A novel rapid visual nucleic acid detection technique for tick-borne encephalitis virus by combining RT-recombinase-aided amplification and CRISPR/Cas13a coupled with a lateral flow dipstick.

Tick-borne encephalitis virus (TBEV), a zoonotic pathogen, can cause severe neurological complications and fatal outcomes in humans. Early diagnosis of TBEV infection is crucial for clinical practice. Although serological assays are frequently employed for detection, the lack of antibodies in the early stages of infection and the cross-reactivity of antibodies limit their efficacy. Conventional molecular diagnostic methods such as RT-qPCR can achieve early and accurate identification but require specialized instrumentation and professionals, hindering their application in resource-limited areas. Our study developed a rapid and visual TBEV molecular detection method by combining RT-recombinase-aided amplification, the CRISPR/Cas13a system, and lateral flow dipsticks. The diagnostic sensitivity of this method is 50 CFU/ml, with no cross-reactivity with a variety of viruses. The detection can be carried out within 1 h at a temperature between 37 and 42 °C, and the results can be visually determined without the need for complex instruments and professionals. Subsequently, this assay was used to analyze clinical samples from 15 patients suspected of TBEV infection and 10 healthy volunteers, and its sensitivity and specificity reached 100 %, which was consistent with the results of RT-qPCR. These results indicate that this new method can be a promising point-of-care test for the diagnosis of tick-borne encephalitis.

Prognostic value of 18F-FDG PET/CT in patients with relapsed multiple myeloma.

This study aimed to assess the prognostic value of 18F-fluorodeoxyglucose positron emission tomography/computer tomography (18F-FDG PET/CT) in patients with relapsed multiple myeloma (MM). Fifty-one consecutive patients with relapsed MM were enrolled in this retrospective study. 18F-FDG parameters based on the Italian Myeloma Criteria for PET Use (IMPeTUs) and clinical data were analyzed for overall survival (OS) and progression-free survival (PFS). The Cox proportional risk model was used for univariate and multivariate analysis, and Kaplan-Meier survival curves were used for survival analysis. The median length of follow-up was 20 months (IQR, 5-29 months), the median PFS for the entire cohort was 8 months (IQR, 3-17 months) and the median OS was 21 months (IQR, 8-49 months). Multivariate survival analysis demonstrated that the Deauville score of BM > 3 [HR 2.900, 95% CI (1.011, 8.319), P = 0.048] and the presence of EMD [HR 3.134, 95% CI (1.245, 7.891), P = 0.015] were independent predictors of poor PFS. The presence of EMD [HR 12.777, 95% CI (1.825, 89.461), P = 0.010] and the reduced platelets count [HR 7.948, 95% CI (1.236, 51.099), P = 0.029] were adversely associated with OS. 18F-FDG PET/CT parameters based on IMPeTUs have prognostic significance in patients with relapsed MM.

Study on the Correlation Between Patent Foramen Ovale and Migraine Based on Meta Analysis.

Objective: This meta-analysis systematically investigates the association between Patent Foramen Ovale (PFO) and the prevalence of migraine. Our goal is to quantify this relationship and evaluate its implications for clinical practice and future research. Methods: An extensive literature search was carried out in various databases, such as PubMed, Embase, The Cochrane Library, Web of Science, CNKI, VIP, WanFang Data, and CBM, up to November 2023. The search focused on case-control, cross-sectional, and cohort studies examining the link between PFO and migraine. The literature screening and data extraction, based on predefined inclusion and exclusion criteria, were independently conducted by two reviewers. The studies' quality was evaluated using the Newcastle-Ottawa Scale (NOS), and RevMan 5.3 software was employed for the meta-analysis. Results: A total of 27 studies involving 8,875 participants were included in the meta-analysis. The results indicate a statistically significant association between PFO and migraine prevalence. Key findings include: (1) Overall, individuals with migraine had higher rates of PFO compared to healthy controls (OR = 3.22, 95% CI = 2.21 to 4.67, P < .00001). (2) The association was stronger in the Migraine with Aura group (OR = 3.69, 95% CI = 1.93 to 7.04, P < .0001) than in the Non-Migraine with Aura group (OR = 1.48, 95% CI = 1.09 to 2.00, P = .01). (3) The prevalence of PFO was notably higher in the Migraine with Aura group compared to the Non-Migraine with Aura group (OR = 2.32, 95% CI = 1.96 to 2.76, P < .00001). Conclusion: The analysis confirms a noteworthy correlation between PFO and migraine, underscoring the relationship and suggesting additional studies need to elucidate the underlying mechanisms and clinical ramifications.

Structural insights into ligand recognition and activation of the succinate receptor SUCNR1.

Succinate, a citric acid cycle intermediate, serves important functions in energy homeostasis and metabolic regulation. Extracellular succinate acts as a stress signal through succinate receptor (SUCNR1), a class A G protein-coupled receptor. Research on succinate signaling is hampered by the lack of high-resolution structures of the agonist-bound receptor. We present cryoelectron microscopy (cryo-EM) structures of SUCNR1-Gi complexes bound to succinate and its non-metabolite derivative cis-epoxysuccinate. Key determinants for the recognition of succinate in cis conformation include R2817.39 and Y832.64, while Y301.39 and R993.29 participate in the binding of both succinate and cis-epoxysuccinate. Extracellular loop 2, through F175ECL2 in its ß-hairpin, forms a hydrogen bond with succinate and caps the binding pocket. At the receptor-Gi interface, agonist binding induces the rearrangement of a hydrophobic network on transmembrane (TM)5 and TM6, leading to TM signaling through TM3 and TM7. These findings extend our understanding of succinate recognition by SUCNR1, aiding the development of therapeutics for the succinate receptor.

ALKBH5 regulates chicken adipogenesis by mediating LCAT mRNA stability depending on m6A modification.

BACKGROUND: Previous studies have demonstrated the role of N6-methyladenosine (m6A) RNA methylation in various biological processes, our research is the first to elucidate its specific impact on LCAT mRNA stability and adipogenesis in poultry. RESULTS: The 6 100-day-old female chickens were categorized into high (n = 3) and low-fat chickens (n = 3) based on their abdominal fat ratios, and their abdominal fat tissues were processed for MeRIP-seq and RNA-seq. An integrated analysis of MeRIP-seq and RNA-seq omics data revealed 16 differentially expressed genes associated with to differential m6A modifications. Among them, ELOVL fatty acid elongase 2 (ELOVL2), pyruvate dehydrogenase kinase 4 (PDK4), fatty acid binding protein 9 (PMP2), fatty acid binding protein 1 (FABP1), lysosomal associated membrane protein 3 (LAMP3), lecithin-cholesterol acyltransferase (LCAT) and solute carrier family 2 member 1 (SLC2A1) have ever been reported to be associated with adipogenesis. Interestingly, LCAT was down-regulated and expressed along with decreased levels of mRNA methylation methylation in the low-fat group. Mechanistically, the highly expressed ALKBH5 gene regulates LCAT RNA demethylation and affects LCAT mRNA stability. In addition, LCAT inhibits preadipocyte proliferation and promotes preadipocyte differentiation, and plays a key role in adipogenesis. CONCLUSIONS: In conclusion, ALKBH5 mediates RNA stability of LCAT through demethylation and affects chicken adipogenesis. This study provides a theoretical basis for further understanding of RNA methylation regulation in chicken adipogenesis.

Structural basis for EROS binding to human phagocyte NADPH oxidase NOX2.

Essential for reactive oxygen species (EROS) protein is a recently identified molecular chaperone of NOX2 (gp91phox), the catalytic subunit of phagocyte NADPH oxidase. Deficiency in EROS is a recently identified cause for chronic granulomatous disease, a genetic disorder with recurrent bacterial and fungal infections. Here, we report a cryo-EM structure of the EROS-NOX2-p22phox heterotrimeric complex at an overall resolution of 3.56Å. EROS and p22phox are situated on the opposite sides of NOX2, and there is no direct contact between them. EROS associates with NOX2 through two antiparallel transmembrane (TM) α-helices and multiple ß-strands that form hydrogen bonds with the cytoplasmic domain of NOX2. EROS binding induces a 79° upward bend of TM2 and a 48° backward rotation of the lower part of TM6 in NOX2, resulting in an increase in the distance between the two hemes and a shift of the binding site for flavin adenine dinucleotide (FAD). These conformational changes are expected to compromise superoxide production by NOX2, suggesting that the EROS-bound NOX2 is in a protected state against activation. Phorbol myristate acetate, an activator of NOX2 in vitro, is able to induce dissociation of NOX2 from EROS with concurrent increase in FAD binding and superoxide production in a transfected COS-7 model. In differentiated neutrophil-like HL-60, the majority of NOX2 on the cell surface is dissociated with EROS. Further studies are required to delineate how EROS dissociates from NOX2 during its transport to cell surface, which may be a potential mechanism for regulation of NOX2 activation.

Multi-scale analysis of acupuncture mechanisms for motor and sensory cortex activity based on SEEG data.

Acupuncture, a traditional Chinese therapy, is gaining attention for its impact on the brain. While existing electroencephalogram and functional magnetic resonance image research has made significant contributions, this paper utilizes stereo-electroencephalography data for a comprehensive exploration of neurophysiological effects. Employing a multi-scale approach, channel-level analysis reveals notable $\delta $-band activity changes during acupuncture. At the brain region level, acupuncture modulated connectivity between the paracentral lobule and the precentral gyrus. Whole-brain analysis indicates acupuncture's influence on network organization, and enhancing $E_{glob}$ and increased interaction between the motor and sensory cortex. Brain functional reorganization is an important basis for functional recovery or compensation after central nervous system injury. The use of acupuncture to stimulate peripheral nerve trunks, muscle motor points, acupoints, etc., in clinical practice may contribute to the reorganization of brain function. This multi-scale perspective provides diverse insights into acupuncture's effects. Remarkably, this paper pioneers the introduction of stereo-electroencephalography data, advancing our understanding of acupuncture's mechanisms and potential therapeutic benefits in clinical settings.

Incremental high average-utility itemset mining: survey and challenges.

The High Average Utility Itemset Mining (HAUIM) technique, a variation of High Utility Itemset Mining (HUIM), uses the average utility of the itemsets. Historically, most HAUIM algorithms were designed for static databases. However, practical applications like market basket analysis and business decision-making necessitate regular updates of the database with new transactions. As a result, researchers have developed incremental HAUIM (iHAUIM) algorithms to identify HAUIs in a dynamically updated database. Contrary to conventional methods that begin from scratch, the iHAUIM algorithm facilitates incremental changes and outputs, thereby reducing the cost of discovery. This paper provides a comprehensive review of the state-of-the-art iHAUIM algorithms, analyzing their unique characteristics and advantages. First, we explain the concept of iHAUIM, providing formulas and real-world examples for a more in-depth understanding. Subsequently, we categorize and discuss the key technologies used by varying types of iHAUIM algorithms, encompassing Apriori-based, Tree-based, and Utility-list-based techniques. Moreover, we conduct a critical analysis of each mining method's advantages and disadvantages. In conclusion, we explore potential future directions, research opportunities, and various extensions of the iHAUIM algorithm.

pH-Responsive Calcium Ions and Crocetin Releasing Hydrogel for Accelerating Skin Wound Healing.

The ideal and highly anticipated dressing for skin wounds should provide a moist environment, possess antibacterial properties, and ensure sustained drug release. In the present work, a hyaluronic acid-based hydrogel was formed by cross-linking crocetin and CaCO3@polyelectrolyte materials (CaCO3@PEM) microspheres with HA hydrogels via hydrogen bond and amido bonding (CaCO3@PEM@Cro@HA hydrogel, CPC@HA hydrogel). Moreover, the CPC@HA hydrogel had the capability of sustained, controlled release of calcium ions and crocetin via pH-sensitive and accelerated skin wound healing. The experiment results showed that the CPC@HA hydrogel exhibited porous network structures, stable physical properties, and had antibacterial properties and biocompatibility in vitro. In addition, the CPC@HA hydrogel covering on the skin wound could reduce inflammation and promote wound healing. The high expression of angiogenic cytokines (CD31) and epidermal terminal differentiation markers (Loricrin) of wound healing tissue suggested the CPC@HA hydrogel also had the function of promoting the remodeling of regenerated skin. Overall, CPC@HA hydrogel has promising potential for clinical applications in accelerating skin wound repair.

Assessment of prolonged proteasome inhibition through ixazomib-based oral regimen on newly diagnosed and first-relapsed multiple myeloma: A real-world Chinese cohort study.

OBJECTIVE: To evaluate the effectiveness, safety, and convenience of in-class transition (iCT) from intravenous bortezomib-based induction to ixazomib-based oral regimens. METHODS: This retrospective real-world study was conducted in 16 Chinese hospitals between October 2017 and April 2023 and analyzed newly diagnosed (NDMM) and first-line relapsed multiple myeloma (FRMM) patients who attained at least a partial response from bortezomib-based induction therapy, followed by an ixazomib-based oral regimen for 2 year or until disease progression or intolerable toxicity. RESULTS: The study enrolled 199 patients, median age: 63 years old, male 55.4%, 53% as high risk (HR), and 47% as standard risk. Cytogenetic risk stratification by metaphase fluorescence in situ hybridization (M-FISH), based on the Mayo Clinic risk stratification system. The median duration of total PI therapy was 11 months, with ixazomib-based treatment spanning 6 months. At the 20-month median follow-up, 53% of patients remained on therapy. The 24-month PFS rate was 84.3% from the initiation of bortezomib-based induction and 83.4% from the start of ixazomib-based treatment. Overall response rate (ORR) was 100% post-bortezomib induction and 90% following 6 cycles of the ixazomib-based regimen. Based on the Sankey diagrams, 89.51% of patients maintained or improved their disease response after 2 cycles of iCT, 6 cycles (90.14%), and 12 cycles (80%). The HR level of Mayo was found to be a significant independent factor in a worse remission (hazard ratio (HR) 2.55; p = 0.033). Ixazomib's safety profile aligned with previous clinical trial data, with 49% of patients experiencing at least one AE of any grade. The most common AEs included peripheral neuropathy, nausea and vomiting, diarrhea, thrombocytopenia, and granulocytopenia. CONCLUSION: In the real-world Chinese MM population, NDMM and FRMM patients responded favorably to PI-based continuous therapy, demonstrating substantial response rates. The ixazomib-based iCT allows for sustained PI-based treatment, offering promising efficacy and tolerable AEs.

Extended Clopidogrel Monotherapy vs DAPT in Patients With Acute Coronary Syndromes at High Ischemic and Bleeding Risk: The OPT-BIRISK Randomized Clinical Trial.

Importance: Purinergic receptor P2Y12 (P2Y12) inhibitor monotherapy after a certain period of dual antiplatelet therapy (DAPT) may be an attractive option of maintenance antiplatelet treatment for patients undergoing percutaneous coronary intervention (PCI) who are at both high bleeding and ischemic risk (birisk). Objective: To determine if extended P2Y12 inhibitor monotherapy with clopidogrel is superior to ongoing DAPT with aspirin and clopidogrel after 9 to 12 months of DAPT after PCI in birisk patients with acute coronary syndromes (ACS). Design, Setting, and Participants: This was a multicenter, double-blind, placebo-controlled, randomized clinical trial including birisk patients with ACS who had completed 9 to 12 months of DAPT after drug-eluting stent implantation and were free from adverse events for at least 6 months at 101 China centers between February 2018 and December 2020. Study data were analyzed from April 2023 to May 2023. Interventions: Patients were randomized either to clopidogrel plus placebo or clopidogrel plus aspirin for an additional 9 months. Main Outcomes and Measures: The primary end point was Bleeding Academic Research Consortium (BARC) types 2, 3, or 5 bleeding 9 months after randomization. The key secondary end point was major adverse cardiac and cerebral events (MACCE; the composite of all-cause death, myocardial infarction, stroke or clinically driven revascularization). The primary end point was tested for superiority, and the MACCE end point was tested for sequential noninferiority and superiority. Results: A total of 7758 patients (mean [SD] age, 64.8 [9.0] years; 4575 male [59.0%]) were included in this study. The primary end point of BARC types 2, 3, or 5 bleeding occurred in 95 of 3873 patients (2.5%) assigned to clopidogrel plus placebo and 127 of 3885 patients (3.3%) assigned to clopidogrel plus aspirin (hazard ratio [HR], 0.75; 95% CI, 0.57-0.97; difference, -0.8%; 95% CI, -1.6% to -0.1%; P = .03). The incidence of MACCE was 2.6% (101 of 3873 patients) in the clopidogrel plus placebo group and 3.5% (136 of 3885 patients) in the clopidogrel plus aspirin group (HR, 0.74; 95% CI, 0.57-0.96; difference, -0.9%; 95% CI, -1.7% to -0.1%; P < .001 for noninferiority; P = .02 for superiority). Conclusions and Relevance: Among birisk patients with ACS who completed 9 to 12 months of DAPT after drug-eluting stent implantation and were free from adverse events for at least 6 months before randomization, an extended 9-month clopidogrel monotherapy regimen was superior to continuing DAPT with clopidogrel in reducing clinically relevant bleeding without increasing ischemic events. Trial Registration: ClinicalTrials.gov Identifier: NCT03431142.

Tertiary lymphoid structures predict survival and response to neoadjuvant therapy in locally advanced rectal cancer.

Tertiary lymphoid structure (TLS) contributes to the anti-tumor immune response, and predicts the prognosis of colorectal cancer patients. However, the potential impact of TLS in shaping the immune status of rectal adenocarcinoma, and the intrinsic relationship between TLS and neoadjuvant therapies (neoTx) remain unclear. We performed hematoxylin-eosin staining, immunohistochemical and biomolecular analyses to investigate TLS and tumor-infiltrating lymphocytes (TILs) in 221 neoTx-treated and 242 treatment-naïve locally advanced rectal cancer (LARC) patients. High TLS density was significantly associated with the absence of vascular invasion, a lower neutrophil-to-lymphocyte ratio, increased TLS maturity, a longer recurrence-free survival (RFS) (hazard ratio [HR] 0.2985 95% confidence interval [CI] 0.1894-0.4706, p < 0.0001) and enhanced infiltration of adaptive immune cells. Biomolecular analysis showed that high TLS-score was strongly associated with more infiltration of immune cells and increased activation of immune-related pathways. TLS+ tumors in pre-treatment specimens were associated with a higher proportion of good respond (62.5% vs. 29.8%, p < 0.0002) and pathological complete remission (pCR) (40.0% vs. 11.1%, p < 0.0001), and significantly increased RFS (HR 0.3574 95%CI 0.1489-0.8578 p = 0.0213) compared with TLS- tumors in the neoTx cohort, which was confirmed in GSE119409 and GSE150082. Further studies showed that neoTx significantly reduced TLS density and maturity, and abolished the prognostic value of TLS. Our study illustrates that TLS may have a key role in mediating the T-cell-inflamed tumor microenvironment, which also provides a new direction for neoTx, especially neoadjuvant immunotherapy, in LRAC patients.

GLP-1(7-36) protected against oxidative damage and neuronal apoptosis in the hippocampal CA region after traumatic brain injury by regulating ERK5/CREB.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) (7-36) amide, an endogenous active form of GLP-1, has been shown to modulate oxidative stress and neuronal cell survival in various neurological diseases. OBJECTIVE: This study investigated the potential effects of GLP-1(7-36) on oxidative stress and apoptosis in neuronal cells following traumatic brain injury (TBI) and explored the underlying mechanisms. METHODS: Traumatic brain injury (TBI) models were established in male SD rats for in vivo experiments. The extent of cerebral oedema was assessed using wet-to-dry weight ratios following GLP-1(7-36) intervention. Neurological dysfunction and cognitive impairment were evaluated through behavioural experiments. Histopathological changes in the brain were observed using haematoxylin and eosin staining. Oxidative stress levels in hippocampal tissues were measured. TUNEL staining and Western blotting were employed to examine cell apoptosis. In vitro experiments evaluated the extent of oxidative stress and neural apoptosis following ERK5 phosphorylation activation. Immunofluorescence colocalization of p-ERK5 and NeuN was analysed using immunofluorescence cytochemistry. RESULTS: Rats with TBI exhibited neurological deterioration, increased oxidative stress, and enhanced apoptosis, which were ameliorated by GLP-1(7-36) treatment. Notably, GLP-1(7-36) induced ERK5 phosphorylation in TBI rats. However, upon ERK5 inhibition, oxidative stress and neuronal apoptosis levels were elevated, even in the presence of GLP-1(7-36). CONCLUSION: In summary, this study suggested that GLP-1(7-36) suppressed oxidative damage and neuronal apoptosis after TBI by activating ERK5/CREB.

Expert Consensus on the Diagnosis and Treatment of NRG1/2 Gene Fusion Solid Tumors.

The fusion genes NRG1 and NRG2 , members of the epidermal growth factor (EGF) receptor family, have emerged as key drivers in cancer. Upon fusion, NRG1 retains its EGF-like active domain, binds to the ERBB ligand family, and triggers intracellular signaling cascades, promoting uncontrolled cell proliferation. The incidence of NRG1 gene fusion varies across cancer types, with lung cancer being the most prevalent at 0.19 to 0.27%. CD74 and SLC3A2 are the most frequently observed fusion partners. RNA-based next-generation sequencing is the primary method for detecting NRG1 and NRG2 gene fusions, whereas pERBB3 immunohistochemistry can serve as a rapid prescreening tool for identifying NRG1 -positive patients. Currently, there are no approved targeted drugs for NRG1 and NRG2 . Common treatment approaches involve pan-ERBB inhibitors, small molecule inhibitors targeting ERBB2 or ERBB3, and monoclonal antibodies. Given the current landscape of NRG1 and NRG2 in solid tumors, a consensus among diagnostic and treatment experts is proposed, and clinical trials hold promise for benefiting more patients with NRG1 and NRG2 gene fusion solid tumors.

Synchronous multiple myeloma and lung adenocarcinoma: A clinical series.

BACKGROUND: Multiple myeloma (MM) is characterised by an increased number of monoclonal immunoglobulin-producing plasma cells that malignantly grow in the bone marrow. Lung cancer is one of the most common malignancies and at the advanced stage may become metastatic to the bone. Rarely, MM and lung cancer are synchronously present in the same patient. RESULTS: In this report, we describe five cases of MM synchronous with lung adenocarcinoma including λ light chain in three cases and Ï° light chain in two cases. Two patients achieved complete remission, and no progression was seen in two patients. CONCLUSION: In conclusion, synchronous MM and lung adenocarcinoma are clinically rare, and diagnosis should be made scrupulously based on morphology, immunology, cytogenetics, molecular biology and biopsy pathology.

A pilot study on a patient with refractory headache: Personalized deep brain stimulation through stereoelectroencephalography.

The integration of stereoelectroencephalography with therapeutic deep brain stimulation (DBS) holds immense promise as a viable approach for precise treatment of refractory disorders, yet it has not been explored in the domain of headache or pain management. Here, we implanted 14 electrodes in a patient with refractory migraine and integrated clinical assessment and electrophysiological data to investigate personalized targets for refractory headache treatment. Using statistical analyses and cross-validated machine-learning models, we identified high-frequency oscillations in the right nucleus accumbens as a critical headache-related biomarker. Through a systematic bipolar stimulation approach and blinded sham-controlled survey, combined with real-time electrophysiological data, we successfully identified the left dorsal anterior cingulate cortex as the optimal target for the best potential treatment. In this pilot study, the concept of the herein-proposed data-driven approach to optimizing precise and personalized treatment strategies for DBS may create a new frontier in the field of refractory headache and even pain disorders.

The Potential of Cyclodextrins as Inhibitors for the BM2 Protein: An In Silico Investigation.

The influenza BM2 transmembrane domain (BM2TM), an acid-activated proton channel, is an attractive antiviral target due to its essential roles during influenza virus replication, whereas no effective inhibitors have been reported for BM2. In this study, we draw inspiration from the properties of cyclodextrins (CDs) and hypothesize that CDs of appropriate sizes may possess the potential to act as inhibitors of the BM2TM proton channel. To explore this possibility, molecular dynamics simulations were employed to assess their inhibitory capabilities. Our findings reveal that CD4, CD5, and CD6 are capable of binding to the BM2TM proton channel, resulting in disrupted water networks and reduced hydrogen bond occupancy between H19 and the solvent within the BM2TM channel necessary for proton conduction. Notably, CD4 completely obstructs the BM2TM water channel. Based on these observations, we propose that CD4, CD5, and CD6 individually contribute to diminishing the proton transfer efficiency of the BM2 protein, and CD4 demonstrates promising potential as an inhibitor for the BM2 proton channel.

Geraniin restricts inflammasome activation and macrophage pyroptosis by preventing the interaction between ASC and NLRP3 to exert anti-inflammatory effects.

Geraniin, a chemical component of the traditional Chinese medicine geranii herba, possesses anti-inflammatory and anti-oxidative activities. However, its anti-inflammatory role in managing NLRP3 inflammasome and pyroptosis remains to be elucidated. To investigate the anti-inflammation mechanism of geraniin, LPS-primed macrophages were incubated with classical activators of NLRP3 inflammasome (such as ATP, Nigericin, or MSU crystals), and MSU crystals were injected into the ankle joints of mice to establish an acute gouty arthritis model. The propidium iodide (PI) staining results showed that geraniin could restrain cell death in the ATP- or nigericin-stimulated bone marrow-derived macrophages (BMDMs). Geraniin decreased the release of lactate dehydrogenase (LDH) and interleukin (IL)-1ß from cytoplasm to cell supernatant. Geraniin also inhibited the expression of caspase-1 p20, IL-1ß in cell supernatant and N-terminal of gasdermin D (GSDMD-NT) while blocking the oligomerization of ASC to form speck. The inhibitory effects of geraniin on caspase-1 p20, IL-1ß, GSDMD-NT, and ASC speck were not observed in NLRP3 knockout (NLRP3-/-) BMDMs. Hence, the resistance of geraniin to inflammasome and pyroptosis was contingent upon NLRP3 presence. Geraniin reduced reactive oxygen species (ROS) production and maintained mitochondrial membrane potential while preventing interaction between ASC and NLRP3 protein. Additionally, geraniin diminished MSU crystal-induced mouse ankle joint swelling and IL-1ß expression. Geraniin blocked the recruitment of neutrophils and macrophages to the synovium of joints. Our results demonstrate that geraniin prevents the assembly of ASC and NLRP3 through its antioxidant effect, thereby inhibiting inflammasome activation, pyroptosis, and IL-1ß release to provide potential insights for gouty arthritis targeted therapy.

Structural insights into the activation and inhibition of CXC chemokine receptor 3.

The chemotaxis of CD4+ type 1 helper cells and CD8+ cytotoxic lymphocytes, guided by interferon-inducible CXC chemokine 9-11 (CXCL9-11) and CXC chemokine receptor 3 (CXCR3), plays a critical role in type 1 immunity. Here we determined the structures of human CXCR3-DNGi complexes activated by chemokine CXCL11, peptidomimetic agonist PS372424 and biaryl-type agonist VUF11222, and the structure of inactive CXCR3 bound to noncompetitive antagonist SCH546738. Structural analysis revealed that PS372424 shares a similar orthosteric binding pocket to the N terminus of CXCL11, while VUF11222 buries deeper and activates the receptor in a distinct manner. We showed an allosteric binding site between TM5 and TM6, accommodating SCH546738 in the inactive CXCR3. SCH546738 may restrain the receptor at an inactive state by preventing the repacking of TM5 and TM6. By revealing the binding patterns and the pharmacological properties of the four modulators, we present the activation mechanisms of CXCR3 and provide insights for future drug development.

Improved adaptive-phase fuzzy high utility pattern mining algorithm based on tree-list structure for intelligent decision systems.

With the rapid development of AI and big data mining technologies, computerized medical decision-making has become increasingly prominent. The aim of high-utility pattern mining (HUPM) is to discover meaningful patterns in medical databases that contribute to maximizing the utility from the perspective of diagnosis. However, HUPM pays less attention to the interpretability and explainability of these patterns in medical decision-making scenarios. This paper proposes a novel algorithm called the Improved fuzzy high-utility pattern mining (IF-HUPM) to address this problem. First, the paper applies a fuzzy preprocessing method to divide the fuzzy intervals of a medical quantitative data set, which enhances the fuzziness and interpretability of the data. Next, in the process of IF-HUPM, both fuzzy tree and list structures are employed to calculate fuzzy high-utility values. By combining the characteristics of the one-stage and two-stage algorithms of HUPM, an adaptive-phase Fuzzy HUPM hybrid frame is proposed. The experimental results demonstrate that the proposed IF-HUPM algorithm enhances both accuracy and efficiency and the mining process requires less time and space on average.