Chimeric antigen receptors of HBV envelope proteins inhibit hepatitis B surface antigen secretion.

OBJECTIVES: Chronic hepatitis B (CHB) caused by HBV infection greatly increases the risk of liver cirrhosis and hepatocellular carcinoma. Hepatitis B surface antigen (HBsAg) plays critical roles in the pathogenesis of CHB. HBsAg loss is the key indicator for cure of CHB, but is rarely achieved by current approved anti-HBV drugs. Therefore, novel anti-HBV strategies are urgently needed to achieve sustained HBsAg loss. DESIGN: We developed multiple chimeric antigen receptors (CARs) based on single-chain variable fragments (scFvs, namely MA18/7-scFv and G12-scFv), respectively, targeting HBV large and small envelope proteins. Their impacts on HBsAg secretion and HBV infection, and the underlying mechanisms, were extensively investigated using various cell culture models and HBV mouse models. RESULTS: After secretory signal peptide mediated translocation into endoplasmic reticulum (ER) and secretory pathway, MA18/7-scFv and CARs blocked HBV infection and virion secretion. G12-scFv preferentially inhibited virion secretion, while both its CAR formats and crystallisable fragment (Fc)-attached versions blocked HBsAg secretion. G12-scFv and G12-CAR arrested HBV envelope proteins mainly in ER and potently inhibited HBV budding. Furthermore, G12-scFv-Fc and G12-CAR-Fc strongly suppressed serum HBsAg up to 130-fold in HBV mouse models. The inhibitory effect lasted for at least 8 weeks when delivered by an adeno-associated virus vector. CONCLUSION: CARs possess direct antiviral activity, besides the well-known application in T-cell therapy. Fc attached G12-scFv and G12-CARs could provide a novel approach for reducing circulating HBsAg.

Crosstalk between metabolism and cell death in tumorigenesis.

It is generally recognized that tumor cells proliferate more rapidly than normal cells. Due to such an abnormally rapid proliferation rate, cancer cells constantly encounter the limits of insufficient oxygen and nutrient supplies. To satisfy their growth needs and resist adverse environmental events, tumor cells modify the metabolic pathways to produce both extra energies and substances required for rapid growth. Realizing the metabolic characters special for tumor cells will be helpful for eliminating them during therapy. Cell death is a hot topic of long-term study and targeting cell death is one of the most effective ways to repress tumor growth. Many studies have successfully demonstrated that metabolism is inextricably linked to cell death of cancer cells. Here we summarize the recently identified metabolic characters that specifically impact on different types of cell deaths and discuss their roles in tumorigenesis.

Balanced Solution versus Normal Saline in Predicted Severe Acute Pancreatitis: A Stepped Wedge Cluster Randomized Trial.

OBJECTIVE: To compare the effect of balanced multielectrolyte solutions(BMES) versus normal saline(NS) for intravenous fluid on chloride levels and clinical outcomes.in patients with predicted severe acute pancreatitis (pSAP). SUMMARY BACKGROUND DATA: Isotonic crystalloids are recommended for initial fluid therapy in acute pancreatitis, but whether the use of BMES in preference to NS confers clinical benefits is unknown. METHODS: In this multicenter, stepped-wedge, cluster-randomized trial, we enrolled patients with pSAP (APACHE II score ≥8 and C-reactive protein >150 mg/L) admitted within 72 hours of the advent of symptoms. The study sites were randomly assigned to staggered start dates for one-way crossover from the NS phase (NS for intravenous fluid) to the BMES phase(Sterofudin for intravenous fluid). The primary endpoint was the serum chloride concentration on trial day3. Secondary endpoints included a composite of clinical and laboratory measures. RESULTS: Overall, 259 patients were enrolled from eleven sites to receive NS(n=147) or BMES(n=112). On trial day3, the mean chloride level was significantly lower in patients who received BMES(101.8 mmol/L(SD4.8) versus 105.8 mmol/L(SD5.9), difference -4.3 mmol/L [95%CI -5.6 to -3.0 mmol/L];P<0.001). For secondary endpoints, patients who received BMES had less systemic inflammatory response syndrome(19/112,17.0% versus 43/147,29.3%, P=0.024) and increased organ failure-free days (3.9 d(SD2.7) versus 3.5days(SD2.7), P<0.001) by trial day7. They also spent more time alive and out of ICU(26.4 d(SD5.2) versus 25.0days(SD6.4), P=0.009) and hospital(19.8 d(SD6.1) versus16.3days(SD7.2), P<0.001) by trial day30. CONCLUSIONS: Among patients with pSAP, using BMES in preference to NS resulted in a significantly more physiological serum chloride level, which was associated with multiple clinical benefits(Trial registration number: ChiCTR2100044432).

A Visible-Light-Driven Self-Powered Nodularin-R Biosensing Platform Controlled by an Integrated Portable Photoelectrochemical Detection Device.

The presence of nodularin-R (NOD-R) in water has gained considerable attention because of its widespread distribution and high toxicity. In this study, an accurate and rapid visible-light-driven self-powered photoelectrochemical (PEC) biosensor was developed by integrating a portable paper-based electrode with a custom-built miniaturized PEC detection device. The newly designed system successfully achieved on-site detection of NOD-R in real water samples based on PEC technology. First, target recognition triggers the initiation of the hybridization chain reaction to generate double-stranded DNA. The thus-formed double-stranded DNA entrapped methylene blue (MB), and the dye molecules were irradiated with visible light for conversion to leuco-MB in the presence of ascorbic acid. The resulting leuco-MB species significantly amplified the PEC signal output of TiO2-MXene, enabling NOD-R detection. Under optimal conditions, the proposed PEC assay strategy demonstrated NOD-R detection within a concentration range from 20 fg mL-1 to 10 ng mL-1 with a detection limit of 19.6 fg mL-1. In addition, a custom-built miniaturized PEC detection device conveniently integrates the detection component with the light source, enabling the real-time collection of results via a wireless module. This innovative self-powered PEC platform provides significant advancements in smooth and intelligent detection compared to traditional PEC detection devices.

Population pharmacokinetics of daptomycin in critically ill patients receiving extracorporeal membrane oxygenation.

BACKGROUND: Daptomycin is widely used in critically ill patients for Gram-positive bacterial infections. Extracorporeal membrane oxygenation (ECMO) is increasingly used in this population and can potentially alter the pharmacokinetic (PK) behaviour of antibiotics. However, the effect of ECMO has not been evaluated in daptomycin. Our study aims to explore the effect of ECMO on daptomycin in critically ill patients through population pharmacokinetic (PopPK) analysis and to determine optimal dosage regimens based on both efficacy and safety considerations. METHODS: A prospective, open-label PK study was carried out in critically ill patients with or without ECMO. The total concentration of daptomycin was determined by UPLC-MS/MS. NONMEM was used for PopPK analysis and Monte Carlo simulations. RESULTS: Two hundred and ninety-three plasma samples were collected from 36 critically ill patients, 24 of whom received ECMO support. A two-compartment model with first-order elimination can best describe the PK of daptomycin. Creatinine clearance (CLCR) significantly affects the clearance of daptomycin while ECMO has no significant effect on the PK parameters. Monte Carlo simulations showed that, when the MICs for bacteria are  ≥1 mg/L, the currently recommended dosage regimen is insufficient for critically ill patients with CLCR > 30 mL/min. Our simulations suggest 10 mg/kg for patients with CLCR between 30 and 90 mL/min, and 12 mg/kg for patients with CLCR higher than 90 mL/min. CONCLUSIONS: This is the first PopPK model of daptomycin in ECMO patients. Optimal dosage regimens considering efficacy, safety, and pathogens were provided for critical patients based on pharmacokinetic-pharmacodynamic analysis.

Withdrawal of immunosuppressants and low-dose steroids in patients with stable IgG4-RD (WInS IgG4-RD): an investigator-initiated, multicentre, open-label, randomised controlled trial.

OBJECTIVES: IgG4-related disease (IgG4-RD) is an immune-mediated, fibroinflammatory disease. Induction treatment with glucocorticoid (GC) is usually effective, but its tendency of relapse makes the strategy for maintenance treatment a challenge. The WInS IgG4-RD (withdraw immunosuppressants (IMs) and steroid in stable IgG4-RD) trial tested whether discontinuation of GC and IM was feasible in stable IgG4-RD. METHODS: The WInS IgG4-RD trial was a multicentre, open-label, randomised controlled trial. Patients with IgG4-RD receiving GC+IM as maintenance treatment with clinically quiescent disease for at least 12 months were randomised (1:1:1) into three groups: group 1: withdraw GC+IM; group 2: withdraw GC but maintain IM; group 3: maintain GC+IM. The primary outcome was the relapse rate of disease within 18 months. The secondary outcomes included the changes of IgG4-RD Responder Index (RI), Physician's Global Assessment (PGA), serum IgG4 and IgG, as well as adverse events. RESULTS: One hundred and forty-six patients were randomised, with 48 patients in group 1, 49 patients in group 2 and group 3, respectively. Within the 18-month follow-up period, disease relapse occurred in 25 out of 48 (52.1%) patients in group 1 vs 7 out of 49 (14.2%) in group 2 and 6 out of 49 (12.2%) in group 3 (p<0.001). The changes in RI and PGA were significantly higher in group 1 than in group 2 (p<0.001) or group 3 (p<0.001). CONCLUSIONS: The maintenance of IMs, with or without low-dose GC, was found to be superior to withdraw GC+IM in preventing relapse for long-time stable IgG4-RD. TRIAL REGISTRATION NUMBER: NCT04124861.

Two adjacent NAC transcription factors regulate fruit maturity date and flavor in peach.

Although maturity date (MD) is an essential factor affecting fresh fruit marketing and has a pleiotropic effect on fruit taste qualities, the underlying mechanisms remain largely unclear. In this study, we functionally characterized two adjacent NAM-ATAF1/2-CUC2 (NAC) transcription factors (TFs), PpNAC1 and PpNAC5, both of which were associated with fruit MD in peach. PpNAC1 and PpNAC5 were found capable of activating transcription of genes associated with cell elongation, cell wall degradation and ethylene biosynthesis, suggesting their regulatory roles in fruit enlargement and ripening. Furthermore, PpNAC1 and PpNAC5 had pleiotropic effects on fruit taste due to their ability to activate transcription of genes for sugar accumulation and organic acid degradation. Interestingly, both PpNAC1 and PpNAC5 orthologues were found in fruit-producing angiosperms and adjacently arranged in all 91 tested dicots but absent in fruitless gymnosperms, suggesting their important roles in fruit development. Our results provide insight into the regulatory roles of NAC TFs in MD and fruit taste.

RNA-binding proteins signature is a favorable biomarker of prognosis, immunotherapy and chemotherapy response for cervical cancer.

Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) still present a huge threaten to women's health, especially the local advanced patients. Hence, developing more effectiveness prognostic signatures is urgently needed. This study constructed and verified a robust RNA-binding proteins (RBPs) related signature through a series of bioinformatics methods and explored the biological function of hub RBP in vitro experiments. As a result, the 10 RBPs signature was successfully established and could act as an independent prognostic biomarker in CESC patients, which displayed the highest sensitivity and specificity in prognosis prediction compared with other clinicopathological parameters. The risk model also presented good performance in risk stratification among CESC patients. Besides, a nomogram was constructed based on pathological stage and the risk signature and exhibited satisfactory accuracy in prognosis prediction. Functional enrichment indicated that the risk signature mainly participated in immune-related pathways and cancer-related pathways, and the infiltration level of immune cells and immune checkpoints showed a significantly higher degree in low-risk patients compared with high-risk patients. Notably, the 10 RBPs signature act as a novel biomarker in immunotherapy and chemotherapy response. In addition, PRPF40B was selected as hub RBP and its transcription and translation levels were obviously increased in CESC tissues, as well as Hela and Siha cells. Knockdown of PRPF40B inhibits the proliferation, migration and invasion of Hela and Siha cells in vitro. In conclusion, our research provides a noticeable strategy in prognostic prediction among CESC patients, which may illuminate the prospect of CESC patients' clinical outcome.

Lewis Acid-Driven Multicomponent Reactions Enable 2-Alkyl Chromanones with Anticancer Activities.

2-Alkyl chromanone scaffold has become prominent in pharmaceuticals and natural compounds. Consequently, devising robust strategies for synthesizing 2-alkyl chromanones remains crucial. Here, multicomponent reactions were employed to synthesize 2-alkyl chromanones containing an oxazole moiety using 3-formylchromones, amines, and N-propargylamides as reactants. This method utilizes readily available feedstocks with a catalytic amount of Zn(OTf)2 and exhibits an impressive substrate scope compared to existing methods. Importantly, the synthesized compounds demonstrated highly selective anticancer activity against the DU145 cell line.

Ratiometric fluorescence method comprising carbon dots and rhodamine 6G encapsulated in metal-organic framework microcubes for curcumin detection.

A ratiometric fluorescence method comprising carbon dots (CDs) and rhodamine 6G (Rh-6G) encapsulated in the microcubes of metal-organic framework (MOF-5) is introduced for the sensitive detection of curcumin (Cur) in condiments. CDs@MOF-5@Rh-6G, synthesized by the adsorption of Rh-6G on MOF-5 embedded with CDs, showed two distinct emission peaks at 435 and 560 nm under excitation at 335 nm, and could be used for Cur detection by ratiometric fluorescence. In the presence of Cur, the fluorescence of the CDs at 435 nm (F435) was quenched by Cur owing to internal filtering and dynamic quenching effects, whereas the emission of Rh-6G at 560 nm (F560) remained unchanged (335 nm is the excitation wavelength, 435 and 560 nm are the emission wavelengths, in which F435/F560 values are used as the output results). Under optimal conditions, a linear relationship was observed between the Cur concentration (in the range 0.1-5 µmol/L) and F435/F560 value for CDs@MOF-5@Rh-6G, with a detection limit of 15 nmol/L. Notably, the proposed method could accurately detect Cur in mustard, curry, and red pepper powders. Therefore, this study could improve the quality control of food and facilitate the development of sensitive ratiometric fluorescence probes.

Semantic Segmentation of Remote Sensing Images Depicting Environmental Hazards in High-Speed Rail Network Based on Large-Model Pre-Classification.

With the rapid development of China's railways, ensuring the safety of the operating environment of high-speed railways faces daunting challenges. In response to safety hazards posed by light and heavy floating objects during the operation of trains, we propose a dual-branch semantic segmentation network with the fusion of large models (SAMUnet). The encoder part of this network uses a dual-branch structure, in which the backbone branch uses a residual network for feature extraction and the large-model branch leverages the results of feature extraction generated by the segment anything model (SAM). Moreover, a decoding attention module is fused with the results of prediction of the SAM in the decoder part to enhance the performance of the network. We conducted experiments on the Inria Aerial Image Labeling (IAIL), Massachusetts, and high-speed railway hazards datasets to verify the effectiveness and applicability of the proposed SAMUnet network in comparison with commonly used semantic segmentation networks. The results demonstrated its superiority in terms of both the accuracies of segmentation and feature extraction. It was able to precisely extract hazards in the environment of high-speed railways to significantly improve the accuracy of semantic segmentation.

Investigation of obesity and its related factors among Chinese medical staff: a cross-sectional pilot study.

BACKGROUND: Many studies have covered the prevalence of obesity in different populations. However, studies on the prevalence and predictors of obesity among medical staff are lacking. The aim of our study is to investigate the prevalence of obesity among medical staff and to identify the related predictors. METHODS: Using a snowballing recruitment strategy in the form of an electronic questionnaire, a cross-sectional survey was conducted among 1201 medical staff from cooperative hospitals between January and March 2022. We designed a questionnaire to investigate the participants' demographic, lifestyle, diet, physical activity, and work status. RESULTS: The overall prevalence of obesity was 8.5%, with males (13.7%) having a greater incidence than females (5.7%) (p < 0.001). Multiple logistic regression analyses showed that alcohol drinking (OR, 2.34; 95% CI 1.23-4.42, p = 0.01), sugar-sweetened beverages consumed > 3/week (OR, 2.50; 95% CI 1.02-6.15, p = 0.046), and working a night shift > 1/week (OR, 2.17; 95% CI 1.02-4.61, p = 0.043) were independent predictive factors for obesity in men. For women, having midnight snack having midnight snack (OR, 2.93;95% CI 1.24-6.96, p = 0.015), good sleep quality (OR, 4.47; 95% CI 1.10-21.70, p = 0.038), and working a night shift > 1/week (OR, 3.62; 95% CI 1.73-7.57, p = 0.001) were independently associated with obesity. CONCLUSIONS: Obesity presented a low prevalence among medical staff. Alcohol drinking, drinking sugar-sweetened beverages > 3/week, and night shift > 1/week predicted a higher risk of obesity in males. In females, having midnight snack, good sleep quality, and night shift > 1/week were independently associated with obesity. LEVEL OF EVIDENCE: V, descriptive study.

[Application value of anti-carbamylated protein antibody in the diagnosis of rheumatoid arthritis].

OBJECTIVE: To investigate the expression level and application value of anti-carbamylated protein (CarP) antibody in rheumatoid arthritis (RA). METHODS: Demographic data and laboratory test results of RA patients, non-RA patients and healthy controls in the physical examination center were reviewed from December 2018 to June 2019 in the Rheumatology and Immunology Department of the People' s Hospital of Xinjiang Uygur Autonomous Region. The serum concentrations of anti-CarP antibodies in all the subjects were measured by ELISA and statistically analyzed. RESULTS: A total of 259 subjects were included in this study, including 158 in the RA group (45 serum-negative RA patients), 59 in the non-RA group and 42 in the healthy control group. The concentration of anti-CarP antibody in RA group [8.31 (5.22, 15.26) U/mL] was higher than that in non-RA group [4.50 (3.35, 5.89) U/mL] and healthy control group [3.46 (2.76, 4.92) U/mL]. The concentration of anti-CarP antibody in non-RA group was not significantly different from that in healthy control group (P=0.10). Receiver operating characteristic (ROC) curve analysis showed that the sensitivity of anti-CarP antibody in the diagnosis of RA was 58.2%, and the specificity was 93.1%. The sensitivity of the combined detection of anti-CarP antibody, anti-cyclic peptide containing citrulline (CCP) antibody and rheumatoid factor (RF) was 82.3%, and the specificity was 96.5%. The positive rate of anti-CarP antibody in serum-negative RA patients was 44.4% (20/45). Univariate Logisitic regression analysis showed that age, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), RF, glucose-6-phosphate isomerase (GPI), anti-CCP antibody and anti-CarP antibody were risk factors for RA. Multivariate Logisitic regression analysis showed that anti-CCP antibody and anti-CarP antibody were independent risk factors for RA. Spearman correlation analysis showed that there was no significant correlation between anti-CarP antibody and swollen joint count (SJC), tenderness joints count (TJC), ESR, disease activity score for 28 joints (DAS28), clinical disease activity index (CDAI), simplified disease activity index (SDAI). The concentration of anti-CarP antibody in RA with bone erosion (n=88) was higher than that in RA without bone erosion (n=70), and there was significant difference between the two groups (P < 0.05). CONCLUSIONS: Anti-CarP antibody is an effective serological marker for the diagnosis of RA. The combined detection of RF, anti-CCP antibody and anti-CarP antibody can improve its diagnostic value, and anti-CarP antibody may be an effective assistant diagnostic tool for serum negative RA. The high serum concentration of anti-CarP antibody in patients with RA may indicate an increased risk of bone erosion and should be treated early, but further cohort studies are needed for follow-up observation.

A Study of the Relationship between Inflammatory Immune Function and Intestinal Flora in Adolescent Patients with First-Episode Depression.

BACKGROUND: Depression has become one of the most common mood disorders in adolescents, with an increasing incidence each year. Abnormal activation of peripheral immunity causes an increase in pro-inflammatory factors, which in turn affects neuroendocrine dysfunction and alters neurobiochemistry, leading to depression. In this study, we aimed to explore the relationship between inflammatory immune function and intestinal flora in adolescents with first-episode depression. METHODS: A total of 170 cases of adolescent patients with first-episode depression who attended our hospital from January 2020 to March 2023 were retrospectively selected as the observation group. Simultaneously, 170 individuals who underwent a healthy physical examination during the same period were chosen as the control group. The enzyme-linked immunosorbent assay (ELISA) was employed to quantify the levels of monoamine neurotransmitters 5-hydroxytryptamine (5-HT), substance P (SP), neuropeptide Y (NPY), serum tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, and IL-6 in the patients. Flow cytometry was utilized to assess the levels of T-lymphocytes CD3+, CD4+, and CD8+ cells. The levels of 16S ribosomal RNA (16SrRNA) method were used to determine the intestinal flora of the subjects in both groups. Inflammatory factor levels, immune function, and intestinal flora expression were observed, and correlation analysis was performed. RESULTS: The levels of 5-HT and NPY in the observation group were lower than those in the control group. The SP level was significantly higher in the observation group compared to the control group (p < 0.05). The observation group demonstrated significantly higher TNF-α, IL-1ß, and IL-6 levels than the control group (p < 0.05). The values of CD3+, CD4+, CD4+/CD8+ in the observation group were lower than those in the control group (p < 0.05), whereas the CD8+ values were notably higher (p < 0.05). Bifidobacterium, Escherichia coli, Lactobacillus, and Bacteroides in the observation group were less than those in the control group (p < 0.05). The content of Bifidobacterium was negatively correlated with the level of TNF-α (r = -0.358, p < 0.001), positively correlated with the level of CD3+, CD4+, CD4+/CD8+ (r = 0.490, 0.169, 0.165, p < 0.05), and negatively correlated with the level of CD8+ (r = -0.154, p < 0.05). The level of Escherichia coli content was negatively correlated with the levels of IL-6, CD3+, CD4+, CD4+/CD8+ (r = -0.483, -0.548, -0.317, -0.328, p < 0.001), and positively correlated with the levels of CD8+ (r = 0.325, p < 0.001). The content of Lactobacillus was positively correlated with the levels of CD3+, CD4+, CD4+/CD8+ (r = 0.552, 0.188, 0.194, p < 0.05), and negatively correlated with the level of CD8+ (r = -0.186, p < 0.05). The content of Bacteroides was positively correlated with the level of CD3+, CD4+, CD4+/CD8+ (r = -0.570, -0.183, -0.193, p < 0.05), and negatively correlated with the level of CD8+ levels were positively correlated (r = 0.187, p < 0.05). CONCLUSIONS: The intestinal flora is related to the level of inflammatory factors and immune function. Further study on the relationship between intestinal flora, inflammatory immune function, and depression could offer novel insights for the prevention and treatment of depressive disorders.

Mesenchymal stem cells reversibly de-differentiate myofibroblasts to fibroblast-like cells by inhibiting the TGF-ß-SMAD2/3 pathway.

BACKGROUND: Myofibroblasts (MFB), one of the major effectors of pathologic fibrosis, mainly derived from the activation of fibroblast to myofibroblast transition (FMT). Although MFBs were historically considered terminally differentiated cells, their potential for de-differentiation was recently recognized and implied with therapeutic value in treating fibrotic diseases, for instance, idiopathic pulmonary fibrosis (IPF) and post allogeneic hematopoietic stem cell transplantation bronchiolitis obliterans (BO). During the past decade, several methods were reported to block or reverse MFB differentiation, among which mesenchymal stem cells (MSC) have demonstrated potential but undetermined therapeutic values. However, the MSC-mediated regulation of FMT and underlying mechanisms remained largely undefined. METHOD: By identifying TGF-ß1 hypertension as the pivotal landmark during the pro-fibrotic FMT, TGF-ß1-induced MFB and MSC co-culture models were established and utilized to investigate regulations by MSC on FMT in vitro. Methods including RNA sequencing (RNA-seq), Western blot, qPCR and flow cytometry were used. RESULT: Our data revealed that TGF-ß1 readily induced invasive signatures identified in fibrotic tissues and initiated MFB differentiation in normal FB. MSC reversibly de-differentiated MFB into a group of FB-like cells by selectively inhibiting the TGF-ß-SMAD2/3 signaling. Importantly, these proliferation-boosted FB-like cells remained sensitive to TGF-ß1 and could be re-induced into MFB. CONCLUSION: Our findings highlighted the reversibility of MSC-mediated de-differentiation of MFB through TGF-ß-SMAD2/3 signaling, which may explain MSC's inconsistent clinical efficacies in treating BO and other fibrotic diseases. These de-differentiated FB-like cells are still sensitive to TGF-ß1 and may further deteriorate MFB phenotypes unless the pro-fibrotic microenvironment is corrected.

Insight into a Target-Induced Photocurrent-Polarity-Switching Photoelectrochemical Immunoassay for Ultrasensitive Detection of Escherichia coli O157:H7.

Sensitive, portable methods of detection for foodborne pathogens hold great significance for the early warning and prevention of foodborne diseases and environmental pollution. Restricted by a complicated matrix and limited signaling strategies, developing a ready-to-use sensing platform with ultrahigh sensitivity remains challenging. In this work, near-infrared (NIR) light-responsive AgBiS2 nanoflowers (NFs) and Cu2O nanocubes (NCs) were introduced to construct a novel target-induced photocurrent-polarity-switchable system and verified for the development of an all-in-one, ready-to-use photoelectrochemical (PEC) immunosensor. NIR-responsive n-type AgBiS2 NFs and p-type Cu2O NCs producing anodic and cathodic photocurrents were conjugated with monoclonal (MAb1) and polyclonal antibodies (PAb2), respectively. Using a sandwich-type immunocomplex bridged by Escherichia coli O157:H7, an efficient photocurrent-polarity-switching PEC system was formed on a paper-based working electrode (PWE). Owing to the spatial separation of the photogenerated carriers and the elimination of false-positive/negative signals by the polarity-switchable photocurrent, the proposed NIR PEC immunoassay for E. coli O157:H7 exhibits a considerably low detection limit of 8 colony-forming units/milliliter (CFU/mL) with a linear range from 25 to 5 × 107 CFU/mL. The platform includes a PWE with an automatic cleaning function and a portable PEC analyzer with smartphone-compatible Bluetooth capability, thus achieving point-of-care testing of E. coli O157:H7. The sensor was applied to the analysis of pork samples artificially contaminated with E. coli O157:H7, and the detection results were in good agreement with the plate counting method, a gold standard in the field. This work aimed to investigate the photoelectric activity of the NIR-responsive p/n-type composites and to provide a new signal-reversal route for the construction of an all-in-one ready-to-use PEC immunosensor for the detection of low-concentration biomolecules.

A Collection of RPA-Based Photoelectrochemical Assays for the Portable Detection of Multiple Pathogens.

Portable, ultrasensitive, and simultaneously quantitative detection of the nucleic acids of multiple foodborne pathogens is critical to public health. However, the current testing methods depend on costly equipment and tedious amplification steps. In this study, we propose a photoelectrochemical (PEC) biosensor combined with recombinase polymerase amplification (RPA) technology (RPA-PEC) for the rapid detection of multiple foodborne pathogens under irradiation of 980 nm light. In particular, two working surfaces were designed on homemade three-dimensional screen-printed paper-based electrodes. The genomic DNAs of Escherichia coli O157:H7 and Staphylococcus aureus was initiated by RPA on the corresponding electrode surfaces, thus forming a lab-on-paper platform. Using the formed DNA-PEC signaler, photocurrents were achieved at 37 °C after only 20 min of RPA. The detection performance was superior to that of conventional agarose gel electrophoresis, with detection limits of 3.0 and 7.0 copies/µL for E. coli O157:H7 and S. aureus, respectively. Our study pioneers a new RPA-PEC method for foodborne pathogens and provides directions for the construction of lab-on-paper platforms for the portable detection of multiple nucleic acids.

Rutin hydrate relieves neuroinflammation in zebrafish models: Involvement of NF-κB pathway as a central network.

Neuroinflammation is prevalent in multiple brain diseases and may also lead to dementia, cognitive impairment, and impaired spatial memory function associated with neurodegenerative diseases. A neuroprotective and antioxidant flavonoid, rutin hydrate (RH), was evaluated for the anti-neuroinflammatory activity mediated by copper sulfate (CuSO4) solution and lipopolysaccharide (LPS) in zebrafish. The results showed that 100 mg/L RH significantly reduced the ratio of neutrophil mobility in caudal hematopoietic tissue (CHT) region caused by CuSO4 and the number of neutrophils co-localized with facial peripheral nerves. In the LPS model, RH co-injection significantly diminished neutrophil and macrophage migration. Therefore, RH exhibited a significant rescue effect on both models. In addition, RH treatment remarkably reduced the effects of neuroinflammation on the locomotor ability, expression levels of genes associated with behavioral disorders, and acetylcholinesterase (AChE) activity. Furthermore, network pharmacology techniques were employed to investigate the potential mechanisms, and the associated genes and enzyme activities were validated in order to elucidate the underlying mechanisms. Network pharmacological analysis and zebrafish model indicated that RH regulated the expressions of NF-κB pathway-related targets (Toll-like receptor 9 (tlr9), nuclear factor kappa B subunit 1 (nfkb1), RELA proto-oncogene (RelA), nitric oxide synthase 2a, inducible (nos2a), tumour necrosis factor alpha-like (tnfα), interleukin 6 (il6), interleukin 1ß (il1ß), chemokine 8 (cxcl8), and macrophage migration inhibitory factor (mif)) as well as six key factors (arachidonic acid 4 alpha-lipoxygenase (alox4a), arachidonate 5-lipoxygenase a (alox5), prion protein a (prnpa), integrin, beta 2 (itgb2), catalase (CAT), and alkaline phosphatase (ALP) enzymes). Through this study, a thorough understanding of the mechanism underlying the therapeutic effects of RH in neuroinflammation has been achieved, thereby establishing a solid foundation for further research on the potential therapeutic applications of RH in neuroinflammatory disorders.

Propofol Regulates HIF-1 α Effect of Expression of Targeted SIRT1 Signal pathway on Kidney Renal Clear Cell Carcinoma.

The objective of this study was to investigate the effect of propofol on kidney renal clear cell carcinoma (KIRC) by regulating hypoxia-inducible factor-1α (HIF-1α) expression and silencing signal regulatory factor 1 (SIRT1) signal pathway. In this regard, human KIRC cell line RCC4 was added into 0, 5 and 10 µ G/ml propofol treatment and was divided into a control group (CG), low dose group (LG) and high dose group (HG). CCK8 was used to detect the proliferative ability of the three groups of cells, ELISA was used to detect the level of inflammatory factors in the cells, Western blot was used to detect the protein expression, qPCR was used to detect the related mRNA expression level, and Transwell method was used to detect the invasive ability of the cells in vitro. The experimental results showed that propofol decreased the proliferation and invasion ability of KIRC cells, up-regulated the expression of TGF- ß 1, IL-6, TNF- α, HIF-1 α, Fas, bax and FasL, and down-regulated the expression of SIRT1 in a dose-dependent manner. It was concluded that propofol can inhibit the SIRT1 signal pathway by up-regulating the level of HIF-1α in KIRC, which can significantly decrease the proliferation and invasion ability of KIRC cells, induce apoptosis and increase the release of intracellular inflammatory factors.

Structure-directed linker optimization of novel HEPTs as non-nucleoside inhibitors of HIV-1 reverse transcriptase.

1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymines (HEPTs) have been previously described as an important class of HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). In our continuously pursuing HEPT optimization efforts, a series of novel HEPTs, featuring -C(OH)CH2R, -CC, or -CHCH2R linker at the benzylic α-methylene unit, were developed as NNRTIs. Among these new HEPTs, the compound C20 with -CHCH3 group at the benzylic α-methylene unit conferred the highest potency toward WT HIV-1 and selectivity (EC50 = 0.23 µM, SI = 150.20), which was better than the lead compound HEPT (EC50 = 7 µM, SI = 106). Also, C20 was endowed with high efficacy against clinically relevant mutant strains (EC50(L100I) = 1.07 µM; EC50(K103N) = 4.33 µM; EC50(Y181C) = 5.57 µM; EC50(E138K) = 1.06 µM; EC50(F227L+V106A) = 5.45 µM) and wild-type HIV-1 reverse transcriptase (RT) with an IC50 value of 0.55 µM. Molecular docking and molecular dynamics simulations, as well as preliminary structure-activity relationship (SAR) analysis of these new compounds, provided a deeper insight into the key structural features of the interactions between HEPT analogs and HIV-1 RT and laid the foundation for further modification on HEPT scaffold.