Pathways of inhibition of filamentous sludge bulking by slowly biodegradable organic compounds.

The organic compound composition of wastewater, serves as a crucial indicator for the operational performance of activated sludge processes and has a major influence on the development of filamentous bulking in activated sludge. This study focused on the impact of typical soluble and slowly-biodegradable organic compounds, investigating the pathways through which these substrates affect the occurrence of filamentous bulking in systems operated under both high- and low-oxygen conditions. Results showed that slowly-biodegradable organic compounds lead to a concentrated distribution of microorganisms within flocs, with inward growth of filamentous bacteria. Both Tween-80 and granular starch treated systems exhibited a significant increase in protein content. The glucose system, utilizing soluble substrates, exhibited a markedly higher total polysaccharide content. Microbial communities in the Tween-80 and granular starch treated systems were characterized by a higher abundance of bacteria known to enhance sludge flocculation and settling, such as Competibacter, Xanthomonadaceae and Zoogloea. These findings are of high significance for controlling the operational performance and stability of activated sludge systems, deepening our understanding and providing a novel perspective for the improvement of wastewater treatment processes.

Construction and validation of a pancreatic cancer prognostic model based on genes related to the hypoxic tumor microenvironment.

BACKGROUND: Pancreatic cancer is one of the most lethal malignancies, characterized by poor prognosis and low survival rates. Traditional prognostic factors for pancreatic cancer offer inadequate predictive accuracy, often failing to capture the complexity of the disease. The hypoxic tumor microenvironment has been recognized as a significant factor influencing cancer progression and resistance to treatment. This study aims to develop a prognostic model based on key hypoxia-related molecules to enhance prediction accuracy for patient outcomes and to guide more effective treatment strategies in pancreatic cancer. AIM: To develop and validate a prognostic model for predicting outcomes in patients with pancreatic cancer using key hypoxia-related molecules. METHODS: This pancreatic cancer prognostic model was developed based on the expression levels of the hypoxia-associated genes CAPN2, PLAU, and CCNA2. The results were validated in an independent dataset. This study also examined the correlations between the model risk score and various clinical features, components of the immune microenvironment, chemotherapeutic drug sensitivity, and metabolism-related pathways. Real-time quantitative PCR verification was conducted to confirm the differential expression of the target genes in hypoxic and normal pancreatic cancer cell lines. RESULTS: The prognostic model demonstrated significant predictive value, with the risk score showing a strong correlation with clinical features: It was significantly associated with tumor grade (G) (b P < 0.01), moderately associated with tumor stage (T) (a P < 0.05), and significantly correlated with residual tumor (R) status (b P < 0.01). There was also a significant negative correlation between the risk score and the half-maximal inhibitory concentration of some chemotherapeutic drugs. Furthermore, the risk score was linked to the enrichment of metabolism-related pathways in pancreatic cancer. CONCLUSION: The prognostic model based on hypoxia-related genes effectively predicts pancreatic cancer outcomes with improved accuracy over traditional factors and can guide treatment selection based on risk assessment.

Short-Term Trigeminal Ganglion Stimulation in Patients with Multi-Branch Trigeminal Herpetic Neuralgia: A Pilot Study.

BACKGROUND: Trigeminal herpetic neuralgia (THN) presents with severe pain hyperalgesia and is a high-risk factor for postherpetic neuralgia (PHN). The current clinical treatments for THN are unsatisfactory, and new treatments are desperately required. OBJECTIVES: This pilot study aimed to evaluate the efficacy of short-term trigeminal ganglion stimulation in treating patients with multi-branch THN. STUDY DESIGN: A prospective pilot study. SETTING: Multi-center study in 3 academic hospitals. METHODS: From July 2021 to October 2022, we enrolled 20 patients with multi-branch THN who received short-term trigeminal ganglion stimulation under general anesthesia from 3 hospitals. All patients completed a 12-month follow-up. The visual analog scale (VAS) and Pittsburgh Sleep Quality Index (PSQI) were used to assess patients' pain and quality of sleep. The Barrow Neurological Institute (BNI) score was used to determine the global outcome of pain relief, and complications were recorded. RESULTS: Significant and sustained pain relief and sleep improvement were achieved by all the patients who underwent trigeminal ganglion electrode stimulation in the present study. Respective BNI scores of 80% and 85% at 3 and 12 months after surgery were considered good. There were no other serious complications except for 2 patients' experiences of transient trigeminal cardiac reflex during the surgery and transient numbness deterioration in one patient's V3 sensory area. LIMITATIONS: The present study is a pilot study. We expect prospective multi-center, large-sample studies in the future. CONCLUSION: Short-term trigeminal ganglion stimulation can be used safely and effectively to treat patients with multi-branch THN and significantly reduce the occurrence of PHN.

Platelet factors ameliorate thoracic aortic aneurysm and dissection by inhibiting the FGF-FGFR cascade activation in aortic-endothelial cell.

Thoracic aortic aneurysm and dissection (TAAD) is closely associated with vascular endothelial dysfunction. Platelet factor 4 (PF4) is crucial for maintaining vascular endothelial cell homeostasis. However, whether PF4 can influence the progression of TAAD remains unknown. In the present study, we constructed a liposome-encapsulated PF4 nanomedicine and verified its effect on BAPN-induced TAAD in vivo. We found that liposome PF4 nanoparticles (Lipo-PF4), more effectively than PF4 alone, inhibited the formation of TAAD. In vitro, PF4 improved endothelial cell function under pathological conditions by inhibiting migratory and angiogenic abilities of human aortic endothelial cells (HAECs). Mechanically, PF4 inhibited the development of TAAD and improved HAECs function by combining with heparin sulfate and blocking fibroblast growth factor-fibroblast growth factor receptor (FGF-FGFR) signaling. Taken together, we developed a nano-drug (Lipo-PF4) that effectively ameliorates the progression of TAAD by improving endothelial function. Lipo-PF4 is expected to be a therapeutic option for TAAD in the future.

Plant diversity value of informal green spaces in tropical coastal urban areas: An empirical study of species, functional, and phylogenetic diversity.

Informal green spaces (IGS) are a hot topic in urban biodiversity studies, but overlooked in urban biodiversity conservation or management, especially in tropical coastal cities, where comprehensive assessments remain scarce. Most existing research has been limited to species diversity (α-diversity), with few studies addressing phylogenetic, functional, and species turnover (ß-diversity) across multiple IGS types. This study bridges these gaps by conducting a detailed vegetation survey in Jiangdong New Area of Haikou City, establishing 213 sites. Within these sites, we examined 343 IGS sample plots and 274 formal green spaces (FGS) sample plots. We assessed species, functional, and phylogenetic diversity using α and ß diversity metrics and analyzed the influence of environmental factors with generalized linear mixed models (GLMMs). The results recorded 235 species of herbaceous plants from 179 genera and 54 families in IGS, including 215 spontaneous species, compared to 154 spontaneous species in FGS. Our findings indicate that IGS exhibited higher species richness and functional richness compared to FGS, though differences in phylogenetic diversity were less pronounced. Key environmental factors like relative humidity, trampling intensity, and proximity to urban areas significantly influenced species richness and abundance in IGS. These findings underscore the critical role of IGS in enhancing biodiversity and resilience in tropical coastal cities, emphasizing the need to integrate IGS into urban planning strategies for sustainable urban ecosystems.

Efficacy and safety of HAIC-FOLFOX plus tyrosine kinase inhibitors and immune checkpoint inhibitors as first-line treatment for unresectable advanced hepatocellular carcinoma: A systematic review and meta-analysis.

BACKGROUND: Advanced hepatocellular carcinoma (HCC) has been treated with targeted therapy, immunotherapy, or a combination of both, however, the overall clinical efficacy is still unsatisfactory. Hepatic arterial infusion chemotherapy (HAIC), as a localized treatment modality, has demonstrated favorable therapeutic efficacy in patients with advanced HCC accompanied by portal vein tumor thrombus and extensive intrahepatic metastasis. In recent years, the combination of HAIC with immune and targeted therapy has gradually gained acceptance in East Asian countries. However, further investigation is necessary to assess the efficacy and safety of this triple therapy. METHOD: PubMed, Embase, the Cochrane Library, and Web of Science databases were systematically searched for studies conducted within the past 5 years on HAIC combined with immunotherapy and targeted therapy as first-line treatment for advanced HCC. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted this meta-analysis. Additionally, the quality of included studies was assessed using the Joanna Briggs Institute (JBI) scale. Outcomes such as overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs)were extracted and pooled from eligible studies. RESULT: Twelve studies involving 1072 patients were enrolled in this meta-analysis. In terms of tumor response, the pooled ORR and DCR were 65.7% (95% CI, 58.7%-72.7%) (I2 = 83%, P = 0.000) and 89.2% (95% CI, 83.9%-93.6%) (I2 = 83%, P = 0.000), respectively. When analyzing PFS, the upper limit of 95% confidence interval of PFS in one study was not reached, which could potentially impact the statistical analysis. Therefore, we analyzed the remaining 11 studies a total of 1019 patients to pool mPFS, ultimately the pooled mPFS was 9.77months (95% CI, 7.73-11.80) (I2 = 93.9%, P = 0.000). Follow-up time in some studies was insufficient, only eight studies reported OS, we systematically analyzed these eight studies and extracted the pooled mOS was 16.65 months (95% CI, 14.17-19.14) (I2 = 76.9%, P = 0.000). In terms of safety, the incidence rates of any grade AEs, ranked from high to low, were as follows: aminotransferase increased (61.3%), nausea and vomiting (40.5%), hypertension (37.8%), thrombocytopenia (37.4%), hyperbilirubinemia (36.7%), abdominal pain (35.6%), leukopenia (34.6%), hypothyroidism (19.0%), rash (14.4%). Grade 3-4 AEs ranked from high to low were as follows: aminotransferase increased (10.8%), thrombocytopenia (7.9%), hypertension (7.4%), leukopenia (5.0%). No treatment-related deaths occurred, patients receiving this triple therapy demonstrated favorable tolerability. CONCLUSION: The combination of hepatic arterial infusion chemotherapy with tyrosine kinase inhibitors and immune checkpoint inhibitors as a first-line therapy for unresectable advanced HCC demonstrates promising therapeutic efficacy and favorable safety.

Single cell transcriptomics reveals dysregulated immnue homeostasis in different stages in HPV-induced cutaneous squamous cell carcinoma.

In order to explore the huge impact of impaired immnue homeostasis on the occurrence and development of cutaneous squamous cell carcinoma (cSCC), and investigate characterization of the cellular components and their changes which is crucial to understanding the pathologic process of HPV-induced cSCC, we diagnosed and followed up on a very rare HPV-induced cSCC patient who progressed at a very fast rate and transferred to death quickly. We performed single-cell RNA sequencing (scRNA-seq) of 11 379 cells from the skin tissues of this patient with four different skin statuses after HPV infection. Immunofluorescence experiments were used for validation. scRNA-seq identified that CD52+ HLA-DOA- macrophages only existed in paracancerous cutaneous squamous cell carcinoma (pc-cSCC) and cSCC tissue. Besides, immune cells including CD8+ exhausted T cells and CD4+ regulatory T cells as well as matrix cells like MMP1+, and MMP11+ fibroblasts were gradually increased. Meanwhile, COMP+ ASPN+ fibroblasts gradually decreased. Cell interaction analysis revealed enhancement in interactions between monocytes/macrophages, fibroblasts and tumour-specific keratinocytes. scRNA-seq was performed in HPV-induced cSCC for the first time, to explore the correlation between infection and tumour. It is the first time to study the development of tumours from different stages of infection in HPV-induced cSCC. In this study, the tumour itself and the tumour microenvironment were both analysed and explored. And it was validated in clinical samples from different patients. Our findings reveal the dynamic immnue homeostasis from normal skin to cSCC tissue, this alteration might drive HPV-induced cSCC.

Discovery of Novel 5-(Pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione Derivatives as Potent and Orally Bioavailable Inhibitors Targeting Ecto-5'-nucleotidase.

Ecto-5-nucleotidase (CD73) is overexpressed in a variety of cancers and associated with the immunosuppressive tumor microenvironment, making it an attractive target for cancer immunotherapy. Herein, we designed and synthesized a series of novel (pyridazine-3-yl)pyrimidine-2,4(1H,3H)-dione derivatives as CD73 inhibitors. These compounds exhibited remarkable inhibitory activity against CD73 in both enzymatic biochemical and cellular assays. Among them, compound 35j proved to be one of the most potent inhibitors and an uncompetitive inhibitor with no obvious cytotoxicity. This compound showed high metabolic stability in rat liver microsomes and favorable pharmacokinetic profiles in rats (T1/2 = 3.37 h, F = 50.24%). Importantly, orally administered 35j significantly inhibited tumor growth in the triple-negative breast cancer 4T1 mouse model (TGI = 73.6%, 50 mg/kg). Immunoassays suggested that 35j remarkably increased the infiltration of positive immune cells, thereby reinvigorating antitumor immunity. These results demonstrate that 35j is a potent CD73 inhibitor worthy of further development.

Regulating V2O5 Layer Spacing by a Polyaniline Molecule Chain to Improve Electrochemical Performance in Salinity Gradient Energy Conversion.

Salinity gradient energy is a chemical potential energy between two solutions with different ionic concentrations, which is also an ocean energy at the junction of rivers and seas. In our original work, the device "activated carbon//(0.083 M Na2SO4, 0.5 M Na2SO4)//vanadium pentoxide" for the conversion of salinity gradient energy was designed, and the conversion value of 6.29 J g-1 was obtained. However, the low specific surface area of the original V2O5 inevitably resulted in limited active sites and slow ionic transport rates, and the inherent lower conductivity and narrower layer spacing of the original V2O5 also resulted in poor electrode kinetic performance and cycle stability, hindering its practical application. To solve the above problems, the present work provides a strategy of using polyaniline (PANI) molecule chain intercalation to regulate the layer spacing of the original V2O5, and through the expansion and traction of the layer spacing, the composite PANI/V2O5 (PVO) with high specific surface area is prepared and used as an anode material for electrochemical conversion of salinity gradient energy application. The significantly increased layer spacing of the crystal plane (001) corresponding to the original V2O5 was confirmed with the PANI by the hydrogen bonding and the van der Waals force. The high specific surface area of the composite provides more electrochemical active sites to realize a fast Na+ migration rate and high specific capacitance. Meanwhile, the inserted PANI molecule chain, which acts not only as a pillar enlarging the Na+ diffusion channel but also as an anchor locking the gap between V2O5 bilayers, improves the structural stability of the V2O5 electrode during the electrochemical conversion process. The proposed insertion strategy for the conductive polymer PANI has created a new way to improve the cycle stability performance of the salinity gradient energy conversion device.

Electroencephalogram-based adaptive closed-loop brain-computer interface in neurorehabilitation: a review.

Brain-computer interfaces (BCIs) represent a groundbreaking approach to enabling direct communication for individuals with severe motor impairments, circumventing traditional neural and muscular pathways. Among the diverse array of BCI technologies, electroencephalogram (EEG)-based systems are particularly favored due to their non-invasive nature, user-friendly operation, and cost-effectiveness. Recent advancements have facilitated the development of adaptive bidirectional closed-loop BCIs, which dynamically adjust to users' brain activity, thereby enhancing responsiveness and efficacy in neurorehabilitation. These systems support real-time modulation and continuous feedback, fostering personalized therapeutic interventions that align with users' neural and behavioral responses. By incorporating machine learning algorithms, these BCIs optimize user interaction and promote recovery outcomes through mechanisms of activity-dependent neuroplasticity. This paper reviews the current landscape of EEG-based adaptive bidirectional closed-loop BCIs, examining their applications in the recovery of motor and sensory functions, as well as the challenges encountered in practical implementation. The findings underscore the potential of these technologies to significantly enhance patients' quality of life and social interaction, while also identifying critical areas for future research aimed at improving system adaptability and performance. As advancements in artificial intelligence continue, the evolution of sophisticated BCI systems holds promise for transforming neurorehabilitation and expanding applications across various domains.

CBD-Loaded Nanostructured Lipid Carriers: Optimization, Characterization, and Stability.

Cannabidiol (CBD) has demonstrated its potential to enhance depression treatment through various biological pathways. However, the application potential of CBD is significantly impeded by its polymorphic nature, limited water solubility, and hepatic first-pass metabolism. To improve chemical stability and water solubility, nanostructured lipid carriers loaded with CBD (CBD-NLCs) were developed using a hot-melt emulsification method and optimized by response surface methodology (RSM). The process parameters were optimized using a four-factor and three-level Box-Behnken experimental design consisting of 29 experiments. The CBD-NLCs were formulated and characterized, demonstrating desirable properties, including a mean particle size of 54.33 nm, a PDI value of 0.118, a zeta potential of -29.7 mV, and an impressive encapsulation efficiency rate of 87.58%. The nanoparticles were found to possess an approximately spherical shape, as revealed by scanning and transmission electron microscopy. The stability studies have demonstrated that CBD-NLCs effectively mitigated the photodegradation of CBD and exhibited a stable behavior for 42 days when stored. The CBD-NLCs displayed a biphasic release profile characterized by an initial burst release (over 50% of CBD released within 20 min) followed by a subsequent gradual and sustained release, aligned with first-order kinetics and Fickian diffusion. These findings demonstrate the potential suitability of this formulation as a carrier for CBD in food fortification and pharmaceutical applications.

The evaluation of rotational lateral ankle laxity in gravity stress position by ultrasonography: normative value in uninjured ankles.

BACKGROUND: The evaluation of lateral ankle laxity remains challenging when diagnosing chronic lateral ankle instability (CLAI). Several studies have reported that internal rotation of the talus as an indicator of rotational lateral ankle laxity (RLAL) increases in patients with CLAI. However, there is no established method for detecting and evaluating the RLAL. This study aimed to report a novel method for evaluating the RLAL in the gravity stress position by measuring the talofibular distance (TFD) using ultrasonography (US) and show the normative value of the TFD. METHODS: The TFDs in the subjects with healthy ankles were prospectively measured 10 mm distal to the ankle joint in the neutral ankle position and gravity stress position using US. The differences in the TFD between the two ankle positions were evaluated. The differences in the TFD by gender and ankle laterality were also evaluated. RESULTS: A total of 52 healthy ankles of 28 subjects (mean age, 24.0 ± 1.6; male/female, 12/16) were finally included. There was a significant difference in the TFD between the neutral ankle position (6.9 ± 0.9 mm) and gravity stress position (9.0 ± 0.9 mm) (p < 0.001). The mean difference in the TFD between the two ankle positions was 2.1 ± 0.6 mm. There were no significant differences in the TFD by gender and ankle laterality. CONCLUSIONS: The present study reported a novel US method for evaluating RLAL by applying gravity stress and the normative value of the TFD.

A gradient model of renal ischemia reperfusion injury to investigate renal interstitial fibrosis.

Background: The progression from acute kidney injury to chronic kidney disease poses a significant health challenge. Nonetheless, a constraint in existing animal models of renal ischemia/reperfusion (I/R) injury is the necessity for a severe injury, almost reaching a life-threatening level, to trigger the subsequent onset of renal fibrosis. Hence, we explored an adapted gradient approach to induce I/R injury, aiming to promote the progression of renal fibrosis while preserving the overall normal functioning of the kidney. Methods: In each group, 6-8 male C57BL/6 mice were used for model construction, with all undergoing sodium pentobarbital anesthesia and left kidney removal. Subsequently, a silk thread was passed beneath the lower renal branch, elevating the right kidney under a 20-g weight's tension via a pulley system for durations of 30, 40, or 60 min. Afterwards, we lowered the kidney, sutured the wound, and administered intraperitoneal saline. Mice in different groups were euthanized following reperfusion for 1, 3, 7, or 28 days. Results: We observed a complete cessation of blood flow in the lower pole, while an incomplete cessation in the upper pole in the elevated kidney. Significant renal impairment was evident on day 1 with a 60min ischemic period (187.0 ± 65.3 vs 17.9 ± 4.8 µmol/L serum creatinine in normal; p < .001), but not with 30 or 40min. On day 1, tubular necrosis and hyaline cast formation was evident in both lower and upper poles. On day 3, renal function returned to normal and remained normal through day 28. Histologic damage resolved in the upper pole over days 3 to 7, resulting in normal histology on day 28. By contrast, there was sustained tubular damage tubular in the lower pole on days 3 and 7, which failed to resolve and led to significant renal fibrosis by day 28. Conclusion: We created a model demonstrating clinically "silent" renal fibrosis.

Study on the differentiation of sensory quality of mainstream Jiang-flavor baijiu in the Chinese market based on Pivot Profile.

Jiang-flavor baijiu (JFB) is a prominent type of Chinese baijiu, known for its unique flavor attributes, sensory experience, and high tasting value. Previous research has mainly focused on the detection and identification of its flavor substances, but in-depth studies on the precise sensory description and differentiation of its flavor qualities are still lacking. In this study, a rapid sensory analysis method, Pivot Profile (PP), was applied to 30 mainstream JFBs in the Chinese market, generating 91 sensory attributes with independent definitions, from which 29 main sensory attributes were established that were easy to perceive and descriptive, as well as convenient for transmitting their sensory qualities and distinguishing differences in price and production region, including color (one descriptor), aroma (21 descriptors), taste, and mouthfeel (seven descriptors). The nine key sensory attributes that distinguish JFB quality are as follows: Jiang, Grain, Chen, Qu, Rancid, Acid, Sweet, Fullness, and Harmony. It was found that price was positively correlated with sensory quality, with greater variation in the quality of samples within the medium price range (RMB 500-1000). All samples from MTCQ1 (the core production area of Maotai Town) performed better in sensory quality. In addition, salted vegetable showed a high degree of regional characteristics, concentrated in most of the production regions of Guizhou Province. Aroma attributes were more suitable than taste and mouthfeel as sensory indicators for distinguishing production regions. This study has opened the direction of systematic construction of sensory description of JFB and provided a successful case for the evaluation of Chinese baijiu using novel sensory analysis techniques.

Interpretable machine learning model for predicting the prognosis of antibody positive autoimmune encephalitis patients.

OBJECTIVE: The objective was to utilize nine machine learning (ML) methods to predict the prognosis of antibody positive autoimmune encephalitis (AE) patients. METHODS: The encephalitis data from the Global Burden of Disease (GBD) study is analyzed to reflect the disease burden of encephalitis. This study included 187 patients with AE. 121 patients as training set and 67 patients as validation set. Decision trees (DT), random forest (RF), extreme gradient boosting (XGBoost), k-nearest neighbor (KNN), support vector machine (SVM), naive bayes (NB), neural network (NN), light gradient boosting machine (LGBM), and logistic regression (LR) are ML methods used to construct predictive models. The constructed models were validated for discrimination, calibration and clinical applicability using validation set data. Shapley additive explanation (SHAP) analysis was used to explain the model. RESULTS: The number of encephalitis worldwide deaths, incidence and prevalence is increasing every year from 2010 to 2021. The training set included 121 patients with AE. Univariate analysis and LASSO screening identified six variables. The results of constructing models using 9 ML methods showed RF had the highest accuracy (0.860), followed by XGBoost (0.826), with F1 scores of 0.844 and 0.807, respectively. Validation set data showed good discrimination, calibration and clinical applicability of the model. The SHAP values of infection, CSF monocyte percentage, and prealbumin were 0.906, 0.790, and 0.644, respectively. LIMITATIONS: As a rare disease, the sample size of this study is relatively small. CONCLUSION: The model constructed using RF and XGBoost has good performance, good discrimination, calibration, clinical applicability, and interpretability.

Multi-strategy fusion improved Northern Goshawk optimizer is used for engineering problems and UAV path planning.

Addressing the imbalance between exploration and exploitation, slow convergence, local optima Traps, and low convergence precision in the Northern Goshawk Optimizer (NGO): Introducing a Multi-Strategy Integrated Northern Goshawk Optimizer (MINGO). In response to challenges faced by the Northern Goshawk Optimizer (NGO), including issues like the imbalance between exploration and exploitation, slow convergence, susceptibility to local optima, and low convergence precision, this paper introduces an enhanced variant known as the Multi-Strategy Integrated Northern Goshawk Optimizer (MINGO). The algorithm tackles the balance between exploration and exploitation by improving exploration strategies and development approaches. It incorporates Levy flight strategies to preserve population diversity and enhance convergence precision. Additionally, to avoid getting trapped in local optima, the algorithm introduces Cauchy mutation strategies, improving its capability to escape local optima during the search process. Finally, individuals with poor fitness are eliminated using the crossover strategy of the Differential Evolution algorithm to enhance the overall population quality. To assess the performance of MINGO, this paper conducts an analysis from four perspectives: population diversity, balance between exploration and exploitation, convergence behavior, and various strategy variants. Furthermore, MINGO undergoes testing on the CEC-2017 and CEC-2022 benchmark problems. The test results, along with the Wilcoxon rank-sum test results, demonstrate that MINGO outperforms NGO and other advanced optimization algorithms in terms of overall performance. Finally, the applicability and superiority of MINGO are further validated on six real-world engineering problems and a 3D Trajectory planning for UAVs.

The first in-human study to evaluate the antiplatelet properties of the clopidogrel conjugate DT-678 in acute coronary syndrome patients and healthy volunteers.

BACKGROUND AND PURPOSE: DT-678 is a novel antiplatelet prodrug, capable of releasing the antiplatelet active metabolite of clopidogrel (AM) upon exposure to glutathione. In this study, we investigated factors responsible for clopidogrel high on-treatment platelet reactivity (HTPR) in acute coronary syndrome (ACS) patients and evaluated the capacity of DT-678 to overcome HTPR. EXPERIMENTAL APPROACH: A total of 300 consecutive ACS patients naive to P2Y12 receptor inhibitors were recruited and genotyped for CYP2C19 alleles. Blood samples were drawn before and after administration of 600-mg clopidogrel. Platelet reactivity index (PRI) and plasma AM concentrations were determined and grouped according to their CYP2C19 genotypes. DT-678 was applied ex vivo to whole blood samples to examine its inhibitory effects. To further examine the antiplatelet effectiveness of DT-678 in vivo, 20 healthy human subjects were recruited in a Phase I clinical trial, and each received a single dose of either 3-mg DT-678 or 75-mg clopidogrel. The pharmacokinetics and pharmacodynamics in different CYP2C19 genotype groups were compared. KEY RESULTS: Statistical analyses revealed that CYP2C19 genotype, body mass index, hyperuricaemia, and baseline PRI were significantly associated with a higher risk of clopidogrel HTPR in ACS patients. The addition of DT-678 ex vivo decreased baseline PRI regardless of CYP2C19 genotypes, overcoming clopidogrel HTPR. This observation was further confirmed in healthy volunteers receiving 3 mg of DT-678. CONCLUSION AND IMPLICATIONS: These results suggest that DT-678 effectively overcomes clopidogrel HTPR resulting from genetic and/or clinical factors in Chinese ACS patients, demonstrating its potential to improve antiplatelet therapy.

Simplified rapid hydration and contrast-associated acute kidney injury among CKD patients stratified by Mehran score: sub-analysis from the TIME Trial.

Simplified rapid hydration has been proven to be non-inferior to standard hydration in preventing contrast-associated acute kidney injury among chronic kidney disease patients undergoing coronary angiography. The current investigation aimed to further confirm the feasibility and safety of the newly proposed hydration method-simplified rapid hydration (SH) in each risk stratification by Mehran risk score (MRS). Eligible patients (n = 954) randomized to the SH group and standard hydration group were allocated into 2 groups based on MRS: low to moderate-risk and high to very high-risk groups. Primary endpoints were the incidence of contrast-associated acute kidney injury (CA-AKI) and acute heart failure (AHF) (SH vs standard hydration). Secondary endpoints included serum creatinine (Scr), blood urea nitrogen (BUN), cystatin-C (Cys-C), and C-reactive protein (CRP) at 24 h, 48 h, and 72 h after PCI procedure, and the incidence of major adverse cardiac events (MACE). MRS was associated with a higher incidence of CA-AKI (OR = 1.101, 95%CI 1.049-1.156, P < 0.001). In the low to moderate-risk and high to very-high-risk groups, the incidence of CA-AKI in the SH and standard hydration group was 3.3% versus 4.9% (P = 0.5342), 10% versus 12% (P = 0.6392), respectively. Meanwhile, there might be subtle differences in renal function indexes and inflammatory indicators between SH and the control group at different time points. The preventive effect of SH in CA-AKI was similar to standard hydration regardless of MRS-guided risk stratification.

Inter3D: Capture of TAD Reorganization Endows Variant Patterns of Gene Transcription.

Topologically associating domain (TAD) reorganization commonly occurs in the cell nucleus and contributes to gene activation and inhibition through the separation or fusion of adjacent TADs. However, functional genes impacted by TAD alteration and the underlying mechanism of TAD reorganization regulating gene transcription remain to be fully elucidated. Here, we first developed a novel approach termed Inter3D to specifically identify genes regulated by TAD reorganization. Our study revealed that the segregation of TADs led to the disruption of intrachromosomal looping at the myosin light chain 12B (MYL12B) locus, via the meticulous reorganization of TADs mediating epigenomic landscapes within tumor cells, thereby exhibiting a significant correlation with the down-regulation of its transcriptional activity. Conversely, the fusion of TADs facilitated intrachromosomal interactions, suggesting a potential association with the activation of cytochrome P450 family 27 subfamily B member 1 (CYP27B1). Our study provides comprehensive insight into the capture of TAD rearrangement-mediated gene loci and moves toward understanding the functional role of TAD reorganization in gene transcription. The Inter3D pipeline developed in this study is freely available at https://github.com/bm2-lab/inter3D and https://ngdc.cncb.ac.cn/biocode/tool/BT7399.

Modular Synthesis of gem-Difluorotetrahydrocarbazolone Scaffolds via Copper-Catalyzed Cascade Reaction of Bromodifluoroacetyl Indoles and Olefins.

A novel and efficient modular synthesis of gem-difluorotetrahydrocarbazolone scaffolds via copper-catalyzed radical cascade cyclization of bromodifluoroacetyl indoles and olefins has been reported. This operationally simple protocol provides straightforward and practical access to a series of privileged gem-difluorotetrahydrocarbazolone scaffolds from readily available starting materials, with the feature of broad functional group tolerance and mild reaction conditions. Moreover, the method could be used for the late-stage functionalization of bioactive molecules, which opens up the possibility for practical applications.