results show that the surface roughness is reduced to 0.171 μm after optimization. Finally, the reliability of the polishing system is verified through the polishing machining test, and the surface quality of titanium alloy brake shell is significantly improved.

Abstract Blastocystis is a species complex that exhibits extensive genetic diversity, evidenced by its classification into several genetically distinct subtypes (ST). Although several studies have shown the relationships between a specific subtype and gut microbiota, there is no study to show the effect of the ubiquitous Blastocystis ST1 on the gut microbiota and host health. Here, we show that Blastocystis ST1 colonization increased the proportion of beneficial bacteria Alloprevotella and Akkermansia, and induced Th2 and Treg cell responses in normal healthy mice. ST1-colonized mice showed decreases in the severity of DSS-induced colitis when compared to non-colonized mice. Furthermore, mice transplanted with ST1-altered gut microbiota were refractory to dextran sulfate sodium (DSS)-induced colitis via induction of Treg cells and elevated short-chain fat acid (SCFA) production. Our results suggest that colonization with Blastocystis ST1, one of the most common subtypes in humans, exerts beneficial effects on host health through modulating the gut microbiota and adaptive immune responses.