From hate to harmony: Leveraging large language models for safer speech in times of COVID-19 crisis.

This study investigates the rampant spread of offensive and derogatory language during the COVID-19 pandemic and aims to mitigate it through machine learning. Employing advanced Large Language Models (LLMs), the research develops a sophisticated framework adept at detecting and transforming abusive and hateful speech. The project begins by meticulously compiling a dataset, focusing specifically on Chinese language abuse and hate speech. It incorporates an extensive list of 30 pandemic-related terms, significantly enriching the resources available for this type of research. A two-tier detection model is then introduced, achieving a remarkable accuracy of 94.42 % in its first phase and an impressive 81.48 % in the second. Furthermore, the study enhances paraphrasing efficiency by integrating generative AI techniques, primarily Large Language Models, with a Latent Dirichlet Allocation (LDA) topic model. This combination allows for a thorough analysis of language before and after modification. The results highlight the transformative power of these methods. They show that the rephrased statements not only reduce the initial hostility but also preserve the essential themes and meanings. This breakthrough offers users effective rephrasing suggestions to prevent the spread of hate speech, contributing to more positive and constructive public discourse.

Enhanced antimicrobial activity against oral bacteria Actinomyces viscous by cinnamaldehyde emulsion microencapsulated with cyclodextrin glycosyltransferase-catalyzed products.

Actinomyces viscous (A. viscous) is well documented as a major cariogenic bacterium in the oral cavity and needs to be inhibited and removed timely. Essential oils (EOs) are recognized as secure antibacterial agents for treating oral diseases, but their volatility and insolubility limit their application. In this study, cinnamaldehyde was screened as the optimum EO for inhibiting the A. viscous growth by a micro-agar dilution method and microencapsulated by cyclodextrin glycosyltransferase (CGTase)-catalyzed products. The antibacterial effects against A. viscous were investigated and compared with the free cinnamaldehyde. Antibacterial diameter, antibacterial efficiency and stability, and time-kill curve results revealed that the cinnamaldehyde emulsion had better antibacterial properties. 1 MIC of the cinnamaldehyde emulsion had an inhibitory zone of 9.92 nm, a 100 % inhibition rate when acting for 2 min or 5 min, and still maintained the same inhibitory effect for 2 years. The extracellular environment showed more pH decrease, conductivity increase, and protein leakage, suggesting damage to the cell membrane. Microstructure and flow cytometric analysis further revealed that the CGTase-catalyzed products induced more changes in the A. viscous membrane integrity. Based on the results, CGTase-catalyzed products can be used as a potential substance for encapsulating EOs for treating oral bacteria.

The Metabolomic Profiling of the Flavonoid Compounds in Red Wine Grapes and the Impact of Training Systems in the Southern Subtropical Region of China.

Flavonoids play an important role in forming wine grapes and wine quality characteristics. The flavonoids of three winter red wine grapes, Yeniang No. 2 (YN2), Marselan (Mar), and Guipu No. 6 (GP6), were analyzed by ultra-high-performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-QQQ-MS). Furthermore, the flavonoids in GP6 grapevines using two types of training systems, namely, trellis (T) and espaliers (E), were also compared in this study. Overall, 196 flavonoid metabolites, including 96 flavones, 38 flavonols, 19 flavanones, 18 polyphenols, 15 anthocyanins, 7 isoflavones, and 3 proanthocyanidins, were identified. The flavonoid profiles were remarkably different among these three grape varieties, while they did not change much in the GP6 managed on trellis and espaliers. Grape varieties with different genetic backgrounds have their own unique flavonoid profiles. Compared with Mar-T, isoflavones and flavonols presented higher contents in GP6-T and YN2-T, which mainly contain glycitein, genistin, calycosin, kaempferide, isotrifoliin, and ayanin. The anthocyanin content was significantly higher in YN2-T than in the other two varieties. YN2 and GP6-T present a more stable color, with significantly more acetylated diglucosides and methylated anthocyanins in YN2-T and GP6-T than in Mar-T. Notably, GP6 had more varied flavonoids and the better characteristics to its flavonoid profile out of these three varieties, due to it containing a higher number of anthocyanins, flavone, and flavonols and the greatest number of different flavonoid metabolites (DFMs), with higher contents than YN2 and Mar. Compared with the trellis training system, the espaliers training system increased the content of flavonoids detected in GP6 grape berries; however, the composition of flavonoids strictly depends on the grape variety.

PTEN regulated by gga-miR-20a-5p is involved in chicken macrophages inflammatory response to APEC infection via autophagy.

Colibacillosis, a bacterial disease caused by avian pathogenic E. coli (APEC), is a prevalent condition in the poultry industry, resulting in substantial economic losses annually. Previously, we identified PTEN as a crucial candidate gene that may play a significant role in chicken's immune response to APEC infection. Bioinformatics analysis indicated that the PTEN protein was unstable, hydrophilic and nuclear localization, with multiple putative phosphorylation sites and a high degree of similarity to duck and goose PTEN. Moreover, PTEN exhibited high expression levels in various tissues such as the stomach, cecum, small intestine, spleen, thymus, harderian gland, muscle, cerebrum, cerebellum, lung, and liver in comparison to heart tissue. Overexpression of PTEN resulted in a significant promotion of the expression level of pro-apoptosis genes and inflammatory mediators, as well as the production of NO, with or without APEC infection, which led to cellular injury. Furthermore, overexpression of PTEN was found to regulate the expression levels of autophagy related genes, regardless of APEC infection. Additionally, PTEN was a target gene of gga-miR-20a-5p and regulated by gga-miR-20a-5p upon APEC infection. Taken together, these findings establish a foundation for investigating the biological function of chicken PTEN, providing a potential target for future treatments against APEC infection as well as the breeding of genetically resistant poultry.

Identification and Validation of Aging Related Genes Signature in Chronic Obstructive Pulmonary Disease.

PURPOSE: Chronic Obstructive Pulmonary Disease (COPD) is regarded as an accelerated aging disease. Aging-related genes in COPD are still poorly understood. METHOD: Data set GSE76925 was obtained from the Gene Expression Omnibus (GEO) database. The "limma" package identified the differentially expressed genes. The weighted gene co-expression network analysis (WGCNA) constructes co-expression modules and detect COPD-related modules. The least absolute shrinkage and selection operator (LASSO) and the support vector machine recursive feature elimination (SVM-RFE) algorithms were chosen to identify the hub genes and the diagnostic ability. Three external datasets were used to identify differences in the expression of hub genes. Real-time reverse transcription polymerase chain reaction (RT-qPCR) was used to verify the expression of hub genes. RESULT: We identified 15 differentially expressed genes associated with aging (ARDEGs). The SVM-RFE and LASSO algorithms pinpointed four potential diagnostic biomarkers. Analysis of external datasets confirmed significant differences in PIK3R1 expression. RT-qPCR results indicated decreased expression of hub genes. The ROC curve demonstrated that PIK3R1 exhibited strong diagnostic capability for COPD. CONCLUSION: We identified 15 differentially expressed genes associated with aging. Among them, PIK3R1 showed differences in external data sets and RT-qPCR results. Therefore, PIK3R1 may play an essential role in regulating aging involved in COPD.

MICB*002:06, a novel exonic variant of MICB (MHC class I chain-related gene B).

MICB*002:06 differs from MICB*002:01:01 by one nucleotide change at nucleotide 33 in exon 1 from C to T.

Arctiin Mitigates Neuronal Injury by Modulating the P2X7R/NLPR3 Inflammasome Signaling Pathway.

Depression, recognized globally as a primary cause of disability, has its pathogenesis closely related to neuroinflammation and neuronal damage. Arctiin (ARC), the major bioactive component of Fructus arctii, has various pharmacological activities, such as anti-inflammatory and neuroprotective effects. Building on previous findings that highlighted ARC's capability to mitigate depression by dampening microglial hyperactivation and thereby reducing neuroinflammatory responses and cortical neuronal damage in mice, the current study delves deeper into ARC's therapeutic potential by examining its impact on hippocampal neuronal damage in depression. Utilizing both chronic unpredictable mild stress (CUMS)-induced depression model in mice and corticosterone (CORT)-stimulated PC12 cell model of neuronal damage, the techniques including Nissl staining, immunohistochemistry, western blotting, ELISA, lactate dehydrogenase assays, colony formation assays, immunofluorescence staining and molecular docking were employed to unravel the mechanisms behind ARC's neuroprotective effects. The findings revealed that ARC not only mitigates hippocampal neuropathological damage and reduces serum CORT levels in CUMS-exposed mice but also enhances cell activity while reducing lactate dehydrogenase release in CORT-stimulated PC12 cells. ARC attenuated neuroinflammatory responses and neuronal apoptosis by inhibiting the overactivation of the P2X7 receptor (P2X7R)/NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome signaling pathway, similar to the effect of A438079 (P2X7R antagonist). Interestingly, pretreatment with A438079 blocked the neuroprotective effect of ARC. Computer modeling predicted that both ARC and A438079 have strong binding with P2X7R and they have the same binding site. These results suggested that ARC may exert a neuroprotective role by binding to P2X7R, thereby inhibiting the P2X7R/NLRP3 inflammasome signaling pathway.

An increment of diversity method for cell state trajectory inference of time-series scRNA-seq data.

The increasing emergence of the time-series single-cell RNA sequencing (scRNA-seq) data, inferring developmental trajectory by connecting transcriptome similar cell states (i.e., cell types or clusters) has become a major challenge. Most existing computational methods are designed for individual cells and do not take into account the available time series information. We present IDTI based on the Increment of Diversity for Trajectory Inference, which combines time series information and the minimum increment of diversity method to infer cell state trajectory of time-series scRNA-seq data. We apply IDTI to simulated and three real diverse tissue development datasets, and compare it with six other commonly used trajectory inference methods in terms of topology similarity and branching accuracy. The results have shown that the IDTI method accurately constructs the cell state trajectory without the requirement of starting cells. In the performance test, we further demonstrate that IDTI has the advantages of high accuracy and strong robustness.

Research progress in stroke risk perception assessment tool.

BACKGROUND: One of the main illnesses in the globe that causes impairment and death in people is stroke. In the globe today, it ranks as the second leading cause of death and the leading cause of death in China. OBJECTIVE: This paper analyses into the critical role of risk perception in developing individual awareness of stroke risk and encouraging proactive preventive health behaviors, essential for effective primary stroke prevention strategies and reduced stroke incidence. It discusses the concept of risk perception, the content and dimensions of global stroke assessment tools, and their application status, aiming to provide insights for their development and intervention research. METHODS: Risk perception encompasses subjective assessments of stroke likelihood and severity, influenced by personal experiences, knowledge of risk factors, beliefs about prevention effectiveness, and emotional responses. Global stroke assessment tools, like the Framingham Stroke Risk Score and CHA2DS2-VASc Score, evaluate stroke risk based on factors such as age, gender, blood pressure, and cholesterol levels. In order to improve risk perception and proactive health management and lower the burden of strokes, the paper assesses the advantages and disadvantages of these tools and makes recommendations for improving accessibility, customizing interventions, running educational campaigns, promoting multidisciplinary collaboration, and integrating technology. RESULTS: By combining the research tools of stroke risk perception, it is found that the evaluation tools are mostly single-dimensional evaluation tools centered on the two dimensions of onset possibility and susceptibility. CONCLUSION: Some scholars have developed multi-dimensional evaluation tools, but the evaluation population is relatively limited, and the evaluation system lacks comprehensiveness and systematization.

An acidic polysaccharide promoting GLP-1 secretion from Dendrobium huoshanense protocorm-like bodies: Structure validation and activity exploration.

Glucagon-like peptide-1 (GLP-1) as a multifunctional hormone is secreted mainly from enteroendocrine L-cells, and enhancing its endogenous secretion has potential benefits of regulating glucose homeostasis and controlling body weight gain. In the present study, a novel polysaccharide (h-DHP) with high ability to enhance plasma GLP-1 level in mice was isolated from Dendrobium huoshanense protocorm-like bodies under the guidance of activity evaluation. Structural identification showed that h-DHP was an acidic polysaccharide with the molecular weight of 1.38 × 105 Da, and was composed of galactose, glucose, arabinose and glucuronic acid at a molar ratio of 15.7: 11.2: 4.5: 1.0 with a backbone consisting of →5)-α-L-Araf-(1→, →3)-α-D-Galp-(1→, →6)-α-D-Galp-(1→, →3,6)-α-D-Galp-(1→, →6)-ß-D-Glcp-(1→ and →4,6)-ß-D-Glcp-(1→ along with branches consisting of α-L-Araf-(1→, α-D-Galp-(1→, α-D-GlcAp-(1→, ß-D-Glcp-(1→ and →4)-ß-D-Glcp-(1→. Animal experiments with different administration routes demonstrated that h-DHP-enhanced plasma GLP-1 level was attributed to h-DHP-promoted GLP-1 secretion in the enteroendocrine L-cells, which was supported by h-DHP-enhanced extracellular GLP-1 level in STC-1 cells. Inhibition of adenylate cyclase and phospholipase C indicated that cAMP and cAMP-triggered intracellular Ca2+ increase participated in h-DHP-promoted GLP-1 secretion. These results suggested that h-DHP has the potential of enhancing endogenous GLP-1 level through h-DHP-promoted and cAMP-mediated GLP-1 secretion from enteroendocrine cells.

USP11 promotes renal tubular cell pyroptosis and fibrosis in UUO mice via inhibiting KLF4 ubiquitin degradation.

The pyroptosis of renal tubular epithelial cells leads to tubular loss and inflammation and then promotes renal fibrosis. The transcription factor Krüppel-like factor 4 (KLF4) can bidirectionally regulate the transcription of target genes. Our previous study revealed that sustained elevation of KLF4 is responsible for the transition of acute kidney injury (AKI) into chronic kidney disease (CKD) and renal fibrosis. In this study, we explored the upstream mechanisms of renal tubular epithelial cell pyroptosis from the perspective of posttranslational regulation and focused on the transcription factor KLF4. Mice were subjected to unilateral ureteral obstruction (UUO) surgery and euthanized on D7 or D14 for renal tissue harvesting. We showed that the pyroptosis of renal tubular epithelial cells mediated by both the Caspase-1/GSDMD and Caspase-3/GSDME pathways was time-dependently increased in UUO mouse kidneys. Furthermore, we found that the expression of the transcription factor KLF4 was also upregulated in a time-dependent manner in UUO mouse kidneys. Tubular epithelial cell-specific Klf4 knockout alleviated UUO-induced pyroptosis and renal fibrosis. In Ang II-treated mouse renal proximal tubular epithelial cells (MTECs), we demonstrated that KLF4 bound to the promoter regions of Caspase-3 and Caspase-1 and directly increased their transcription. In addition, we found that ubiquitin-specific protease 11 (USP11) was increased in UUO mouse kidneys. USP11 deubiquitinated KLF4. Knockout of Usp11 or pretreatment with the USP11 inhibitor mitoxantrone (3 mg/kg, i.p., twice a week for two weeks before UUO surgery) significantly alleviated the increases in KLF4 expression, pyroptosis and renal fibrosis. These results demonstrated that the increased expression of USP11 in renal tubular cells prevents the ubiquitin degradation of KLF4 and that elevated KLF4 promotes inflammation and renal fibrosis by initiating tubular cell pyroptosis.

[Auricular pressure beans combined with Compound Tung-Leaf Burn Oil relieve perioperative anxiety and pain in patients undergoing circumcision].

OBJECTIVE: To observe the effect of auricular pressure beans (APN) combined with Compound Tung-Leaf Burn Oil (CTBO) on perioperative anxiety and pain in patients undergoing circumcision. METHODS: This study included 100 patients undergoing circumcision with the disposable circumcision anastomosis stapler in our hospital from August 2023 to November 2023, of whom 50 received routine circumcision nursing care (the control group) and other 50 APN combined with compound CTBO in addition (the observation group). We compared between the two groups the anxiety scores before any intervention, 30 minutes before and 24 hours and 10 days after operation, the pain scores 24 hours postoperatively and at the first change of wound dressing, the frequency of 3-day postoperative sleep awakenings, the incidence of complications, and the satisfaction of the patients. RESULTS: Totally, 94 patients completed the study, 46 in the observation and 48 in the control group. The anxiety scores exhibited no statistically significant difference between the two groups of patients before any intervention (P > 0.05), but were markedly lower in the observation than in the control group at 30 minutes before and 24 hours and 10 days after surgery (P<0.05), and so were the pain scores 24 hours after surgery and at the first change of wound dressing (P<0.05), and the frequency of 3-day postoperative sleep awakenings (P<0.05). The satisfaction rate of the patients was remarkably higher (P<0.05) while the incidence of complications significantly lower in the observation group than in the control (P<0.05). CONCLUSION: Auricular pressure beans combined with Compound Tung-Leaf Burn Oil can effectively alleviate perioperative anxiety, reduce postoperative pain and improve satisfaction of the patients undergoing circumcision.

Design, synthesis, and in vivo and in vitro biological screening of pseudolaric acid B derivatives as potential anti-tumor agents.

Pseudolaric Acid B (PAB), a natural product with remarkable anti-tumor activity, is a starting point for new anticancer therapeutics. We designed and synthesized 27 PAB derivatives and evaluated their anti-proliferative activities against four cancer cell lines: MCF-7, HCT-116, HepG2, and A549. Compared with unmodified PAB, the PAB derivatives showed stronger anti-proliferative activity. The ability of compound D3 (IC50 = 0.21 µM) to inhibit HCT-116 cells was approximately 5.3 times that of PAB (IC50 = 1.11 µM) and the antiproliferative action was unrelated to cytotoxicity (SI=20.38), indicating its superior safety profile (PAB; SI=0.95). Compound D3 effectively suppressed the EdU-positive rate and reduced colony formation, arrested HCT-116 cells in the S and G2/M phases and induced apoptosis. In vivo experiments further demonstrated low toxicity of compound D3 while suppressing tumor growth in mice. In summary, given its strong anti-proliferative effect and relative safety, further development of compound D3 is warranted.

Beta-blocker drives the conjugative transfer of multidrug resistance genes in pure and complex biological systems.

Drug resistance poses a high risk to human health. Extensive use of non-antibiotic drugs contributes to antibiotic resistance genes (ARGs) transfer. However, how they affect the spread of broad-host plasmids in complex biological systems remains unknown. This study investigated the effect of metoprolol on the transfer frequency and host range of ARGs in both intrageneric and intergeneric pure culture systems, as well as in anammox microbiome. The results showed that environmental concentrations of metoprolol significantly promoted the intrageneric and intergeneric conjugative transfer. Initially, metoprolol induced excessive oxidative stress, resulting in high cell membrane permeability and bacterial SOS response. Meanwhile, more pili formation increased the adhesion and contact between bacteria, and the abundance of conjugation-related genes also increased significantly. Activation of the electron transport chain provided more ATP for this energy-consuming process. The underlying mechanism was further verified in the complex anammox conjugative system. Metoprolol induced the enrichment of ARGs and mobile genetic elements. The enhanced bacterial interaction and energy generation facilitated the high conjugative transfer frequency of ARGs. In addition, plasmid-borne ARGs tended to transfer to opportunistic pathogens. This work raises public concerns about the health and ecological risks of non-antibiotic drugs.

Qiliqiangxin Alleviates Imbalance of Inflammatory Cytokines in Patients with Dilated Cardiomyopathy: A Randomized Controlled Trial.

OBJECTIVE: Qiliqiangxin (QLQX) capsule- a traditional Chinese medicine used for treating heart failure (HF), can modulate inflammatory cytokines in rats with myocardial infarction. However, its immune-regulating effect on dilated cardiomyopathy (DCM) remains unknown. The aim of this study was to investigate whether QLQX has a unique regulatory role in the imbalance of pro- and anti-inflammatory cytokines in patients with DCM. METHODS: The QLQX-DCM is a randomized- double-blind trial conducted at 24 tertiary hospitals in China. A total of 345 patients with newly diagnosed virus-induced DCM were randomly assigned to receive QLQX capsules or placebo while receiving optimal medical therapy for HF. The primary endpoints were changes in plasma inflammatory cytokines and improvements in left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter (LVEDd) over the 12-month treatment. RESULTS: At the 12-month follow-up, the levels of IFN-γ, IL-17, TNF-α, and IL-4 decreased significantly, while the level of IL-10 increased in both groups compared with baselines (all P<0.0001). Furthermore-these changes, coupled with improvements in LVEF, NT-proBNP and New York Heart Association (NYHA) functional classification, excluding the LVEDd in the QLQX group, were greater than those in the placebo group (all P<0.001). Additionally, compared with placebo, QLQX treatment also reduced all-cause mortality and rehospitalization rates by 2.17% and 2.28%, respectively, but the difference was not statistically significant. CONCLUSION: QLQX has the potential to alleviate the imbalance of inflammatory cytokines in patients with DCM, potentially leading to further improvements in cardiac function when combined with anti-HF standard medications.

Microbial communities and functions are structured by vertical geochemical zones in a northern peatland.

Northern peatlands are important carbon pools; however, differences in the structure and function of microbiomes inhabiting contrasting geochemical zones within these peatlands have rarely been emphasized. Using 16S rRNA gene sequencing, metagenomic profiling, and detailed geochemical analyses, we investigated the taxonomic composition and genetic potential across various geochemical zones of a typical northern peatland profile in the Changbai Mountains region (Northeastern China). Specifically, we focused on elucidating the turnover of organic carbon, sulfur (S), nitrogen (N), and methane (CH4). Three geochemical zones were identified and characterized according to porewater and solid-phase analyses: the redox interface (<10 cm), shallow peat (10-100 cm), and deep peat (>100 cm). The redox interface and upper shallow peat demonstrated a high availability of labile carbon, which decreased toward deeper peat. In deep peat, anaerobic respiration and methanogenesis were likely constrained by thermodynamics, rather than solely driven by available carbon, as the acetate concentrations reached 90 µmol·L-1. Both the microbial community composition and metabolic potentials were significantly different (p < 0.05) among the redox interface, shallow peat, and deep peat. The redox interface demonstrated a close interaction between N, S, and CH4 cycling, mainly driven by Thermodesulfovibrionia, Bradyrhizobium, and Syntrophorhabdia metagenome-assembled genomes (MAGs). The archaeal Bathyarchaeia were indicated to play a significant role in the organic carbon, N, and S cycling in shallow peat. Although constrained by anaerobic respiration and methanogenesis, deep peat exhibited a higher metabolic potential for organic carbon degradation, primarily mediated by Acidobacteriota. In terms of CH4 turnover, subsurface peat (10-20 cm) was a CH4 production hotspot, with a net turnover rate of ∼2.9 nmol·cm-3·d-1, while the acetoclastic, hydrogenotrophic, and methylotrophic methanogenic pathways all potentially contributed to CH4 production. The results of this study improve our understanding of biogeochemical cycles and CH4 turnover along peatland profiles.

Cobalt exposure and pulmonary function reduction in chronic obstructive pulmonary disease patients: the mediating role of club cell secretory protein.

BACKGROUND: Cobalt (Co) is a metal which is widely used in the industrial production. The previous studies found the toxic effects of environmental Co exposure on multiple organs. However, the correlation of blood Co concentration with lung function was inconsistent in patients with chronic obstructive pulmonary disease (COPD). METHODS: All 771 stable COPD patients were recruited. Peripheral blood and clinical information were collected. The levels of blood Co and serum CC16 were measured. RESULTS: Cross-sectional study suggested that the level of blood Co was inversely and dose-dependently related to lung function parameters. Each 1 ppm elevation of blood Co was related to 0.598 L decline in FVC, 0.465 L decline in FEV1, 6.540% decline in FEV1/FVC%, and 14.013% decline in FEV1%, respectively. Moreover, higher age, enrolled in winter, current-smoking, higher smoking amount, and inhaled corticosteroids prominently exacerbated the negative correlation between blood Co and lung function. Besides, serum CC16 content was gradually reduced with blood Co elevation in COPD patients. Besides, serum CC16 was positively correlated with lung function, and inversely related to blood Co. Additionally, decreased CC16 substantially mediated 11.45% and 6.37% Co-triggered downregulations in FEV1 and FEV1%, respectively. CONCLUSION: Blood Co elevation is closely related to the reductions of pulmonary function and serum CC16. CC16 exerts a significantly mediating role of Co-related to pulmonary function decrease among COPD patients.

Design, synthesis and biological evaluation of thieno[3,2-c]pyrazol-urea derivatives as potent glycogen synthase kinase 3ß inhibitors based on the DFG-out conformation.

Glycogen synthase kinase 3ß (GSK-3ß) is a potential therapeutic target for the treatment of a variety of human diseases. Here, we report the design and synthesis of a series of thieno[3,2-c]pyrazol-urea derivatives and evaluation of their GSK-3ß inhibitory activity. Among these analogues, the compound without substitution on terminal phenyl ring (3a) was found to be the most potent GSK-3ß inhibitor with an IC50 of 74.4 nM, while substitution on the terminal phenyl (3b-3p) led to decreased potency, independent of the position, size, or electronic properties of the substituents. Kinase selectivity assay revealed that 3a showed good selectivity over a panel of kinases, but was less selective over CDK1, CDK2 and CDK5. Additionally, the pharmacological properties of the synthesized compounds were investigated computationally by the SwissADME and the results showed that most of the compounds have good ADME profiles.

Resveratrol by elevating the SIRT1 BDNF, GDNF and PSD95 levels reduce heroin addiction related behaviors.

OBJECTIVE: To study the effects of resveratrol on heroin addiction-related behaviors and to preliminarily explore the possible intervention mechanism of resveratrol in heroin dependence. METHODS: The effects of resveratrol on heroin withdrawal symptoms were observed by naloxone; The effect of resveratrol on heroin reward memory acquisition was detected by CPP paradigm; The effect of resveratrol on the mental excitability of heroin was tested by open field experiment; The effect of resveratrol on heroin spatial learning and memory was tested by water maze test. Western blot was used to detect Sirtuin 1 (SIRT1) Expression of brain-derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF), and postsynaptic density protein (PSD95). RESULTS: The behavioral results showed that the withdrawal behavior of the resveratrol intervention group was reduced compared with the heroin chronic dependence group (P<0.05), and the shift score of the conditioned place preference test of the resveratrol intervention group was reduced compared with the heroin chronic dependence group (P<0.05) The spatial learning and memory ability of the water maze in the resveratrol intervention group was improved compared with the heroin chronic dependence group (P<0.05), and the mental excitability of the resveratrol intervention group was lower than that of the heroin chronic dependence group (P<0.05), but higher than that of the saline group (P<0.05); SIRT1 The expression levels of BDNF, GDNF and PSD95 protein were significantly increased (P<0.05). CONCLUSION: The behavioral results of this study suggest that resveratrol can be used as a potential drug to treat heroin dependence. At the same time, SIRT1 The expression of BDNF, GDNF, and PSD95 increased; SIRT1, BDNF, GDNF, and PSD95 play an essential role in heroin addiction.

An artificially evolved gene for herbicide-resistant rice breeding.

Discovering and engineering herbicide-resistant genes is a crucial challenge in crop breeding. This study focuses on the 4-hydroxyphenylpyruvate dioxygenase Inhibitor Sensitive 1-Like (HSL) protein, prevalent in higher plants and exhibiting weak catalytic activity against many ß-triketone herbicides (ß-THs). The crystal structures of maize HSL1A complexed with ß-THs were elucidated, identifying four essential herbicide-binding residues and explaining the weak activity of HSL1A against the herbicides. Utilizing an artificial evolution approach, we developed a series of rice HSL1 mutants targeting the four residues. Then, these mutants were systematically evaluated, identifying the M10 variant as the most effective in modifying ß-THs. The initial active conformation of substrate binding in HSL1 was also revealed from these mutants. Furthermore, overexpression of M10 in rice significantly enhanced resistance to ß-THs, resulting in a notable 32-fold increase in resistance to methyl-benquitrione. In conclusion, the artificially evolved M10 gene shows great potential for the development of herbicide-resistant crops.