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Previous studies have shown that paricalcitol (PA) has a protective effect on the kidneys. However, the exact molecular mechanism by which PA affects diabetic nephropathy (DN) progression remains uncertain. PBMCs of patients with DN were isolated, and CYP2J2 and VDR levels were detected by qPCR. Pearson correlation analysis was utilized to detect the relationship between uACR and CYP2J2 and VDR and between CYP2J2 and VDR. The protective effects of PA on DN have been examined by TUNEL, HE staining, ELISA, and Flow cytometry assays in STZ‐induced mice. Moreover, THP‐1 cells were stimulated with HG/LPS for in vitro studies. ELISA, qPCR, western blot, and Flow cytometry assays were utilized to assess the effects of PA on DN progression by regulating CYP2J2. The interaction between CYP2J2 and VDR was analyzed by CHIP‐qPCR and luciferase experiments. CYP2J2 and VDR levels were downregulated and uACR level was upregulated in DN patients. CYP2J2 and VDR were positively correlated in PBMCs. Both CYP2J2 and VDR are inversely correlated with uACR. Moreover, after PA treatment, 11, 12‐EET levels increased, inflammatory factor levels decreased, and M2 macrophage polarization was promoted in STZ‐induced mice and HG/LPS‐triggered THP‐1 cells. Depletion of CYP2J2 and VDR decreased 11, 12‐EET level, enhanced inflammatory factor levels, and inhibited M2 macrophage polarization, which were reversed by CYP2J2 overexpression in HG/LPS‐treated cells. Furthermore, VDR bound to the CYP2J2 promoter and promoted CYP2J2 transcriptional expression. The present work pointed out a new use for PA to inhibit DN progression by increasing EET level, inhibiting inflammatory response, and inducing M2 macrophage polarization via regulating the VDR/CYP2J2 axis. [ABSTRACT FROM AUTHOR]

Located in the southwest of Jiangxi Province, Dayu County has the most abundant tungsten resources in China. In this paper, 2969 agricultural soil samples were collected downstream of the tungsten mining area in Dayu, and all samples were tested for the contents of potentially toxic elements (PTEs) such as Cd, Pb, Zn, Cr, Cu, Ni, Hg, as well as the mining-related elements W, Sn, Mo and pH. In addition, 135 soil samples were measured for chemical morphology of Cd. The results show that the distribution patterns of Cd, Pb, Zn, Cu and W, Sn, Mo are relatively consistent, which are considered to be affected by upstream mining activities. Hg is possibly overlaying the effects of human production and living activities. Cr and Ni are considered as a natural source. From the perspective of total concentration, the ecological risk of PTEs in the study area was low, with over 80% of the samples being evaluated as safe. However, based on chemical fraction of Cd, more than 75% of the samples were assessed as moderately or severely contaminated. The serious acidification of soil in the study area is the main reason for the increase activity of Cd and its ecological risk. [ABSTRACT FROM AUTHOR]

Summary: The Moringa seed protein (MOS) is a new protein resource, the development and utilisation of MOS is still in its early stages due to the late introduction of its varieties. To improve the range of available MOS protein, this study investigated the effects of different pH levels on the ultrasonic modification of MOS protein (UMOWP), exploring the feasibility of UMOWP emulsion systems in food. The zeta potential analysis revealed that the isoelectric point (pI) of UMOWP was 5.8. The secondary structures of UMOWP could be regulated by pH. Moreover, different secondary structures led to different tertiary structures and chemical bonds in UMOWP. Compared with pH values near pI, surface hydrophobicity significantly increased but the total S–S group and particle size decreased away from pI. Furthermore, UMOWP partially dissociated at pH 3, and the degree of dissociation was weaker at pH 9 and pH 11. These structural changes led to significant improvements in the emulsification properties of UMOWP at pH 11, resulting in better environmental stability of the emulsion. These findings provide a foundation for the potential application of MOS proteins in the food industry. [ABSTRACT FROM AUTHOR]

The ER Ca2+ channel ryanodine receptor 2 (RyR2) is required for maintenance of insulin content and glucose-stimulated insulin secretion, in part, via regulation of the protein IRBIT in the insulinoma cell line INS-1. Here, we examined store-operated and depolarization-dependent Ca2+entry using INS-1 cells in which either RyR2 or IRBIT were deleted. Store-operated Ca2+ entry (SOCE) stimulated with thapsigargin was reduced in RyR2KO cells compared to controls, but was unchanged in IRBITKO cells. STIM1 protein levels were not different between the three cell lines. Basal and stimulated (500 μM carbachol) phospholipase C (PLC) activity was also reduced specifically in RyR2KO cells. Insulin secretion stimulated by tolbutamide was reduced in RyR2KO and IRBITKO cells compared to controls, but was potentiated by an EPAC-selective cAMP analog in all three cell lines. Cellular PIP2 levels were increased and cortical f-actin levels were reduced in RyR2KO cells compared to controls. Whole-cell Cav channel current density was increased in RyR2KO cells compared to controls, and barium current was reduced by acute activation of the lipid phosphatase pseudojanin preferentially in RyR2KO cells over control INS-1 cells. Action potentials stimulated by 18 mM glucose were more frequent in RyR2KO cells compared to controls, and insensitive to the SK channel inhibitor apamin. Taken together, these results suggest that RyR2 plays a critical role in regulating PLC activity and PIP2 levels via regulation of SOCE. RyR2 also regulates β-cell electrical activity by controlling Cav current density and SK channel activation. [ABSTRACT FROM AUTHOR]

Software defect prediction (SDP) is an important technology which is widely applied to improve software quality and reduce development costs. It is difficult to train the SDP model when software to be test only has limited historical data. Cross-project defect prediction (CPDP) has been proposed to solve this problem by using source project data to train the defect prediction model. Most of CPDP methods build defect prediction models based on the similarity of feature space or data distance between different projects. However, when the target project has a small amount of label data, these methods usually do not consider this part of data information. Therefore, when the distribution between source project and target project is quite different, these methods are difficult to achieve good prediction performance. To solve this problem, this paper proposes a CPDP method based on a semisupervised clustering (namely, Tsbagging). Tsbagging has two stages; in the first stage, we cluster to the source project data based on the limited labeled data in the target project and assign different weights to these source project data according to the clustering results. In the second stage, we use bagging method to train the prediction model based on the weight assigned in the first stage. The experimental results show that the performance achieved by Tsbagging is better than other existing SDP methods. [ABSTRACT FROM AUTHOR]

This study evaluated the effects of d -galactose (DG) concentration on the functional characteristics, physicochemical properties, structure and non-covalent binding ability of pH shifting treated soybean glycinin (S–11S). Multispectral and microscopic imaging analysis showed that the pH shifting induced soybean glycinin self-assembly into more stable small particle size aggregates, and the functional properties of S–11S were significantly enhanced. The introduction of DG further enhances the functional properties of S–11S, and the solubility and emulsification activity of the composite system are inversely proportional to the concentration of DG. In order to clarify the reason for the change, multispectral analysis found that the tertiary structure of S–11S was de-folded and the disordered structure was increased, which induced S–11S and DG to form smaller and stable nanoparticles than S–11S through hydrophobic forces and hydrogen bonding, and the optimal binding ratio was 10.8:1. In addition, the simulation results of molecular dynamics and molecular docking are in agreement with the experimental results. Therefore, the addition of DG can stabilize the overly discrete S–11S conformation and improve its functional characteristics. These results provide a theoretical basis for the application of modified protein and monosaccharide composite products in food and materials. [Display omitted] • PH-shifting changed the multilevel structure and functional properties of 11S. • Stoichiometry of the modified 11S and d -galactose in the complex was 10.8. • Weak-affinity complex was formed mainly via hydrophobic interaction and H bonding. • The stability and functional properties of complex were better than modified 11S. [ABSTRACT FROM AUTHOR]

• The modified glycinin (S-11S) is complexed with d -galactose (DG). • Heat promotes the covalent interaction of S-11S and DG at Cys and Phe sites. • The structure of the S-11S/DG colloidal particles is altered by heating. • Temperature affects the aggregation behavior of the S-11S/DG colloidal particles. • The S-11S/DG colloidal particles formed network gel easily. The molecular structure and morphologies of complex colloidal particles with modified glycine (S-11S) and d -galactose were studied by multispectral, microscopic imaging and chromatographic techniques at different temperatures, and the self-assembly and aggregation mechanisms were determined. Overall, high-temperature-treated S-11S and d -galactose associate at cysteine and phenylalanine sites and self-assemble into colloidal particles of greater stability than glycinin and S-11S via ionic and disulfide bonds. The structure and subunit content of composite colloidal particles were changed. Assessing the sub-microstructure reveals that temperature can regulate the directional aggregation of complex colloidal particles. The elasticity of the complex colloidal particles is maximum enhanced at 95 ℃ as confirmed by the rheological. Thus, the heat-treated aggregation of the soy protein and its complex was evaluated to provide a new theoretical basis for the application of soy protein in gels and other areas and contribute to the design of new soy protein products. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effects of lipid microspheres coated with prostaglandin E1 (lipo‐PGE1) on peritoneal transport function and inflammation in patients with end‐stage renal disease undergoing continuous ambulatory peritoneal dialysis (CAPD). Methods: In total, 89 patients were randomly allocated to the lipo‐PGE1 and control groups. All the patients received conventional treatment, and those in the lipo‐PGE1 group received lipo‐PGE1 intravenously for 2 weeks. The levels of β2‐microglobulin (β2‐MG), cystatin C, albumin, urea, creatinine, interleukin‐6 (IL‐6), matrix metalloproteinase‐2 (MMP‐2), and high‐sensitivity C‐reactive protein (hs‐CRP) were measured before and at 1 and 2 weeks after treatment. Results: In the lipo‐PGE1 group, the peritoneal clearance rates of β2‐MG, cystatin C, and albumin were significantly increased comparing with pre‐treatment values, and the IL‐6 appearance rate (AR) in the peritoneal dialysate and the serum levels of IL‐6 and hs‐CRP were markedly decreased (p < 0.05). The lipo‐PGE1 group had significantly higher peritoneal clearance rates of β2‐MG and cystatin C and lower IL‐6 AR in the peritoneal dialysate than the control group (p < 0.05). Conclusions: Lipid microspheres coated with prostaglandin E1 may increase the peritoneal clearance of moderately sized molecules and macromolecules with insignificant effect on the clearance of small molecules. The reduction in IL‐6 level following treatment with lipo‐PGE1 may alleviate inflammation. [ABSTRACT FROM AUTHOR]

Cadmium has become the foremost inorganic pollutant in farmland in China. It is widely accumulated in karst areas in southwest China, especially in Guangxi Province. In this study, vertical soil profiles, rice grains and corresponding root-soil samples were collected in Guangxi. The Cd contents of soil and rice grain samples and several soil properties, including organic matter, Fe2O3, Al2O3, CaO, MgO, SiO2 contents and pH were tested. Meanwhile, sequential extraction procedure were used to analysis the chemical fractions of Cd in root-soil samples. Based on the measured data, influencing factors on bioaccumulation of Cd and its contamination risk in study area were discussed. The results indicate that the bioaccumulation and mobility of Cd from soil to rice grain are restrained by high soil pH, high contents of organic matter, clay mineral and carbonate. Guangxi has strong development of karst landform, with the continuous process of soil formation, the activity of Cd in the soils in such areas will gradually become stable. In general, the environmental risk of soil cadmium contamination in karst areas of Guangxi is relatively low. But preventing soil acidification is the significant measure to prevent the environmental risk of it. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether Niban protein plays a role in renal interstitial fibrosis by regulating renal tubular epithelial cell apoptosis and explore the underlying mechanism. Methods: Unilateral ureteral obstruction (UUO) model was performed in C57B/6J mice, and divided into sham operation group and groups of days 3, days 7, and days 14. Niban expression was detected by immunohistochemistry and Western blot. TUNEL assays were used to detected apoptosis. Niban siRNA and overexpression Niban plasmid were transfected in HK-2 cells respectively to explore apoptosis related mechanisms of Niban during angiotensin II (AngII) – and endoplasmic reticulum (ER) stress-induced injury. Results: With the development of obstruction, Niban's expression decreased gradually while apoptosis increased. Silencing of Niban not only increased the AngII- and ER stress-induced apoptosis, but also promoted the expression of caspase 8, caspase 9, Bip, and Chop. Overexpression of Niban reduced AngII-induced apoptosis and the expression of caspase 8 and caspase 9. Conclusions: Niban protein is involved in apoptosis regulation in HK-2 cells, and most likely via caspase-dependent pathway. [ABSTRACT FROM AUTHOR]

The architecture of software‐defined network (SDN)enhances the openness of the network by separating the control and forwarding functions, but the centralized SDN control form is susceptible to distributed denial of service (DDoS) attacks. In this paper, entropy value and back‐propagation neural network (BPNN) were applied to the DDoS attack detection of SDN, and then the two detection algorithms were simulated in MATLAB software and compared with the K‐means algorithm. The results showed that in the face of four DDoS attacks, SYN Flood, ACK Flood, UDP Flood and ICMP Flood, the BPNN‐based DDoS detection had higher accuracy and less detection time; the switch that adopted the BPNN‐based DDoS detection algorithm adjusted the traffic ratio back to normal level faster when facing DDoS attacks, reducing the impact on other switches and maintaining the traffic stability of the network. © 2024 Institute of Electrical Engineer of Japan and Wiley Periodicals LLC. [ABSTRACT FROM AUTHOR]

Aims: To validate cardiovascular risk prediction models for individuals with diabetes using the UK Biobank in order to assess their applicability. Methods: We externally validated 19 cardiovascular risk scores from seven risk prediction models (Chang et al., Framingham, University of Hong Kong‐Singapore [HKU‐SG], Li et al, RECODe [risk equations for complications of type 2 diabetes], SCORE [Systematic Coronary Risk Evaluation] and the UK Prospective Diabetes Study Outcomes Model 2 [UKPDS OM2]), identified from systematic reviews, using UK Biobank data from 2006 to 2021 (n = 23 685; participant age 40–71 years, 63.5% male). We evaluated performance by assessing the discrimination and calibration of the models for the endpoints of mortality, cardiovascular mortality, congestive heart failure, myocardial infarction, stroke, and ischaemic heart disease. Results: Over a total of 269 430 person‐years of follow‐up (median 11.89 years), the models showed low‐to‐moderate discrimination performance on external validation (concordance indices [c‐indices] 0.50–0.71). Most models had low calibration with overprediction of the observed risk. RECODe outperformed other models across four comparable endpoints for discrimination: all‐cause mortality (c‐index 0.67, 95% confidence interval [CI] 0.65–0.69), congestive heart failure (c‐index 0.71, 95% CI 0.69–0.72), myocardial infarction (c‐index 0.67, 95% CI 0.65–0.68); and stroke (c‐index 0.65, 95% CI 0.62–0.68), and for calibration (except for all‐cause mortality). The UKPDS OM2 had comparable performance to RECODe for all‐cause mortality (c‐index 0.67, 95% CI 0.66–0.69) and cardiovascular mortality (c‐index 0.71, 95% CI 0.70–0.73), but worse performance for other outcomes. The models performed better for younger participants and somewhat better for non‐White ethnicities. Models developed from non‐Western datasets showed worse performance in our UK‐based validation set. Conclusions: The RECODe model led to better risk estimations in this predominantly White European population. Further validation is needed in non‐Western populations to assess generalizability to other populations. [ABSTRACT FROM AUTHOR]

• The PEG-g-PEI and folic acid grafted PDA nanoplatform has good stability and photothermal conversion efficiency. • The nanocomposites internalize more miR-21i into cancer cells by FR-mediated endocytosis and help lysosome escape of miR-21i. • The nanocomposites inhibit proliferation and induce apoptosis of breast cancer cells under photothermal and gene therapies. • The nanocomposites showed in vivo satisfactory tumor growth inhibition effects under photothermal and gene therapies. Gene-photothermal synergistic therapy shows great potential for breast cancer treatment. Polydopamine (PDA) is a widely used photothermal therapeutic agent and delivery vector. Herein, a tumor-targeted nanoplatform of PDA grafted with PEG-g-PEI and folic acid (FA) (PPF) was elaborately fabricated for precisely intracellular delivery of microRNA-21 inhibitor (miR-21i). The multifunctional nanoplatform possessed a narrow size distribution, good stability, and excellent photothermal conversion efficiency. In vitro FA modification more effectively promoted the intracellular uptake of the nanocomposites by MCF-7 and 4T1 cells, and facilitated the miR-21i escape from the lysosomes, thus significantly inhibiting cell proliferation and inducing tumor cell apoptosis. More importantly, in vivo satisfactory tumor growth inhibition effects were observed in PPF/miR21 and laser co-treated group due to the near-infrared (NIR) responsive PDA and conjugated tumor-targeting FA. In conclusion, this nanocarrier delivery system exhibit enhanced anti-cancer effect, indicating the outstanding advantages of synergistic therapy by intergrating photothermal, gene, and accurate cancer-targeted treatment into one system, which will provide a valuable strategy for the clinical treatment of breast cancer. [ABSTRACT FROM AUTHOR]

The performance of cell blocks (CBs) can vary significantly depending on the specimen collection and processing techniques used. This study compared the efficiency of three distinct specimen collection methods for endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) samples. From June 2021 to June 2023, the study involved 1450 patients who underwent EBUS-TBNA, resulting in the sampling of 1941 lesions. For these samples, three distinct specimen processing methods were employed to prepare tissue coagulum clot-based CBs. Specifically, the filter paper method was employed in 470 cases (yielding 626 samples), the centrifugation method in 500 cases (yielding 673 samples), and the funnel filtration method in 480 cases (yielding 642 samples). Out of these 1941 samples, the diagnostic yield for samples obtained using filter paper, centrifugation, and funnel filtration methods was 84.7 %, 87.7 %, and 92.5 %, respectively. In the subgroup of patients diagnosed with non-small cell lung cancer, the adequacy rate for molecular testing in samples processed through filter paper, centrifugation, and funnel filtration methods was 57.7 %, 82.0 %, and 88.3 %, respectively. In the centrifugation group, the combination of the CBs and cell pellet achieved an adequacy rate of 96.5 %. The cellular yield of CBs from EBUS-TBNA was significantly enhanced using centrifugation and funnel filtration methods. The funnel filtration method offered a more convenient and cost-effective approach, reducing cellular loss due to sample dispersion in the fixative medium. The use of the centrifugation method to prepare CBs, along with the retrieval of cell pellets from the residual fixative medium, can maximize the specimen adequacy rate for molecular testing. [ABSTRACT FROM AUTHOR]

In order to evaluate the safety of tebuconazole as a fungicide in bananas, after a simple and rapid pre-treatment, the residues of tebuconazole in different parts of banana were detected by high-performance liquid chromatography (HPLC) within 35 days. The mean recoveries and relative standard deviations in banana samples were 87.17 ~ 96.68% and 2.85 ~ 8.49%, respectively. The half-lives of tebuconazole in whole banana, banana pulp, and banana peel were 7.31 ~ 8.68 days, 11.12 ~ 13.39 days, and 4.06 ~ 5.74 days, respectively. It can be seen that tebuconazole dissipated fastest in the peel and slowest in the pulp. And the contents of tebuconazole in banana pulp and banana peel were 3 ~ 35% and 65 ~ 97%, respectively, which can be seen that tebuconazole was mainly distributed in the peel, and only a small part was transmitted to the pulp. Results also showed that the residual amounts of tebuconazole in banana pulp were increased at the first three days and then gradually dissipated, and were below the maximum residue limit (MRL) in China. The results of dietary intake risk assessment showed that the HQ (hazard quotient) were 0.45 ~ 2.69%, which were within the acceptable range. Overall, our research results show that tebuconazole in the field control of banana freckle disease has high security and low risk with the application dose of 133 g/L and diluted 1000 times in water, and can provide an important reference for the rational use of tebuconazole as a systemic fungicide in the field. [ABSTRACT FROM AUTHOR]

Estimating the population of defects is a key reference for completion evaluation in crowdsourced testing. Current studies commonly use the biological capture–recapture model (CRC model) to estimate the population of defects in crowdsourced tests with good results. However, the lack of consideration of false negatives for defects in existing studies leads to imprecise estimation of completion in crowdsourced testing, which in turn influences decision support during crowdsourced testing. This study analyzes the basic assumptions of the CRC model in biology and maps them to the field of crowdsourced testing, improves the Lincoln–Peterson estimator and sample coverage estimator utilizing false negative assumptions, and compares them with original estimators in 29 real crowdsourced testing projects. The experimental results show that our improved estimators can effectively reduce the estimation relative error of the population of defects caused by false negatives. [ABSTRACT FROM AUTHOR]

• High concordance was found between tissue-NGS and plasma-NGS in cases with ctDNA. • Plasma samples without detectable ctDNA caused most of the inconsistent results. • Plasma-NGS showed high sensitivity in detecting SNV and indel mutations. • Plasma-NGS was significantly less capable of detecting CNVs and gene fusions. • Tissue-NGS remains the preferred method for molecular testing in NSCLC patients. Genotype-guided personalized therapy has become an essential part of routine clinical care in non-small cell lung cancer (NSCLC) patients. However, small tissue specimens often yield inadequate molecular testing material. Plasma ctDNA-based liquid biopsy is an increasingly common non-invasive alternative to tissue biopsy. This study examined the similarities and differences in the molecular profiling of tissue and plasma samples to provide insight into sample selection in clinical practice. Sequencing data from 190 NSCLC patients who underwent concurrent tissue-based next-generation sequencing (tissue-NGS) and plasma-based NGS (plasma-NGS) using a 168-gene panel were analyzed. Tissue-NGS identified genomic alterations in 97.4% (185/190) of the enrolled patients and plasma-NGS identified genomic alterations in 72.1% (137/190) of the enrolled patients. Considering all NSCLC guideline-recommended biomarkers in the entire cohort of 190 cases, 81 patients had positive concordant mutations detected in both tissue and plasma samples, while 69 patients had no predefined alterations detected in either tissue or plasma samples. Additional mutations were found in the tissues of 34 patients and the plasma of six patients. The overall concordance rate between tissue and plasma samples was 78.9% (150/190). The tissue-NGS and plasma-NGS sensitivities were 95.0% and 71.9%, respectively. In the 137 patients with detectable ctDNA in plasma samples, the concordance rate between tissue and plasma samples reached 91.2%, and the sensitivity of plasma-NGS reached 93.5%. Our findings indicate that plasma-NGS is less capable of detecting genetic alterations than tissue-NGS, especially for copy number variations and gene fusions. Tissue-NGS remains the preferred method for evaluating the molecular profile of NSCLC patients when tumor tissue is available. We suggest that the concurrent use of liquid biopsy and tissue biopsy is the optimal approach in clinical practice; alternatively, plasma can be used as substitute material when tissue is unavailable. [ABSTRACT FROM AUTHOR]

Introduction: Fatigue is a common but often overlooked symptom in dialysis patients. Factors affecting fatigue in dialysis patients are currently unclear. There are few studies on the effects of mental factors and dialysis modality on fatigue. This study aims to explore the potential relationship between fatigue and insomnia, as well as psychiatric disorders such as anxiety and depression among patients who undergo peritoneal dialysis (PD) or hemodialysis (HD). Methods: There were 96 HD patients and 160 PD patients at our hospital who voluntarily participated in the survey. A questionnaire survey was conducted to gather general characteristics of the patients and to evaluate fatigue, sleep quality, anxiety, and depression levels among PD and HD patients. Results: The overall fatigue score was 53.83 ± 14.22 for the PD group and 57.92 ± 16.35 for the HD group. Notably, the fatigue level was lower in the PD group compared to the HD group (p < 0.05). Univariate analysis indicated that fatigue was associated with occupational status and income in the PD group, as well as educational level and income in the HD group (p < 0.05). Correlation analysis revealed that patients in both groups who were older and had higher scores for insomnia, anxiety, and depression experienced more severe fatigue. Moreover, body mass index was positively correlated with fatigue status in the PD group, while duration of dialysis showed a positive association with fatigue in the HD group. Multivariate regression analysis identified income and depression as major factors influencing fatigue in the PD group, and duration of dialysis, income, and depression in the HD group. Conclusion: Patients who undergo dialysis exhibit high levels of fatigue, with the severity of fatigue being less pronounced in the PD group compared to the HD group. Fatigue in these patients is associated with the duration of dialysis, income level, and presence of depression. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related deaths in the world. It is urgent to search for safe and effective therapies to address the CRC crisis. The siRNA-based RNA interference targeted silencing of PD-L1 has extensive potential in CRC treatment but is limited by the lack of efficient delivery vectors. In this work, the novel cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODNs)/siPD-L1 co-delivery vectors AuNRs@MS/CpG ODN@PEG-bPEI (ASCP) were successfully prepared by two-step surface modification of CpG ODNs-loading and polyethylene glycol-branched polyethyleneimine-coating around mesoporous silica-coated gold nanorods. ASCP promoted dendritic cells (DCs) maturation by delivering CpG ODNs, exhibiting excellent biosafety. Next, mild photothermal therapy (MPTT) mediated by ASCP killed tumor cells and released tumor-associated antigens, further promoting DC maturation. Furthermore, ASCP exhibited mild photothermal heating-enhanced performance as gene vectors, resulting in an increased PD-L1 gene silencing effect. Enhanced DCs maturity and enhanced PD-L1 gene silencing significantly promoted the anti-tumor immune response. Finally, the combination of MPTT and mild photothermal heating-enhanced gene/immunotherapy effectively killed MC38 cells, leading to strong inhibition of CRC. Overall, this work provided new insights into the design of mild photothermal/gene/immune synergies for tumor therapy and may contribute to translational nanomedicine for CRC treatment. [ABSTRACT FROM AUTHOR]

Oxidative stress is a critical pathogenic factor for age-related macular degeneration (AMD). Autophagy serves as a mechanism to counteract oxidative stress. LAMTOR1 regulates mTORC1 activity by recruiting or disassembling it on the lysosome under the addition or deprivation of amino acids. This regulation inhibits or enhances autophagy. Our study investigates whether oxidative stress impacts LAMTOR1, thereby adapting to oxidative conditions. We employed oxidative stressors, menadione (VK3) and 4-hydroxynonenal (4-HNE), and observed a reduction of LAMTOR1 in both human and mouse retinal pigment epithelium (RPE) following short-term (1h) and prolonged exposures (24h). Nrf2 overexpression increased both lamtor1 mRNA and LAMTOR1 protein in the RPE. To determine if Nrf2 regulates lamtor1 transcription, we cloned the deletion mutants of the lamtor1 promoter into a luciferase reporter. Although the promoter contained antioxidant response elements, transcriptional activity depended on the interaction between Nrf2 and the constructs containing the transcriptional start site. Moreover, Nrf2-driven transcription was significantly reduced by an inhibitor of histone acetyltransferase, p300. Correspondingly, Nrf2 overexpression increased levels of acetylated histone 3 and p300. The reduction in LAMTOR1 by 4-HNE was reversed by pepstatin A and NH 4 Cl which block lysosomal degradation. 4-HNE increased TFEB nuclear translocation which was reversed by LAMTOR1 overexpression. In vivo , LAMTOR1 levels decreased in the photoreceptor and RPE layers of NaIO 3 -injected mice, compared to PBS-injected controls. In conclusion, oxidative injury reduces LAMTOR1, predominantly through lysosomal degradation although Nrf2-mediated histone acetylation enhances lamtor1 transcription. This study reveals a previously unrecognized regulatory mechanism of lamtor1 by oxidative stress, suggesting a novel role for LAMTOR1 in the pathogenesis of AMD. [Display omitted] • Oxidative stressors reduced LAMTOR1 in retinal pigment epithelium. • The reduction of LAMTOR1 depended on lysosomal degradation and epigenetic regulation. • LAMTOR1 overexpression reversed TFEB nuclear translocation by 4-HNE. • LAMTOR1 reduced in the photoreceptor and RPE layers in oxidant-stressed mice. [ABSTRACT FROM AUTHOR]

Ischemia–reperfusion injury (IRI) is one of the major causes of acute kidney injury (AKI). tRNA derived fragments (tRFs/tiRNAs) are groups of small noncoding RNAs derived from tRNAs. To date, the role of tRFs/tiRNAs in renal IRI has not been reported. Herein, we aimed to investigate the involvement of tRFs/tiRNAs in the occurrence and development of ischemia–reperfusion-induced AKI. Moderate/severe renal IRI mouse models were established by bilateral renal pedicle clamping. The tRF/tiRNA profiles of healthy controls and moderate/severe IRI-stressed kidney tissues were sequenced by Illumina NextSeq 500. Candidate differentially expressed tiRNAs were further verified by RT-qPCR. Biological analysis was also performed. Overall, 152 tRFs/tiRNAs were differentially expressed in the moderate ischemic injury group compared with the normal control group (FC > 2, p < 0.05), of which 47 were upregulated and 105 were downregulated; in the severe ischemic injury group, 285 tRFs/tiRNAs were differentially expressed (FC > 2, p < 0.05), of which 157 were upregulated, and 128 were downregulated. RT-qPCR determination of eight abundantly expressed tiRNAs was consistent with the sequencing results. Gene Ontology analysis for target genes of the tRFs/tiRNAs showed that the most enriched cell components, molecular functions and biological processes were Golgi apparatus, cytoplasmic vesicles, protein binding, cellular protein localization and multicellular organism development. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that these target genes were mainly involved in the natural killer cell mediated cytotoxicity pathway, citrate cycle, and regulation of actin cytoskeleton signaling pathway. Our results indicated that tRFs/tiRNAs were involved in renal IRI. These tRFs/tiRNAs may be effective partly via regulation of renal immunity, inflammation and metabolism processes. Candidate genes, including tiRNA-Gly-GCC-003, tiRNA-Lys-CTT-003, and tiRNA-His-GTG-002, might be potential biomarkers and therapeutic targets of ischemia–reperfusion injury-induced acute kidney injury. [ABSTRACT FROM AUTHOR]

The colonization of bacterial pathogens is a major concern in wound infection and becoming a public health issue. Herein, a core–shell structured Ag@MSN (silver core embedded with mesoporous silica, AM)-based nanoplatform was elaborately fabricated to co-load ciprofloxacin (CFL) and tumor necrosis factor-α (TNF-α) small interfering RNA (siTNF-α) (AMPC@siTNF-α) for treating the bacterial-infected wound. The growth of bacterial pathogens was mostly inhibited by released silver ions (Ag+) and CFL from AMPC@siTNF-α. Meanwhile, the loaded siTNF-α was internalized by macrophage cells, which silenced the expression of TNF-α (a pro-inflammatory cytokine) in macrophage cells and accelerated the wound healing process by reducing inflammation response. In the in vivo wound model, the Escherichia coli (E. coli)-infected wound in mice almost completely disappeared after treatment with AMPC@siTNF-α, and no suppuration symptom was observed during the course of the treatment. Importantly, this nanoplatform had negligible side effects both in vitro and in vivo. Taken together, this study strongly demonstrates the promising potential of AMPC@siTNF-α as a synergistic therapeutic agent for clinical wound infections. [ABSTRACT FROM AUTHOR]

EPS66A was derived from an unidentified Streptomyces sp. HL-66 by chemical fraction and disease-resistance assays. It was identified as a polysaccharide through a series of chemical characterization, including infrared spectrum analysis, methylation, gas chromatography–mass spectrometry, nuclear magnetic resonance, and high-performance gel permeation chromatography. To determine its effect in plant, EPS66A was applied to tobacco leaves infected with TMV, resulting in the plant with enhanced systemic resistance with a significant reduction of TMV severity. Plant defense was confirmed by early responses, including hypersensitive response (HR) indicated by programed cell death, moderate alkalization, oxidative burst, increase in nitric oxide (NO) and salicylic acid (SA). Furthermore, EPS66A induced callose deposition to form defense barriers against pathogen invasion and the expression of pathogenesis-related (PR) genes, which confirmed the second level of plant defense. Therefore, EPS66A served as a resistance inducer, which was reorganized by tobacco cells that triggered the production of signal molecules. The signals moved in long distance and systemically in plant, which coordinated the expression of defense responses. The study provided a new perspective in understanding the mechanism of EPS66A in regulating plants on environmental adaptability and provided a theoretical foundation for designing safe and sustainable pesticides. [ABSTRACT FROM AUTHOR]

Background: Dynamic orchestration of metabolic pathways during continuous fasting remains unclear.Objective: We investigated the physiological effects of Bigu-style fasting and underlying metabolic reprogramming in healthy adults.Methods: We conducted a 5-d Bigu trial in 43 healthy subjects [age 23.2 ± 2.4 y; BMI (in kg/m2) 22.52 ± 1.79]. Physiological indicators and body composition were monitored daily during fasting day 1 (F1D) to F5D and after 10-d refeeding postfasting (R10D) and R30D. Blood samples were collected in the morning. Risk factors associated with inflammation, aging, cardiovascular diseases, malnutrition, and organ dysfunction were evaluated by biochemical measurements. Untargeted plasma metabolomics and gut microbial profiling were performed using plasma and fecal samples. Data were analyzed by repeated measures ANOVA with Greenhouse-Geisser correction. Correlation analyses for metabolite modules and taurine were analyzed by Spearman's rank and Pearson tests, respectively.Results: Heart rate was accelerated throughout the fasting period. Risk factors associated with inflammation and cardiovascular diseases were significantly lowered during or after Bigu (P < 0.05). Body composition measurement detected an overconsumption of fat starting from F3D till 1 mo after refeeding. Metabolomics unveiled a coupling between gluconeogenesis and cholesterol biosynthesis beyond F3D. Plasma taurine significantly increased at F3D by 31%-46% followed by a reduction to basal level at F5D (P < 0.001), a pattern inversely correlated with changes in glucose and de novo synthesized cholesterol (r = -0.407 and -0.296, respectively; P < 0.001). Gut microbial profiling showed an enrichment of taurine-utilizing bacteria at F5D, which was completely recovered at R10D.Conclusions: Our data demonstrate that 5-d Bigu is potentially beneficial to health in young adults. A starvation threshold of 3-d fasting is necessary for maintaining glucose and cholesterol homeostasis via a taurine-microbiota regulatory loop. Our findings provide novel insights into the physiological and metabolic responses of the human body to continuous Bigu-style fasting. This trial was registered at http://www.chictr.org.cn as ChiCTR1900022917. [ABSTRACT FROM AUTHOR]

Background: Establishing a high-accuracy and non-invasive method is essential for evaluating cardiovascular disease. Skin cholesterol is a novel marker for assessing the risk of atherosclerosis and can be used as an independent risk factor of early assessment of atherosclerotic risk.Methods: We propose a non-invasive skin cholesterol detection method based on absorption spectroscopy. Detection reagents specifically bind to skin cholesterol and react with indicator to produce colored products, the skin cholesterol content can be obtained through absorption spectrum information on colored products detected by non-invasive technology. Gas chromatography is used to measure cholesterol extracted from the skin to verify the accuracy and reliability of the non-invasive test method. A total of 342 subjects were divided into normal group (n = 115), disease group (n = 110) and risk group (n = 117). All subjects underwent non-invasive skin cholesterol test. The diagnostic accuracy of the measured value was analyzed by receiver-operating characteristic (ROC) curve.Results: The proposed method is able to identify porcine skin containing gradient concentration of cholesterol. The values measured by non-invasive detection method were significantly correlated with gas chromatography measured results (r = 0.9074, n = 73, p < 0.001). Bland-Altman bias was - 72.78 ± 20.03 with 95% limits of agreement - 112.05 to - 33.51, falling within the prespecified clinically non-significant range. We further evaluated the method of patients with atherosclerosis and risk population as well as normal group, patients and risk atherosclerosis group exhibited higher skin cholesterol content than normal group (all P < 0.001). The area under the ROC curve for distinguishing Normal/Disease group was 0.8642 (95% confidence interval, 0.8138 to 0.9146), meanwhile, the area under the ROC curve for distinguishing Normal/Risk group was 0.8534 (95% confidence interval, 0.8034 to 0.9034).Conclusions: The method demonstrated its capability of detecting different concentration of skin cholesterol. This non-invasive skin cholesterol detection system may potentially be used as a risk assessment tool for atherosclerosis screening, especially for a large population. [ABSTRACT FROM AUTHOR]

Aims: Type 2 diabetes mellitus (T2DM) is commonly complicated by renal impairment. Polyethylene glycol loxenatide (PEX168) is a novel long‐acting glucagon‐like peptide‐1 receptor agonist for T2DM. PEX168 pharmacokinetics was studied to identify requirements for dose‐modification in T2DM complicated by renal impairment. Methods: This was a single‐centre, open‐labelled, parallel‐group, single‐dose, phase I clinical trial of patients with mild and moderate renal impairment, and with or without T2DM. Age‐, sex‐ and body mass index‐matched subjects with normal renal function, and with or without T2DM were recruited as controls. Subjects received a single abdominal subcutaneous injection of PEX168 200 μg. Pharmacokinetic samples were taken at 0, 24, 48, 72, 96, 120, 144, 216, 312, 480, 648 and 720 hours. Results: Twenty‐three patients were included in the pharmacokinetics analysis. Vz/F and CL/F were lower in the moderate impairment group than in the other groups. The mean t1/2 (163 hours) in the moderate impairment group was prolonged compared to the mild impairment (117 hours) and normal (121 hours) groups. AUC0–inf increased by 13 and 100.7% in patients with mild and moderate renal impairment, respectively. Most adverse events were mild gastrointestinal disorders, with only 1 serious adverse event observed. Conclusion: A single dose of 200 μg of PEX168 was in general well tolerated in patients with renal impairment. The in vivo clearance rate of PEX168 in patients with moderate renal impairment is slower than in patients with mild renal impairment and normal renal function and dose adjustment might be required (ClinicalTrials.org #NCT02467790). [ABSTRACT FROM AUTHOR]

The Qilian Mountain permafrost is the only place where gas hydrate occurs onshore China at present and its gas hydrate distribution is very complex and irregular. What patterns affecting the accumulation of gas hydrate or what process controlling the formation of gas hydrate are not clear in the study area. Aiming at a gas hydrate geological system, the geological process of gas hydrate formation was studied, based on geological data and analytical results obtained from drilling wells in the Qilian Mountain permafrost. As a result, three stages for the geological process of gas hydrate formation are put forward in the study area. During the late Mid-Jurassic, the upper Triassic generated and provided a major gas source for gas hydrate, secondarily in combination with gas associated with oil generated from the middle Jurassic. The main gas source migrated upward via faults of F1 and F2, partly and occasionally mixed with the coal-bed methane and the microbial methane produced in the shallow strata. It was blocked jointly by thrust faults and thick mudstone or oil shale to be initially accumulated in gas reservoir. From Cretaceous to Pleistocene, the sedimentary strata experienced erosion and the initial gas accumulation turned into residual gas after series of the Qinghai-Tibet plateau uplift. Since the early middle Pleistocene, glaciations formed a gas hydrate stability zone (GHSZ) and the residual gas was coupled with GHSZ to form gas hydrate subsequently. Hence three patterns for the coupling of the residual gas with GHSZ are summarized in the study area. When the residual gas happened to lie within GHSZ, the residual gas directly formed gas hydrate, which was indicated by the drilling results that gas anomalies were encountered within GHSZ as well as occurrences of gas hydrate in the field. When the residual gas was below GHSZ, the residual gas would continually migrate into GHSZ to form gas hydrate, which was indicated by the drilling results that gas anomalies had ever been encountered even if below GHSZ as well as occurrences of gas hydrate within GHSZ in the field. When the residual gas was above GHSZ, the residual gas remained or escaped, which was indicated by the drilling results that gas anomalies even with a high pressure abnormity were encountered in the shallower strata above GHSZ without occurrences of gas hydrate within GHSZ in the field. [ABSTRACT FROM AUTHOR]

Forest ecosystems have been confirmed to be a sink of the global mercury (Hg) in the biogeochemical cycle. However, few studies have investigated the distribution of Hg in forest ecosystems on a regional scale in China. This work aimed to investigate the concentrations, distribution and influential factors of Hg in the Qinling Mountains forests in central China. Foliage, litter and soil profile samples were collected at 24 sampling sites across the Qinling Mountains forests. The results of the present study showed that the concentrations of Hg in foliage, litter, organic soils and mineral soils were maintained at relatively low levels compared with those in subtropical forests of Southwest China. The average Hg concentrations followed the order litter (74 ± 34 ng g−1) > organic soil (71 ± 37 ng g−1) > mineral soil (34 ± 21 ng g−1) > foliage (31 ± 15 ng g−1). Mercury in foliage showed no obvious spatial pattern, likely due to differences in tree species and ages across the sampling sites. Higher concentrations of Hg in litter were observed on the southern slope (low altitude), while the distribution of Hg in organic soils was the opposite. Both the tree species and environmental parameters (altitude, temperature and precipitation) controlled the Hg concentrations in litter by regulating the decomposition rate of the litter. There were significantly positive correlations between the Hg concentrations and soil organic carbon, nitrogen and sulfur in all soil layers, indicating that organic matter has a high geochemical affinity for Hg in soils. Because of the lower turnover rate and the higher accumulation of organic matter in high altitude and low temperature areas, Hg loss from biogeochemical cycling processes was effectively reduced. The spatial distribution of Hg in forests soil can be shaped by the distribution of organic matter at the regional scale. • Hg concentrations in litter and soils retain at relatively low levels. • Hg concentrations have significant positive correlation with SOC, N and S in all soil layers. • Hg concentrations decrease with the depth increase in soil profiles. • The lower turnover rate of C reduced the Hg loss from biogeochemical cycling processes. [ABSTRACT FROM AUTHOR]

• An optimal method was proposed to estimate chromium (Cr) concentration in arable soil. • The Savitzky-Golay (SG) spectral pretreatment can be used as a good pretreatment method for estimating Cr concentration. • The Principal Component Analysis (PCA) could effectively reduce the dimensionality of the hyperspectral data. • The optimal principal components (PCs) were obtained by comparing the influence of the different PCs on the estimation performance of the hyperspectral models. The heavy metal pollution in arable soil poses a significant threat to human health. Thus, it is of great significance to investigate the contamination of heavy metal elements in the soil. As the soil polluted by heavy metal is sensitive to spectral reflectance, thus the hyperspectral remote sensing technology could be a valuable tool for retrieving heavy metal components in the soil. This study, taking chromium (Cr) concentration as an example, proposes an optimal model for estimating heavy metal components in the soil by comprehensively taking account of the spectral pretreatment, dimensionality reduction with optimal parameters, and hyperspectral model. To this end, both the linear model, i.e., partial least squares regression (PLSR), and the nonlinear model, i.e., the gradient boosting decision tree (GBDT), are applied in this study. It is found in the study area, the Savitzky-Golay (SG) method can be regarded as an excellent spectral pretreatment for the hyperspectral data regardless of the applied model. By contrast, the dimensionality reduction in terms of the Principal Component Analysis (PCA) is closely related to hyperspectral model: the optimal principal components (PCs) in the estimation of Cr concentration are the first 9 PCs for the GBDT (nonlinear model), while that for the PLSR (linear model) become the first 8 PCs. Moreover, the examination of hyperspectral model shows the GBDT model has slightly better performance than the PLSR model for the Cr concentration estimation under most conditions. Finally, when the spectral pretreatment, dimensionality reduction, and hyperspectral model are fully considered, the best retrieval model for the Cr concentration in the study area is the SG-PCA-GBDT model. Numeric measures of model accuracy show the proposed model has a determination coefficient of 0.80 and a residual prediction deviation of 2.04, which provides a potentially new method for estimating Cr concentration in the polluted soil. [ABSTRACT FROM AUTHOR]

Environmental contamination by heavy metals is a public health concern. However, understandings of sources and pathways of heavy metal accumulation in crops, especially in major agricultural areas, is insufficient. In this study, atmospheric dust, coal, vehicle exhaust particles, maize and corresponding soils were collected from a major agricultural area in Northeast China and analyzed for heavy metal (Cd, Hg, Pb, As, Cu, Zn, Ni, Cr) contents and Pb isotopic compositions. Compared to the risk screening values for soil contamination of agricultural land in China, the soils in the study area have relatively low heavy metal concentrations. However, the contamination factor (CF), pollution load index (PLI) and geo-accumulation index (I geo) indicated a slight degree of heavy metal (particularly Cd) accumulation during the past few decades. The concentrations of Cd, Cu, Hg and Pb decreased from leaves, roots, stalks to grains, whereas it decreased from roots, grains, leaves to stalks for Zn and from roots, leaves, stalks to grains for As, Cr and Ni. The calculated bioconcentration factor (BCF) values indicated that Cd had a high possibility of entering maize roots from soil, while it was relatively difficult for Cr and Pb to accumulate in maize roots. The order of the mean translocation factor (TF) values was Zn (1.41) > Cu (0.31) > Hg (0.27) > Cd (0.15) > Pb (0.11) > Cr (0.11) > As (0.11) > Ni (0.08), suggesting that Zn had the highest mobility from root to grain, while >90% of absorbed Ni was sequestered in roots. Based on a simple binary model, the approximate contributions of Pb in vehicle emissions and coal to atmospheric dust were 78.1% and 21.9%, respectively, suggesting that Pb in atmospheric dust was mainly from vehicle emissions. For maize organs, airborne Pb was the dominant source contributor to maize stalks and grains, with approximate contributions of 78.3% and 15.1% to leaves and roots, respectively. Our study suggested that Pb accumulation in maize plants might be mainly derived from atmospheric deposition related to vehicle emissions. Hence, more efficient managerial strategies should be adopted to protect food safety and human health. • Cd and As in cropland soils of Jilin Province show a slight degree of accumulation. • Cd has a higher possibility of entering the maize root from soil than Cr and Pb. • Zn has highest mobility from root to grain, >90% of Ni was sequestered in the root. • Airborne Pb is the dominant source contributor to maize stalks, leaves and grains. [ABSTRACT FROM AUTHOR]