5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology.

Drugs frequently require interactions with multiple targets-via a process known as polypharmacology-to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, including the 5-HT2C receptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HT2C receptor ligands or creating drugs with a defined polypharmacological profile, especially aimed at G protein-coupled receptors (GPCRs), remain extremely difficult. Here, we solved two structures of the 5-HT2C receptor in complex with the highly promiscuous agonist ergotamine and the 5-HT2A-C receptor-selective inverse agonist ritanserin at resolutions of 3.0 Å and 2.7 Å, respectively. We analyzed their respective binding poses to provide mechanistic insights into their receptor recognition and opposing pharmacological actions. This study investigates the structural basis of polypharmacology at canonical GPCRs and illustrates how understanding characteristic patterns of ligand-receptor interaction and activation may ultimately facilitate drug design at multiple GPCRs.

Abundance of Low-Energy Oxygen Vacancy Pairs Dictates the Catalytic Performance of Cerium-Stabilized Zirconia.

Cerium-stabilized zirconia (Ce1-xZrxOy, CZO) is renowned for its superior oxygen storage capacity (OSC), a key property long believed to be beneficial to catalytic oxidation reactions. However, 50% Ce-containing CZO recorded with the highest OSC has disappointingly poor performance in catalytic oxidation reactions compared to those with higher Ce contents but lower OSC ability. Here, we employ global neural network (G-NN)-based potential energy surface exploration methods to establish the first ternary phase diagram for bulk structures of CZO, which identifies three critical compositions of CZO, namely, 50, 60, and 80% Ce-containing CZO that are thermodynamically stable under typical synthetic conditions. 50% Ce-containing CZO, although having the highest OSC, exhibits the lowest O vacancy (Ov) diffusion rate. By contrast, 60% Ce-containing CZO, despite lower OSC (33.3% OSC compared to that of 50% Ce-containing CZO), reaches the highest Ov diffusion ability and thus offers the highest CO oxidation catalytic performance. The physical origin of the high performance of 60% Ce-containing CZO is the abundance of energetically favorable Ov pairs along the ⟨110⟩ direction, which reduces the energy barrier of Ov diffusion in the bulk and promotes O2 activation on the surface. Our results clarify the long-standing puzzles on CZO and point out that 60% Ce-containing CZO is the most desirable composition for typical CZO applications.

N6-methyladenosine reader protein IGF2BP1 suppresses CD8 + T cells-mediated tumor cytotoxicity and apoptosis in colon cancer.

Tumor immune escape is an important manner for colon cancer to escape effective killing by immune system. Currently, the immune checkpoint PD-1/PD-L1-targeted immunotherapy has emerged as a promising therapeutic strategy in colon cancer. Here, present work aims to investigate the biological function of N6-methyladenosine (m6A) reader insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) in regulating colon cancer's immune escape and CD8 + T cells-mediated tumor cytotoxicity and apoptosis. Results illustrated that IGF2BP1 was closely correlated to the colon cancer patients' poor clinical outcome. Functionally, upregulation of IGF2BP1 suppressed the CD8+ T-cells mediated antitumor immunity through reducing their tumor cytotoxicity. Mechanistically, MeRIP-Seq revealed that programmed death ligand 1 (PD-L1) mRNA had a remarkable m6A modified site on 3'-UTR genomic. Moreover, PD-L1 acted as the target of IGF2BP1, which enhanced the stability of PD-L1 mRNA. Overall, these results indicated that IGF2BP1 targeted PD-L1 to accelerate the immune escape in colon cancer by reducing CD8 + T cells-mediated tumor cytotoxicity in m6A-dependent manner. The findings demonstrate the potential of m6A-targeted immune checkpoint blockade in colon cancer, providing a novel insight for colon cancer immune escape and antitumor immunity in further precise treatment.

ALKBH5 Drives Immune Suppression Via Targeting AXIN2 to Promote Colorectal Cancer and Is a Target for Boosting Immunotherapy.

BACKGROUND & AIMS: Immune checkpoint blockade therapy benefits only a small subset of patients with colorectal cancer (CRC), and identification of CRC-intrinsic events modulating immune checkpoint blockade efficacy is an unmet need. We found that AlkB homolog 5 (ALKBH5), an RNA N6-methyladenosine eraser, drives immunosuppression and is a molecular target to boost immune checkpoint blockade therapy in CRC. METHODS: Clinical significance of ALKBH5 was evaluated in human samples (n = 205). Function of ALKBH5 was investigated in allografts, CD34+ humanized mice, and Alkbh5 knockin mice. Immunity change was determined by means of flow cytometry, immunofluorescence, and functional investigation. Methylated RNA immunoprecipitation sequencing and RNA sequencing were used to identify ALKBH5 targets. Vesicle-like nanoparticle-encapsulated ALKBH5-small interfering RNA was constructed for targeting ALKBH5 in vivo. RESULTS: High ALKBH5 expression predicts poor prognosis in CRC. ALKBH5 induced myeloid-derived suppressor cell accumulation but reduced natural killer cells and cytotoxic CD8+ T cells to induce colorectal tumorigenesis in allografts, CD34+ humanized mice, and intestine-specific Alkbh5 knockin mice. Mechanistically, AXIN2, a Wnt suppressor, was identified as a target of ALKBH5. ALKBH5 binds and demethylates AXIN2 messenger RNA, which caused its dissociation from N6-methyladenosine reader IGF2BP1 and degradation, resulting in hyperactivated Wnt/ß-catenin. Subsequently, Wnt/ß-catenin targets, including Dickkopf-related protein 1 (DKK1) were induced by ALKBH5. ALKBH5-induced DKK1 recruited myeloid-derived suppressor cells to drive immunosuppression in CRC, and this effect was abolished by anti-DKK1 in vitro and in vivo. Finally, vesicle-like nanoparticle-encapsulated ALKBH5-small interfering RNA, or anti-DKK1 potentiated anti-PD1 treatment in suppressing CRC growth by enhancing antitumor immunity. CONCLUSIONS: This study identified an ALKBH5-N6-methyladenosine-AXIN2-Wnt-DKK1 axis in CRC, which drives immune suppression to facilitate tumorigenesis. Targeting of ALKBH5 is a promising strategy for sensitizing CRC to immunotherapy.

Combination of Ternary Electrochemiluminescence System of BNQDs/AgMOG-K2S2O8 and Electrochemiluminescence Resonance Energy Transfer Strategy for Ultrasensitive Immunoassay of Amyloid-ß Protein.

In this work, based on boron nitride quantum dots (BNQDs) as energy donors and MnO2@MWCNTs-COOH as energy receptors, we designed an efficient electrochemiluminescence resonance energy transfer (ECL-RET) immunosensor for the detection of amyloid-ß (Aß42) protein, a biomarker of Alzheimer's disease (AD). First, the signal amplification of a ternary ECL system composed of BNQDs (as the ECL emitter), K2S2O8 (as the coreactant), and silver metal-organic gels (AgMOG, as the coreaction accelerator) was realized, and PDDA as stabilizer was added, a strong and stable initial ECL signal was obtained. AgMOG could not only support a large amount of BNQDs and Aß42 capture antibody (Ab1) through Ag-N bond but also exhibit excellent ECL catalytic performance and enhance the luminescent intensity of BNQDs@PDDA-K2S2O8 system. In addition, due to the broad absorption spectrum of MnO2@MWCNTs-COOH and the extensive overlap with the ECL emission spectrum of BNQDs, the quenching probe Ab2-MnO2@MWCNTs-COOH could be introduced into the ternary system through a sandwich immune response. On this basis, the signal on-off ECL immunosensor was constructed to achieve the ultrasensitive detection of Aß42 through signal transformation. Under the optimal conditions, the prepared ECL biosensor manifested a wide linear range (10 fg/mL-100 ng/mL) with a detection limit of 2.89 fg/mL and showed excellent stability, selectivity, and repeatability, which provided an effective strategy for the ultrasensitive detection of biomarkers in clinical analysis.

Electrochemiluminescence Biosensor Based on a Duplex-Specific Nuclease and Dual-Output Toehold-Mediated Strand Displacement Cascade Amplification Strategy for Sensitive Detection of MicroRNA-499.

The timely and accurate diagnosis of acute myocardial infarction (AMI) is of great significance to reduce mortality and morbidity associated with the condition. Herein, we developed an electrochemiluminescence (ECL) biosensor for the detection of the potential AMI biomarker microRNA-499 (miRNA-499), which was based on duplex-specific nuclease-assisted target recycling and dual-output toehold-mediated strand displacement (TMSD). First, miRNA-499 was converted into a large amount of single-stranded DNA through the DSN-assisted target recycling, which was further incubated with the DNA triple-stranded complex (S) to implement TMSD cycles. Thus, the Ru(bpy)32+-labeled signal strands were released and captured by the capture probe on the electrode surface, resulting in an intense ECL signal. Owing to the prominent cascade signal amplification, the constructed biosensor exhibited a good linear response to miRNA-499 within the range of 100 aM-100 pM with a detection limit of 69.99 aM. Furthermore, it demonstrated superior selectivity, stability, and reproducibility. In addition, the biosensor was successfully applied to detect miRNA-499 in real human serum samples, demonstrating its potential for nucleic acid detection in the early diagnosis of diseases.

Pretreatment with an antibiotics cocktail enhances the protective effect of probiotics by regulating SCFA metabolism and Th1/Th2/Th17 cell immune responses.

BACKGROUND: Probiotics are a potentially effective therapy for inflammatory bowel disease (IBD); IBD is linked to impaired gut microbiota and intestinal immunity. However, the utilization of an antibiotic cocktail (Abx) prior to the probiotic intervention remains controversial. This study aims to identify the effect of Abx pretreatment from dextran sulfate sodium (DSS)-induced colitis and to evaluate whether Abx pretreatment has an enhanced effect on the protection of Clostridium butyricum Miyairi588 (CBM) from colitis. RESULTS: The inflammation, dysbiosis, and dysfunction of gut microbiota as well as T cell response were both enhanced by Abx pretreatment. Additionally, CBM significantly alleviated the DSS-induced colitis and impaired gut epithelial barrier, and Abx pretreatment could enhance these protective effects. Furthermore, CBM increased the benefit bacteria abundance and short-chain fatty acids (SCFAs) level with Abx pretreatment. CBM intervention after Abx pretreatment regulated the imbalance of cytokines and transcription factors, which corresponded to lower infiltration of Th1 and Th17 cells, and increased Th2 cells. CONCLUSIONS: Abx pretreatment reinforced the function of CBM in ameliorating inflammation and barrier damage by increasing beneficial taxa, eliminating pathogens, and inducing a protective Th2 cell response. This study reveals a link between Abx pretreatment, microbiota, and immune response changes in colitis, which provides a reference for the further application of Abx pretreatment before microbiota-based intervention.

Proteus appendicitidis sp. nov., isolated from the appendiceal pus of an appendicitis patient in Yongzhou, China.

A Gram-negative, facultatively anaerobic, short rod-shaped bacterium, designated as strain HZ0627T, was isolated from the appendiceal pus of a patient with appendicitis in Yongzhou, Hunan, China. This strain was subjected to comprehensive phenotypic, phylogenetic, and genomic analyses using polyphasic taxonomic methods. Phylogenetic analysis of the 16S rRNA gene sequence revealed that this strain belonged to the genus Proteus and the family Morganellaceae, whereas that based on the rpoB gene sequence and phylogenomic analysis demonstrated that this strain was distinctly separated from other type strains of Proteus species. Moreover, whole-genome-based analyses, including in silico DNA-DNA hybridization (isDDH) and average nucleotide identity (ANI), revealed that strain HZ0627T had much lower isDDH rates (24.5-55.6%) and ANI (82.04-93.90%) than those of the thresholds (i.e., 70% and 95%, respectively) for species delineation, when compared to the type strains of other Proteus species. The cellular fatty acid profile of strain HZ0627T was dominated by C16:0 (34.5%), cyclo C17:0 (25.8%), C14:0 (12.6%), C16:1 iso I/14:0 3-OH (7.7%), C18:1ω7c/18:1ω6c (6.5%), and C16:1ω7c/16:1ω6c (4.9%), which clearly differentiated it from the documented type strains of Proteus species. In addition, several specific physiological traits, including optimal growth temperature, tolerance to sodium chloride, and carbon source utilization, differed from those of other Proteus species. Therefore, we propose the name Proteus appendicitidis sp. nov. for strain HZ0627T (= CCTCC AB 2022380T = KCTC 92986T), which represents the type strain of this novel Proteus species.

Synthesis and Upconversion Luminescence Fine-tuning of Yb3+/Ho3+-Doped Indium and Gallium Oxide Nanoparticles.

Rare earth (RE) dopants can modulate the bandgap of oxides of indium and gallium and provide extra upconversion luminescence (UCL) abilities. However, relevant UCL fine-tuning strategies and energy mechanisms have been less studied. In this research, InGaO, Ho3+ monodoped and Yb3+/Ho3+ codoped In2O3, and Ho3+ monodoped Yb3Ga5O12 nanoparticles (NPs) were synthesized by a solvothermal method. The effects of Yb3+ and Ho3+ dopants on the crystal structures, UCL properties, and optical bandgaps of the oxides were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), UCL spectroscopy, and measurements of decay times, pump power dependence, and transmittance spectra. The crystal structures of oxide products of indium and gallium were significantly modified with RE dopants. In2O3 and Yb3Ga5O12 were selected as the host materials. For Yb3+/Ho3+ codoped In2O3 NPs, there existed energy transfers from the defect states of In2O3 to Ho3+ and from Yb3+ to Ho3+. With a fixed Ho3+ concentration, In2O3:0%Yb3+,2%Ho3+ NPs showed the optimal UCL properties mainly due to In2O3-Ho3+ energy transfer and Ho3+-Yb3+ energy-back-transfer, while with a fixed Yb3+ concentration, In2O3:5%Yb3+,3%Ho3+ NPs with a slight Yb2O3 impurity and Yb3Ga5O12:2%Ho3+ NPs did mainly due to Ho3+-Ho3+ cross-relaxation. Besides, the optical bandgaps of In2O3 and Yb3Ga5O12 were noticeably broadened with RE dopants. These findings can offer feasible directions for the synthesis and UCL fine-tuning of RE-doped oxides of indium and gallium and improve their multifunction application prospects in the fields of semiconductor and UCL nanomaterials.

Quantitative Analysis of Myocardial Work in Gestational Diabetes Mellitus Using Noninvasive Left Ventricular Pressure-Strain Loop Measurement.

BACKGROUND: Gestational diabetes mellitus (GDM) poses a risk for cardiovascular damage during pregnancy. This study focused on evaluating changes in left ventricular myocardial performance in GDM patients using the left ventricular pressure-strain loop (LV-PSL) method and examining risk factors associated with reduced myocardial function. METHODS: A prospective, randomized study involving 112 pregnant women diagnosed with GDM was conducted from June 2021 to June 2024. Additionally, 84 healthy pregnant women from the same period served as the control group. Utilizing both conventional echocardiography and two-dimensional speckle tracking echocardiography, left ventricular myocardial work metrics were assessed using LV-PSL technology. RESULTS: GDM patients demonstrated significantly reduced values for global longitudinal strain (GLS), global work index (GWI), global work efficiency (GWE), and global constructive work (GCW) (p < 0.05), while conventional ultrasound measures showed no significant difference between GDM and control groups. GWI, GWE, GCW, and GLS had high predictive value for cardiac function changes in GDM patients, with GWE showing the highest predictive value {Area under curve (AUC) = 0.866, cutoff value = 95.5%, specificity = 0.77, sensitivity = 0.87}. GWI, GWE, and GCW were negatively correlated with GLS (r = -0.532, -0.411, -0.425, all p < 0.001), whereas global wasted work (GWW) showed a positive correlation with GLS (r = 0.325 and p < 0.001). These parameters were also correlated with HbA1c levels (r = -0.316, -0.256, -0.260, all p < 0.001 for negative correlations, and r = 0.172, p < 0.05 for positive correlations). Multivariate logistic regression indicated that 1-h OGTT (mmol/L), 2-h OGTT (mmol/L), and HbA1c (%) were significant predictors of left ventricular systolic function (GWE) in GDM patients. CONCLUSIONS: LV-PSL is an effective tool for early detection of left ventricular systolic function impairment in GDM patients.

The Applicability of Polyetheretherketone and Titanium Mesh in Cranioplasty: A Retrospective Comparative Analysis.

OBJECTIVE: To compare the clinical application effect and safety of polyetheretherketone (PEEK) and titanium mesh (TM) in cranioplasty. METHODS: Four-year retrospective comparison of patients (96 cases) undergoing synthetic cranioplasty with PEEK or TM. The patients were divided into the PEEK group (24 cases) and the TM group (72 cases) according to the implants, and the patient demographics, general conditions before the operation, postoperative complications, length of postoperative hospital stay, total costs, satisfaction with shaping and long-term complications were compared between the 2 groups. RESULTS: Patients in the PEEK group were younger than those in the TM group (P=0.019). Hospitalization costs were significantly higher in the PEEK group than in the TM group (P<0.001). The incidence of postoperative subcutaneous effusion was 33% in the PEEK group and 6.9% in the TM group, which suggests that patients in the PEEK group had a higher risk of postoperative subcutaneous effusion (P=0.001). There was no significant difference in the incidence of long-term complications and cosmetic satisfaction between the 2 groups at 4 years postoperatively. CONCLUSIONS: In this study, both titanium mesh and PEEK are reliable implants for cranioplasty. Titanium mesh is widely used in cranioplasty due to its cost-effective performance. PEEK has gradually gained recognition due to the characteristics of the material and surgical procedure, but the price needs to be further reduced, and attention should be paid to the occurrence and treatment of early postoperative subcutaneous effusion.

Physicochemical Properties and Biological Activities of Quinoa Polysaccharides.

Quinoa, known as the "golden grain" for its high nutritional value, has polysaccharides as one of its sources of important nutrients. However, the biological functions of quinoa polysaccharides remain understudied. In this study, two crude polysaccharide extracts of quinoa (Q-40 and Q-60) were obtained through sequential precipitation with 40% and 60% ethanol, with purities of 58.29% (HPLC) and 62.15% (HPLC) and a protein content of 8.27% and 9.60%, respectively. Monosaccharide analysis revealed that Q-40 contained glucose (Glc), galacturonic acid (GalA), and arabinose (Ara) in a molar ratio of 0.967:0.027:0.006. Q-60 was composed of xylose (xyl), arabinose (Ara), galactose, and galacturonic acid (GalA) with a molar ratio of 0.889:0.036:0.034:0.020. The average molecular weight of Q-40 ranged from 47,484 to 626,488 Da, while Q-60 showed a range of 10,025 to 47,990 Da. Rheological experiments showed that Q-40 exhibited higher viscosity, while Q-60 demonstrated more elastic properties. Remarkably, Q-60 showed potent antioxidant abilities, with scavenging rates of 98.49% for DPPH and 57.5% for ABTS. Antibacterial experiments using the microdilution method revealed that Q-40 inhibited the growth of methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli), while Q-60 specifically inhibited MRSA. At lower concentrations, both polysaccharides inhibited MDA (MD Anderson Cancer Center) cell proliferation, but at higher concentrations, they promoted proliferation. Similar proliferation-promoting effects were observed in HepG2 cells. The research provides important information in the application of quinoa in the food and functional food industries.

Room-Temperature Synthesized Iron/Cobalt Metal-Organic Framework Nanosheets with Highly Efficient Catalytic Activity toward Luminol Chemiluminescence Reaction.

Two-dimensional (2D) iron/cobalt metal-organic framework nanosheets (Fe/Co-MOF NSs) were synthesized via the cooperative self-assembly reaction of Fe3+/Co2+ and terephthalic acid at room temperature. The as-prepared 2D Fe/Co-MOF NSs display superior performance in catalysis of the chemiluminescence (CL) reaction between luminol and H2O2. The CL spectrum, UV-vis absorption spectroscopy, radical scavenger experiments, and electron spin resonance (ESR) spectroscopy are utilized to research the possible CL mechanism of the luminol-H2O2-Fe/Co-MOF NSs system. All results indicate that Fe/Co-MOF NSs present outstanding peroxidase-like activity and could catalyze H2O2 to produce 1O2, O2·-, and ·OH, which could react rapidly with the luminol anion radical and result in strong CL. With the highly efficient CL of the luminol-H2O2-Fe/Co-MOF NSs system, a sensitive sensor for the detection of dopamine (DA) is developed based on the inhibitory effect of DA on the CL intensity. Good linearity over the range of 50-800 nM is achieved with a limit of detection of 20.88 nM (S/N = 3). This research demonstrates that 2D Fe/Co-MOF NSs is a highly effective catalyst for luminol CL reaction and has great application potential in the CL field.

Mycelium Composite with Hierarchical Porous Structure for Thermal Management.

High-performance porous materials with a low carbon footprint provide sustainable alternatives to petroleum-based lightweight foams and can help meet carbon neutrality goals. However, these materials generally face a trade-off between thermal management capabilities and structural strength. Here, a mycelium composite with a hierarchical porous structure, including both macro- and microscale pores, produced from multiple and advanced mycelial networks (elastic modulus of 1.2 GPa) binding loosely distributed sawdust is demonstrated. The morphological, biological, and physicochemical properties of the filamentous mycelium and composites are discussed in terms of how they are influenced by the mycelial system of the fungi and the way they interact with the substrate. The composite shows a porosity of 0.94, a noise reduction coefficient of 0.55 at a frequency range of 250-3000 Hz (for a 15 mm thick sample), a thermal conductivity of 0.042 W m-1  K-1 , and an energy absorption of 18 kJ m-3 at 50% strain. It is also hydrophobic, repairable, and recyclable. It is expected that the hierarchical porous structural composite with excellent thermal and mechanical properties can make a significant impact on the future development of highly sustainable alternatives to lightweight plastic foams.

Integration of taxa abundance and occurrence frequency to identify key gut bacteria correlated to clinics in Crohn's disease.

Bacteria abundance alternation in the feces or mucosa of Crohn's disease (CD) patients has long been applied to identify potential biomarkers for this disease, while the taxa occurrence frequency and their correlations with clinical traits were understudied. A total of 97 samples from the feces and gut mucosa were collected from CD patients and healthy controls (HCs), 16S rRNA-based analyses were performed to determine the changes in taxa abundance and occurrence frequency along CD and to correlate them with clinical traits. The results showed that bacteria communities were divergent between feces and mucosa, while the taxa abundance and occurrence frequency in both partitions showed similar exponential correlations. The decrease of specific fecal bacteria was much more effective in classifying the CD and HCs than that of the mucosal bacteria. Among them, Christensenellaceae_R-7_group and Ruminococcus were predicted as biomarkers by using random forest algorithm, which were persistently presented (> 71.40% in frequency) in the feces of the HCs with high abundance, whereas transiently presented in the feces (< 5.5% in frequency) and mucosa (< 18.18% in frequency) of CD patients with low abundance. Co-occurrence network analysis then identified them as hub taxa that drive the alternations of other bacteria and were positively correlated to the circuiting monocytes. The loss of specific bacteria in the healthy gut may cause great disturbance of gut microbiota, causing gut bacteria dysbiosis and correlated to immune disorders along CD, which might not only be developed as effective noninvasive biomarkers but also as therapy targets.

Brassinosteroid-Activated BRI1-EMS-SUPPRESSOR 1 Inhibits Flavonoid Biosynthesis and Coordinates Growth and UV-B Stress Responses in Plants.

UV-B light is a potential stress factor in plants, but how plants coordinate growth and UV-B stress responses is not well understood. Here, we report that brassinosteroid (BR) signaling inhibits UV-B stress responses in Arabidopsis (Arabidopsis thaliana) and various crops by controlling flavonol biosynthesis. We further demonstrate that BRI1-EMS-SUPPRESSOR 1 (BES1) mediates the tradeoff between plant growth and UV-B defense responses. BES1, a master transcription factor involved in BR signaling, represses the expression of transcription factor genes MYB11, MYB12, and MYB111, which activate flavonol biosynthesis. BES1 directly binds to the promoters of these MYBs in a BR-enhanced manner to repress their expression, thereby reducing flavonol accumulation. However, exposure to broadband UV-B down-regulates BES1 expression, thus promoting flavonol accumulation. These findings demonstrate that BR-activated BES1 not only promotes growth but also inhibits flavonoid biosynthesis. UV-B stress suppresses the expression of BES1 to allocate energy to flavonoid biosynthesis and UV-B stress responses, allowing plants to switch from growth to UV-B stress responses in a timely manner.

Dietary polyphenols: regulate the advanced glycation end products-RAGE axis and the microbiota-gut-brain axis to prevent neurodegenerative diseases.

Advanced glycation end products (AGEs) are formed in non-enzymatic reaction, oxidation, rearrangement and cross-linking between the active carbonyl groups of reducing sugars and the free amines of amino acids. The Maillard reaction is related to sensory characteristics in thermal processed food, while AGEs are formed in food matrix in this process. AGEs are a key link between carbonyl stress and neurodegenerative disease. AGEs can interact with receptors for AGEs (RAGE), causing oxidative stress, inflammation response and signal pathways activation related to neurodegenerative diseases. Neurodegenerative diseases are closely related to gut microbiota imbalance and intestinal inflammation. Polyphenols with multiple hydroxyl groups showed a powerful ability to scavenge ROS and capture α-dicarbonyl species, which led to the formation of mono- and di- adducts, thereby inhibiting AGEs formation. Neurodegenerative diseases can be effectively prevented by inhibiting AGEs production, and interaction with RAGEs, or regulating the microbiota-gut-brain axis. These strategies include polyphenols multifunctional effects on AGEs inhibition, RAGE-ligand interactions blocking, and regulating the abundance and diversity of gut microbiota, and intestinal inflammation alleviation to delay or prevent neurodegenerative diseases progress. It is a wise and promising strategy to supplement dietary polyphenols for preventing neurodegenerative diseases via AGEs-RAGE axis and microbiota-gut-brain axis regulation.

Incidence and survival of adenocarcinoma with mixed subtypes in patients with colorectal cancer.

BACKGROUND: Limited attention was paid to adenocarcinoma with mixed subtypes (AM) of the colon and rectum due to its low incidence. This study aims to assess the frequency and survival rates of tumors in the population. METHODS: The data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2019. The incidence of tumors was evaluated based on patient gender, age, race, and location. Univariate and multivariate Cox analyses were performed to identify risk factors associated with tumor survival. Additionally, a nomogram was constructed using these risk factors to predict cancer-specific survival (CSS) at 1, 2, and 3 years. Receiver operating characteristic (ROC) and calibration curves were applied to examine the model's accuracy. RESULTS: The overall incidence of colorectal AM reached its highest level in 2016 (2.350 (95% CI: 2.241-2.462)). AM is more frequent in elderly patients and predominantly located in the rectum. By forest plot for multivariable Cox regression analysis, patient age, the number of regional positive lymph nodes and lymph nodes removed, tumor N/M stage, and postoperative chemotherapy were identified as independent risk indicators for CSS. Nomogram was constructed and validated as a feasible prediction model of CSS in patients with colorectal AM. CONCLUSION: The presence of colorectal AM in elderly patients, particularly in the rectum, is frequent and often associated with poor prognosis. Our nomograms can offer a relatively accurate prediction of CSS of patients with AM after tumor resection.

Fugitive emissions of volatile organic compounds from the pharmaceutical industry in China based on leak detection and repair monitoring, atmospheric prediction, and health risk assessment.

In this study, a leak detection and repair program was conducted on five pharmaceutical factories in China to analyze the volatile organic compounds (VOCs) emission characteristics of leaking equipment. The results indicated that the monitored components were mainly flanges, accounting for 70.23% of the total, and open-ended lines were the components most prone to leaks. The overall percentage of VOCs emissions reduction after the repair was 20.50%, and flanges were the most repairable components, with an average emission reduction of 47.5 kg/a for each flange. In addition, atmospheric predictions were conducted for the VOCs emissions before and after the repair of the components at the research factories. The atmospheric predictions showed that emissions from equipment and facilities have a noticeable impact on VOCs concentration at boundary and the emissions are positively correlated with the pollution source strength. The hazard quotient of the investigated factories was lower than the acceptable risk level set by the US Environmental Protection Agency (EPA). The quantitative assessment of the lifetime cancer risk showed that the risk levels of factories A, C, and D exceeded the EPA's acceptable risk level, and the on-site workers were exposed to inhalation cancer risk.

Effect of wound infiltration of dexmedetomidine in lumbar spine surgery on postoperative wound pain: A meta-analysis.

In a meta-study, we evaluated the effectiveness and security of the combination of topical anaesthetic and dexmedetomidine in the treatment of postoperative pain in patients with lumbar disease. Four databases were systematically searched for possible related articles. Only English-language research was taken into account on the Internet. Furthermore, we only took into account the studies that were published prior to 2023. Only those that fulfilled the eligibility criteria were considered: (1) in adults who were about to undergo spine operation, (2) dexmedetomidine combined with local anaesthesia, (3) Visual Analog Scale scores at 4 and 24 h after the event and (4) this was a randomized or nonrandomized, controlled study. The meta-analysis was carried out with Revman 5.3 software. A ROBINS-I-based instrument was used to evaluate controlled studies. All trials were synthesized by computing the end results with either a fixed or a random effect model, which was dependent on statistical diversity. Five trials showed a marked reduction in wound pain at 4 h after the operation in patients who were treated with dexmedetomidine for lumbar spinal surgery (MD, -0.81; 95% CI, -1.24, -0.35; p = 0.0005). In the case of lumbar spinal operations, the addition of dexmedetomidine to the postoperative treatment resulted in a marked reduction in the pain at 24 h post-operation (MD, -0.64; 95% CI, -0.79, -0.48; p < 0.0001). The quality of the data we evaluated was 'moderate' to 'good'; thus, we have limited confidence in the impact estimation, and the actual impact might be significantly different from what we had expected. Additional studies should concentrate on practices that are well known to cause severe postoperative pain, especially for cases where the improvement of pain management may lead to substantial clinical benefits in terms of reduction of morbidity or cost-effectiveness in terms of quicker healing and release.