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Abstract With the continuous expansion of the photovoltaic industry, the application of solar photovoltaic power generation systems is becoming increasingly widespread. Due to the obvious intermittency and volatility of photovoltaic power generation, integration of large‐scale photovoltaic power generation into the power grid can cause certain impacts on the security and stability of the grid. Photovoltaic power prediction is essential to solve this problem, as it can improve the quality of photovoltaic grid connection, optimize grid scheduling, and ensure the safe operation of the grid. In this article, the deep learning method is selected for photovoltaic power prediction. Based on the analysis of the OctConv (Octave Convolution) network structure, the AOctConv (Attention Octave Convolution) convolutional neural network structure is proposed, which is combined with the ResNet50 backbone network to obtain AOC‐ResNet50. It is then applied to the prediction of the generation of photovoltaic power. The prediction performance is compared with the ResNet50 network and the Oct‐ResNet50 network, and it is found that the AOC‐ResNet50 network has the best prediction performance, with an MAE of only 0.176888. Based on the exemplar work, a framework is proposed to illustrate this method. Its general application is discussed.

Abstract Background To investigate the prognostic differences following the achievement of a pathological complete response (pCR) through neoadjuvant chemotherapy across different molecular subtypes of breast invasive ductal carcinoma. Methods Data from the Surveillance, Epidemiology, and End Results (SEER) were identified for patients undergoing neoadjuvant chemotherapy who achieved pathological complete response for invasive ductal carcinoma of the breast between 2010 and 2019.Comparing the clinicopathological characteristics of patients across different molecular subtypes. Univariate and Cox multivariate analyses were utilized to identify independent predictors of overall survival (OS) and cancer-specific survival (CSS). The Kaplan–Meier method is used to compare OS and CSS among different molecular subtypes. After propensity score matching, subgroup analysis results were presented through forest plots. Results This study included 9,380 patients diagnosed with invasive ductal carcinoma, who were categorized into four molecular subtypes: 2,721 (29.01%) HR + /HER-2 + , 1,661 (17.71%) HR + /HER2-, 2,082 (22.20%) HR-/HER2 + , and 2,916 (31.08%) HR-/HER-2-. HR + /HER-2- subgroup exhibited a significantly higher proportion of patients under 50 years old than the other subtype groups (54.67% vs 40.2%, 50.35% and 51.82%, p

Abstract Background Delirium, marked by acute cognitive decline, poses a life-threatening issue among older individuals, especially after cardiac surgery, with prevalence ranging from 15 to 80%. Postoperative delirium is linked to increased morbidity and mortality. Although clinical trials suggest preventability, there is limited research on intranasal insulin (INI) for cardiac surgery-related delirium. INI has shown promise in managing cognitive disorders. It rapidly elevates brain hormone levels, enhancing memory even in non-impaired individuals. While effective in preventing delirium in gastrointestinal surgery, its impact after cardiac surgery remains understudied, especially for middle-aged patients. Method This is a prospective randomized, double-blind, single-center controlled trial. A total of 76 eligible participants scheduled for elective on-pump cardiac surgery will be enrolled and randomly assigned in a 1:1 ratio to either receive Intranasally administered insulin (INI) or intranasally administered normal saline. The primary outcome of our study is the incidence of postoperative delirium (POD). Secondary outcomes include duration of ICU, postoperative hospital length of stay, all in-hospital mortality, the change in MMSE scores pre- and post-operation, and incidence of postoperative cognitive dysfunction at 1 month, 3 months, and 6 months after operation. Moreover, we will subjectively and objectively evaluate perioperative sleep quality to investigate the potential impact of nasal insulin on the development of delirium by influencing sleep regulation. Discussion Our study will aim to assess the impact of intranasal administration of insulin on the incidence of postoperative delirium in middle-aged patients undergoing on-pump elective cardiac surgery. If intranasal insulin proves to be more effective, it may be considered as a viable alternative for preventing postoperative delirium. Trial registration ChiCTR ChiCTR2400081444. Registered on March 1, 2024.

Abstract Tumor neovascularization is essential for the growth, invasion, and metastasis of tumors. Recent studies have highlighted the significant role of N6-methyladenosine (m6A) modification in regulating these processes. This review explores the mechanisms by which m6A influences tumor neovascularization, focusing on its impact on angiogenesis and vasculogenic mimicry (VM). We discuss the roles of m6A writers, erasers, and readers in modulating the stability and translation of angiogenic factors like vascular endothelial growth factor (VEGF), and their involvement in key signaling pathways such as PI3K/AKT, MAPK, and Hippo. Additionally, we outline the role of m6A in vascular-immune crosstalk. Finally, we discuss the current development of m6A inhibitors and their potential applications, along with the contribution of m6A to anti-angiogenic therapy resistance. Highlighting the therapeutic potential of targeting m6A regulators, this review provides novel insights into anti-angiogenic strategies and underscores the need for further research to fully exploit m6A modulation in cancer treatment. By understanding the intricate role of m6A in tumor neovascularization, we can develop more effective therapeutic approaches to inhibit tumor growth and overcome treatment resistance. Targeting m6A offers a novel approach to interfere with the tumor’s ability to manipulate its microenvironment, enhancing the efficacy of existing treatments and providing new avenues for combating cancer progression.

Abstract The investigation of aberrations in lipid metabolism within tumor has become a burgeoning field of study that has garnered significant attention in recent years. Lipids can serve as a potent source of highly energetic fuel to support the rapid growth of neoplasia, in where the ER-mitochondrial membrane domains (ERMMDs) provide an interactive network for facilitating communication between ER and mitochondria as well as their intermembrane space and adjunctive proteins. In this review, we discuss fatty acids (FAs) anabolic and catabolic metabolism, as well as how CPT1A-VDAC-ACSL clusters on ERMMDs participate in FAs transport, with a major focus on ERMMDs mediated collaborative loop of FAO, Ca2+ transmission in TCA cycle and OXPHOS process. Here, we present a comprehensive perspective on the regulation of aberrant lipid metabolism through ERMMDs conducted tumor physiology might be a promising and potential target for tumor starvation therapy.

In addition to the cardinal motor symptoms, pain is a major non-motor symptom of Parkinson's disease (PD). Neuroinflammation in the substantia nigra pars compacta and dorsal striatum is involved in neurodegeneration in PD. But the polarization of microglia and astrocytes in the dorsal striatum and their contribution to motor deficits and hyperalgesia in PD have not been characterized. In the present study, we observed that hemiparkinsonian mice established by unilateral 6-OHDA injection in the medial forebrain bundle exhibited motor deficits and mechanical allodynia. In these mice, both microglia and astrocytes in the dorsal striatum were activated and polarized to M1/M2 microglia and A1/A2 astrocytes as genes specific to these cells were upregulated. These effects peaked 7 days after 6-OHDA injection. Meanwhile, striatal astrocytes in parkinsonian mice also displayed hyperpolarized membrane potentials, enhanced voltage-gated potassium currents, and dysfunction in inwardly rectifying potassium channels and glutamate transporters. Systemic administration of minocycline, a microglia inhibitor, attenuated the expression of genes specific to M1 microglia and A1 astrocytes in the dorsal striatum (but not those specific to M2 microglia and A2 astrocytes), attenuated the damage in the nigrostriatal dopaminergic system, and alleviated the motor deficits and mechanical allodynia in parkinsonian mice. By contrast, local administration of minocycline into the dorsal striatum of parkinsonian mice mitigated only hyperalgesia. This study suggests that M1 microglia and A1 astrocytes in the dorsal striatum may play important roles in the development of pathophysiology underlying hyperalgesia in the early stages of PD.

Abstract Background Compared to traditional thoracotomy, transapical transcatheter aortic valve implantation (TAVI) surgery offers reduced trauma and faster recovery, fostering the adoption of enhanced recovery after surgery (ERAS) protocols in cardiac surgery. Despite these advancements, postoperative pain management has received insufficient attention. The potential effects of multi-mode analgesia, including ultrasound-guided serratus anterior plane block (SAPB), on postoperative pain and early quality of recovery have not been widely studied, lacking comprehensive prospective evidence. Therefore, this study aims to investigate the impact of SAPB combined with general anesthesia on early recovery quality and analgesic efficacy in transapical TAVI patients. Methods This prospective, randomized controlled study will enroll 70 patients undergoing transapical TAVI, randomly allocated to either the SAPB group or the control group. The primary outcome, assessed using Quality of Recovery-40 (QOR-40) scale, focuses on the quality of recovery at 24 h and 48 h postoperatively. Secondary outcomes include the visual analog scale (VAS) pain scores at rest and during coughing at 6 h, 12 h, 24 h, and 48 h after surgery, frequency of patient-controlled analgesia (PCA) utilization at 24 h and 48 h, opioid consumption at 24 h and 48 h, time and frequency of rescue analgesia and severe pain at 24 h and 48 h, incidence of nausea and vomiting at 48 h after surgery, and dosage of antiemetic drugs. Discussion The purpose of our study is to evaluate the effects of ultrasound-guided SAPB combined with general anesthesia on postoperative early quality of recovery and analgesia in transapical TAVI patients. The results obtained may provide valuable insight for the implementation of multi-mode analgesia and enhanced ERAS in this specific patient population. Trial registration China Clinical Trial Register ChiCTR2300068584. Registered on 24 February 2023.

Abstract Background Off-pump coronary artery bypass grafting (OPCABG) presents distinct hemodynamic characteristics, yet the relationship between intraoperative hypotension and short-term adverse outcomes remains clear. Our study aims to investigate association between intraoperative hypotension and postoperative acute kidney injury (AKI), mortality and length of stay in OPCABG patients. Methods Retrospective data of 494 patients underwent OPCABG from January 2016 to July 2023 were collected. We analyzed the relationship between intraoperative various hypotension absolute values (MAP > 75, 65 65 mmHg emerges as a significant independent protective factor for AKI in OPCABG and IOH is related to length of hospital stay. Proactive intervention targeting intraoperative hypotension may provide a potential opportunity to reduce postoperative renal injury and hospital stay. Trial registration ChiCTR2400082518. Registered 31 March 2024. https://www.chictr.org.cn/bin/project/edit?pid=225349 .

Hepatocellular carcinoma (HCC) remains the fourth leading cause of cancer-associated death globally with a lack of efficient therapy. The pathogenesis of HCC is a complex and multistep process, highly reliant on de novo lipogenesis, from which tumor cells can incorporate fatty acids to satisfy the necessary energy demands of rapid proliferation and provide survival advantages. Triptolide (TP) is a bioactive ingredient exhibiting potent abilities of anti-proliferation and lipid metabolism regulation, but its clinical application is constrained because of its toxicity and non-specific distribution. The present study has developed galactosylated bovine serum albumin nanoparticles loaded with TP (Gal-BSA-TP NPs) to alleviate systemic toxicity and increase tumor-targeting and antitumor efficacy. Furthermore, Gal-BSA-TP NPs could inhibit de novo lipogenesis via the p53-SREBP1C-FASN pathway to deprive the fuel supply of HCC, offering a specific strategy for HCC treatment. In general, this study provided a biocompatible delivery platform for targeted therapy for HCC from the perspective of de novo lipogenesis.

Abstract Tumors desmoplastic microenvironments are characterized by abundant stromal cells and extracellular matrix (ECM) deposition. Cancer-associated fibroblasts (CAFs), as the most abundant of all stromal cells, play significant role in mediating microenvironments, which not only remodel ECM to establish unique pathological barriers to hinder drug delivery in desmoplastic tumors, but also talk with immune cells and cancer cells to promote immunosuppression and cancer stem cells-mediated drug resistance. Thus, CAFs mediated desmoplastic microenvironments will be emerging as promising strategy to treat desmoplastic tumors. However, due to the complexity of microenvironments and the heterogeneity of CAFs in such tumors, an effective deliver system should be fully considered when designing the strategy of targeting CAFs mediated microenvironments. Engineered exosomes own powerful intercellular communication, cargoes delivery, penetration and targeted property of desired sites, which endow them with powerful theranostic potential in desmoplastic tumors. Here, we illustrate the significance of CAFs in tumors desmoplastic microenvironments and the theranostic potential of engineered exosomes targeting CAFs mediated desmoplastic microenvironments in next generation personalized nano-drugs development. Graphical Abstract

The fault characteristics of voltage source converter-based high voltage direct current （VSC-HVDC） transmission systems connected to offshore wind farms differ from those of conventional power systems. Consequently， there exists a potential risk of inadequate adaptability when conventional relay protection schemes are applied to the VSC-HVDC transmission system. This paper analyzes the impact of harmonic components induced by asymmetrical electrical quantities， negative sequence suppression， and current-limiting measures on the performance of differential protection during fault ride-through （FRT）. Sensitivity calculation formulas for differential protection considering sequence components are derived， and adaptability analysis is conducted. It is noted that differential protection is susceptible to odd-order harmonics during fault conditions， while negative sequence suppression and current-limiting measures may also diminish its sensitivity. Extensive simulation calculations are carried out using a simulated system of a practical demonstration project. The findings indicate a decrease in the sensitivity and reliability of conventional differential protection schemes.

IntroductionIn Northeast China, Dorper and Australian White rams are commonly crossbred with small-tailed Han (STH) ewes to improve the offspring's meat yield and quality. However, the differences in traits and the flavor between the crossbred sheep and STH sheep remain unclear. In addition, the candidate genes potentially influencing the meat quality in the three sheep breeds require further verification.MethodsA total of 18 2-month-old healthy rams were raised over a period of 5 months, which included 6 STH, 6 Dorper and small-tailed Han crossbred (Do × STH), and 6 Australian white and small-tailed Han crossbred (Au × STH) offspring. The differences in slaughter, meat quality traits, fatty acid and amino acid composition in the muscular longissimus dorsi (MLD), and volatile compounds in the semitendinosus muscle were compared between the sheep breeds. The candidate genes related to intramuscular fat (IMF) content and fatty acids were validated.ResultsThe results of this study revealed that the crossbred sheep had higher body weight, carcass weight, bone weight, net meat weight, and IMF content than the STH sheep (p < 0.05). The Do × STH offspring had a higher pH value (24 h), moisture content, and cooking percentage; they also had redder and brighter meat color. The content of myristate, palmitic, and margaric acids in the crossbred sheep was higher than that in the STH sheep (p < 0.05). The Do × STH offspring had the highest saturated fatty acid content (p < 0.05). The Au × STH offspring had the highest protein content (p < 0.05). The arachidonic acid and amino acid (Asp, Ala, Ile, Leu, Lys, Thr, and essential amino acid) contents were higher in the STH sheep than in the crossbred sheep (p < 0.05). The odor activity value (OAV) analysis showed that most of the aldehydes in the Au × STH offspring had higher values. The PDK4 gene expression was positively associated with the IMF content and was negatively correlated with the linoleic acid content in the Do × STH sheep (p < 0.05). The TMEM273 gene expression was positively associated with linoleic and arachidonic acid contents and was negatively correlated with oleic and palmitic acid contents in the Do × STH sheep (p < 0.05).DiscussionThe results showed the differences between the crossbred sheep and STH sheep and provided the candidate genes related to meat quality in sheep.

High oxidative stress and inflammatory cell infiltration are major causes of the persistent bone erosion and difficult tissue regeneration in rheumatoid arthritis (RA). Triptolide (TPL) has become a highly anticipated anti-rheumatic drug due to its excellent immunomodulatory and anti-inflammatory effects. However, the sudden drug accumulation caused by the binding of “stimulus-response” and “drug release” in a general smart delivery system is difficult to meet the shortcoming of extreme toxicity and the demand for long-term administration of TPL. Herein, we developed a dual dynamically cross-linked hydrogel (SPT@TPL), which demonstrated sensitive RA microenvironment regulation and microenvironment modulation-independent TPL release for 30 days. The abundant borate ester/tea polyphenol units in SPT@TPL possessed the capability to respond and regulate high reactive oxygen species (ROS) levels on-demand. Meanwhile, based on its dense dual crosslinked structure as well as the spontaneous healing behavior of numerous intermolecular hydrogen bonds formed after the breakage of borate ester, TPL could remain stable and slowly release under high ROS environments of RA, which dramatically reduced the risk of TPL exerting toxicity while maximized its long-term efficacy. Through the dual effects of ROS regulation and TPL sustained-release, SPT@TPL alleviated oxidative stress and reprogrammed macrophages into M2 phenotype, showing marked inhibition of inflammation and optimal regeneration of articular cartilage in RA rat model. In conclusion, this hydrogel platform with both microenvironment initiative regulation and TPL long-term sustained release provides a potential scheme for rheumatoid arthritis.

Parkinson’s disease (PD) is a ubiquitous brain cell degeneration disease and presents a significant therapeutic challenge. By injecting 6-hydroxydopamine (6-OHDA) into the left medial forebrain bundle, rats were made to exhibit PD-like symptoms and treated by intranasal administration of a low-dose (2 × 105) or high-dose (1 × 106) human neural stem cells (hNSCs). Apomorphine-induced rotation test, stepping test, and open field test were implemented to evaluate the motor behavior and high-performance liquid chromatography was carried out to detect dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin, and 5-hydroxyindole-3-acetic acid in the striatum of rats. Animals injected with 6-OHDA showed significant motor function deficits and damaged dopaminergic system compared to the control group, which can be restored by hNSCs treatment. Treatment with hNSCs significantly increased the tyrosine hydroxylase-immunoreactive cell count in the substantia nigra of PD animals. Moreover, the levels of neurotransmitters exhibited a significant decline in the striatum tissue of animals injected with 6-OHDA when compared to that of the control group. However, transplantation of hNSCs significantly elevated the concentration of DA and DOPAC in the injured side of the striatum. Our study offered experimental evidence to support prospects of hNSCs for clinical application as a cell-based therapy for PD.

Abstract Background Laparoscopic nephrectomy is a commonly utilized surgical approach for the management of renal cancer. Despite its widespread acceptance, postoperative pain management remains a significant challenge for many patients undergoing this procedure. Traditional pain management techniques, including opioid and nonsteroidal anti-inflammatory drug administration, may not provide adequate pain relief and may result in adverse effects. In recent years, erector spinae plane block (ESPB) has emerged as a promising regional anesthesia technique due to its simplicity, safety, and potential efficacy in reducing postoperative pain. ESPB has demonstrated effectiveness in reducing postoperative pain in various surgical procedures. However, the efficacy of ESPB in laparoscopic nephrectomy for renal cancer has not been extensively studied. As such, further investigation is necessary to determine the potential benefits of ESPB in this context. The addition of adjuvants such as dexmedetomidine and dexamethasone to nerve blocks has been shown to improve both the duration and quality of the block. Multiple studies have demonstrated the safety and efficacy of these adjuvants in reducing postoperative pain and opioid consumption and improving patient satisfaction. The use of dexmedetomidine and dexamethasone as adjuvants for nerve blocks represents a promising approach for enhancing regional anesthesia and analgesia. In light of these findings, we have incorporated dexmedetomidine and dexamethasone into our nerve block protocol. Methods This study is a randomized controlled trial conducted at a single center, with 50 participants being randomized in a 1:1 ratio to either the ESPB group or the control group. The trial aims to investigate the efficacy of ESPB in patients diagnosed with kidney cancer who are scheduled for laparoscopic nephrectomy. The primary outcome measure is the total consumption of intraoperative sufentanil. Secondary outcomes include the VAS score at rest and during coughing at 1 h, 6 h, 12 h, 24 h, and 48 h after surgery; total intraoperative remifentanil consumption; the number of times rescue analgesia is required; and the incidence of nausea and vomiting in the first 24 h after surgery. This study is registered for a duration of 1 year and is being conducted in China. Discussion The objective of our study is to evaluate the potential benefits of erector spinae plane block (ESPB) in patients undergoing laparoscopic nephrectomy, with a focus on the impact of dexmedetomidine and dexamethasone as adjuvants on the quality and duration of the block, as well as postoperative pain and opioid consumption. By investigating the effects of these adjuvants in the context of ESPB, we hope to contribute to the growing body of literature on the use of adjuvants in nerve blocks and provide further insight into the potential benefits of this approach for improving patient outcomes following laparoscopic nephrectomy. This trial was approved by the Ethics Committee of the Second Affiliated Hospital of Army Medical University. Trial registration China Clinical Trial Register ChiCTR2300068578 . Registered on 20 February 2023.

High-yielding dairy cows need diets that meet their energy demand and contain sufficient essential nutrients such as n-3 fatty acids (FAs). Conjugated linoleic acid (CLA) is able to relieve the energy metabolism, but common corn silage and concentrate-based diets contain insufficient amounts of essential fatty acids (EFA). Abomasal infusion was used in the current study to supplement cows from 9 weeks antepartum to 9 weeks postpartum with either coconut oil (CTRL, n = 8), EFA (n = 9), or conjugated linoleic acid (CLA, n = 9), or a combination of both (EFA + CLA, n = 10). The study focused on the effects of FAs on peripheral tissues, such as longissimus muscle (MLD) and adipose tissues, which were harvested after slaughter. Fatty acid composition, muscle fiber and fat cell morphology, muscle fiber type transition, and gene expression were analyzed. Supplemented FAs and their metabolites were increased (p < 0.05) in MLD and intermuscular fat (INTF) but not in subcutaneous fat (SCF). The intramuscular fat content and gene expression of ACACA and FASN were increased in CLA-supplemented cows (p < 0.05). Supplementation did not affect the muscle fiber size and fiber type composition. Supplemented CLA had more effects than EFA, improving the energy balance of cows accompanied with increased triglyceride formation and storage.

Background: Isoflurane is a commonly used general anesthetic widely employed in clinical surgeries. Recent studies have indicated that isoflurane might induce negative impacts on the nervous system, notably by triggering neuronal apoptosis. This process is pivotal to the development and emergence of neurological disorders; its misregulation could result in functional deficits and the initiation of diseases within nervous system. However, the potential molecular mechanism of isoflurane on the neuronal apoptosis remains fully unexplored. This study aims to investigate the regulatory role of the sirtuin 1-mechanistic target of rapamycin (SIRT1-mTOR) signaling pathway in autophagy during isoflurane-induced apoptosis of fetal rat brain neuronal cells. Methods: Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, real-time quantitative polymerase chain reaction (qPCR), and Western blot were utilized to evaluate the apoptotic status of hippocampal tissue cells in fetal mice after sevoflurane exposure. Our further investigation was commenced with flow cytometry, immunofluorescence, qPCR, and Western blot to determine the impact of autophagy on sevoflurane-induced apoptosis in these neurons. On the other hand, we conducted an additional set of analyses, including flow cytometric analysis, qPCR, and Western blot, to further elucidate the neuroprotective potential of autophagy in neural cells of fetal mice subjected to sevoflurane-induced apoptosis. Results: Our findings indicated that a 3% sevoflurane treatment led to a significant rise in apoptosis among fetal rat hippocampal tissue cells and neurons. Levels of apoptosis-associated proteins, cleaved-caspase-3 and Bcl-2 associated X protein (Bax), were found to be markedly higher, coinciding with an enhancement in autophagy as evidenced by increased microtubule-associated proteins 1A/1B-light chain 3 (LC3) and decreased p62 expression. Concurrently, there was a notable up-regulation of sirtuin 1 (SIRT1) and a down-regulation of mechanistic target of rapamycin (mTOR) expression. In conclusion, our research elucidated the pivotal function of cellular autophagy in an apoptosis induced by sevoflurane in fetal rat nerve cells. Through experimental manipulation, we observed that interference with SIRT1 resulted in a reduction of both cleaved-caspase-3 and Bax levels. This intervention also beget a diminished expression of the autophagy-associated factor LC3 and an up-regulation of p62. Furthermore, inhibition against mTOR reversed the effects induced by SIRT1 interference, suggesting a complex interplay amid these regulatory pathways. Conclusions: SIRT1 possesses a capacity to modulate apoptosis in the hippocampal neurons of fetal rats triggered by sevoflurane, with mTOR functioning as an inhibitory factor within this signaling pathway.

Abstract Background Notwithstanding that the past decade has witnessed unprecedented medical progress, gastric cancer (GC) remains a leading cause of cancer death, highlighting the need for effective prognostic markers. The Memorial Sloan Kettering Prognostic Score (MPS) has been validated as a valuable prognostic tool for patients with metastatic pancreatic adenocarcinoma (mPDAC). This study aimed to assess the prognostic value of the MPS in advanced GC. Methods Data from 367 patients were analyzed in the present study. The MPS for each patient was calculated based on the sum of scores based on the neutrophil‐to‐lymphocyte ratio and serum albumin levels. Multivariate analyses were performed to identify the independent clinicopathological parameters associated with overall survival (OS). Further subgroup analyses based on clinicopathological features were conducted. Results Patients with MPS 0 (n = 161), MPS 1 (n = 158), and MPS 2 (n = 48) exhibited significantly different OS, with a median survival duration of 20.7 (95%CI: 12.2–29.2), 14.9 (95%CI: 12.5–17.3), and 12.7 (95%CI: 9.3–16.0) months, respectively (p

Diabetic cardiomyopathy (DCM) is a major determinant of mortality in diabetic populations, and the potential strategies are insufficient. Canagliflozin has emerged as a potential cardioprotective agent in diabetes, yet its underlying molecular mechanisms remain unclear. We employed a high-glucose challenge (60 mM for 48 h) in vitro to rat cardiomyocytes (H9C2), with or without canagliflozin treatment (20 µM). In vivo, male C57BL/6J mice were subjected to streptozotocin and a high-fat diet to induce diabetes, followed by canagliflozin administration (10, 30 mg·kg−1·d−1) for 12 weeks. Proteomics and echocardiography were used to assess the heart. Histopathological alterations were assessed by the use of Oil Red O and Masson’s trichrome staining. Additionally, mitochondrial morphology and mitophagy were analyzed through biochemical and imaging techniques. A proteomic analysis highlighted alterations in mitochondrial and autophagy-related proteins after the treatment with canagliflozin. Diabetic conditions impaired mitochondrial respiration and ATP production, alongside decreasing the related expression of the PINK1-Parkin pathway. High-glucose conditions also reduced PGC-1α-TFAM signaling, which is responsible for mitochondrial biogenesis. Canagliflozin significantly alleviated cardiac dysfunction and improved mitochondrial function both in vitro and in vivo. Specifically, canagliflozin suppressed mitochondrial oxidative stress, enhancing ATP levels and sustaining mitochondrial respiratory capacity. It activated PINK1-Parkin-dependent mitophagy and improved mitochondrial function via increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK). Notably, PINK1 knockdown negated the beneficial effects of canagliflozin on mitochondrial integrity, underscoring the critical role of PINK1 in mediating these protective effects. Canagliflozin fosters PINK1-Parkin mitophagy and mitochondrial function, highlighting its potential as an effective treatment for DCM.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation, cartilage destruction, pannus formation and bone erosion. Various immune cells, including macrophages, are involved in RA pathogenesis. The heterogeneity and plasticity of macrophages render them pivotal regulators of both the induction and resolution of the inflammatory response. Predominantly, two different phenotypes of macrophages have been identified: classically activated M1 macrophages exacerbate inflammation via the production of cytokines, chemokines and other inflammatory mediators, while alternatively activated M2 macrophages inhibit inflammation and facilitate tissue repair. An imbalance in the M1/M2 macrophage ratio is critical during the initiation and progression of RA. Macrophage polarization is modulated by various transcription factors, epigenetic elements and metabolic reprogramming. Curcumin, an active component of turmeric, exhibits potent immunomodulatory effects and is administered in the treatment of multiple autoimmune diseases, including RA. The regulation of macrophage polarization and subsequent cytokine production as well as macrophage migration is involved in the mechanisms underlying the therapeutic effect of curcumin on RA. In this review, we summarize the underlying mechanisms by which curcumin modulates macrophage function and polarization in the context of RA to provide evidence for the clinical application of curcumin in RA treatment.

Introduction Rheumatoid arthritis (RA) is a progressive inflammatory autoimmune disease characterised by chronic systemic inflammation, which can cause swelling, stiffening and destruction of articular cartilage and bone. Early diagnosis and treatment of RA can improve outcomes and slow the progression of joint damage. Preliminary exploratory research had hinted an expected effect of modified Zhiwang decoction (MZWD) in treating early RA. However, few randomised clinical trials have evaluated the effectiveness of MZWD in early RA. Therefore, a parallel-group randomised controlled trial was designed to evaluate the efficacy and safety of MZWD combined with methotrexate (MTX) on early RA.Methods and analysis This is a prospective, parallel-group, single-centre randomised controlled clinical study. A total of 150 patients will be randomly assigned to either the treatment (n=75) or control group (n=75). The treatment group will receive MZWD and MTX, and the control group will receive MTX for 12 weeks. The primary outcome of this study is Disease Activity Score-28, and the secondary outcomes are Fatigue Scale-14, Visual Analogue Scale pain scores and traditional Chinese medicine symptom scores. Safety outcomes, including adverse events and results of ECG and laboratory tests, will be monitored.Ethics and dissemination Ethics approval was obtained from the Clinical Research Ethics Committee of the China-Japan Friendship Hospital (no. 2022-KY-124) on 8 July 2022. The findings will be disseminated in peer-reviewed publications.Trial registration number ClinicalTrials.gov Registry (NCT05508815).

ABSTRACTLow meat performance is the defect of Small Tail Han sheep. Intramuscular fat affects meat quality and largely determined by adipogenesis. In previous study, miR136 was showed one of differentially expressed microRNAs between preadipocytes and mature adipocytes of Small Tail Han sheep but its role in adipogenesis is still not elucidated. Here, we investigated the effect of miR136 on adipogenesis and the underlying mechanism. qPCR data showed that miR136 level increased with preadipocytes proliferation while declined with preadipocytes differentiation. Moreover, miR136 mimics blocked lipid droplet formation, reduced lipid content and triglyceride accumulation while miR136 inhibitor showed the opposite effects, revealing that miR136 promoted preadipocytes proliferation but inhibited preadipocytes differentiation. Bioinformatics and biochemical validation manifested that PPARGC1B was a target of miR136. Furthermore, miR136 mimics decreased PPARγ and C/EBPα expression accompanied by PPARGC1B expression descending. Reverse effects were observed with miR136 inhibitor. Besides, overexpression of miR136 elevated IGF1 expression. Collectively, our data first exhibited a regulatory role of miR136 in adipogenesis, which is promoting preadipocytes proliferation through elevating IGF1 expression while inhibiting preadipocytes differentiation through targeting PPARGC1B and further declined PPARγ and C/EBPα expression. The modulation of PPARGC1B by miR136 may provide a new potential target for increasing intramuscular fat.

Abstract Nucleus- and cell-specific interrogation of individual basal forebrain (BF) cholinergic circuits is crucial for refining targets to treat comorbid chronic pain-like and depression-like behaviour. As the ventral pallidum (VP) in the BF regulates pain perception and emotions, we aim to address the role of VP-derived cholinergic circuits in hyperalgesia and depression-like behaviour in chronic pain mouse model. In male mice, VP cholinergic neurons innervate local non-cholinergic neurons and modulate downstream basolateral amygdala (BLA) neurons through nicotinic acetylcholine receptors. These cholinergic circuits are mobilized by pain-like stimuli and become hyperactive during persistent pain. Acute stimulation of VP cholinergic neurons and the VP-BLA cholinergic projection reduces pain threshold in naïve mice whereas inhibition of the circuits elevated pain threshold in pain-like states. Multi-day repetitive modulation of the VP-BLA cholinergic pathway regulates depression-like behaviour in persistent pain. Therefore, VP-derived cholinergic circuits are implicated in comorbid hyperalgesia and depression-like behaviour in chronic pain mouse model.

Antibiotic misuse is becoming a worldwide public health issue due to serious risk to human health and environment. Residual antibiotics in environment mainly come from the wastewater from pharmaceutical factories, aquaculture, animal husbandry and hospitals. Antibiotics are included in the newly published List of Newly Controlled Pollutants (2022 Edition) (Draft for Comments). However, test standards are still lacking. Highly accurate results of the trace amounts of antibiotics distributed in the environment can be obtained by mass spectrometry coupled with chromatography. Nonetheless, sample pretreatment is time-consuming and expert-required. Compared with laboratory detection, ambient miniature mass spectrometry can realize on-site detection of the antibiotics without or with little pretreatment. On-site detection can be used for rapid qualitative and semi-quantitative detection, which can reflect the levels of water body pollution and accurately trace the pollutant sources. On-site detection also can provide technical support for the regulatory governance of antibiotics. But now no-studies have been reported on the on-site detection of environmental antibiotics in the field. It is urgent to develop a rapid detection method for antibiotic residues in the environment to assess antibiotic pollution and provide support for regulation. In this paper, the detection of antibiotics was carried out based on flash desorption and acetone assisted photoionization source miniature ion trap mass spectrometry, the detection parameters of antibiotics were systematically optimized including gas flow and injection time sequence, and a rapid and high throughput detection method of antibiotics was established. The efficiency of thermal desorption was improved using pulse purging mode and halogen lamp flash thermal desorption, and the signal intensities of high boiling point antibiotics were significantly increased. Quantitative detection of antibiotics was realized by isotope internal standard, and preliminary detection of antibiotics in water was carried out. This method does not need complicated pre-processing and can be completed in 1 min. The detection limits of isoniazid (INZ), ethionamide (ETN) and voriconazole (VCZ) were 636, 160, 35 μg/L, respectively, calculated based on S/N=3 at the injection volume of 1 μL. It is applicable to the field, high-throughput and highly sensitive detection of antibiotics.

Abstract N6-methyladenosine (m6A) methylation is the most universal internal modification in eukaryotic mRNA. With elaborate functions executed by m6A writers, erasers, and readers, m6A modulation is involved in myriad physiological and pathological processes. Extensive studies have demonstrated m6A modulation in diverse tumours, with effects on tumorigenesis, metastasis, and resistance. Recent evidence has revealed an emerging role of m6A modulation in tumour immunoregulation, and divergent m6A methylation patterns have been revealed in the tumour microenvironment. To depict the regulatory role of m6A methylation in the tumour immune microenvironment (TIME) and its effect on immune evasion, this review focuses on the TIME, which is characterized by hypoxia, metabolic reprogramming, acidity, and immunosuppression, and outlines the m6A-regulated TIME and immune evasion under divergent stimuli. Furthermore, m6A modulation patterns in anti-tumour immune cells are summarized.

Summary: Analysis of synaptic strength and plasticity provides functional insights of complicated neural circuits. Here, we describe steps for cell- and projection-specific optogenetic manipulation of divergent basal ganglia circuits using anterograde and retrograde viral vectors. We quantitatively analyze synaptic function of these circuits utilizing a patch-clamp technique. This protocol is applicable to probe potential circuit targets for treatment of brain diseases.For complete details on the use and execution of this protocol, please refer to Ji et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Maladaptive plastic changes in the brain are critical for pain maintenance. The authors identify a nigro–subthalamo–parabrachial pathway and reveal that reversing a series of neuronal and synaptic malfunctions in this pathway in acute and chronic pain mitigates hyperalgesia, providing potential therapeutic targets for pain modulation.

Background. Chemoimmunotherapy has become the first-line treatment for unresectable esophageal squamous cell carcinoma (ESCC). Still, reliable biomarkers to identify patients who could benefit from this combined therapy remain uncertain. This study focused on elucidating the predictive significance of the monocyte-to-lymphocyte ratio (MLR) and establishing the prognostic nomogram for unresectable ESCC treated with chemoimmunotherapy. Methods. Data of clinical features, peripheral blood parameters, and treatment records were collected in unresectable ESCC patients who received PD-1/PD-L1 inhibitors plus chemotherapy as the first-line treatment from September 2017 to August 2021. The nomogram based on MLR and clinical parameters for predicting the overall survival (OS) was developed and validated. Results. Out of 81 patients enrolled, patients with a lower MLR had significantly longer progression-free survival (PFS) and OS than patients with a higher pretreatment MLR (p = 0.0067; p = 0.00069). The OS nomogram integrating MLR, performance status (PS) score, and body mass index (BMI) achieved a C-index of 0.770 (95%CI 0.645–0.896). The area under the ROC curve (AUC) value of the nomogram predicting 12-, 18-, and 24-month OS rates were 0.855, 0.792, and 0.744, respectively, which were higher than the clinical TNM staging system or the MLR. Stratified by the nomogram-generated scores, three risk groups (low, moderate, and high) in survival curves manifested a distinct difference (p < 0.0001). Conclusion. MLR emerged as an independent predictive factor for PFS and OS in treatment-naive unresectable ESCC patients treated with chemoimmunotherapy. The constructed nomogram of MLR and clinical parameters was a reliable model for prognostic estimation.

To make an effective correlation analysis on the factors influencing the corrosion and perforation of high sulfur associated gas pipeline in Tahe Oilfield, the pipeline flow parameters were calculated using multiphase flow transient model, and a method combining Pearson correlation coefficient with Apriori association rule mining algorithm was proposed to determine the associativity rules that affecting corrosion perforation. Results showed that the multiphase flow transient model revealed the variation laws of pipeline temperature, pressure, flow rate, and liquid holdup along the pipeline. Meanwhile, the degrees of influences of medium parameters and flow parameters on corrosion were as follow: liquid holdup (0.732) > temperature (0.696) > pressure (0.677) =CO2 partial pressure (0.677) = H2S partial pressure (0.677) > gas flow rate (0.618) = gas wall shear force (0.618) > pipe inclination (0.577). The strong correlation rules between the corrosion rate and H2S partial pressure, temperature, liquid holdup, flow rate and pipeline inclination were determined. Besides, the correctness of the association rules was further verified by the high temperature and high pressure dynamic reactor experiment.

Cytokine storms are an important mechanism of sepsis. TNF-α is an important cytokine. As a regulator of TNF superfamily receptors, RIPK1 not only serves as the basis of the scaffold structure in complex I to promote the activation of the NF-κB and MAPK pathways but also represents an important protein in complex II to promote programmed cell death. Ubiquitination of RIPK1 is an important regulatory function that determines the activation of cellular inflammatory pathways or the activation of death pathways. In this paper, we introduce the regulation of RIPK1, RIPK1 PANoptosome’s role in Inflammatory and sepsis, and perspectives.

ObjectiveNecroptosis has recently been found to be associated with the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). This study was undertaken to explore the role of RIPK1-dependent necroptosis in the pathogenesis of RA and the potential new treatment options.MethodsThe plasma levels of receptor-interacting protein kinase 1 (RIPK1) and mixed lineage kinase domain-like pseudokinase (MLKL) in 23 controls and 42 RA patients were detected by ELISA. Collagen-induced arthritis (CIA) rats were treated with KW2449 by gavage for 28 days. Arthritis index score, H&E staining, and Micro-CT analysis were used to evaluate joint inflammation. The levels of RIPK1-dependent necroptosis related proteins and inflammatory cytokines were detected by qRT-PCR, ELISA and Western blot, and the cell death morphology was detected by flow cytometry analysis and high-content imaging analysis.ResultsThe plasma levels of RIPK1 and MLKL in RA patients were higher than those in healthy people, and were positively correlated with the severity of RA. KW2449 could reduce joint swelling, joint bone destruction, tissue damage, and the plasma levels of inflammatory cytokines in CIA rats. Lipopolysaccharide combined with zVAD (LZ) could induce necroptosis in RAW 264.7 cells, which could be reduced by KW2449. RIPK1-dependent necroptosis related proteins and inflammatory factors increased after LZ induction and decreased after KW2449 treatment or knockdown of RIPK1.ConclusionThese findings suggest that the overexpression of RIPK1 is positively correlated with the severity of RA. KW2449, as a small molecule inhibitor targeting RIPK1, has the potential to be a therapeutic strategy for RA treatment by inhibiting RIPK1-dependent necroptosis.

Summary: The subthalamic nucleus (STN) controls basal ganglia outputs via the substantia nigra pars reticulata (SNr) and the globus pallidus internus (GPi). However, the synaptic properties of these projections and their roles in motor control remain unclear. We show that the STN-SNr and STN-GPi projections differ markedly in magnitude and activity-dependent plasticity despite the existence of collateral STN neurons projecting to both the SNr and GPi. Stimulation of either STN projection reduces locomotion; in contrast, inhibition of either the STN-SNr projection or collateral STN neurons facilitates locomotion. In 6-OHDA-hemiparkinsonian mice, the STN-SNr projection is dramatically attenuated, but the STN-GPi projection is robustly enhanced; apomorphine inhibition of the STN-GPi projection through D2 receptors is significantly augmented and improves locomotion. Optogenetic inhibition of either the STN-SNr or STN-GPi projection improves parkinsonian bradykinesia. These results suggest that the STN-GPi and STN-SNr projections are differentially involved in motor control in physiological and parkinsonian conditions.

BACKGROUND Available selenium is an important index to evaluate the supply capacity of selenium from the soil to plants. Unfortunately, there is no general method for the determination of available selenium in soil in China. Chemical extraction and soil solution methods are commonly used to evaluate bioavailability of selenium. Furthermore, there are problems such as the lack of universally applicable extractant types, incomplete extraction of target states, and dissolution of non-target states. The diffusive gradient in thin-films (DGT) technique is a method based on dissociation and diffusion kinetics which has been successfully used to assess the bioavailability of selenium. However, it is not clear whether the DGT technique can be used in natural selenium-rich soil. OBJECTIVES To investigate the feasibility of the DGT technique to evaluate the bioavailability of selenium in natural selenium-rich soil. METHODS Natural selenium-rich soils from Shangshu and Fenkou in Zhejiang Province were chosen as the research objects. Fe-oxide DGT, Zr-oxide DGT, chemical extraction, and soil solution methods were used to evaluate selenium bioavailability. RESULTS (1) The average of available selenium measured by Fe-oxide DGT was 0.17±0.076μg/L, whereas the average of available selenium measured by Zr-oxide DGT was 0.20±0.13μg/L. Zr-oxide DGT cannot be used effectively to reflect the content of selenium in plants due to the specific adsorption characteristics to Se4+. Fe-oxide DGT was suitable for the bioavailability evaluation of selenium in soil rather than Zr-oxide DGT. (2) There was a significant positive correlation between the selenium content in plants (Cplant-Se) and the available selenium content determined by the three methods. The correlation between available Se by Fe-oxide DGT and Se concentration in plants (r=0.705) was greater than the chemical extraction method and soil solution method. (3) The Kd value and R value calculated from DGT and soil solution methods indicated that the soil of the Shangshu area had stronger selenium mobility than the Fenkou area, but the rate of Se supply from the soil solid phase to the soil solution was less than the Fenkou area. CONCLUSIONS DGT is more suitable for evaluating selenium bioavailability compared with chemical extraction and soil solution methods because it has more advantages in testing performance and reflecting the information of soil dynamics process.

The immune system plays a crucial role in regulating osteoclast formation and function and has significance for the occurrence and development of immune-mediated bone diseases. Kidney-tonifying Chinese herbs, based on the theory of traditional Chinese medicine (TCM) to unify the kidney and strengthen the bone, have been widely used in the prevention and treatment of bone diseases. The common botanical drugs are tonifying kidney-yang and nourishing kidney-yin herbs, which are divided into two parts: one is the compound prescription of TCM, and the other is the single preparation of TCM and its active ingredients. These botanical drugs regulate osteoclastogenesis directly and indirectly by immune cells, however, we have limited information on the differences between the two botanical drugs in osteoimmunology. In this review, the mechanism by which kidney-tonifying Chinese herbs inhibiting osteoclastogenesis was investigated, emphasizing the immune response. The differences in the mechanism of action between tonifying kidney-yang herbs and nourishing kidney-yin herbs were analysed, and the therapeutic value for immune-mediated bone diseases was evaluated.

Countersunk bolt joints with sleeves have been used in composite connection structures, and their fatigue performances need to be studied. Based on the experimental investigation conducted on the single lap CFRP/titanium alloy bolted joint with 3-countersunk head bolt and sleeves, the fatigue models of composite laminates and metal structures were established to analyze the fatigue performances of the structure, and finite element analysis on joints without sleeves was also carried out to study the influences of the sleeves on fatigue performance of the joint. The results show that the use of sleeves can more effectively improve the fatigue performance of the joint compared to that only using interference fit. The fatigue life of laminate is increased by about 3.6 times, the titanium alloy plate increased by about 2.7 times, and the bolts are increased by about 14 times. Only the titanium alloy plate of the joint fails, but not the fastener. Combined with analysis on the experimental results, it is found that the fatigue failure mode of bolted joints structure will change with different load levels due to the different fatigue properties between composite materials and metal materials; and the metal structure is prone to be damaged under a certain load level.

PurposeRheumatoid arthritis (RA) is a chronic autoimmune disease (AD) characterized by persistent synovial inflammation, bone erosion and progressive joint destruction. This research aimed to elucidate the potential roles and molecular mechanisms of N6-methyladenosine (m6A) methylation regulators in RA.MethodsAn array of tissues from 233 RA and 126 control samples was profiled and integrated for mRNA expression analysis. Following quality control and normalization, the cohort was split into training and validation sets. Five distinct machine learning feature selection methods were applied to the training set and validated in validation sets.ResultsAmong the six models, the LASSO_λ-1se model not only performed better in the validation sets but also exhibited more stringent performance. Two m6A methylation regulators were identified as significant biomarkers by consensus feature selection from all four methods. IGF2BP3 and YTHDC2, which are differentially expressed in patients with RA and controls, were used to predict RA diagnosis with high accuracy. In addition, IGF2BP3 showed higher importance, which can regulate the G2/M transition to promote RA-FLS proliferation and affect M1 macrophage polarization.ConclusionThis consensus of multiple machine learning approaches identified two m6A methylation regulators that could distinguish patients with RA from controls. These m6A methylation regulators and their target genes may provide insight into RA pathogenesis and reveal novel disease regulators and putative drug targets.

Objective To clarify the association between Fas gene polymorphisms and the level of soluble Fas(sFas) in the serum of rheumatoid arthritis (RA) patients in southwest China. Methods Fas rs2234767 and rs1800682 single mucleotide polymorphisms(SNP) were genotyped in a case-control study with 183 RA patients and 195 controls, using polymerase chain reaction restriction fragment length polymorphism(PCR-RFLP). sFas level in peripheral blood of RA patients and healthy people with different genotypes were detected by ELISA. Results There was no statistically significant difference between the patients with RA and the healthy subjects with respect to Fas rs2234767 and rs1800682 genotype distribution. However, patients carrying the rs1800682G/G genotype had a significantly decreased sFas level in serum compared with those carrying the AA genotype (P＜0.05). Conclusions Fas polymorphisms do not represent a major genetic risk factor for RA susceptibility. However, Fas rs1800682 polymorphism may influence sFas level in serum and response in patients with rheumatoid arthritis of Chinese population in southwest.

BACKGROUND The absorption of heavy metals in soil by crops is affected by various factors such as crop types, collection sites and physical and chemical soil properties. In recent years, soil acidification of an area in the Jinqu Basin has increased year by year, and the degree of acidification has gradually deepened. OBJECTIVES In order to find out the content characteristics of heavy metals in soil and crops, the influence of soil acidification on the absorption of heavy metals by crops was studied. METHODS Based on 264 samples of root soil-rice samples from a typical area of the Jinqu Basin, the characteristics and influencing factors of heavy metal content in soil and crops were studied. RESULTS The results showed that: (1) The variation coefficient of most heavy metal elements in 264 soil samples was greater than 0.5. Significant positive correlations (P < 0.01) occurred among the elements of As, Cd, Cr, Cu, Ni, and Zn in soil. 23 soil samples of Cd exceeded the standard, and the over-standard rate was 8.7%. The soil samples number of other elements(As, Cr, Cu, Hg, Ni, Pb and Zn) exceeding the standard were no more than 2. (2) The contents of Cu, Zn and Cd in rice were positively correlated, and the enrichment coefficient of the toxic heavy metal element Cd was higher than that of plant nutrient elements Cu and Zn. (3) Zn and Cu in rice were positively correlated with soil pH at P < 0.1. Bioconcentration factor (BCF) of Cd, Cr and Hg were negatively correlated with pH. CONCLUSIONS It is believed that adjusting soil acidity will reduce the activity of Cd, Hg and other heavy metal elements in the soil, in order to achieve the goal of minimizing the absorption and transport of heavy metal elements in crops. The research results provide scientific data for local food production safety decision and reference for land management and protection.

BACKGROUND Selenium (Se) is an essential beneficial trace element for human and animals; taking an appropriate amount of selenium is an important sign to improve the quality of life. Eating selenium-rich agricultural products is an important way for humans to obtain and supplement selenium in low-Se regions. Investigating the content characteristics of soil selenium, delineating the distribution of selenium-enriched soil resources and identifying the influencing factors of soil selenium migration and enrichment can provide a sound basis for the efficient utilization of selenium-enriched soil resources and scientific development of selenium-enriched agricultural products. OBJECTIVES To reveal the content, distribution characteristics and influencing factors of selenium in soils from the study area. METHODS Soil samples were collected from the western area of Muchuan County, Sichuan Province. AFS, ICP-MS and XRF were used to determine the elemental content (Se, Al2O3, TFe2O3, OrgC, Cd) and pH values. The content, distribution and influencing factors of soil selenium in the study area were evaluated using statistical and correlation analysis. RESULTS The results showed that: (1) The content of selenium in the study area ranged from 0.08 to 1.30mg/kg, with an average value of 0.39±0.15mg/kg. The selenium-rich land was 112km2, accounting for 52% of the total area, of which the nuisanceless selenium-rich land was 35km2. Soil Cd content was the main factor causing the great difference between selenium-enrich soil and nuisanceless selenium-rich soil. (2) The geological background was closely related to the soil selenium content, which was mainly controlled by carbonate rocks, sandstone and siltstone intercalated with carbonaceous strata. The source of soil selenium was stable. (3) The soil selenium content decreased with pH and ba value, meanwhile, they increased with TFe2O3 and S content. The effect of organic matter on soil selenium was significantly greater than TFe2O3, indicating that the adsorption capacity of TFe2O3 for selenium in this area was lower than organic matter. CONCLUSIONS Selenium-enriched land resources are abundant in the study area. The content of soil selenium is affected by geological background and physical and chemical properties. It is suggested that local governments make full use of relevant resources to develop selenium-enriched agricultural products. At the same time, attention should be paid to the balanced fertilization of organic fertilizers. The collaborative analysis of factors affecting the migration and enrichment of selenium in the soil-crop system should be further strengthened.

1-(4-(Pyrrolidin-1-yl-methyl)phenyl)-3-(4-((3-(trifluoromethyl) phenyl)amino)quinazolin-6-yl)urea (ZCJ14), a novel epidermal growth factor receptor (EGFR) inhibitor, with diarylurea moiety, displays anticancer effect. In the present study, an LCMS/MS method was established to determine the concentration of ZCJ14 in rat plasma. Furthermore, the method was applied to investigate the pharmacokinetic characteristics of ZCJ14. Chromatographic separation of ZCJ14 and internal standard (IS) [1-phenyl-3-(4-((3-(trifluoromethyl)phenyl)amino) quinazolin-6-yl)urea] was accomplished by gradient elution using the Kromasil C18 column. The selected reaction monitoring transitions were performed at m/z 507.24→436.18 and 424.13→330.96 for ZCJ14 and IS, resp. The established method was linear over the concentration range of 10–1000 ng mL−1. The intra- and inter-day precisions were < 11.0 % (except for LLOQ which was up to 14.3 %) and the respective accuracies were within the range of 87.5–99.0 %. The extraction recovery and matrix effect were within the range of 88.4–104.5 % and 87.3–109.9 %, resp. ZCJ14 was stable under all storage conditions. The validated method was successfully applied to the pharmacokinetic study of ZCJ14 in rats, and the pharmacokinetic parameters have been determined. The oral bioavailability of ZCJ14 was found to be 46.1 %. Overall, this accurate and reliable quantification method might be useful for other diarylurea moiety-containing drugs.

Polyunsaturated fatty acids (PUFAs) play important roles in the aetiology and pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD). However, the underlying molecular mechanisms are not understood. We analysed a public GEO dataset, GSE89632, to identify differentially expressed genes (DEGs) in MAFLD. Weighted gene coexpression network analysis (WGCNA) was used to reveal the core gene regulation network and to explore the PUFA-related hub genes in MAFLD. We experimentally verified these genes by quantitative reverse transcription PCR in high-fat diet (HFD)-fed mice. A total of 286 common DEGs (89 upregulated; 197 downregulated), mostly related to inflammatory and immune responses, were identified. Six modules were constructed using WGCNA, and 2 modules showed significant correlations with PUFAs. After combining these 2 modules with DEGs, the top 10 hub genes were identified. We further established a MAFLD mouse model with liver steatosis, as proved by HE and Oil Red O staining. Of the hub genes, ADAM metallopeptidase with thrombospondin type 1 motif 1 (adamts1) (p = 0.005) and transforming growth factor β3 (tgfβ3) (p < 0.001) showed significantly lower mRNA expression in MAFLD in vivo. adamts1 and tgfβ3 bridged PUFAs and MAFLD, which might be potential causative genes and therapeutic targets of MAFLD.

BackgroundThe emergence of immune checkpoint inhibitors has changed the landscape of first-line treatment of patients with advanced gastric cancer. Currently, the prognostic significance of inflammatory markers in first-line immunotherapy combined with chemotherapy for gastric cancer is currently unclear. This study aimed to identify inflammatory markers with potential to predict treatment outcome in advanced gastric cancer patients receiving immunotherapy combined with chemotherapy.MethodsThis retrospective study enrolled untreated advanced or metastatic gastric or gastro-esophageal junction cancer patients from 5 clinical trials (the clinical trial cohort) and the real world (the real-word cohort). Inflammatory markers included in the analysis included neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), and derived neutrophil-to-lymphocyte ratio (dNLR). Receiver operating characteristic (ROC) curves were constructed to identify optimal cut-off values. The prognostic potential of the markers was determined using Kaplan–Meier analysis, univariate and multivariate Cox-regression analyses in the clinical trial cohort and the findings were validated in the real-world cohort.ResultsIn the clinical trial cohort (n=45), MLR, PLR and SII were associated with PFS but not OS (All P

Background: Despite the increasing prevalence rate of nonalcoholic fatty liver disease (NAFLD) worldwide, efficient pharmacotherapeutic regimens against NAFLD still need to be explored. Previous studies found that pioglitazone and metformin therapy could partly ameliorate NAFLD, but their combination therapy effects have not been researched. In the present study, we assessed the protective effects of metformin and pioglitazone combination therapy on liver lipid metabolism in high-fat diet (HFD)-fed mice and investigated the molecular mechanism. Methods: Male C57BL/6 mice were divided into five groups: normal control; HFD control; metformin monotherapy; pioglitazone monotherapy and combined therapy. After 8 weeks of pharmacological intervention, glucose and lipid metabolism characteristics, hepatic histology, lipidomics profiling and RNA-seq analysis were performed. Results: The combination of pioglitazone and metformin significantly ameliorated HFD-induced metabolic disturbance and the hepatic oil red O area. A lipidomics analysis showed that combined therapy could significantly reduce the high levels of free fatty acids (FFA), diacylglycerol and triglycerides, while a set of glycerophospholipids and sphingolipids were increased in the combined therapy group. Consistently, an RNA-seq analysis also showed a remarkable reduction in genes associated with FFA uptake and de novo lipogenesis, including Cd36, Fads1, Fads2, Fasn, Scd1, Elovl5 and Pklr in the combined therapy group. Conclusions: Pioglitazone and metformin might have a synergistic protective effect on NAFLD by improving hepatic lipid profiles in HFD-induced mice. Further studies are needed to verify the clinical effects.

The fatigue performance of composite structures in wet environment will be degraded seriously, which will affect the structure safety. Therefore, the influence of wet environment should be taken into consideration when determining the structure life. The tensile fatigue properties of carbon fiber reinforced composite orthotropic laminates in wet and dry state at room temperature were tested. The influence of saturated moisture absorption on the tensile fatigue properties was studied. The S-N curves of two kinds of environments were obtained. On this basis, the finite element models were established, and the fatigue life and damage evolution of the orthotropic laminate after moisture absorption were predicted. The calculated results agree well with the test results, which prove the validity of the model. The results show that the saturated moisture absorption has a great influence on the tensile fatigue properties of orthogonal laminate. After moisture absorption, the tensile fatigue life of the laminates is significantly lower than that of the laminates in dry state, and the slope of S-N curve is slightly lower. The fiber damage initiation and propagation of laminate are also different from those in dry state.

Important forensic evidence traced from crime scenes, such as fecal materials, can help in the forensic investigation of criminal cases. Intestines are the largest microbial pool in the human body whose microbial community is considered to be the human “second fingerprint”. The present study explored the potential for community characteristics of gut microbes in forensic medicine. Fecal microbiota profiles of healthy individuals from three representative Han populations (Guangzhou, Shantou and Meizhou) in Guangdong Province, China were evaluated using High-throughput sequencing of V3-V4 hypervariable regions of the 16SrRNA gene. Results of the present study showed that at the genus level, Shantou, Guangzhou, and Meizhou behaved as Enterotype1, Enterotype2, and Enterotype3, which were mainly composed of Bacteroides, Prevotella, and Blautia, respectively. Based on OTU abundance at the genus level, using the random forest prediction model, it was found that there might be potential for distinguishing individuals of Guangzhou, Meizhou, and Shantou according to their fecal microbial community. Moreover, the findings of the microbial community of fecal samples in the present study were significantly different from that of saliva samples reported in our previous study, and thus it is evident that the saliva and feces can be distinguished. In conclusion, this study reported the fecal microbial signature of three Han populations, which may provide basic data for the potential application in forensic practice, containing body fluid identification, and geographical inference.

BackgroundChanges in the intestinal microenvironment affected bone destruction in rheumatoid arthritis (RA), and spleen deficiency (SD) was closely related to the intestinal microenvironment. In this study, we aimed to explore the aggravation of SD on collagen-induced arthritis (CIA) and the bone protection of compound Xiong Fu powder (XFP) on CIA with SD (SD-CIA) based on the intestinal microenvironment.MethodAn SD-CIA rat model was established using Rheum officinale Baill. decoction combined with CIA and then treated with XFP. The aggravating action of SD on CIA rats and the efficacy of XFP were evaluated using AI scores, H&E staining of the joint, and level of serum anti–collagen type II antibody (Col II Ab). Bone destruction was assessed by micro-CT and TRACP staining. In addition, flow cytometry, qRT-PCR, and ELISA were used to evaluate gut mucosal immunity. Moreover, metagenomic sequencing was used to determine the distribution and function of the gut microbiota.ResultsCompared with that in CIA rats, bone destruction in SD-CIA rats was aggravated, as manifested by increased AI scores, more severe joint pathological changes and radiological damage, and increased number of osteoclasts (OCs) in the ankle joint. Meanwhile, the proportion of Tregs/Th17 cells was biased toward Th17 cells in Peyer’s patches. Furthermore, the gene levels of TNF-α, IL-1β, IL-6, and IL-17 were increased. In contrast, the expression of IL-10 and sIgA was decreased in the jejunum and ileum. XFP treatment improved bone damage and intestinal mucosal immune disorders compared with the SD-CIA group. In addition, the distribution and function of the gut microbiota were altered in the SD-CIA group. After XFP treatment, the community and function of the gut microbiota were regulated, manifested as increased abundance of several Lactobacillus species, such as L. acidophilus, which regulates the intestinal Tregs/Th17 cells and quorum sensing pathways, followed by promoting probiotic adhesion to the intestines.ConclusionSD can aggravate bone destruction in CIA rats. Compound XFP may attenuate bone destruction in SD-CIA rats by regulating the intestinal microenvironment. One of the mechanisms is the cross-talk between sIgA secretion regulated by intestinal mucosal Tregs and Th17 cells and adhesion of Lactobacillus mediated by quorum sensing.

Small cell neuroendocrine carcinoma (SCNEC) is rare in the gynecologic tract, which has high invasive and metastatic ability. Due to the aggressive behavior and lack of treatment, patients have an extremely poor prognosis. Here we report a 66-year-old female diagnosed with SCNEC in the gynecologic tract, mixed with endometrioid adenocarcinoma, squamous cell, and adenosquamous carcinoma. A tumor mutational burden of 13.14 Muts/Mb was detected by next-generation sequencing. The patient underwent a palliative operation of total hysterectomy with bilateral adnexectomy but suffered from disease progression in a short time after the operation. Chemotherapy (paclitaxel + carboplatin) combined with immunotherapy (toripalimab) was conducted every 3 weeks, achieving a partial response after 2 cycles of treatment. After 5 cycles of combined treatment, the patient consolidated with monotherapy of toripalimab for about half a year and achieved a complete response. Until December 2021, the patient has achieved 27 months of progression-free survival and maintains a continued complete response. This case is presented due to the rare combination of pathological types and durable response to treatment especially immunotherapy, suggesting the potential value of immunotherapy in SCNEC of the gynecologic tract.

The sharing economy has the characteristics of resource-saving and environment-friendly, which is consistent with the goal of reducing food waste, and the cooperative consumption brought by sharing also is in line with the principles of food surplus redistribution and food waste management.In the current practice of reducing food waste in China, the sharing economy model, which is mature in other fields, has less penetration into the food sector, although the overseas food sharing models had become very popular, which definitely exerts a positive effect in reducing food wastage.Therefore, focusing on reducing food sharing practices, the paper combed foreign literature research for the relationship between reducing food waste and sharing practices，the food sharing models and the innovative ideas on reducing food waste in the era of digital economy.On this basis, it also proposed that it is necessary to investigate how to apply the sharing model of platform economy to the food waste management in China and put more intensive energy on the research topics on sharing participants, sharing fields, sharing platform and sharing policy.