Deciphering environmental factors influencing phytoplankton community structure in a polluted urban river.

Tuojiang River Basin is a first-class tributary of the upper reaches of the Yangtze River-which is the longest river in China. As phytoplankton are sensitive indicators of trophic changes in water bodies, characterizing phytoplankton communities and their growth influencing factors in polluted urban rivers can provide new ideas for pollution control. Here, we used direct microscopic count and environmental DNA (eDNA) metabarcoding methods to investigate phytoplankton community structure in Tuojiang River Basin (Chengdu, Sichuan Province, China). The association between phytoplankton community structure and water environmental factors was evaluated by Mantel analysis. Additional environmental monitoring data were used to pinpoint major factors that influenced phytoplankton growth based on structural equation modeling. At the phylum level, the dominant phytoplankton taxa identified by the conventional microscopic method mainly belonged to Bacillariophyta, Chlorophyta, and Cyanophyta, in contrast with Chlorophyta, Dinophyceae, and Bacillariophyta identified by eDNA metabarcoding. In α-diversity analysis, eDNA metabarcoding detected greater species diversity and achieved higher precision than the microscopic method. Phytoplankton growth was largely limited by phosphorus based on the nitrogen-to-phosphorus ratios > 16:1 in all water samples. Redundancy analysis and structural equation modeling also confirmed that the nitrogen-to-phosphorus ratio was the principal factor influencing phytoplankton growth. The results could be useful for implementing comprehensive management of the river basin environment. It is recommended to control the discharge of point- and surface-source pollutants and the concentration of dissolved oxygen in areas with excessive nutrients (e.g., Jianyang-Ziyang). Algae monitoring techniques and removal strategies should be improved in 201 Hospital, Hongrihe Bridge and Colmar Town areas.

Photoredox-Catalyzed Alkylamination of Alkenes via Oxidative Radical-Polar Crossover and Site-Selective 1,5-Hydrogen Atom Transfer.

We reported the visible-light-mediated photoredox-catalyzed oxidative radical-polar crossover and 1,5-hydrogen atom transfer combined site-selective remote C(sp3)-N cross-coupling alkylamination of alkenes. Various anilines and hydroxamides (1,5-hydrogen atom transfer reagents) could be tolerated. The mechanistic studies indicated the radical nature of the reaction and the indispensability of light and photocatalyst. Stern-Volmer fluorescence quenching and cyclic voltammetry experiments have been used to outline the proposed reaction pathway.

The Iron Binding Ability Maps the Fate of Food-Derived Transferrins: A Review.

As the demand for lactoferrin increases, the search for cost-effective alternative proteins becomes increasingly important. Attention naturally turns to other members of the transferrin family such as ovotransferrin. The iron-binding abilities of these proteins influence their characteristics, although the underlying mechanisms remain unclear. This overview systematically summarizes the effects of the iron-binding ability on the fate of food-derived transferrins (lactoferrin and ovotransferrin) and their potential applications. The findings indicate that iron-binding ability significantly influences the structure of food-derived transferrins, particularly their tertiary structure. Changes in structure influence their physicochemical properties, which, in turn, lead to different behaviors in response to environmental variations. Thus, these proteins exhibit distinct digestive characteristics by the time they reach the small intestine, ultimately performing varied physiological functions in vivo. Consequently, food-derived transferrins with different iron-binding states may find diverse applications. Understanding this capability is essential for developing food-derived transferrins and driving innovation in lactoferrin-related industries.

Transformer-based AI technology improves early ovarian cancer diagnosis using cfDNA methylation markers.

Epithelial ovarian cancer (EOC) is the deadliest women's cancer and has a poor prognosis. Early detection is the key for improving survival (a 5-year survival rate in stage I/II is over 70% compared to that of 25% in stage III/IV) and can be achieved through methylation markers from circulating cell-free DNA (cfDNA) using a liquid biopsy. In this study, we first identify top 500 EOC markers differentiating EOC from healthy female controls from 3.3 million methylome-wide CpG sites and validated them in 1,800 independent cfDNA samples. We then utilize a pretrained AI transformer system called MethylBERT to develop an EOC diagnostic model which achieves 80% sensitivity and 95% specificity in early-stage EOC diagnosis. We next develop a simple digital droplet PCR (ddPCR) assay which archives good performance, facilitating early EOC detection.

Analysis of Risk Factors of Sarcopenia in Patients with Maintenance Hemodialysis and Its Correlation with Emotional Status and Quality of Life.

Objective: Sarcopenia is more common in maintenance hemodialysis (MHD) patients, and the aim of this study is to analyze the risk factors associated with sarcopenia in MHD patients, along with its correlation to emotional status and quality of life. Methods: This is a cross-sectional cohort study. A total of 111 MHD patients who were treated in the Department of Nephrology of our hospital were selected as the study subjects by convenience sampling. The quality of life and emotional status were evaluated by health survey scale (SF-36), self-rating anxiety scale (SAS) and self-rating depression scale (SDS). Regression analysis was used to explore the influencing factors of sarcopenia. Correlation analysis was used to investigate the correlation between sarcopenia and quality of life and emotional status. Results: The prevalence of sarcopenia was 59.8%. The results showed that age, gender, body mass index (BMI), dialysis time, economic status, marital status and pre-dialysis creatinine were significant factors affecting the development of sarcopenia in hemodialysis patients (p<0.05). The SF-36 total score was significantly lower in the sarcopenia group (72.05±12.28 vs 78.03±10.55) than in the non-sarcopenia group, but the anxiety scale score (52.97±4.67 vs 36.2±3.36) and depression scale score (57.67±4.58 vs 38.71±3.77) were significantly higher than those in the non-sarcopenia group (p< 0.001). Correlation analysis showed that sarcopenia was positively correlated with SAS and SDS scores and negatively correlated with SF-36 total score (p < 0.05). Conclusion: The risk of sarcopenia was higher among MHD patients who were older, male, single, with a longer MHD duration, lower economic status, lower BMI, comorbid diabetes and lower levels of creatinine.

Gradual Transverse Transport of Naturally Tibialized Fibula Using Hexapod Frames to Treat Neglected Type V Tibial Segmental Defects.

OBJECTIVE: Although several reconstructive methods have been developed to manage large segmental tibial bone defects including bone transport (distraction osteogenesis), contralateral fibular graft, allograft, tibiofibular synostosis, Masquelet technique, and 3D printed scaffold, neglected large tibial defects in adults remain challenging problems. This study describes gradual transverse transport of naturally tibialized fibula using hexapod frames in management of adult patients with neglected large tibial defects. METHODS: We retrospectively reviewed four cases of transverse transport of naturally tibialized fibula from November 2018 to February 2022. We measured the length of the tibial defect and the transported fibular segment, the mid-diaphyseal diameter and cortical thickness of the affected fibula, contralateral fibula, and tibia. The parameters measured both preoperatively and postoperatively were leg length discrepancy, hip-knee-ankle angle, medial proximal tibial angle, posterior proximal tibial angle, lateral distal tibial angle, range of motion of the knee and ankle joints, and Lower Extremity Functional Scores (LEFS). Patients' satisfaction rates using Likert scale were also recorded. RESULTS: Among four female patients, three suffered from tibial osteomyelitis, and one was due to congenital pseudarthrosis of the tibia. The average follow-up time was 2.7 ± 1.4 years. The average length of tibial defect was 14.0 ± 0.8 cm. The average preoperative shortening of the affected leg was 9.0 ± 2.5 cm, which changed to 0.6 ± 0.8 cm postoperatively. The median length of the transported fibular segment was 15.2 cm. Two patients had varus deformity, two had recurvatum, and one had procurvatum preoperatively. Postoperative radiological measurement showed all deformities corrected and no ankle valgus deformity developed during follow-up. All patients achieved union and can fully weight bear on the affected extremity. The average fixator time was 12.9 ± 2.9 months. The average preoperative and postoperative LEFS, respectively, were 53.5 ± 5.0, 70.5 ± 1.3, with a significant difference (p = 0.003). Three patients reported very satisfied with the outcome, and one patient reported satisfied. Three patients had pin tract infections, and one patient had skin necrosis which healed after additional surgery. One patient had surgical release of the hamstring tendons due to flexion contracture of the knee. Two patients had 15° of reduction in ankle range of motion. One patient had transient common peroneal nerve palsy which spontaneously recovered within 6 weeks. CONCLUSION: The transverse transport of naturally tibialized fibula was both a safe and effective method to treat the long-standing type V tibial segmental defect.

The epithelial Na+ channel (ENaC) in ovarian granulosa cells modulates Ca2+ mobilization and gonadotrophin signaling for estrogen homeostasis and female fertility.

Ovarian granulosa cells are essential to gonadotrophin-regulated estrogen production, female cycle maintenance and fertility. The epithelial Na+ channel (ENaC) is associated with female fertility; however, whether and how it plays a role in ovarian cell function(s) remained unexplored. Here, we report patch-clamp and Na+ imaging detection of ENaC expression and channel activity in both human and mouse ovarian granulosa cells, which are promoted by pituitary gonadotrophins, follicle stimulating hormone (FSH) or luteinizing hormone (LH). Cre-recombinase- and CRISPR-Cas9-based granulosa-specific knockout of ENaC α subunit (Scnn1a) in mice resulted in failed estrogen elevation at early estrus, reduced number of corpus luteum, abnormally extended estrus phase, reduced litter size and subfertility in adult female mice. Further analysis using technologies including RNA sequencing and Ca2+ imaging revealed that pharmacological inhibition, shRNA-based knockdown or the knockout of ENaC diminished spontaneous or stimulated Ca2+ oscillations, lowered the capacity of intracellular Ca2+ stores and impaired FSH/LH-stimulated transcriptome changes for estrogen production in mouse and/or human granulosa cells. Together, these results have revealed a previously undefined role of ENaC in modulating gonadotrophin signaling in granulosa cells for estrogen homeostasis and thus female fertility.

Bifurcation study, phase portraits and optical solitons of dual-mode resonant nonlinear Schrodinger dynamical equation with Kerr law non-linearity.

This study investigates the dynamic characteristics of the dual-mode resonant non-linear Schrodinger equation with a Bhom potential. Hydrodynamics, nonlinear optical fibre communication, elastic media, and plasma physics are just a few of the mathematical physics and engineering applications for this model. The study aims to achieve two main objectives: first, to discuss bifurcation analysis, and second, to extract optical soliton solutions using the extended hyperbolic function method. The study successfully derives various wave solutions, including bright, singular, periodic singular and dark solitons, based on the governing model. The findings conferred in this article show a crucial advancement in understanding the propagation of waves in non-linear media. Additionally, bifurcation of phase portraits of ordinary differential equation consistent with the partial differential equation under consideration is conducted. We also highlight specific constraint conditions that ensure the presence of these obtained solutions. The existing literature shows that these methods are first time applied on this model.

Enterovirus A71 2A-S125A acts as an attenuated vaccine candidate, indicating a universal approach in developing enterovirus vaccines.

Enteroviruses are important human pathogens with diverse serotypes, posing a major challenge to develop vaccines for individual serotypes, the success of polio vaccines in controlling and eradicating polio, along with the recent emergence and high prevalence of enterovirus-caused infectious diseases, highlights the importance of enterovirus vaccine development. Given our previous report on enteroviruses weakened by the 2 A S/T125A mutation, we assessed the potential of the EV-A71 2A-125A mutant as a vaccine candidate to address this challenge. We found that the 2A-125A mutant caused transient mild symptoms, low viral loads, and no significant pathological changes mild pathological changes in hSCARB2-KI mice, producing long-lasting cross-neutralizing antibodies against two EV-A71 wild strains. Pre-exposure to the 2A-125A mutant substantially protected against the EV-A71 Isehara wild-type strain, causing minor pathologies, significantly reducing muscle and lung inflammation, and preventing neurological damage, with reduced viral loads in vivo. Pre-exposure also distinctly suppressed the expression of pro-inflammatory cytokines, correlating to the severity of clinical symptoms. Collectively, the EV-A71 2A-125A mutant was attenuated and could generate a robust and protective immune response, suggesting its potential as a vaccine candidate and global solution for specific enterovirus vaccine development.

Visible-light-induced C-H alkylation of 2-amino-1,4-naphthoquinones.

Simple and practical strategies for visible-light-induced C-H alkylation of 2-amino-1,4-naphthoquinones with cyclobutanone oxime esters and hydroxamic acid derivatives have been developed under mild and redox-neutral conditions. These two reactions can be carried out at room temperature and obtain a variety of 2-amino-1,4-naphthoquinone derivatives with cyano and amide groups. Moreover, the cyanoalkylation reaction of 2-amino-1,4-naphthoquinones can proceed smoothly in the absence of photocatalysts.

The P2 protein of wheat yellow mosaic virus acts as a viral suppressor of RNA silencing in Nicotiana benthamiana to facilitate virus infection.

Wheat yellow mosaic virus (WYMV) causes severe viral wheat disease in Asia. The WYMV P1 protein encoded by RNA2 has viral suppressor of RNA silencing (VSR) activity to facilitate virus infection, however, VSR activity has not been identified for P2 protein encoded by RNA2. In this study, P2 protein exhibited strong VSR activity in Nicotiana benthamiana at the four-leaf stage, and point mutants P70A and G230A lost VSR activity. Protein P2 interacted with calmodulin (CaM) protein, a gene-silencing associated protein, while point mutants P70A and G230A did not interact with it. Competitive bimolecular fluorescence complementation and competitive co-immunoprecipitation experiments showed that P2 interfered with the interaction between CaM and calmodulin-binding transcription activator 3 (CAMTA3), but the point mutants P70A and G230A could not. Mechanical inoculation of wheat with in vitro transcripts of WYMV infectious cDNA clone further confirmed that VSR-deficient mutants P70A and G230A decreased WYMV infection in wheat plants compared with the wild type. In addition, RNA silencing, temperature, ubiquitination and autophagy had significant effects on accumulation of P2 protein in N. benthamiana leaves. In conclusion, WYMV P2 plays a VSR role in N. benthamiana and promotes virus infection by interfering with calmodulin-related antiviral RNAi defense.

Correction: Influence of different irrigation methods on the alfalfa rhizosphere soil fungal communities in an arid region.

[This corrects the article DOI: 10.1371/journal.pone.0268175.].

Binding sites and design strategies for small molecule GLP-1R agonists.

Glucagon-like peptide-1 receptor (GLP-1R) is a pivotal receptor involved in blood glucose regulation and influencing feeding behavior. It has received significant attention in the treatment of obesity and diabetes due to its potent incretin effect. Peptide GLP-1 receptor agonists (GLP-1RAs) have achieved tremendous success in the market, driving the vigorous development of small molecule GLP-1RAs. Currently, several small molecules have entered the clinical research stage. Additionally, recent discoveries of GLP-1R positive allosteric modulators (PAMs) are also unveiling new regulatory patterns and treatment methods. This article reviews the structure and functional mechanisms of GLP-1R, recent reports on small molecule GLP-1RAs and PAMs, as well as the optimization process. Furthermore, it combines computer simulations to analyze structure-activity relationships (SAR) studies, providing a foundation for exploring new strategies for designing small molecule GLP-1RAs.

Experimental study on the biomechanical stability of complex acetabular fractures in the quadrilateral area: application of a dynamic anterior titanium-plate screw system.

BACKGROUND AND OBJECTIVE: Complex acetabular fractures involving quadrilateral areas are more challenging to treat during surgery. To date, there has been no ideal internal fixation for these acetabular fractures. The purpose of this study was to evaluate the biomechanical stability of complex acetabular fractures using a dynamic anterior titanium-plate screw system of the quadrilateral area (DAPSQ) by simulating the standing and sitting positions of pelvic specimens. MATERIALS AND METHODS: Eight formal in-preserved cadaveric pelvises aged 30-50 years were selected as the research objects. First, one hip of the normal pelvises was randomly used as the control model (group B) for measurement, and then one hip of the pelvises was randomly selected to make the fracture model in the 8 intact pelvises as the experimental model (group A) for measurement. In group A, acetabular both-column fractures in the quadrilateral area were established, and the fractures were fixed by DAPSQ. The biomechanical testing machine was used to load (simulated physiological load) from 400 N to 700 N at a 1 mm/min speed for 30 s in the vertical direction when the specimens were measured at random in simulated standing or sitting positions in groups. The horizontal displacement and longitudinal displacement of the acetabular fractures in the quadrilateral area were measured in both the standing and sitting simulations. RESULTS: As the load increased, no dislocation or internal fixation breakage occurred during the measurements. In the standing position, the horizontal displacement of the quadrilateral area fractures in group A and group B appeared to be less than 1 mm with loads ranging from 400 N to 700 N, and there was no significant difference between group A and group B (p > 0.05). The longitudinal displacement appeared to be greater than 1 mm with a load of 700 mm in group A (700 N, 2 cases), and the difference was significant between group A and group B (p < 0.05). In the sitting position, the horizontal and longitudinal displacements of the quadrilateral areas were within 0.5 mm in group A and group B, and there was no significant difference between group A and group B (p > 0.05). CONCLUSION: For complex acetabular fractures in the quadrilateral area, DAPSQ fixation may provide early sitting stability, but it is inappropriate for patients to stand too early.

Intra-annual vegetation changes and spatial variation in China over the past two decades based on remote sensing and time-series clustering.

Vegetation is an important link between land, atmosphere, and water, making its changes of great significance. However, existing research has predominantly focused on long-term vegetation changes, neglecting the intra-annual variations of vegetation. Hence, this study is based on the Enhanced Vegetation Index (EVI) data from 2000 to 2022, with a time step of 16 days, to analyze the intra-annual patterns of vegetation changes in China. The average intra-annual EVI values for each municipal-level administrative region were calculated, and the time-series k-means clustering algorithm was employed to divide these regions, exploring the spatial variations in China's intra-annual vegetation changes. Finally, the ridge regression and random forest methods were utilized to assess the drivers of intra-annual vegetation changes. The results showed that: (1) China's vegetation status exhibits a notable intra-annual variation pattern of "high in summer and low in winter," and the changes are more pronounced in the northern regions than in the southern regions; (2) the intra-annual vegetation changes exhibit remarkable regional disparities, and China can be optimally clustered into four distinct clusters, which align well with China's temperature and precipitation zones; and (3) the intra-annual vegetation changes demonstrate significant correlations with meteorological factors such as dew point temperature, precipitation, maximum temperature, and sea-level pressure. In conclusion, our study reveals the characteristics, spatial patterns and driving forces of intra-annual vegetation changes in China, which contribute to explaining ecosystem response mechanisms, providing valuable insights for ecological research and the formulation of ecological conservation and management strategies.

Dual driving forces for corporate environmental responsibility performance: The synergistic effects of government environmental regulation and market multi-agent green supervision.

The 26th United Nations Climate Change Conference reached a series of agreements on implementing the Paris Agreement, empowering governments to independently establish emission reduction goals and encouraging market participants to invest in sustainable development. It highlighted that enhancing corporate environmental responsibility performance (CERP), driven by the collaborative efforts of government and market forces, is key to achieving global sustainability. In this context, this study is the first attempt to investigate the synergistic effects of government environmental regulation (GER) and market multi-agent green supervision (MGS) on CERP. The findings are as follows. First, GER, encompassing the multidimensional environmental responsibilities of governments, has not effectively spurred CERP. MGS, incorporating the green concerns of diverse investors and intermediaries, serves as a significant catalyst for enhancing CERP. The synergy between GER and MGS, involving multi-stakeholder collaborative governance, plays a significant motivating role in promoting CERP. Second, financing constraints and executives' attention to corporate environmental responsibility (CER) are two key channels through which the synergy between GER and MGS influences CERP. Third, firms located in regions with better economic development, those operating in non-heavily polluting industries, or non-state-owned firms exhibit heightened proactivity in improving CERP under the synergy between GER and MGS. This paper expands research on multi-agent collaborative environmental governance from the regional macro-perspective to the micro-firm level, providing a fresh perspective and theoretical basis. The novel findings offer valuable insights for policymakers and firms, especially in economies similar to China, in containing growing environmental challenges and advancing global sustainability.

Metformin synergizes with gilteritinib in treating FLT3-mutated leukemia via targeting PLK1 signaling.

Fms-like tyrosine kinase 3 (FLT3) mutations, present in over 30% of acute myeloid leukemia (AML) cases and dominated by FLT3-internal tandem duplication (FLT3-ITD), are associated with poor outcomes in patients with AML. While tyrosine kinase inhibitors (TKIs; e.g., gilteritinib) are effective, they face challenges such as drug resistance, relapse, and high costs. Here, we report that metformin, a cheap, safe, and widely used anti-diabetic agent, exhibits a striking synergistic effect with gilteritinib in treating FLT3-ITD AML. Metformin significantly sensitizes FLT3-ITD AML cells (including TKI-resistant ones) to gilteritinib. Metformin plus gilteritinib (low dose) dramatically suppresses leukemia progression and prolongs survival in FLT3-ITD AML mouse models. Mechanistically, the combinational treatment cooperatively suppresses polo-like kinase 1 (PLK1) expression and phosphorylation of FLT3/STAT5/ERK/mTOR. Clinical analysis also shows improved survival rates in patients with FLT3-ITD AML taking metformin. Thus, the metformin/gilteritinib combination represents a promising and cost-effective treatment for patients with FLT3-mutated AML, particularly for those with low income/affordability.

The impacts of percutaneous coronary intervention to treat chronic total occlusion of right coronary artery on the 5-year prognosis: A single-centered retrospective study.

BACKGROUND: Chronic total occlusions (CTO) occur in about 20% of patients referred for coronary angiography, and right coronary artery (RCA) CTO has been reported in 38-50% of the entire CTO population. Limited data on angiographic and procedural characteristics of RCA-CTO and the risk of adverse cardiac events asks for a detailed study. METHODS: From 2010 to 2013, patients with attempted revascularization of at least one CTO lesion were included and followed up to 5 years after PCI. Eligible patients are assigned to RCA-CTO and non-RCA-CTO groups based on their target vessels. The primary endpoint was major adverse cardiovascular events (MACEs; a composite of all-cause death, myocardial infarction (MI) or rehospitalization for heart failure), and secondary endpoints were cardiac death, target lesion revascularization (TLR) and target vessel revascularization (TVR). RESULTS: The present study included 2659 eligible patients, among which 1285 patients were assigned to the RCA-CTO group, whereas 1374 patients were assigned to the non-RCA-CTO group. Lesions in RCA had longer lesion length, higher J-CTO score, higher rates of severe vessel tortuosity, a higher percentage of Rentrop grade 2-3, and more likely to be re-try lesion than those in LAD or LCX (all P < 0.01). CTO lesions in RCA reached less successful recanalization and post-procedural TIMI 3 flow (all <0.01). Multivariate Cox analysis revealed that RCA-CTO was not associated with primary outcome MACEs. Besides MACEs, RCA-CTO was also not associated with cardiac death, but was significantly associated with TLR and TVR (adjusted HR: 1.37 [95% CI:1.07-1.76], P = 0.01; adjusted HR: 1.43 [95% CI:1.13-1.82], P = 0.003). CONCLUSION: RCA-CTO lesions, which had more complex angiographic features, independently contributed to TLR and TVR but not to MACEs or cardiac death in the 5 years of follow-up.

Effects of the Thiol Methyltransferase Inhibitor (±)-2,3-Dichloro-α-Methylbenzylamine (DCMB) on the Pharmacokinetics and Metabolism of Vicagrel in Rats.

P2Y12 receptor inhibitors are commonly used in clinical antiplatelet therapy, typically alongside other medications. Vicagrel, a promising P2Y12 receptor inhibitor, has submitted a new drug marketing application to the United States Food and Drug Administration. Its primary metabolites and some metabolic pathways are identical to those of clopidogrel. The aim of this study was to investigate the effects of the thiol methyltransferase inhibitor (±)-2,3-dichloro-α-methylbenzylamine (DCMB) on the metabolism and pharmacokinetics of vicagrel. In vitro incubation with human and rat liver microsomes revealed that DCMB significantly inhibited the methylation of vicagrel's thiol metabolite M15-1. Rats were orally administered 6 mg/kg [14C]vicagrel (100 µCi/kg) 1 hour after peritoneal injection with or without DCMB (80 mg/kg). Compared with the control group, the plasma of DCMB-pretreated rats exhibited maximum plasma concentration (C max) decrease and time to reach C max (T max) delay for all vicagrel-related substances, the methylation product of the thiol metabolite (M9-2), and the derivatization product of the active thiol metabolite (MP-M15-2). However, no significant changes in area under the curve (AUC) or half-life (t 1/2) were observed. DCMB had negligible effect on the total radiological recovery of vicagrel within 72 hours, although the rate of vicagrel excretion slowed down within 48 hours. DCMB had a negligible impact on the metabolic pathway of vicagrel. Overall, the present study found that DCMB did not significantly affect the total exposure, metabolic pathways, metabolite profiles, or total excretion rates of vicagrel-related metabolites in rats, but led to C max decrease, T max delay, and slower excretion rate within 48 hours. SIGNIFICANCE STATEMENT: This study used liquid chromatography-tandem mass spectrometry combined with radiolabeling technology to investigate the effects of the thiol methyltransferase inhibitor (±)-2,3-dichloro-α-methylbenzylamine on the absorption, metabolism, and excretion of vicagrel in rats. This work helps to better understand the in vivo metabolism of active thiol metabolites of P2Y12 inhibitors such as clopidogrel, vicagrel, etc.

Necroptosis enhances 'don't eat me' signal and induces macrophage extracellular traps to promote pancreatic cancer liver metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with dismal prognosis due to distant metastasis, even in the early stage. Using RNA sequencing and multiplex immunofluorescence, here we find elevated expression of mixed lineage kinase domain-like pseudo-kinase (MLKL) and enhanced necroptosis pathway in PDAC from early liver metastasis T-stage (T1M1) patients comparing with non-metastatic (T1M0) patients. Mechanistically, MLKL-driven necroptosis recruits macrophages, enhances the tumor CD47 'don't eat me' signal, and induces macrophage extracellular traps (MET) formation for CXCL8 activation. CXCL8 further initiates epithelial-mesenchymal transition (EMT) and upregulates ICAM-1 expression to promote endothelial adhesion. METs also degrades extracellular matrix, that eventually supports PDAC liver metastasis. Meanwhile, targeting necroptosis and CD47 reduces liver metastasis in vivo. Our study thus reveals that necroptosis facilitates PDAC metastasis by evading immune surveillance, and also suggest that CD47 blockade, combined with MLKL inhibitor GW806742X, may be a promising neoadjuvant immunotherapy for overcoming the T1M1 dilemma and reviving the opportunity for radical surgery.