Synthesis and Anti-Liver Fibrosis Research of Aspartic Acid Derivatives.

Liver fibrosis plays an important role in the progression of liver disease, but there is a severe shortage of direct and efficacious pharmaceutical clinical interventions. Literature research indicates that aspartic acid exhibits hepatoprotective properties. In this paper, 32 target compounds were designed and synthesized utilizing aspartic acid as the lead compound, of which 22 were new compounds not reported in the literature. These compounds were screened for their inhibitory effects on the COL1A1 promoter to assess in vitro anti-liver fibrosis activity and summarized structure-activity relationships. Four compounds exhibited superior potency with inhibition rates ranging from 66.72% to 97.44%, substantially higher than EGCG (36.46 ± 4.64%) and L-Asp (11.33 ± 0.35%). In an LPS-induced inflammation model of LX-2 cells, both 41 and 8a could inhibit the activation of LX-2 cells, reducing the expression of COL1A1, fibronectin, and α-SMA. Upon further investigation, 41 and 8a ameliorated liver fibrosis by inhibiting the IKKß-NF-κB signaling pathway to alleviate inflammatory response. Overall, the study evaluated the anti-liver fibrosis effects of aspartic acid derivatives, identified the potency of 41, and conducted a preliminary exploration of mechanisms, laying the foundation for the discovery of novel anti-liver fibrosis agents.

Bioinformatics analysis based on high-throughput sequencing data to identify hub genes related to different clinical types of COVID-19.

This article aims to explore hub genes related to different clinical types of cases with COVID-19 and predict the therapeutic drugs related to severe cases. The expression profile of GSE166424 was divided into four data sets according to different clinical types of COVID-19 and then calculated the differential expression genes (DEGs). The specific genes of four clinical types of COVID-19 were obtained by Venn diagram and conducted enrichment analysis, protein-protein interaction (PPI) networks analysis, screening hub genes, and ROC curve analysis. The hub genes related to severe cases were verified in GSE171110, their RNA-specific expression tissues were obtained from the HPA database, and potential therapeutic drugs were predicted through the DGIdb database. There were 536, 266, 944, and 506 specific genes related to asymptomatic infections, mild, moderate, and severe cases, respectively. The hub genes of severe specific genes were AURKB, BRCA1, BUB1, CCNB1, CCNB2, CDC20, CDC6, KIF11, TOP2A, UBE2C, and RPL11, and also differentially expressed in GSE171110 (P < 0.05), and their AUC values were greater than 0.955. The RNA tissue specificity of AURKB, CDC6, KIF11, UBE2C, CCNB2, CDC20, TOP2A, BUB1, and CCNB1 specifically enhanced on lymphoid tissue; CCNB2, CDC20, TOP2A, and BUB1 specifically expressed on the testis. Finally, 55 drugs related to severe COVID-19 were obtained from the DGIdb database. Summary, AURKB, BRCA1, BUB1, CCNB1, CCNB2, CDC20, CDC6, KIF11, TOP2A, UBE2C, and RPL11 may be potential diagnostic biomarkers for severe COVID-19, which may affect immune and male reproductive systems. 55 drugs may be potential therapeutic drugs for severe COVID-19.

Efficient photocatalytic degradation of ciprofloxacin by graphite felt-supported MnS/Polypyrrole composite: Dominant reactive species and reaction mechanisms.

The accumulation of antibiotics in aquatic environments poses a serious threat to human health. Photocatalytic degradation is a promising method for removing antibiotics from water, but its practical implementation requires improvements in photocatalyst activity and recovery. Here, a novel graphite felt-supported MnS/Polypyrrole composite (MnS/PPy/GF) was constructed to achieve effective adsorption of antibiotics, stable loading of photocatalyst, and rapid separation of spatial charge. Systematic characterization of composition, structure and photoelectric properties indicated the efficient light absorption, charge separation and migration of the MnS/PPy/GF, which achieved 86.2% removal of antibiotic ciprofloxacin (CFX), higher than that of MnS/GF (73.7%) and PPy/GF (34.8%). The charge transfer-generated 1O2, energy transfer-generated 1O2, and photogenerated h+ were identified as the dominant reactive species, which mainly attacked the piperazine ring in the photodegradation of CFX by MnS/PPy/GF. The •OH was confirmed to participate in the defluorination of CFX via hydroxylation substitution. The MnS/PPy/GF-based photocatalytic process could ultimately achieve the mineralization of CFX. The facile recyclability, robust stability, and excellent adaptability to actual aquatic environments further confirmed MnS/PPy/GF is a promising eco-friendly photocatalyst for antibiotic pollution control.

Interfacial Covalent Bonding Endowing Ti3 C2 -Sb2 S3 Composites High Sodium Storage Performance.

Antimony sulfide is attracting enormous attention due to its remarkable theoretical capacity as anode for sodium-ion batteries (SIBs). However, it still suffers from poor structural stability and sluggish reaction kinetics. Constructing covalent chemical linkage to anchor antimony sulfide on two-dimension conductive materials is an effective strategy to conquer the challenges. Herein, Ti3 C2 -Sb2 S3 composites are successfully achieved with monodispersed Sb2S3 uniformly pinned on the surface of Ti3 C2 Tx MXene through covalent bonding of Ti-O-Sb and S-Ti. Ti3 C2 Tx MXene serves as both charge storage contributor and flexible conductive buffer to sustain the structural integrity of the electrode. Systematic analysis indicates that construction of efficient interfacial chemical linkage could bridge the physical gap between Sb2S3 nanoparticles and Ti3 C2 Tx MXene, thus promoting the interfacial charge transfer efficiency. Furthermore, the interfacial covalent bonding could also effectively confine Sb2S3 nanoparticles and the corresponding reduced products on the surface of Ti3 C2 Tx MXene. Benefited from the unique structure, Ti3 C2 -Sb2 S3 anode delivers a high reversible capacity of 475 mAh g-1 at 0.2 A g-1 after 300 cycles, even retaining 410 mAh g-1 at 1.0 A g-1 after 500 cycles. This strategy is expected to shed more light on interfacial chemical linkage towards rational design of advanced materials for SIBs.

Aromatic Schiff bases confer inhibitory efficacy against New Delhi metallo-ß-lactamase-1 (NDM-1).

The irregular use of antibiotics has created a natural selection pressure for bacteria to adapt resistance. Bacterial resistance caused by metallo-ß-lactamases (MßLs) has been the most prevalent in terms of posing a threat to human health. The New Delhi metallo-ß-lactamase-1 (NDM-1) has been shown to be capable of hydrolyzing almost all ß-lactams. In this work, eight aromatic Schiff bases 1-8 were prepared and identified by enzyme kinetic assays to be the potent inhibitors of NDM-1 (except 4). These molecules exhibited a more than 95 % inhibition, and an IC50 value in the range of 0.13-19 µM on the target enzyme, and 3 was found to be the most effective inhibitor (IC50 = 130 nM). Analysis of structure-activity relationship revealed that the o-hydroxy phenyl improved the inhibitory activity of Schiff bases on NDM-1. The inhibition mode assays including isothermal titration calorimetry (ITC) disclosed that both compounds 3 and 5 exhibited a reversibly mixed inhibition on NDM-1, with a Ki value of 1.9 and 10.8 µM, respectively. Antibacterial activity tests indicated that a dose of 64 µg·mL-1 Schiff bases resulted in 2-128-fold reduction in MICs of cefazolin on E. coli producing NDM-1 (except 4). Cytotoxicity assays showed that both Schiff bases 3 and 5 have low cytotoxicity on the mouse fibroblast (L929) cells at a concentration of up to 400 µM. Docking studies suggested that the hydroxyl group interacts with Gln123 and Glu152 of NDM-1, and the amino groups interact with the backbone amide groups of Glu152 and Asp223. This study provided a novel scaffold for the development of NDM-1 inhibitors.

Effect of hydrothermal pretreatment on the degrease performance and liquid substances transformation of kitchen waste.

Hydrothermal treatment (HT) is a pragmatic approach for pretreatment of kitchen waste (KW). This work investigated the effect of hydrothermal pretreatment (HTP) on the deoiling, desalting and liquid substances transformation of KW. The orthogonal test method was used to study the effects of three factors at five levels, including solid to liquid ratio (A1-5), heating time (B1-5) and hydrothermal temperature (C1-5). The results indicated that the floatable oil content was improved significantly after HTP. The highest floatable oil content was 84.54 mL/kg at the hydrothermal condition of 1/1.5, 20 min and 100 °C, which was 2.42 times higher than the control. The maximum desalination ratio (92.66%) was at A5B1C5 (1/2.5, 5 min, 100 °C), which was 4.48 times higher than control group (No.0) (20.67%). The VFAs concentration was the highest (11441.05 mg/kg) at 1/2.5, 5 min and 100 °C, which increased by 711.03% compared to the No.0 (1410.78 mg/kg). In addition, the maximum TOC value was obtained at 53530.84 mg/kg. After HTP, the acetic acid and butyric acid concentrations of the liquid phase increased, while the ethanol concentration decreased. The contents of T,NH4+-N and organic nitrogen in the liquid phase of the HTP system increased, while NO3--N remained at a low level (4.96-20.48 mg/kg). The range and variance analysis showed that the temperature had the greatest effect on the deoiling and the liquid substances transformation of KW among these three factors, followed by solid to liquid ratio and heating time. Based on the orthogonal experiment, the optimal parameters for KW deoiling were A3 (1/1.5), B4 (25 min) and C5 (100 °C). This work provided a reference for the KW deoiling and hence improve the efficient utilization of KW.

pH-Responsive Behavior of Pickering Emulsions Stabilized by a Selenium-Containing Surfactant and Alumina Nanoparticles.

Herein, we describe pH-responsive Pickering emulsions stabilized by a sodium carboxylate-derived selenium surfactant (C10-Se-C10·(COONa)2) in combination with positively charged alumina nanoparticles. Unlike other bola-type carboxylate surfactants (e.g., disodium eicosanoate), C10-Se-C10·(COONa)2 is soluble in water with a low Krafft temperature (36.1 °C). The emulsions are sensitive to pH variations, and efficient demulsification can be achieved by a pH trigger. The carboxylic sodium group in the C10-Se-C10·(COONa)2 structure can be reversibly cycled between its anionic and nonionic states (carboxylic acid), resulting in a pH-controlled electrostatic attraction between the surfactant and alumina. The Pickering emulsion can be reversibly switched between "on" (stable) and "off" (unstable) states by pH at least four times. Compared with the emulsions stabilized by specially synthesized stimuli-responsive particles or surfactants, the method reported here is much easier to implement and requires very low concentrations of the surfactant and nanoparticles, with potential applications in the fields of biomedicine, drug delivery, and cosmetics.

Nitrogen doped porous carbon coated antimony as high performance anode material for sodium-ion batteries.

Sb holds the promise of being a high performance anode for sodium ion batteries(SIBs), while effective preparation of decent antimony(Sb) based anode materials for sodium storage is still under exploration. Herein, we propose a simple approach to achieve a high performance anode, using polyaniline as the carbon source and SbCl3as the metal source. Synergetic polymerization and hydrolysis reactions combined with subsequent thermal reduction endow Sb/C-PANI electrode possessing ultrafine Sb nanoparticles symmetrically distributed in the nitrogen(N) doped porous carbon matrix. The Sb/C-PANI electrode exhibits excellent sodium storage performance, featured for a high reversible capacity of 469.5 mAh g-1after 100 cycles at 100 mA g-1and 336.5 mAh g-1after 300 cycles under 500 mA g-1. Such impressive performance will advance the development of Sb based anode materials for sodium storage. The present approach provides a compatible strategy for preparation of anode materials with high reversible capacity and long lifespan.

Interactions between magnetic particles and polyaluminum chloride on the coagulation behavior in humic acid-kaolin synthetic water treatment.

Understanding the interactions between magnetic particles (MPs) and polyaluminum chloride (PACl) is essential to elucidate the magnetic seeding coagulation (MSC) process. However, little is known about how MPs interact with the different Al species coexisting in the PACl. Here, the relationships among pollutants removal, residual Al distribution, and floc properties were comparatively studied in the MSC and traditional coagulation (TC) processes to address this issue. The response surface analysis indicated that the interaction between PACl and MPs dosages exhibited significant effects on turbidity and DOC removal. Negligible changes of dissolved Al after MPs addition indicated the weak connection between Ala and MPs. The formation of MPs-Alb-HA complexes resulted in the increase of turbidity removal from 90.2% to 96.0% and the reduction of colloidal Al from 0.67 to 0.30 mg L-1. Humic-like components could be adsorbed on MPs forming MPs-HA complexes, which enhanced the DOC removal from 55% to 58.5%. MPs addition produced loose flocs with a small floc fractal dimension value (1.74), so the average size and strength of flocs in the MSC process (425 µm and 49.7%) were lower than that in the TC process (464 µm and 58.3%). The cumulative volume percentage of large flocs (>700 µm) was decreased from 29.7% to 20.7% with MPs addition, indicating the disruption of large flocs and the reproduction of more fragments. The effective separation of these fragments by magnetic attraction maintained the efficient coagulation performance. This study provides new insights into the interaction mechanism of MPs and PACl in the MSC process.

Recirculation ratio regulates denitrifying sulfide removal and elemental sulfur recovery by altering sludge characteristics and microbial community composition in an EGSB reactor.

Expanded granular sludge blanket (EGSB) is regarded as a promising reactor to carry out denitrifying sulfide removal (DSR) and elemental sulfur (S0) recovery. Although the recirculation ratio is an essential parameter for EGSB reactors, how it impacts the DSR process remains poorly understood. Here, three lab-scale DSR-EGSB reactors were established with the different recirculation ratios (3:1, 6:1 and 9:1) to evaluate the corresponding variations in pollutant removal, S0 recovery, anaerobic granular sludge (AGS) characteristics and microbial community composition. It was found that an intermediate recirculation ratio (6:1) could facilitate long-term reactor stability. Adequate recirculation ratio could enhance S0 recovery, but an excessive recirculation ratio (9:1) was likely to cause AGS fragmentation and biomass loss. The S0 desorbed more from sludge at higher recirculation ratios, probably due to the enhanced hydraulic disturbance caused by the increased recirculation ratios. At the low recirculation ratio (3:1), S0 accumulation as inorganic suspended solids in AGS led to a decrease in VSS/TSS ratio and mass transfer efficiency. Although typical denitrifying and sulfide-oxidizing bacteria (e.g., Azoarcus, Thauera and Arcobacter) were predominant in all conditions, facultative and heterotrophic functional bacteria (e.g., Azoarcus and Thauera) were more adaptable to higher recirculation ratios than autotrophs (e.g., Arcobacter, Thiobacillus and Vulcanibacillus), which was conducive to the formation of bacterial aggregates to response to the increased recirculation ratio. The study revealed recirculation ratio regulation significantly impacted the DSR-EGSB reactor performance by altering AGS characteristics and microbial community composition, which provides a novel strategy to improve DSR performance and S0 recovery.

Real-time monitoring of D-Ala-D-Ala dipeptidase activity of VanX in living bacteria by isothermal titration calorimetry.

The d,d-dipeptidase enzyme VanX is the main cause of vancomycin resistance in gram-positive bacteria because of hydrolysis of the D-Ala-D-Ala dipeptide used in cell-wall biosynthesis. Continuous assay of VanX has proven challenging due to lack of a chromophoric substrate. Here, we report a direct approach for continuous assay of VanX in vitro and in vivo from hydrolysis of D-Ala-D-Ala, based on the heat-rate changes measured with isothermal titration calorimetry (ITC). With the ITC approach, determination of kinetic parameters of VanX hydrolyzing D-Ala-D-Ala and the inhibition constant of d-cysteine inhibitor yielded KM of 0.10 mM, kcat of 11.5 s-1, and Ki of 18.8 µM, which are consistent with the data from ninhydrin/Cd(II) assays. Cell-based ITC studies demonstrated that the VanX expressed in E. coli and in clinical strain VRE was inhibited by d-cysteine with IC50 values of 29.8 and 28.6 µM, respectively. Also, the total heat from D-Ala-D-Ala (4 mM) hydrolysis decreases strongly (in absolute value) from 1.26 mJ for VRE to 0.031 mJ for E. faecalis, which is consistent with the large MIC value of vancomycin of 512 µg/mL for VRE and the much smaller value of 4 µg/mL for E. faecalis. The ITC approach proposed here could be applied to screen and evaluate small molecule inhibitors of VanX or to identify drug resistant bacteria.

miR-92a regulates coelomocytes apoptosis in sea cucumber Apostichopus japonicus via targeting Aj14-3-3ζ in vivo.

miR-92a, a well-documented oncogene, was previously found to be differentially expressed in diseased sea cucumber Apostichopus japonicus by high-throughput sequencing. In this study, we identified Aj14-3-3ζ as a novel target of miR-92a in this species and investigated their regulatory roles in vivo. The negative expression profiles between miR-92a and Aj14-3-3ζ protein were detected in both LPS-exposed primary coelomocytes and Vibrio splendidus-challenged sea cucumbers. Over-expression of miR-92a by injection of miR-92a agomir significantly depressed the mRNA and protein expression of Aj14-3-3ζ and promoted coelomocytes apoptosis with 5.04-fold increase in vivo, which was consistent with those from siRNA-mediated Aj14-3-3ζ knockdown assay. In contrast, miR-92a antagomir significantly elevated the mRNA and protein expression of Aj14-3-3ζ and decreased coelomocytes apoptosis. Taken together, our result confirmed that miR-92a is involved in apoptotic signaling pathway regulation perhaps via targeting Aj14-3-3ζ in sea cucumbers, which will enhance our understanding of miR-92a regulatory roles in sea cucumber pathogenesis.

A novel TNFAIP8 gene mediates l-arginine metabolism in Apostichopus japonicus.

Tumor necrosis factor (TNF)-α-induced protein 8 (TNFAIP8) family is a newly identified protein with vital roles in maintaining immune homeostasis. In the current study, we first cloned and characterized a TNFAIP8 gene from the invertebrate sea cucumber Apostichopus japonicus. The gene was designated as AjTNFAIP8. The full-length cDNA of AjTNFAIP8 was 1455 bp long and encoded a matured protein of 201 amino acid residues. Structural analysis indicated that AjTNFAIP8 had a death effector domain (DED)-like domain and composed of six α-helices. Multiple sequence alignment and phylogenetic analysis supported that AjTNFAIP8 is a new member of the TNFAIP8 family. Analysis of basal transcription in five tissues revealed the constitutive expression of AjTNFAIP8 in the detected tissues with highest expression in the respiratory tree and minimum expression in the tentacle. Vibrio splendidus infection and LPS stimulation could significantly downregulate the mRNA expression of AjTNFAIP8. More importantly, the transcription of pro-inflammatory molecule NOS and its production of NO content were significantly increased after AjTNFAIP8 silencing, with the suppression of agmatinase transcript and arginase activity. These results clearly indicated that AjTNFAIP8 is an essential negative regulator in innate immunity. Basic information for further exploration of the functional mechanisms of TNFAIP8 family in other marine invertebrate is provided.

Molecular cloning and functional characterization of cathepsin B from the sea cucumber Apostichopus japonicus.

Cathepsin B (CTSB), a member of lysosomal cysteine protease, is involved in multiple levels of physiological and biological processes, and also plays crucial roles in host immune defense against pathogen infection in vertebrates. However, the function of CTSB within the innate immune system of invertebrates, particularly in marine echinoderms, has been poorly documented. In this study, the immune function of CTSB in Apostichopus japonicus (designated as AjCTSB), a commercially important and disease vulnerable aquaculture specie, was investigated by integrated molecular and protein approaches. A 2153 bp cDNA representing the full-length of AjCTSB was cloned via overlapping ESTs and RACE fragments. AjCTSB contained an open reading frame of 999 bp encoding a secreted protein of 332 amino acid residues with a predicted molecular mass of 36.8 kDa. The deduced amino acid of AjCTSB shared a typical activity center containing three conserved amino acid residues (Cys108, His277 and Asn297). Phylogenetic tree analysis also supported that AjCTSB was a new member of CTSB family with clustering firstly with invertebrate CTSBs. Quantitative real time PCR analysis revealed that AjCTSB was ubiquitously expressed in all examined tissues with the highest levels in intestine. The Vibrio splendidus challenged sea cucumber and LPS-exposed coelomocytes could both significantly boost the expression of AjCTSB. Moreover, the purified recombinant AjCTSB exhibited dose-dependent CTSB activities at the concentration ranged from 0 to 0.24 µg µL-1. Further functional analysis indicated that coelomocytes apoptosis was significantly inhibited by 0.16-fold in vivo and the apoptosis execution Ajcaspase 3 was extremely reduced in Apostichopus japonicus coelomocytes treated with specific AjCTSB siRNA. Collectively, all these results suggested that AjCTSB was an important immune factor and might be served as apoptosis enhancers in pathogen challenged sea cucumber.

Down-regulation of Homer1b/c attenuates group I metabotropic glutamate receptors dependent Ca²âº signaling through regulating endoplasmic reticulum Ca²âº release in PC12 cells.

The molecular basis for group I metabotropic glutamate receptors (mGluR1 and 5) coupling to membrane ion channels and intracellular calcium pools is not fully understood. Homer is a family of post synaptic density proteins functionally and physically attached to target proteins at proline-rich sequences. In the present study, we demonstrate that Homer1b/c is constitutively expressed in PC12 cells, whereas Homer1a, the immediate early gene product, can be up-regulated by brain derived neurotrophic factor (BDNF) and glutamate. Knockdown of Homer1b/c using specific target small interfering RNA (siRNA) did not interfere the expression of mGluR1, mGluR5 and their downstream effectors, including inositol-1,4,5-trisphosphate receptors (IP3R), phospholipase C (PLC) and Gq proteins. By analyzing Ca(2+) imaging in PC12 cells, we demonstrated that Homer1b/c is an essential regulator of the Ca(2+) release from the endoplasmic reticulum (ER) induced by the activation of group I mGluRs, IP3R and ryanodine receptors (RyR). Furthermore, the group I mGluRs activation-dependent refilling of the Ca(2+) stores in both resting and depolarizing conditions were strongly attenuated in the absence of Homer1b/c. Together, our results demonstrate that in PC12 cells Homer1b/c is a regulator of group I mGluRs related Ca(2+) homeostasis that is essential for the maintenance of normal Ca(2+) levels in the ER.

Design, synthesis, and bioactivity investigation of novel cyclic lipopeptide antibiotics targeting top-priority multidrug-resistant gram-negative bacteria.

OBJECTIVES: Polymyxins are the last-line therapy for top-priority multidrug-resistant (MDR) gram-negative bacteria. However, polymyxin nephrotoxicity impedes its clinical application. This study aimed to design, synthesize, and identify a novel and promising polymyxin derivative with high efficacy and low toxicity. METHODS: To design polymyxin derivatives, we reduced the hydrophobicity of the two hydrophobic domains (fatty acyl chain and D-Phe6-L-Leu7) and modified the positive charged L-2,4-diaminobutyric acid (Dab) residues. Twenty-five derivatives were synthesized, and their antibacterial activities in vitro and renal cytotoxicities were determined. The nephrotoxicity and pharmacokinetic parameters of compound 12 were examined in rats. Antibacterial efficacy in vivo was evaluated using a mouse systemic infection model. Surface plasmon resonance analysis, compound 12-rifampicin combination therapy, and scanning electron microscopy were used to study the mechanism of action of compound 12. RESULTS: This research found a new compound, identified as compound 12, which showed similar or increased antibacterial activity against all tested sensitive and carbapenem-resistant gram-negative bacteria. It exhibited reduced renal cytotoxicity and nephrotoxicity, a favorable pharmacokinetic profile, and maintained or improved antibacterial efficacy in vivo. Importantly, its anti-Pseudomonas aeruginosa activity significantly improved. Compound 12, when combined with rifampicin, enhanced the activity of rifampin against gram-negative bacteria. Compound 12 also showed a high affinity for lipopolysaccharide and disrupted cell membrane integrity. CONCLUSION: Reducing the hydrophobicity of the two domains reduced renal cytotoxicity and nephrotoxicity. Shortening the side chain of Dab3 by one carbon maintained or increased its antibacterial activity both in vitro and in vivo. Furthermore, only the length of the side chain of Dab9 could be shortened by one carbon among the Dab1,5 and Dab8,9 residues. The bactericidal effects of compound 12 were related to the disruption of cell membrane integrity. Compound 12 may be a promising candidate for combating sensitive and carbapenem-resistant gram-negative bacterial infections, especially Pseudomonas aeruginosa.

Association between the levels of toxic heavy metals and schizophrenia in the population of Guangxi, China: A Case-Control Study.

The relationship between body levels of heavy metals and the risk of schizophrenia remains unclear. This study investigates the relationship between plasma levels of toxic heavy metals and the risk of schizophrenia among adults in Guangxi, China. Plasma concentrations of lead (Pb), cadmium (Cd), arsenic (As), and chromium (Cr) were measured using inductively coupled plasma mass spectrometry (ICP-MS). To evaluate both the single and combined effects of metal exposure on the risk of schizophrenia, we employed multivariate logistic regression, Bayesian Kernel Machine Regression (BKMR), and generalized Weighted Quantile Sum (gWQS) models. Additionally, we employed the Comparative Toxicogenomics Database (CTD) to analyze the mechanistic pathways through which metal mixtures may induce schizophrenia. Relative mRNA expression levels were measured using Real-Time Quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to predict potential biological functions. In logistic regression models, compared to the lowest exposure group (Q1), the odds ratios (ORs) for Pb in groups Q2, Q3, and Q4 were 2.18 (95% CI: 1.20 - 3.94), 4.74 (95% CI: 2.52 - 8.95), and 3.62 (95% CI: 1.80 - 7.28), respectively. Both BKMR and gWQS models indicated a positive correlation between the combined effects of toxic heavy metal mixtures and the risk of schizophrenia, with Pb demonstrating the most substantial impact, particularly in older adults and females. Elevated levels of tumor necrosis factor (TNF) and interleukin-1 beta (IL-1ß) were observed in patients with schizophrenia, while the expression of tumor protein p53 (TP53) was significantly reduced. These findings underscore the critical need to avoid exposure to toxic heavy metals to prevent schizophrenia, highlighting significant public health implications.

Multifunctional nanoparticles potentiate in-situ tumor vaccines via reversing insufficient Photothermal therapy by disrupting tumor vasculature.

Photothermal therapy can trigger immunogenic cell death and release personalized in-situ tumor vaccine, activating immune responses to eliminate systemic tumors beyond the irradiated zone. However, the immune response of the in-situ tumor vaccines is often undermined by the residual tumor cells and their induced immunosuppressive tumor microenvironment (TME), which is attributed to insufficient photothermal effects stemming from the limited accumulation of photosensitizers. To overcome these limitations, we developed multi-functional nanoparticles (VI@Gd-NPs) that integrate a tumor vasculature-specific disrupting agent (Vadimezan, Phase III clinical drug), a photosensitizer (Indocyanine Green, ICG), and a magnetic resonance imaging contrast agent (Gadolinium, Gd) through chemical self-assembly. By selectively disrupting the tumor vasculature, these nanoparticles enhance the intratumoral delivery of photosensitizers (ICG and blood cells), and Gd. With the guidance of Gd-enhanced MRI, the improved delivery facilitates comprehensive photothermal ablation and regulates the TME, further initiating the in-situ tumor vaccine. Notably, this approach significantly enhances anti-tumor immune responses, improves survival rates, and reduces tumor recurrence and metastasis in various animal models. Moreover, depleting CD8+ T cells reverses these therapeutic benefits, highlighting the critical role of adaptive T cell immunity. Therefore, the VI@Gd-NPs treatment holds great potential for reigniting the in-situ tumor vaccine of photothermal therapy.

Rho-associated protein kinase isoforms stimulate proliferation of vascular smooth muscle cells through ERK and induction of cyclin D1 and PCNA.

Abnormal proliferation and migration of vascular smooth muscle cells (VSMC) plays an important role in vascular diseases. The Rho-associated protein kinase (ROCK) signaling pathway is now well recognized for its role in VSMC migration and proliferation. Recently, a number of studies revealed that different isoforms of ROCK have distinct functions in VSMCs. We have reported that ROCK1, rather than ROCK2, induces platelet-derived growth factor (PDGF)-BB-stimulated migration of VSMCs. In the current study, we aimed to investigate the roles of ROCK1/2 in PDGF-induced rat aorta VSMC proliferation by manipulating ROCK gene expression. The results revealed that knock-down of both ROCK1 and ROCK2 by siRNA technology decreased PDGF-BB-generated VSMC proliferation by inhibiting the expression of proliferating cell nuclear antigen (PCNA) and cyclin D1. In addition, up-regulation of ROCK1 expression through transfection, further increased the proliferation of VSMCs induced by PDGF-BB. The ERK inhibitor U0126 reduced the proliferation and expression of PCNA and cyclinD1, and ROCK1 and ROCK2 siRNA decreased the level of ERK in the nucleus. These results demonstrated that ROCK1 and ROCK2 could promote VSMC proliferation through ERK nuclear translocation, regulating the expression of PCNA and cyclin D1 protein.

What alleviates depression among medical workers in emergency risk events? The function of subjective social status.

Medical workers often face serious family-work conflicts and are prone to depressive symptoms. The present study aimed at investigating associations between family-work conflict and depression in emergencies, and at exploring psychological processes involved in this association. A total of 1347 participants were recruited to complete questionnaires. Results showed that the positive effect of family-work conflict on depression was mediated by the basic psychological needs satisfaction, and subjective social status moderated this relationship as a buffer. For individuals with high levels of subjective social status, the direct and indirect effects of family-work conflict on depression were weaker. This study identified the mediating and moderating mechanisms of family-work conflict and depression. The implications of these findings in both theoretical and practical terms will be discussed.