Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

The potent potential of MFAP2 in prognosis and immunotherapy of triple-negative breast cancer.

BACKGROUNDS: Microfibril-associated protein 2 (MFAP2) is a protein presenting in the extracellular matrix that governs the activity of microfibrils through its interaction with fibrillin. While the involvement of MFAP2 in metabolic disorders has been documented, its expression and prognostic significance in triple-negative breast cancer (TNBC) remain unexplored. METHODS: We acquired datasets pertaining to breast cancer (BC) from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Next, a Venn diagram was used to identify the differentially expressed genes (DEGs). The DEGs were used to perform Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction (PPI), immune and survival analysis. The expressions of MFAP2, PD-1 and PD-L1 were examined by immunohistochemistry and western blot and their relationship with clinical pathological parameters were analyzed by clinical specimen samples from patients with TNBC. Tumor Immune Estimation Resource (TIMER, https://cistrome.shinyapps.io/timer/ ) was adopted to calculate the immune infiltration level of TNBC. The link between gene expression and tumor mutational burden (TMB) was described using Spearman's correlation analysis. RESULTS: We identified 66 differentially expressed genes (DEGs) that were up-regulated. Among these DEGs, MFAP2 was found to be overexpressed in TNBC and was associated with a lower probability of survival. This finding was confirmed through the use of immunohistochemistry and western blot techniques. Additionally, MFAP2 was found to be related to various pathological parameters in TNBC patients. Mechanistically, gene set enrichment analysis (GSEA) revealed that MFAP2 primarily influenced cellular biological behavior in terms of epithelial mesenchymal transition, glycolysis, and apical junction. Notably, MFAP2 expression was positively correlated with the abundance of macrophages, while a negative correlation was observed with the abundance of B cells, CD4 + T cells, CD8 + T cells, neutrophils and dendritic cells through immune analysis. Furthermore, it was observed that MFAP2 displayed a negative correlation not only with tumor mutational burden (TMB), a recognized biomarker for PD-1/PD-L1 immunotherapy, but also with PD-L1 in samples of TNBC. CONCLUSION: MFAP2 may be an important prognostic biomarker for TNBC, as well as a viable target for immunotherapy in this disease.

Parasite infestation patterns differ between ticks and chigger mites on two rodent host species in Taiwan.

Parasites are typically concentrated on a few host individuals, and identifying the mechanisms underlying aggregated distribution can facilitate a more targeted control of parasites. We investigated the infestation patterns of hard ticks and chigger mites on two rodent species, the striped field mouse, Apodemus agrarius, and the lesser ricefield rat, Rattus losea, in Taiwan. We also explored abiotic and biotic factors that were important in explaining variation in the abundance of ticks and chiggers on rodent hosts. Ticks were more aggregated than chiggers on both rodent species. Factors important for the variation in parasitic loads, especially biotic factors, largely differed between ticks and chiggers. Variation partitioning analyses revealed that a larger proportion of variation in chiggers than in ticks can be explained, especially by abiotic factors. If, as proposed, the higher number of parasites in males is due to a larger range area or immunity being suppressed by testosterone, when A. agrarius males host more ticks, they are expected to also host more chiggers, given that chiggers adopt a similar host finding approach to that of ticks. Instead, the similar abundance of chiggers in male and female A. agrarius implies that a large home range or suppressed immunity does not predispose males to inevitably host more parasites. More variations were explained by abiotic than biotic factors, suggesting that controlling practices are more likely to be successful by focusing on factors related to the environment instead of host traits. Our study indicated that the extent of parasitism is rarely determined by a sole factor, but is an outcome of complex interactions among animal physiology, animal behavior, characteristics of parasites, and the environments.

Green supply chain finance strategies with market competition and financial constraints.

In the context of sustainable development, market competition is intensifying, and financial constraints have emerged as a significant hindrance to green project investment. Green Supply Chain Finance (GSCF), characterized by long-term collaboration, has emerged as a crucial financial approach to mitigate corporate financial limitations and channel capital flows into environmentally friendly industries. We propose a two-echelon supply chain with one supplier and two competing retailers over a single period and investigate ordering, sales, and financing decisions simultaneously under competition. Retailers constrained by financial considerations may secure GSCF or traditional bank financing (BF) loans. This study investigates the influence of competition on pricing and sales strategies during the selling season. The results demonstrate that retailers select between clearance and responsive selling strategies based on the level of market competition. During the ordering season, retailers share the product market equally when interest rates are uniform, and the supplier formulates a supply chain contract while considering the financing interest rate. In the presence of differential interest rates, retailers may not always opt for the GSCF, even when they offer an interest rate advantage, due to the comprehensive impacts of operational and financial strategies. Remarkably, competitive retailers do not choose the GSCF when their initial green investment capital surpasses a certain threshold.

Association Between Systemic Immune Inflammation Indexes and DVT in Patients With Malignancy Requiring PICC Insertion.

Background: In order to reduce the risk of leakage of cytotoxic agents, peripherally inserted central catheters (PICC) are widely used in patients diagnosed with malignancy before chemotherapy. While inflammation has been demonstrated to be associated with deep vein thrombosis (DVT), the connection between systemic immune inflammation indexes and the formation of PICC-DVT remains unclear. Purpose: This study aims to evaluate the association between PICC-DVT and systemic immune inflammation indexes including platelet-to-lymphocyte ratio (PLR), systemic immune-inflammatory index (SII), and systemic inflammatory response index (SIRI). Methods: From August 2018 to October 2021, we enrolled consecutive patients diagnosed with malignancy who underwent PICC implantation before chemotherapy. DVT was assessed using color Doppler ultrasonography. Results: Among the 513 patients, 57 patients (11.1%) developed PICC-DVT. The optimal cutoff values for PLR, SII and SIRI were 260.1, 1318.7, and 2.7, respectively. Based on the multiple logistic regression analysis, correlations were found between PICC-DVT and elevated PLR (p = .014), SII (p = .012), and SIRI (p = .022). Patients with malignancy having higher values of PLR, SII or SIRI tended to be more likely to develop PICC-DVT. Conclusions: The systemic immune inflammation indexes increases the risk of PICC-DVT and could be used as auxiliary predictive tests for PICC-DVT.

The association between blood pressure variability and renal damage in patients with primary aldosteronism.

This research examines the association between blood pressure variability (BPV) and renal damage in a cohort of 129 primary aldosteronism (PA) patients, employing ambulatory blood pressure monitoring (ABPM) for comparative analysis with individuals diagnosed with essential hypertension (EH). The study reveals that PA patients exhibited significantly elevated levels of cystatin C and urine microalbumin/creatinine ratio (UACR). Additionally, a higher prevalence of non-dipping blood pressure patterns in PA patients suggests an increased risk of circadian blood pressure regulation disturbances. Notably, while most BPV indices were comparable between the two groups, the standard deviation of 24-h weighted diastolic blood pressure was markedly lower in the PA cohort, distinguishing it as a unique variable. Through multiple linear regression analysis, the duration of hypertension, angiotensin II concentrations, and daytime systolic blood pressure standard deviation emerged as significant determinants of estimated glomerular filtration rate (eGFR) in PA patients. Furthermore, UACR was significantly influenced by variables including the 24-h weighted standard deviation (wSD) of systolic BP, glycosylated hemoglobin levels, nocturnal systolic BP peaks, aldosterone-renin ratio (ARR), and total cholesterol, with the most pronounced association observed with the 24-h wSD of systolic BP (ß = 0.383).The study also found significant correlations between the 24-h wSD of systolic BP, ARR, HbA1c, serum potassium levels, and 24-h urinary microalbumin, underscoring the critical role of the 24-h wSD of systolic BP (ß = 0.267). These findings underscore the imperative of an integrated management strategy for PA, addressing the intricate interconnections among metabolic abnormalities, blood pressure variability, and renal health outcomes.

Metabolomics reveals high fructose-1,6-bisphosphate from fluoride-resistant Streptococcus mutans.

BACKGROUND: Fluoride-resistant Streptococcus mutans (S. mutans) strains have developed due to the wide use of fluoride in dental caries prevention. However, the metabolomics of fluoride-resistant S. mutans remains unclear. OBJECTIVE: This study aimed to identify metabolites that discriminate fluoride-resistant from wild-type S. mutans. MATERIALS AND METHODS: Cell supernatants from fluoride-resistant and wild-type S. mutans were collected and analyzed by liquid chromatography-mass spectrometry. Principal components analysis and partial least-squares discriminant analysis were performed for the statistical analysis by variable influence on projection (VIP > 2.0) and p value (Mann-Whitney test, p < 0.05). Metabolites were assessed qualitatively using the Human Metabolome Database version 2.0 ( http://www.hmdb.ca ), or Kyoto Encyclopedia of Genes and Genomes ( http://www.kegg.jp ), and Metaboanalyst 6.0 ( https://www.metaboanalyst.ca ). RESULTS: Fourteen metabolites differed significantly between fluoride-resistant and wild-type strains in the early log phase. Among these metabolites, 5 were identified. There were 32 differential metabolites between the two strains in the stationary phase, 13 of which were identified. The pyrimidine metabolism for S. mutans FR was matched with the metabolic pathway. CONCLUSIONS: The fructose-1,6-bisphosphate concentration increased in fluoride-resistant strains under acidic conditions, suggesting enhanced acidogenicity and acid tolerance. This metabolite may be a promising target for elucidating the cariogenic and fluoride resistant mechanisms of S. mutans.

Engineered CD47 protects T cells for enhanced antitumour immunity.

Adoptively transferred T cells and agents designed to block the CD47-SIRPα axis are promising cancer therapeutics that activate distinct arms of the immune system1,2. Here we administered anti-CD47 antibodies in combination with adoptively transferred T cells with the goal of enhancing antitumour efficacy but observed abrogated therapeutic benefit due to rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors. Anti-CD47-antibody-mediated CAR T cell clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered the CD47 variant CD47(Q31P) (47E), which engages SIRPα and provides a 'don't eat me' signal that is not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E are resistant to clearance by macrophages after treatment with anti-CD47 antibodies, and mediate substantial, sustained macrophage recruitment to the tumour microenvironment. Although many of the recruited macrophages manifested an M2-like profile3, the combined therapy synergistically enhanced antitumour efficacy. Our study identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T-cell-directed therapeutics with those designed to activate macrophages. It delivers a therapeutic approach that is capable of simultaneously harnessing the antitumour effects of T cells and macrophages, offering enhanced potency against solid tumours.

A NAC transcription factor represses a module associated with xyloglucan content and regulates aluminum tolerance.

The transcriptional regulation of aluminum (Al) tolerance in plants is largely unknown, although Al toxicity restricts agricultural yields in acidic soils.. Here, we identified a NAM, ATAF1/2, and cup-shaped cotyledon 2 (NAC) transcription factor that participates in Al tolerance in Arabidopsis (Arabidopsis thaliana). Al substantially induced the transcript and protein levels of ANAC070, and loss-of-function anan070 mutants showed remarkably increased Al sensitivity, implying a beneficial role of ANAC070 in plant tolerance to Al toxicity. Further investigation revealed that more Al accumulated in the roots of anac070 mutants, especially in root cell walls, accompanied by a higher hemicellulose and xyloglucan level, implying a possible interaction between ANAC070 and genes that encode proteins responsible for the modification of xyloglucan, including xyloglucan endo-transglycosylases/hydrolase (XTH) or ANAC017. Yeast one hybrid analysis revealed a potential interaction between ANAC070 and ANAC017, but not for other XTHs. Furthermore, dual-luciferase reporter assay, RT-qPCR, and GUS analysis revealed that ANAC070 could directly repress the transcript levels of ANAC017, and knockout of ANAC017 in the anac070 mutant partially restored its Al sensitivity phenotype, indicating that ANAC070 contributes to Al tolerance mechanisms other than suppression of ANAC017 expression. Further analysis revealed that the core transcription factor SENSITIVE TO PROTON RHIZOTOXICITY1 (STOP1) and its target genes, which control Al tolerance in Arabidopsis, may also be involved in ANAC070-regulated Al tolerance. In summary, we identified a transcription factor, ANAC070, that represses the ANAC017-XTH31 module to regulate Al tolerance in Arabidopsis.

The use of sodium-glucose cotransporter 2 inhibitors and the incidence of uveitis in type 2 diabetes: a population-based cohort study.

Introduction: To survey the potential correlation between the application of sodium-glucose cotransporter 2 (SGLT2) inhibitors and the incidence of uveitis in individuals with type 2 diabetes mellitus (T2DM). Material and methods: A retrospective cohort study using the National Health Insurance Research Database (NHIRD) was conducted. The T2DM patients using SGLT2 inhibitors and those taking other anti-diabetic medications were assigned to the SGLT2 group and the control group, respectively, with a 1 : 2 ratio via the propensity score-matching (PSM) method. The major outcome in this study is the development of uveitis according to the diagnostic codes. The Cox proportional hazard regression was adopted to yield the adjusted hazard ratio (aHR) with 95% confidence interval (CI) between the groups. Results: There were 147 and 371 new uveitis episodes in the SGLT2 and control groups after the follow-up period up to 5 years. The incidence of uveitis in the SGLT2 group (aHR = 0.736, 95% CI: 0.602-0.899, p = 0.0007) was significantly lower than that in the control group after adjusting for the effect of all the confounders. In the subgroup analyses, the SGLT2 inhibitors showed a higher correlation with low uveitis incidence in T2DM patients aged under 50 than T2DM individuals aged over 50 years (p = 0.0012), while the effect of SGLT2 inhibitors on the incidence of anterior and posterior uveitis development was similar (p = 0.7993). Conclusions: The use of SGLT2 inhibitors could be an independent protective factor for uveitis development in T2DM population.

MDM2 accelerated renal senescence via ubiquitination and degradation of HDAC1.

Senescence, an intricate and inevitable biological process, characterized by the gradual loss of homeostasis and declining organ functions. The pathological features of cellular senescence, including cell cycle arrest, metabolic disruptions, and the emergence of senescence-associated secretory phenotypes (SASP), collectively contribute to the intricate and multifaceted nature of senescence. Beyond its classical interaction with p53, murine double minute gene 2 (MDM2), traditionally known as an E3 ubiquitin ligase involved in protein degradation, plays a pivotal role in cellular processes governing senescence. Histone deacetylase (HDAC), a class of histone deacetylases mainly expressed in the nucleus, has emerged as a critical contributor to renal tissues senescence. In this study we investigated the interplay between MDM2 and HDAC1 in renal senescence. We established a natural aging model in mice over a 2-year period that was verified by SA-ß-GAL staining and increased expression of senescence-associated markers such as p21, p16, and TNF-α in the kidneys. Furthermore, we showed that the expression of MDM2 was markedly increased, while HDAC1 expression underwent downregulation during renal senescence. This phenomenon was confirmed in H2O2-stimulated HK2 cells in vitro. Knockout of renal tubular MDM2 alleviated renal senescence in aged mice and in H2O2-stimulated HK2 cells. Moreover, we demonstrated that MDM2 promoted renal senescence by orchestrating the ubiquitination and subsequent degradation of HDAC1. These mechanisms synergistically accelerate the aging process in renal tissues, highlighting the intricate interplay between MDM2 and HDAC1, underpinning the age-related organ function decline.

Measurement of HIV Rev-Rev Response Element Functional Activity.

Retroviruses must overcome cellular restrictions to the nucleocytoplasmic export of viral mRNAs that retain introns in order to complete their replication cycle. HIV accomplishes this using a system comprised of a trans-acting viral protein, Rev, and a cis-acting RNA secondary structure in the viral genome, the Rev-Response Element (RRE). HIV primary isolates differ with respect to the sequence and functional activity of the Rev-RRE system. Here, we describe a high throughput assay system for analyzing Rev-RRE functional activity using packageable viral vectors.

Prediction of Vasoactive-Inotropic Score on Prolonged Mechanical Ventilation in Adult Congenital Heart Disease Patients After Surgical Treatment Combined with Coronary Artery Bypass Grafting.

INTRODUCTION: This study aimed to investigate the predictive value of the vasoactive-inotropic score (VIS) at different time points for postoperative prolonged mechanical ventilation (PMV) in adult congenital heart disease patients undergoing surgical treatment combined with coronary artery bypass grafting. METHODS: Patients were divided into two groups that developed PMV or not. The propensity score matching method was applied to reduce the effects of confounding factors between the two groups. VIS at different time points (VIS at the end of surgery, VIS6h, VIS12h, and VIS12h max) after surgery were recorded and calculated. The value of VIS in predicting PMV was analyzed by the receiver operating characteristic (ROC) curve, and multivariate logistic regression was used to analyze independent risk factors. RESULTS: Among 250 patients, 52 were in the PMV group, and 198 were in the non-PMV group. PMV rate was 20.8%. After propensity score matching, 94 patients were matched in pairs. At each time point, the area under the ROC curve predicted by VIS for PMV was > 0.500, among which VIS at the end of surgery was the largest (0.805). The optimal cutoff point for VIS of 6.5 could predict PMV with 78.7% sensitivity and 72.3% specificity. VIS at the end of surgery was an independent risk factor for PMV (odds ratio=1.301, 95% confidence interval 1.091~1.551, P<0.01). CONCLUSION: VIS at the end of surgery is an independent predictor for PMV in patients with adult congenital heart disease surgical treatment combined with coronary artery bypass grafting.

Placental inflammatory injury induced by chlorinated polyfluorinated ether sulfonate (F-53B) through NLRP3 inflammasome activation.

Chlorinated polyfluorinated ether sulfonate, commercially known as F-53B, has been associated with adverse birth outcomes. However, the reproductive toxicology of F-53B on the placenta remains poorly understood. To address this gap, we examined the impact of F-53B on placental injury and its underlying molecular mechanisms in vivo. Pregnant C57BL/6 J female mice were randomly allocated to three groups: the control group, F-53B 0.8 µg/kg/day group, and F-53B 8 µg/kg/day group. After F-53B exposure through free drinking water from gestational day (GD) 0.5-14.5, the F-53B 8 µg/kg/day group exhibited significant increases in placental weights and distinctive histopathological alterations, including inflammatory cell infiltration, heightened syncytiotrophoblast knots, and a loosened trophoblastic basement membrane. Within the F-53B 8 µg/kg/day group, placental tissue exhibited increased apoptosis, as indicated by increased caspase3 activation. Furthermore, F-53B potentially induced the NF-κB signaling pathway activation through IκB-α phosphorylation. Subsequently, this activation upregulated the expression of inflammatory cytokines and components of the NLRP3 inflammasome, including activated caspase1, IL-1ß, IL-18, and cleaved gasdermin D (GSDMD), ultimately leading to pyroptosis in the mouse placenta. Our findings reveal a pronounced inflammatory injury in the placenta due to F-53B exposure, suggesting potential reproductive toxicity at concentrations relevant to the human population. Further toxicological and epidemiological investigations are warranted to conclusively assess the reproductive health risks posed by F-53B.

Transcription factor EgGRP2A regulates EgFATA expression and promotes oleic acid accumulation in oil palm (Elaeis guineensis).

The oil palm (Elaeis guineensis) is emerging as the world's most important and prolific oilseed crop, celebrated for its impressive oil yield. However, the molecular intricacies that govern lipid metabolism and fatty acid accumulation in oil palm fruits remain relatively underexplored. This study reveals a significant correlation between the expression of EgGRP2A, a transcription factor, and the expression of EgFATA in the oil palm. Yeast one-hybrid analysis and electrophoretic mobility shift assays (EMSA) reveal and confirm the binding interactions between EgGRP2A and the promoter region of EgFATA. Subsequent experiments in oil palm protoplasts show that transient overexpression of EgGRP2A leads to a marked upregulation of EgFATA expression. Conversely, downregulation of EgGRP2A in transgenic oil palm embryoids leads to a significant reduction in EgFATA expression. Metabolite profiling in the transgenic embryoids reveals a significant reduction in unsaturated fatty acids, particularly oleic acid. These findings promise profound insights into the regulatory orchestration of EgFATA and the synthesis of fatty acids, particularly oleic acid, in the oil palm. Furthermore, the results lay the foundation for future breeding and genetic improvement efforts aimed at increasing oleic acid content in oil palm varieties.

A simple and sensitive ultra-high performance liquid chromatography tandem mass spectrometry method for the quantitative analysis of VX-548 in monkey plasma: Method validation and application to pharmacokinetic study.

VX-548 is an orally active and highly selective NaV 1.8 inhibitor that is undergoing development for the treatment of acute pain. The aim of this study was to develop a liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for the measurement of VX-548 in monkey plasma. VX-548 was extracted from the plasma using acetonitrile-mediated protein precipitation. The quantitative analysis was performed on a Thermo Vantage TSQ mass spectrometer with ibrutinib as an internal standard. Chromatography was performed on a Waters ACQUITY UPLC BEH C18 column with 0.1% aqueous formic acid and acetonitrile as mobile phase. The precursor-to-product ion transitions were m/z 474.2 > 165.0 and m/z 441.2 > 138.1 for VX-548 and internal standard, respectively. This developed method was successfully validated in the concentration range of 1-1000 ng/mL. The calibration curve showed excellent linearity with a correlation coefficient of >0.999. The precision expressed as relative standard deviation (RSD) was <8.4%, whereas the accuracy denoted as relative error (RE) ranged from -5.0% to 9.1%. The mean recovery was >84%. VX-548 was stable in monkey plasma after storage under certain conditions. The validated method was successfully applied to the pharmacokinetic study of VX-548 in monkey plasma after single oral (2 mg/kg) and intravenous (1 mg/kg) administrations.

Improving the inhibitory resistance of xylanase FgXyn11C from Fusarium graminearum to SyXIP-I by site-directed mutagenesis.

The aim of this study was to improve the inhibitory resistance of xylanase FgXyn11C from Fusarium graminearum to XIP in cereal flour. Site saturation mutagenesis was performed using computer-aided redesign. Firstly, based on multiple primary structure alignments, the amino acid residues in the active site architecture were identified, and specific residue T144 in the thumb region of FgXyn11C was selected for site-saturation mutagenesis. After screening, FgXyn11CT144F was selected as the best mutant, as it displayed the highest enzymatic activity and resistance simultaneously compared to other mutants. The specific activity of FgXyn11CT144F was 208.8 U/mg and it exhibited complete resistance to SyXIP-I. Compared with the wild-type, FgXyn11CT144F displayed similar activity and the most resistant against SyXIP-I. The optimal temperature and pH of the wild-type and purified FgXyn11CT144F were similar at pH 5.0 and 30 °C. Our findings provided preliminary insight into how the specific residue at position 144 in the thumb region of FgXyn11C influenced the enzymatic properties and interacted with SyXIP-I. The inhibition sensitivity of FgXyn11C was reduced through directed evolution, leading to creation of the mutant enzyme FgXyn11CT144F. The FgXyn11CT144F resistance to SyXIP-I has potential application and can also provide references for engineering other resistant xylanases of the GHF11.

SARS-CoV-2 prevalence in wildlife 2020-2022: a worldwide systematic review and meta-analysis.

The widespread transmission of SARS-CoV-2 in humans poses a serious threat to public health security, and a growing number of studies have discovered that SARS-CoV-2 infection in wildlife and mutate over time. This article mainly reports the first systematic review and meta-analysis of the prevalence of SARS-CoV-2 in wildlife. The pooled prevalence of the 29 included articles was calculated by us using a random effects model (22.9%) with a high heterogeneity (I2 = 98.7%, p = 0.00). Subgroup analysis and univariate regression analysis found potential risk factors contributing to heterogeneity were country, wildlife species, sample type, longitude, and precipitation. In addition, the prevalence of SARS-CoV-2 in wildlife increased gradually over time. Consequently, it is necessary to comprehensively analyze the risk factors of SARS-CoV-2 infection in wildlife and develop effective control policies, as well as to monitor the mutation of SARS-CoV-2 in wildlife at all times to reduce the risk of SARS-CoV-2 transmission among different species.

Litter quality and climate regulate the effect of invertebrates on litter decomposition in terrestrial and aquatic ecosystems: A global meta-analysis.

Although the exclusion effects of invertebrate decomposers on litter decomposition have been extensively studied in different experimental contexts, a thorough comparison of the exclusion effects of invertebrate decomposers with different body sizes on litter decomposition and its possible regulatory factors in terrestrial and aquatic ecosystems is still lacking. Here, through a meta-analysis of 1207 pairs of observations from 110 studies in terrestrial ecosystems and 473 pairs of observations from 60 studies in aquatic ecosystems, we found that invertebrate exclusion reduced litter decomposition rates by 36 % globally, 30 % in terrestrial ecosystems, and 44 % in aquatic ecosystems. At the global scale, the exclusion effects of macroinvertebrates and mesoinvertebrates on litter decomposition rates (reduced by 38 % and 36 %, respectively) were greater than those of the combination of macroinvertebrates and mesoinvertebrates (reduced by 30 %). In terrestrial and aquatic ecosystems, the effects of invertebrate exclusion on litter decomposition rates were mainly regulated by climate and initial litter quality, but the effects of invertebrate exclusion with different body sizes were regulated differently by climate, initial litter quality, and abiotic environmental variables. These findings will help us better understand the role of invertebrate decomposers in litter decomposition, especially for invertebrate decomposers with different body sizes, and underscore the need to incorporate invertebrate decomposers with different body sizes into dynamic models of litter decomposition to examine the potential effects and regulatory mechanisms of land-water-atmosphere carbon fluxes.

Clinical analysis and quality of life survey of hemophilia B patients in the central and western regions of China.

Objective: To study the current status of hemophilia B (HB) patients in the central and western regions of China. Methods: This cross-sectional, multicenter study was conducted in seven provinces in the central and western regions of China from April 2019 to June 2023. Samples were collected for the factor IX activity, inhibitor screen, and gene mutation. Furthermore, the status of six index joints and quality of life (QoL) were assessed. Results: A total of 185 HB patients (mild 15, moderate 75, and severe 95) with a median age of 12.17 years were enrolled. 30.3% (56/185) of patients had a family history of HB. 34.6% (64/185) of HB patients had diagnostic delay and 38.5% (69/179) experienced treatment delay. The incidence of inhibitors was 6.1% (11/179). We identified 123 genetic variants in this study, with missense mutations being the most common. 84.0% (89/106) of HB mothers were genetically identified as carriers, with 27.7% (13/47) of carriers having clotting factor levels less than 0.40 IU/ml. 71.4% (132/185) of HB patients had a history of joint hemorrhage, with a rate of target joint in these patients was 64.4% (85/132). Lower extremity joints were most often affected in patients. The Hemophilia Joint Health Score (HJHS) score was significantly positively correlated with the Hemophilia Early Arthropathy Detection with Ultrasound in China (HEAD-US-C) (r = 0.542, P < 0.001). Patients who received prevention treatment, inhibitor negative, without treatment delay, and without high-intensity replacement therapy showed a higher total score of the short form-36 health survey (SF-36). Conclusions: One-third of HB patients had delay in diagnosis and treatment, and the incidence of inhibitors was 6.1%. Target joints were present in nearly half of HB patients. Missense was the main mutation type. 84.0% of mothers of HB patients in this study were found to be carriers. HEAD-US-C and HJHS can complement each other in the evaluation of joint status and give a valid basis for early clinical management. Early detection and preventive treatment, as well as reducing high-intensity replacement therapy and inhibitor generation, can effectively improve the QoL of patients.