Allicin inhibits the growth of HONE-1 and HNE1 human nasopharyngeal carcinoma cells by inducing ferroptosis.

Allicin (AL) is one of garlic-derived organosulfides and has a variety of pharmacological effects. Studies have reported that AL has notable inhibitory effects on liver cancer, gastric cancer, breast cancer, and other cancers. However, there are no relevant reports about its role in human nasopharyngeal carcinoma. Ferroptosis is an iron-dependent form of non-apoptotic regulated cell death. Increasing evidence indicates that induction of ferroptosis can inhibit the proliferation, migration, invasion, and survival of various cancer cells, which act as a tumor suppressor in cancer. In this study, we confirmed that AL can inhibit cell proliferation, migration, invasion, and survival in human nasopharyngeal carcinoma cells. Our finding shows that AL can induce the ferroptosis axis by decreasing the level of GSH and GPX4 and promoting the induction of toxic LPO and ROS. AL-mediated cytotoxicity in human nasopharyngeal carcinoma cells is dependent on ferroptosis. Therefore, AL has good anti-cancer properties and is expected to be a potential drug for the treatment of nasopharyngeal carcinoma.

Clinical outcomes of pelvic bone marrow sparing radiotherapy for cervical cancer: A systematic review and meta-analysis of randomised controlled trials.

Background: Concurrent chemoradiotherapy (CRT) is the standard treatment for locally advanced cervical cancer. We investigated how additional bone marrow sparing (BMS) affects the clinical outcomes. Methods: We queried MEDLINE, Embase, Web of Science Core Collection, Google Scholar, Sinomed, CNKI, and Wanfang databases for articles published in English or Chinese between 2010/01/01 and 2023/10/31. Full-text manuscripts of prospective, randomised trials on BMS in cervical cancer patients treated with definitive or postoperative CRT were included. Risk of bias (RoB) was assessed using Cochrane Collaboration's RoB tool. Random-effects models were used for the meta-analysis. Results: A total of 17 trials encompassing 1297 patients were included. The majority were single-centre trials (n = 1268) performed in China (n = 1128). Most trials used CT-based anatomical BMS (n = 1076). There was a comparable representation of trials in the definitive (n = 655) and postoperative (n = 582) settings, and the remaining trials included both.Twelve studies reported data on G ≥ 3 (n = 782) and G ≥ 2 (n = 754) haematologic adverse events. Both G ≥ 3 (OR 0.39; 95 % CI 0.28-0.55; p < 0.001) and G ≥ 2 (OR 0.29; 95 % CI 0.18-0.46; p < 0.001) toxicity were significantly lowered, favouring BMS. Seven studies (n = 635) reported data on chemotherapy interruptions, defined as receiving less than five cycles of cisplatin, which were significantly less frequent in patients treated with BMS (OR 0.44; 95 % CI 0.24-0.81; p = 0.016). There was no evidence of increased gastrointestinal or genitourinary toxicity.There were no signs of significant heterogeneity. Four studies were assessed as high RoB; sensitivity analyses excluding these provided comparable results for main outcomes. The main limitations include heterogeneity in BMS methodology between studies, low representation of populations most affected by cervical cancer, and insufficient data to assess survival outcomes. Conclusions: The addition of BMS to definitive CRT in cervical cancer patients decreases hematologic toxicity and the frequency of interruptions in concurrent chemotherapy. However, data are insufficient to verify the impact on survival and disease control.

The survival prediction of advanced colorectal cancer received neoadjuvant therapy-a study of SEER database.

PURPOSE: The aim of study was to screen factors associated with the overall survival of colorectal cancer patients with lymph nodes metastasis who received neoadjuvant therapy and construct a nomogram model. METHODS: All enrolled subjects of the SEER database were randomly assigned to the training and testing group in a ratio of 3:2. The patients of Tangdu Hospital were seemed as validation group. Univariate cox regression analysis, lasso regression and random forest survival were used to screen variables related to the survival of advanced CRC patients received neoadjuvant therapy in the training group. Area under curves were adopted to evaluate the 1,3,5-year prediction value of the optimal model in three cohorts. Calibration curves were drawn to observe the prediction accuracy of the nomogram model. Decision curve analysis was used to assess the potential clinical value of the nomogram model. RESULTS: A total of 1833 subjects were enrolled in this study. After random allocation, 1055 cases of the SEER database served as the training group, 704 cases as the testing group and 74 patients from our center as the external validation group. Variables were screened by univariate cox regression used to construct a nomogram survival prediction model, including M, age, chemotherapy, CEA, perineural invasion, tumor size, LODDS, liver metastasis and radiation. The AUCs of the model for predicting 1-year OS in the training group, testing and validation group were 0.765 (0.703,0.827), 0.772 (0.697,0.847) and 0.742 (0.601,0.883), predicting 3-year OS were 0.761 (0.725,0.780), 0.742 (0.699,0.785), 0.733 (0.560,0.905) and 5-year OS were 0.742 (0.711,0.773), 0.746 (0.709,0.783), 0.838 (0.670,0.980), respectively. The calibration curves showed the difference between prediction probability of the model and the actual survival was not significant in three cohorts and the decision curve analysis revealed the practice clinical application value. And the prediction value of model was better for young CRC than older CRC patients. CONCLUSION: A nomogram model including LODDS for the prognosis of advanced CRC received neoadjuvant therapy was constructed and verified based on the SEER database and single center practice. The accuracy and potential clinical application value of the model performed well, and the model had better predictive value for EOCRC than LOCRC.

Silencing UBE2K inhibits the growth of glioma cells by inducing the autophagy-related apoptosis.

Glioma is a central nervous system (CNS) malignant tumor with high heterogeneity and mortality, which severely threatens the health of patients. The overall survival of glioma patients is relatively short and it is critical to identify new molecular targets for developing effective treatment strategies. UBE2K is a ubiquitin conjugating enzyme with oncogenic function in several malignant tumors. However, whether UBE2K participates in gliomas remains unknown. Herein, in glioma cells, UBE2K was found highly expressed in U87 and U251 cells. Subsequently, U87 and U251 cells were transfected with si-UBE2K to silence UBE2K, with the si-NC transfection as the negative control. In both U87 and U251 cells, the cell viability was sharply reduced by transfecting si-UBE2K for 48 and 72 h. Markedly decreased colony number, reduced number of migrated cells and invaded cells, and declined relative wound healing rate were observed in si-UBE2K transfected U87 and U251 cells. Moreover, the Bcl-2 level was markedly reduced, while the Bax and cleaved-caspase-3 levels were sharply increased in U87 and U251 cells after the si-UBE2K transfection. Furthermore, the p62 level was signally declined, while the Beclin-1 and LC-3 II/I levels were greatly increased in U87 and U251 cells by the si-UBE2K transfection. Furthermore, the facilitating effect of si-UBE2K on the apoptosis and autophagy in U87 and U251 cells was abolished by the coculture of 3-MA, an inhibitor of autophagy. Collectively, UBE2K facilitated the in vitro growth of glioma cells, possibly by inhibiting the autophagy-related apoptosis, which might be a promising target for treating glioma.

Spatial-temporal analysis of hepatitis E in Hainan Province, China (2013-2022): insights from four major hospitals.

Objective: Exploring the Incidence, Epidemic Trends, and Spatial Distribution Characteristics of Sporadic Hepatitis E in Hainan Province from 2013 to 2022 through four major tertiary hospitals in the Province. Methods: We collected data on confirmed cases of hepatitis E in Hainan residents admitted to the four major tertiary hospitals in Haikou City from January 2013 to December 2022. We used SPSS software to analyze the correlation between incidence rate and economy, population density and geographical location, and origin software to draw a scatter chart and SAS 9.4 software to conduct a descriptive analysis of the time trend. The distribution was analyzed using ArcMap 10.8 software (spatial autocorrelation analysis, hotspot identification, concentration, and dispersion trend analysis). SAS software was used to build an autoregressive integrated moving average model (ARIMA) to predict the monthly number of cases in 2023 and 2024. Results: From 2013 to 2022, 1,922 patients with sporadic hepatitis E were treated in the four hospitals of Hainan Province. The highest proportion of patients (n = 555, 28.88%) were aged 50-59 years. The annual incidence of hepatitis E increased from 2013 to 2019, with a slight decrease in 2020 and 2021 and an increase in 2022. The highest number of cases was reported in Haikou, followed by Dongfang and Danzhou. We found that there was a correlation between the economy, population density, latitude, and the number of cases, with the correlation coefficient |r| value fluctuating between 0.403 and 0.421, indicating a linear correlation. At the same time, a scatter plot shows the correlation between population density and incidence from 2013 to 2022, with r2 values fluctuating between 0.5405 and 0.7116, indicating a linear correlation. Global Moran's I, calculated through spatial autocorrelation analysis, showed that each year from 2013 to 2022 all had a Moran's I value >0, indicating positive spatial autocorrelation (p < 0.01). Local Moran's I analysis revealed that from 2013 to 2022, local hotspots were mainly concentrated in the northern part of Hainan Province, with Haikou, Wenchang, Ding'an, and Chengmai being frequent hotspot regions, whereas Baoting, Qiongzhong, and Ledong were frequent cold-spot regions. Concentration and dispersion analysis indicated a clear directional pattern in the average density distribution, moving from northeast to southwest. Time-series forecast modeling showed that the forecast number of newly reported cases per month remained relatively stable in 2023 and 2024, fluctuating between 17 and 19. Conclusion: The overall incidence of hepatitis E in Hainan Province remains relatively stable. The incidence of hepatitis E in Hainan Province increased from 2013 to 2019, with a higher clustering of cases in the northeast region and a gradual spread toward the southwest over time. The ARIMA model predicted a relatively stable number of new cases each month in 2023 and 2024.

Drug-coated balloon angioplasty for the treatment of intracranial arterial stenosis in a young stroke patient: A case report.

BACKGROUND: Intracranial arterial narrowing is a significant factor leading to brief episodes of reduced blood flow to the brain, known as transient ischemic attacks, or full-blown strokes. While atherosclerosis is commonly associated with intracranial arterial narrowing, it is frequently of a non-atherosclerotic nature in younger patients. CASE SUMMARY: Here, we present the case of a young stroke patient with narrowing of the middle cerebral artery (MCA), characterized as non-atherosclerotic lesions, who experienced an ischemic stroke despite receiving standard drug therapy. The patient underwent digital subtraction angiography (DSA) to assess the entire network of blood vessels in the brain, revealing significant narrowing (approximately 80%) in the M1 segment of the right MCA. Subsequently, the patient underwent Drug-Coated Balloon Angioplasty to treat the stenosis in the right MCA's M1 segment. Follow-up DSA confirmed the resolution of stenosis in this segment. Although the remaining branches showed satisfactory blood flow, the vessel wall exhibited irregularities. A review of DSA conducted six months later showed no evident stenosis in the right MCA, with a smooth vessel wall. CONCLUSION: The use of drug-coated balloon angioplasty demonstrated favorable outcomes in repairing and reshaping the blood vessel wall in young patients. Therefore, it may be considered a promising treatment option for similar cases.

Reduction of Beany Flavor and Improvement of Nutritional Quality in Fermented Pea Milk: Based on Novel Bifidobacterium animalis subsp. lactis 80.

Peas (Pisum sativum L.) serve as a significant source of plant-based protein, garnering consumer attention due to their high nutritional value and non-GMO modified nature; however, the beany flavor limits its applicability. In this study, the effects of Bifidobacterium animalis subsp. Lactis 80 (Bla80) fermentation on the physicochemical characteristics, particle size distribution, rheological properties, and volatile flavor compounds of pea milk was investigated. After fermentation by Bla80, the pH of pea milk decreased from 6.64 ± 0.01 to 5.14 ± 0.01, and the (D4,3) distribution decreased from 142.4 ± 0.47 µm to 122.7 ± 0.55 µm. In addition, Lactic acid bacteria (LAB) fermentation significantly reduced the particle size distribution of pea milk, which was conducive to improving the taste of pea milk and also indicated that Bla80 had the probiotic potential of utilizing pea milk as a fermentation substrate. According to GC-MS analysis, 64 volatile compounds were identified in fermented pea milk and included aldehydes, alcohols, esters, ketones, acids, and furans. Specifically, aldehydes in treated samples decreased by 27.36% compared to untreated samples, while esters, ketones, and alcohols increased by 11.07%, 10.96%, and 5.19%, respectively. These results demonstrated that Bla80 fermentation can significantly decrease the unpleasant beany flavor, such as aldehydes and furans, and increase fruity or floral aromas in treated pea milk. Therefore, Bla80 fermentation provides a new method to improve physicochemical properties and consumer acceptance of fermented pea milk, eliminating undesirable aromas for the application of pea lactic acid bacteria beverage.

Isoporous Membranes by the Symmetric Triblock Copolymer: A Strategy to Improve the Mechanical Strength without Sharply Changing the Pore Size and Permselectivity.

Isoporous membranes produced from diblock copolymers commonly display a poor mechanical property that shows many negative impacts on their separation application. It is theoretically predicted that dense films produced from symmetric triblock copolymers show much stronger mechanical properties than those of homologous diblock copolymers. However, to the best of our knowledge, symmetric triblock copolymers have rarely been fabricated into isoporous membranes before, and a full understanding of separation as well as mechanical properties of membranes prepared from triblock copolymers and homologous diblock copolymers has not been conducted, either. In this work, a cleavable symmetric triblock copolymer with polystyrene as the side block and poly(4-vinylpyridine) (P4VP) as the middle block was synthesized and designed by the RAFT polymerization using the symmetric chain transfer agent, which located at the center of polymer chains and could be removed to produce homologous diblock copolymers with half-length while having the same composition as that found in triblock copolymers. The self-assembly of these two copolymers in thin films and casting solutions was first investigated, observing that they displayed similar self-organized structures under these two conditions. When fabricated into isoporous membranes, they showed similar pore sizes (5-7% difference) and comparable rejection performance (∼10% difference). However, isoporous membranes produced from triblock copolymers showed significantly improved mechanical strength and higher toughness (2-10 times larger) as evidenced by the compacting resistance, strain-stress determination, and nanoindentation testing, suggesting the unique and novel structure-performance relationship in the isoporous membranes produced from symmetric triblock copolymers. The above finding will guide the way to fabricate mechanically robust isoporous membranes without notably changing the separation performance from rarely used symmetric triblock copolymers, which can be synthesized by the controlled polymerization as facilely as that found for diblock copolymers.

HAFormer: Unleashing the Power of Hierarchy-Aware Features for Lightweight Semantic Segmentation.

Both Convolutional Neural Networks (CNNs) and Transformers have shown great success in semantic segmentation tasks. Efforts have been made to integrate CNNs with Transformer models to capture both local and global context interactions. However, there is still room for enhancement, particularly when considering constraints on computational resources. In this paper, we introduce HAFormer, a model that combines the hierarchical features extraction ability of CNNs with the global dependency modeling capability of Transformers to tackle lightweight semantic segmentation challenges. Specifically, we design a Hierarchy-Aware Pixel-Excitation (HAPE) module for adaptive multi-scale local feature extraction. During the global perception modeling, we devise an Efficient Transformer (ET) module streamlining the quadratic calculations associated with traditional Transformers. Moreover, a correlation-weighted Fusion (cwF) module selectively merges diverse feature representations, significantly enhancing predictive accuracy. HAFormer achieves high performance with minimal computational overhead and compact model size, achieving 74.2% mIoU on Cityscapes and 71.1% mIoU on CamVid test datasets, with frame rates of 105FPS and 118FPS on a single 2080Ti GPU. The source codes are available at https://github.com/XU-GITHUB-curry/HAFormer.

Application of Synthetic TOF-MRA-CT Fusion Imaging in Preoperative Planning for Aneurysm Clipping Surgery: A Comparative Study with 3D-CTA.

OBJECTIVE: Some patients with intracranial aneurysms (IAs) cannot undergo three-dimensional computed tomography angiography (3D-CTA) or digital subtraction angiography (DSA) due to contraindications to contrast agents or radiation. Time-of-flight magnetic resonance angiography (TOF-MRA) offers a contrast-free alternative but lacks cranial bone detail critical for surgical planning. This study evaluates the feasibility of using 3DSlicer to fuse TOF-MRA with thin-section CT images to generate synthetic images resembling CTA for surgical clipping planning. METHODS: This prospective study included 22 patients with unruptured IAs (UIAs) and 8 with ruptured IAs (RIAs) undergoing aneurysm clipping surgery (≥3mm). TOF-MRA and CT/3D-CTA scans were fused using 3DSlicer. Neuroradiologists and neurosurgeons independently assessed 3D-CTA and synthetic TOF-MRA-CT images for aneurysm detection rates, morphology, and dimensions. Evaluation metrics included Dice Similarity Coefficient (DSC) and 95% Hausdorff Distance (HD). RESULTS: Evaluation of aneurysm detection rates, morphology, and dimensions showed no significant differences between synthetic TOF-MRA-CT fusion images and 3D-CTA (all p>0.05). Neuroradiologist assessments revealed strong concordance in aneurysm morphology between synthetic TOF-MRA-CT fusion images and 3D-CTA (κ=0.867, p<0.001). The DSC (0.937 ± 0.012) and HD (4.54 ± 0.26) indicated a high degree of image overlap between synthetic TOF-MRA-CT fusion images and 3D-CTA. Surgeons rated the consistency of aneurysm morphology between synthetic TOF-MRA-CT fusion images and intraoperative findings as strongly concordant (κ=0.873, p<0.001). CONCLUSION: Synthetic TOF-MRA-CT fusion images closely match 3D-CTA for ≥3mm aneurysms, demonstrating comparable diagnostic and surgical clipping planning effectiveness. They represent a promising alternative for personalized preoperative planning, particularly when contrast agents are contraindicated.

Quantitative susceptibility mapping of subcortical iron deposition in Parkinson disease and multiple system atrophy: clinical correlations and diagnostic implications.

Background: Parkinson disease (PD) and multiple system atrophy (MSA) are neurodegenerative disorders characterized by the accumulation of alpha-synuclein. Distinguishing between these conditions remains a significant challenge. This study thus employed quantitative susceptibility mapping (QSM) to evaluate subcortical iron deposition and its clinical implications in patients with PD or MSA and a group of healthy controls (HCs). Methods: The study included 26 patients with MSA, 40 patients with PD, and 35 HCs. We used magnetic resonance imaging (MRI)-based QSM to measure iron accumulation in the substantia nigra pars compacta (SNc), substantia nigra pars reticulata (SNr), and globus pallidus internus (GPi). We assessed differences between groups, examined correlations with clinical scores, and conducted receiver operating characteristic (ROC) curve analysis. Results: Compared to those with PD, patients with MSA showed more severe motor and nonmotor impairment. QSM analysis indicated a significant increase in iron levels in the SNc, SNr, and GPi regions in patient groups compared to HCs. In patients with MSA, a notable positive correlation was found between SNc QSM values and Non-Motor Symptoms Scale scores (r=0.4; P=0.043). In patients with PD, a positive association was observed between iron levels in the SNc and Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) (r=0.395; P=0.012) and Hamilton Depression Rating Scale scores (r=0.313; P=0.049). Furthermore, iron content in the GPi inversely correlated with rapid-eye movement sleep behavior disorder questionnaire-Hong Kong scores (r=-0.342; P=0.031). The SNr region demonstrated the best ability to discriminate between MSA and PD with an area under the curve (AUC) of 0.67, followed by the GPi (AUC =0.64) and SNc (AUC =0.57). Conclusions: QSM effectively quantified subcortical iron deposition in the PD, MSA, and HC groups. The correlations found between iron levels and clinical manifestations provide insights into the pathophysiological processes of these disorders, highlighting the potential of QSM as a diagnostic tool for differentiation.

Rumen microbiota succession throughout the perinatal period and its association with postpartum production traits in dairy cows: A review.

The transition period for dairy cows usually refers to the 3 weeks pre-calving to the 3 weeks post-calving. During this period, dairy cows undergo metabolic and physiological adaptations because of their susceptibility to metabolic and infectious diseases. Poor feeding management under these circumstances may adversely affect the health and subsequent production performance of the cows. Owing to long-term adaptation and evolution, the rumen has become a unique ecosystem inhabited by a complex microbial community closely associated with its natural host. Dietary components are metabolized by the rumen microbiota, and volatile fatty acids and microbial protein products can be used as precursor substances for synthesizing meat and milk components. The successful transition of perinatal dairy cows includes changes in diet, physiology, and the rumen microbiota. Rumen microbial profiles have been confirmed to be heritable and repairable; however, adverse circumstances affect rumen microbial composition, host digestion and metabolism, as well as postpartum production traits of dairy cows for a certain period. Preliminary evidence indicates a close relationship between the rumen microbiota and animal performance. Therefore, changes in rumen microbes during the transition period and the intrinsic links between the microbiota and host postpartum phenotypic traits need to be better understood to optimize production performance in ruminants.

Predicting anion diffusion in bentonite using hybrid machine learning model and correlation of physical quantities.

Radionuclide diffusion will be influenced by numerous factors. Establishing a model that can elucidate the internal correlation between mesoscopic diffusion and the microscopic structure of bentonite can enhance the comprehension of radionuclide diffusion mechanisms. In this study, a light gradient boosting machine (LightGBM) was employed to predict the effective diffusion coefficients of HCrO4-, I-, and CoEDTA2- in bentonite. The model's hyperparameters were optimized using the particle swarm optimization (PSO) algorithm. Several correlated physical quantities, such as mesoscopic parameters (total porosity, rock capacity factor, and ion molar conductivity) and microscopic parameters (ionic radius and montmorillonite stacking number) were incorporated to develop a machine learning model that incorporated micro- and meso-scale features. The predictive performance of PSO-LightGBM was verified using diffusion experiments, which investigated the diffusion of HCrO4-, I-, and CoEDTA2- at compacted dry densities of 1200-1800 kg/m3 using a through-diffusion method. Spearman correlation and Shapley additive explanation analyses revealed that the compacted dry density, ionic diffusion coefficient in water, ionic radius, and total porosity were the top-four influencing factors among the 16 input features. Partial dependence plot analysis elucidated the relationship between the effective diffusion coefficient and each input feature. The analysis results were consistent with the experimental findings, demonstrating the reliability of machine learning. Due to the incorporation of multi-scale features, the PSO-LightGBM model demonstrated enhanced predictive accuracy, linking the microstructure of bentonite to radionuclide diffusion, and providing a comprehensive interpretation of the diffusion mechanism.

Development of a Rayleigh-Brillouin scattering spectrometer for fast high-gas-temperature measurements.

We proposed a Rayleigh-Brillouin scattering (RBS) spectrometer based on a virtually imaged phased array (VIPA) for fast measurements of high-gas temperature. We measured the RBS spectra of air in the temperature range of 374 to 1073 K with an acquisition time of 7 s. We used the Tenti S6 model to fit the spectra and retrieve the absolute temperature values. The root mean square errors of spectra fit residual were less than 3.05%, and the absolute error of the retrieved temperature was less than 39 K. This study demonstrated the ability of the RBS spectrometer to realize fast high-temperature measurement and its potential for combustion control applications.

Identification of potential PIM-2 inhibitors via ligand-based generative models, molecular docking and molecular dynamics simulations.

Proviral Integrations of Moloney-2 (PIM-2) kinase is a promising target for various cancers and other diseases, and its inhibitors hold potential for treating related diseases. However, there is currently no clinically available PIM-2 inhibitor. In this study, we constructed a generative model for de novo PIM-2 inhibitor design based on artificial intelligence, performed molecular docking and molecular dynamics (MD) simulations to develop an efficient PIM-2 inhibitor generative model and discover potential PIM-2 inhibitors. First, we designed a generative model based on a Bi-directional Long Short-Term Memory (BiLSTM) framework combined with a transfer learning strategy and generated a new PIM-2 small molecule library using existing active drug databases. The generated compound library was then virtually screened by molecular docking and scaffold similarity comparison, identifying 10 initial hit compounds with better performance. Next, using the inhibitor in the crystal structure as a positive control, we performed two rounds of MD simulations, with lengths of 100 ns and 500 ns, respectively, to study the dynamic stability of the protein-ligand systems of the 10 compounds with PIM-2. Analyzed the interactions with key hinge region residues, binding free energies, and changes in the ATP pocket size. The generative model demonstrates good molecular generation capability and can generate efficient novel molecules with similar physicochemical properties as active PIM-2 drugs. Among the 10 initially selected hit compounds, 5 compounds C3 (- 29.69 kcal/mol), C4 (- 33.31 kcal/mol), C5 (- 28.59 kcal/mol), C8 (- 34.68 kcal/mol), and C9 (- 25.88 kcal/mol) have higher binding energies with PIM-2 than the positive drug 3YR (- 26.18 kcal/mol). The MD simulation results are consistent with the docking analysis, these compounds have lower and more stable RMSD values for the complex systems with the reported positive drug 3YR and PIM-2 complex system. They can form long-term stable interactions with active site and the hinge region of PIM-2, which suggests these compounds are likely to have potent inhibitory effects on PIM-2. This study provides an efficient generative model for PIM-2 inhibitor research and discovers 5 potential novel PIM-2 inhibitors.

[Gene-gene/gene-environment interaction of transforming growth factor-ß signaling pathway and the risk of non-syndromic oral clefts].

OBJECTIVE: To explore the association between polymorphisms of transforming growth factor-ß (TGF-ß) signaling pathway and non-syndromic cleft lip with or without cleft palate (NSCL/P) among Asian populations, while considering gene-gene interaction and gene-environment interaction. METHODS: A total of 1 038 Asian NSCL/P case-parent trios were ascertained from an international consortium, which conducted a genome-wide association study using a case-parent trio design to investigate the genes affec-ting risk to NSCL/P. After stringent quality control measures, 343 single nucleotide polymorphism (SNP) spanning across 10 pivotal genes in the TGF-ß signaling pathway were selected from the original genome-wide association study(GWAS) dataset for further analysis. The transmission disequilibrium test (TDT) was used to test for SNP effects. The conditional Logistic regression models were used to test for gene-gene interaction and gene-environment interaction. Environmental factors collected for the study included smoking during pregnancy, passive smoking during pregnancy, alcohol intake during pregnancy, and vitamin use during pregnancy. Due to the low rates of exposure to smoking during pregnancy and alcohol consumption during pregnancy (<3%), only the interaction between maternal smoking during pregnancy and multivitamin supplementation during pregnancy was analyzed. The threshold for statistical significance was rigorously set at P =1.46×10-4, applying Bonferroni correction to account for multiple testing. RESULTS: A total of 23 SNPs in 4 genes yielded nominal association with NSCL/P (P<0.05), but none of these associations was statistically significant after Bonferroni' s multiple test correction. However, there were 6 pairs of SNPs rs4939874 (SMAD2) and rs1864615 (TGFBR2), rs2796813 (TGFB2) and rs2132298 (TGFBR2), rs4147358 (SMAD3) and rs1346907 (TGFBR2), rs4939874 (SMAD2) and rs1019855 (TGFBR2), rs4939874 (SMAD2) and rs12490466 (TGFBR2), rs2009112 (TGFB2) and rs4075748 (TGFBR2) showed statistically significant SNP-SNP interaction (P<1.46×10-4). In contrast, the analysis of gene-environment interactions did not yield any significant results after being corrected by multiple testing. CONCLUSION: The comprehensive evaluation of SNP associations and interactions within the TGF-ß signaling pathway did not yield any direct associations with NSCL/P risk in Asian populations. However, the significant gene-gene interactions identified suggest that the genetic architecture influencing NSCL/P risk may involve interactions between genes within the TGF-ß signaling pathway. These findings underscore the necessity for further investigations to unravel these results and further explore the underlying biological mechanisms.

[A ssociations of short-term ambient particulate matter exposure and MTNR1B gene with triglyceride-glucose index: A family-based study].

OBJECTIVE: To explore the effects of short-term particulate matter (PM) exposure and the melatonin receptor 1B (MTNR1B) gene on triglyceride-glucose (TyG) index utilizing data from Fang-shan Family-based Ischemic Stroke Study in China (FISSIC). METHODS: Probands and their relatives from 9 rural areas in Fangshan District, Beijing, were included in the study. PM data were obtained from fixed monitoring stations of the National Air Pollution Monitoring System. TyG index was calculated by fasting triglyceride and glucose concentrations. The associations of short-term PM exposure and rs10830963 polymorphism of the MTNR1B gene with the TyG index were assessed using mixed linear models, in which covariates such as age, sex, and lifestyles were adjusted for. Gene-environment inter-action analysis was furtherly performed using the maximum likelihood methods to explore the potential effect modifier role of rs10830963 polymorphism in the association of PM with TyG index. RESULTS: A total of 4 395 participants from 2 084 families were included in the study, and the mean age of the study participants was (58.98±8.68) years, with 53. 90% females. The results of association analyses showed that for every 10 µg/m3 increase in PM2.5 concentration, TyG index increased by 0.017 (95%CI: 0.007-0.027), while for per 10 µg/m3 increment in PM10, TyG index increased by 0.010 (95%CI: 0.003-0.017). And the associations all had lagged effects. In addition, there was a positive association between the rs10830963 polymorphism and the TyG index. For per increase in risk allele G, TyG index was elevated by 0.040 (95%CI: 0.004-0.076). The TyG index was 0.079 (95%CI: 0.005-0.152) higher in carriers of the GG genotype compared with carriers of the CC genotype. The interaction of rs10830963 polymorphism with PM exposure had not been found to be statistically significant in the present study. CONCLUSION: Short-term exposure to PM2.5 and PM10 were associated with higher TyG index. The G allele of rs10830963 polymorphism in the MTNR1B gene was associated with the elevated TyG index.

Lipid Nanoparticle-Mediated Delivery of CRISPR-Cas9 Against Rubicon Ameliorates NAFLD by Modulating CD36 Along with Glycerophospholipid Metabolism.

Non-alcoholic fatty liver disease (NAFLD) is a prominent cause of various chronic metabolic hepatic diseases with limited therapeutics. Rubicon, an essential regulator in lysosomal degradation, is reported to exacerbate hepatic steatosis in NAFLD mice and patients, indicating its probability of being a therapeutic target for NAFLD treatment. In this study, the therapeutic potential of Rubicon blockage is investigated. Lipid nanoparticles carrying Rubicon-specific CRISPR-Cas9 components exhibited liver accumulation, cell internalization, and Rubicon knockdown. A single administration of the nanoparticles results in attenuated lipid deposition and hepatic steatosis, with lower circulating lipid levels and decreased adipocyte size in NAFLD mice. Furthermore, the increase of phosphatidylcholine and phosphatidylethanolamine levels can be observed in the NAFLD mice livers after Rubicon silencing, along with regulatory effects on metabolism-related genes such as CD36, Gpcpd1, Chka, and Lpin2. The results indicate that knockdown of Rubicon improves glycerophospholipid metabolism and thereby ameliorates the NAFLD progression, which provides a potential strategy for NAFLD therapy via the restoration of Rubicon.

Successful treatment with tislelizumab plus chemotherapy for SMARCA4-deficient undifferentiated tumor: a case report.

SMARCA4-deficient undifferentiated tumor (SMARCA4-dUT) is a devastating subtype of thoracic tumor with SMARCA4 inactivation and is characterized by rapid progression, poor prognosis, and high risk of postoperative recurrence. However, effective treatments for SMARCA4-dUT are lacking. Herein, we describe a patient with SMARCA4-dUT who exhibited an impressive response to the anti-programmed cell death protein-1 (PD-1) antibody (tislelizumab) in combination with conventional chemotherapy (etoposide and cisplatin). To the best of our knowledge, this is the first case of SMARCA4-dUT treated with chemotherapy, comprising etoposide and cisplatin, combined with anti-PD-1 inhibitors. Immunotherapy combined with etoposide and cisplatin may be a promising strategy to treat SMARCA4-dUT.

Compact step-added T-type PAC for enhanced hydrogen detection: A photoacoustic frequency shift approach.

In this study, we introduce an innovative photoacoustic frequency shift (PAFS) technique for hydrogen (H2) detection, complemented by both theoretical models and practical experiments. To mitigate cross-sensitivity, we analyzed the sound speeds of six different gases, confirming minimal interference with H2 due to significant velocity disparities. Central to our approach is the design of a miniaturized step-added T-type Photoacoustic Cell (PAC), with parameters meticulously optimized for enhanced performance. Using COMSOL Multiphysics' Thermal Viscous Acoustics module, we conducted simulations to evaluate the quality factor and acoustic pressure, both crucial for the sensor's efficiency. Additionally, we assessed the system's stability, influenced by gas flow, through gas velocity distribution analyses using the Computational Fluid Dynamics module. Experimental investigations focused on the system's sensing performance, revealing a distinct frequency shift of âˆ¼45 Hz for every 1 % change in H2 concentration, with a high linear correlation (R2 = 0.99825). The system's response and recovery times were measured at 1.09 s and 1.25 s, respectively. Long-term stability, evaluated over 3000 s using Allan deviation, indicated a minimum detection limit (MDL) of 102.47 ppm at an integration time of 375 s. These findings validate the efficacy of the step-added T-type PAC in H2 detection.