Screening potential dye sensitizers for water splitting photocatalysts using a genetic algorithm.

Addressing the global fossil energy crisis necessitates the efficient utilization of sustainable energy sources. Hydrogen, a green fuel, can be generated using sunlight, water, and a photocatalyst. Employing sensitizers holds promise for enhancing photocatalyst performance, enabling high rates of hydrogen evolution through increased visible light absorption. However, sifting through millions of diverse molecules to identify suitable dyes for specific photocatalysts poses a significant challenge. In this study, we integrate genetic algorithm and geometry-frequency-noncovalent extended tight binding methods to efficiently screen 2.6 million potential sensitizers with a D-π-A-π-AA structure within a short timeframe. Subsequently, these optimized sensitizers are rigorously reassessed by using DFT/TDDFT methods, elucidating why they may serve as superior dyes compared to the reference dye WS5F, particularly in terms of light absorption, driving force, binding energy, etc. Additionally, our methodology uncovers molecular motifs of particular interest, including the furan π-bridge and the double cyano anchoring acceptor, which are prevalent in the most promising set of molecules. The developed genetic algorithm workflow and dye design principles can be extended to various compelling projects, such as dye-sensitized solar cells, organic photovoltaics, photo-induced redox reactions, pharmaceuticals, and beyond.

Overexpressing Bcl-2 enhances murine chimeric antigen receptor T cell therapy against solid tumor.

Chimeric antigen receptor T (CART) cell therapy has demonstrated promising potential in the treatment of hematologic malignancies. However, its application to solid tumors is limited due to the restrictive nature of the tumor microenvironment, resulting in functional failure and poor persistence of CART cells. Overexpression of Bcl-2 in human CART cells (hCART) has been found to significantly enhance their anti-apoptotic effects both in vitro and in vivo. Nevertheless, the evaluation of hCART cells in preclinical studies has predominantly relied on immunodeficient mice xenograft tumor models, making it challenging to assess the impact of hCART cells on normal tissues and the immune system. We established a murine CART (mCART) that overexpresses Bcl-2 and targets the epidermal growth factor receptor variant III (EGFRvIII), named EGFRvIII·mCART-Bcl2. It demonstrated superior proliferation, cytotoxicity, and anti-apoptotic capabilities in vitro. In an immunocompetent mouse model of abdominal metastasis of colorectal cancer, EGFRvIII·mCART-Bcl2 exhibited improved survival of CART in the abdomen, increased tumor clearance, and significantly prolonged overall mouse survival. In summary, our study provides evidence that the introduction of Bcl-2 into mCART cells can enhance their therapeutic efficacy against solid tumors while ensuring safety.

Mechanically strained osteocyte-derived exosomes contained miR-3110-5p and miR-3058-3p and promoted osteoblastic differentiation.

BACKGROUND: Osteocytes are critical mechanosensory cells in bone, and mechanically stimulated osteocytes produce exosomes that can induce osteogenesis. MicroRNAs (miRNAs) are important constituents of exosomes, and some miRNAs in osteocytes regulate osteogenic differentiation; previous studies have indicated that some differentially expressed miRNAs in mechanically strained osteocytes likely influence osteoblastic differentiation. Therefore, screening and selection of miRNAs that regulate osteogenic differentiation in exosomes of mechanically stimulated osteocytes are important. RESULTS: A mechanical tensile strain of 2500 µÎµ at 0.5 Hz 1 h per day for 3 days, elevated prostaglandin E2 (PGE2) and insulin-like growth factor-1 (IGF-1) levels and nitric oxide synthase (NOS) activity of MLO-Y4 osteocytes, and promoted osteogenic differentiation of MC3T3-E1 osteoblasts. Fourteen miRNAs differentially expressed only in MLO-Y4 osteocytes which were stimulated with mechanical tensile strain, were screened, and the miRNAs related to osteogenesis were identified. Four differentially expressed miRNAs (miR-1930-3p, miR-3110-5p, miR-3090-3p, and miR-3058-3p) were found only in mechanically strained osteocytes, and the four miRNAs, eight targeted mRNAs which were differentially expressed only in mechanically strained osteoblasts, were also identified. In addition, the mechanically strained osteocyte-derived exosomes promoted the osteoblastic differentiation of MC3T3-E1 cells in vitro, the exosomes were internalized by osteoblasts, and the up-regulated miR-3110-5p and miR-3058-3p in mechanically strained osteocytes, were both increased in the exosomes, which was verified via reverse transcription quantitative polymerase chain reaction (RT-qPCR). CONCLUSIONS: In osteocytes, a mechanical tensile strain of 2500 µÎµ at 0.5 Hz induced the fourteen differentially expressed miRNAs which probably were in exosomes of osteocytes and involved in osteogenesis. The mechanically strained osteocyte-derived exosomes which contained increased miR-3110-5p and miR-3058-3p (two of the 14 miRNAs), promoted osteoblastic differentiation.

Mutation of SIVA, a candidate metastasis gene identified from clonally related bilateral breast cancers, promotes breast cancer cell spread in vitro and in vivo.

Metastasis is the most dreaded outcome after a breast cancer diagnosis, and little is known regarding what triggers or promotes breast cancer to spread distally, or how to prevent or eradicate metastasis effectively. Bilateral breast cancers are an uncommon form of breast cancers. In our study, a percentage of bilateral breast cancers were clonally related based on copy number variation profiling. Whole exome sequencing and comparative sequence analysis revealed that a limited number of somatic mutations were acquired in this "breast-to-breast" metastasis that might promote breast cancer distant spread. One somatic mutation acquired was SIVA-D160N that displayed pro-metastatic phenotypes in vivo and in vitro. Over-expression of SIVA-D160N promoted migration and invasion of human MB-MDA-231 breast cancer cells in vitro, consistent with a dominant negative interfering function. When introduced via tail vein injection, 231 cells over-expressing SIVA-D160N displayed enhanced distant spread on IVIS imaging. Over-expression of SIVA-D160N promoted invasion and anchorage independent growth of mouse 4T1 breast cancer cells in vitro. When introduced orthotopically via mammary fat pad injection in syngeneic Balb/c mice, over-expression of SIVA-D160N in 4T1 cells increased orthotopically implanted mammary gland tumor growth as well as liver metastasis. Clonally related bilateral breast cancers represented a novel system to investigate metastasis and revealed a role of SIVA-D160N in breast cancer metastasis. Further characterization and understanding of SIVA function, and that of its interacting proteins, may elucidate mechanisms of breast cancer metastasis, providing clinically useful biomarkers and therapeutic targets.

High capacities of carbon capture and photosynthesis of a novel organic carbon-fixing microalgae in municipal wastewater: From mutagenesis, screening, ability evaluation to mechanism analysis.

The development of wastewater treatment processes capable of reducing and fixing carbon is currently a hot topic in the wastewater treatment field. Microalgae possess a natural carbon-fixing advantage, and microalgae that can symbiotically coexist with indigenous bacteria in actual wastewater attract more significant attention. Ultraviolet (UV) mutagenesis and dissolved organic carbon (DOC) acclimation were applied to strengthen the carbon-fixing performance of microalgae in this study. The mechanisms associated with microalgal water purification ability, gene regulation at the molecular level and photosynthetic potential under different trophic modes resulting from carbon fixation and transformation were disclosed. The superior performance of Chlorella sp. MHQ2 was eventually screened out among a large number of mutants generated from 3 wild-type Chlorella strains. Results indicated that the dry cell weight of the optimal species Chlorella sp. HQ mutant MHQ2 was 1.91 times that of the wild strain in the pure algal system, more carbon from municipal wastewater (MW) were transferred to the microalgae and re-entered into the biological cycle through resource utilization. In addition, COD, NH3-N and TP removal efficiencies of MW by Chlorella sp. MHQ2 were found to increase to 95.8% (1.1-times), 96.4% (1.4-times), and 92.9% (1.2-times), respectively, under the extra DOC supply and the assistance of indigenous bacteria in the MW. In the transcriptome analysis of the logarithmic phase, the glycolytic pathway was inhibited, and the pentose phosphate pathway was mainly carried out for microalgal life activities, further promoting efficient energy utilization. Upon analysis of carbon capture capacity and photosynthetic potential in trophic mode, the addition of NaHCO3 increased the photosynthetic rate of Chlorella sp. MHQ2 in mixotrophy whereas it was attenuated in autotrophy. This study could provide a new perspective for the study of resource utilization and microalgae carbon- fixing mechanisms in the actual wastewater treatment process.

The salt sensitivity of Drd4-null mice is associated with the upregulations of sodium transporters in kidneys.

To explore the mechanism of the hypertension in dopamine receptor-4 (Drd4) null mice, we determined the salt sensitivity and renal sodium transport proteins in Drd4-/- and Drd4+/+ mice with varied salt diets. On normal NaCl diet (NS), mean arterial pressures (MAP, telemetry) were higher in Drd4-/- than Drd4+/+; Low NaCl diet (LS) tended to decrease MAP in both strains; high NaCl diet (HS) elevated MAP with sodium excretion decreased and pressure-natriuresis curve shifted to right in Drd4-/- relative to Drd4+/+ mice. Drd4-/- mice exhibited increased renal sodium-hydrogen exchanger 3 (NHE3), sodium-potassium-2-chloride cotransporter (NKCC2), sodium-chloride cotransporter (NCC), and outer medullary α-epithelial sodium channel (αENaC) on NS, decreased NKCC2, NCC, αENaC, and αNa+-K+-ATPase on LS, and increased αENaC on HS. NKCC2, NCC, αENaC, and αNa+-K+-ATPase in plasma membrane were greater in Drd4-/- than in Drd4+/+ mice with HS. D4R was expressed in proximal and distal convoluted tubules, thick ascending limbs, and outer medullary collecting ducts and colocalized with NKCC2 and NCC. The phosphorylation of NKCC2 was enhanced but ubiquitination was reduced in the KO mice. There were no differences between the mouse strains in serum aldosterone concentrations and urinary dopamine excretions despite their changes with diets. The mRNA expressions of renal NHE3, NKCC2, NCC, and αENaC on NS were not altered in Drd4-/- mice. Thus, increased protein expressions of NHE3, NKCC2, NCC and αENaC are associated with hypertension in Drd4-/- mice; increased plasma membrane protein expression of NKCC2, NCC, αENaC, and αNa+-K+-ATPase may mediate the salt sensitivity of Drd4-/- mice.

A Naturally Active Spy Transposon Discovered from the Insect Genome of Colletes gigas as a Promising Novel Gene Transfer Tool.

Novel active DNA transposons, such as Spy transposons from the PHIS superfamily, are identified through bioinformatics in this study. The native transposases cgSpy and cvSpy displayed transposition activities of approximately 85% and 35% compared to the hyperactive piggyBac transposase (hyPB). The cgSpy transposon showed unique characteristics, including a lack of overproduction inhibition and reduced efficiency for insertion sizes between 3.1 to 8.5 kb. Integration preferences of cgSpy are found in genes and regulatory regions, making it suitable for genetic manipulation. Evaluation in T-cell engineering demonstrated that cgSpy-mediated chimeric antigen receptor (CAR) modification is comparable to the PB system, indicating its potential utility in cell therapy. This study unveils the promising application of the active native transposase, Spy, from Colletes gigas, as a valuable tool for genetic engineering, particularly in T-cell manipulation.

Validation of Baveno VII criteria for clinically significant portal hypertension by two-dimensional shear wave elastography.

BACKGROUND: The Baveno VII consensus proposed criteria for the non-invasively diagnosis of clinically significant portal hypertension (CSPH) in patients with compensated advanced chronic liver disease (cACLD). The performance of Baveno VII criteria for assessing CSPH by two-dimensional shear wave elastography (2D-SWE) had not been well validated. We aimed to validate the performance of Baveno VII criteria for rule-in and rule-out CSPH by 2D-SWE. METHOD: This is an international multicenter study including cACLD patients from China and Croatia with paired liver stiffness measurement (LSM), spleen stiffness measurement (SSM) by 2D-SWE, and hepatic venous pressure gradient (HVPG) were included. CSPH was defined as HVPG ≥ 10 mmHg. RESULT: A total of 146 patients with cACLD were enrolled, and finally 118 patients were included in the analysis. Among them, CSPH was documented in 79 (66.9%) patients. Applying the Baveno VII criteria for rule-out CSPH by 2D-SWE, [LSM ≤ 15 kPa and platelet count ≥ 150 × 109/L] OR SSM < 21 kPa, could exclude CSPH with sensitivity > 90% (93.5 or 98.7%) but negative predictive value < 90% (74.1 or 85.7%). Using the Baveno VII criteria for rule-in CSPH by 2D-SWE, LSM ≥ 25 kPa OR SSM ≥ 50 kPa, could diagnose CSPH with 100% specificity and 100% positive predictive values. CONCLUSION: Baveno VII criteria by 2D-SWE showed a good diagnostic performance for ruling in but not for ruling out CSPH, which might become an emerging non-invasive elastography tool to select the patients who needed non-selective beta blocker therapy.

Clinical evaluation of Giomer and self-etch adhesive compared with nanofilled resin composite and etch-and-rinse adhesive - Results at 8 years.

OBJECTIVE: This study aimed to evaluate the long-term clinical performance of Giomer and a self-etch adhesive system compared with a nanofilled resin composite and etch-and-rinse adhesive system in Class I and Class II restorations. METHOD: The study was designed to be double-blinded with intra-individual control. 48 patients with 54 pairs of cavities (class I or class II) were recruited. Each pair of restorations was placed with either BEAUTIFIL II (BF) and FL-BOND II (FL) or Filtek Z350 (Z350) and Scotchbond Multi-Purpose (SMP). Clinical evaluation was performed at baseline, 6-month, 18-month, 4-year and 8-year after placement according to modified USPHS criteria. Kaplan-Meier survival analysis and log rank tests were performed (SPSS 20.0, IBM Corporation, US) to compare the survival probability of different restorations.A generalized linear mixed model (GLMM) was adopted to assess the performance of the materials. The McNemar test was used to show significant changes for all the evaluation criteria and difference between them. RESULTS: At the eight-year recall, 32 patients with 67 restorations were present. There were twelve restorations in total recorded as failure due to loss of retention, restoration fracture, secondary caries, tooth fracture or endodontic treatment due to pulp necrosis. The survival probabilities and calculated annual failure rate(AFR) of BF and Z350 restorations at 8-year were 87.2 % vs 87.8 % and 1.6 % vs 1.5 % respectively with no significant difference (p > 0.05)between the two materials. Over the recall time range of eight years, decreased possibility of alpha rating was observed for retention, marginal adaptation, marginal staining and surface roughness for both materials (p < 0.05). Decreased possibility of alpha rating was observed for surface staining and secondary caries for Z350 (p < 0.05) and restoration fracture for BF (p < 0.05), respectively. Comparing the two restorative systems over eight years, no significant difference was seen for linear decline of the possibility of alpha rating for any of the criteria evaluated (p > 0.05). CONCLUSION: Giomer material and the self-etch adhesive system had comparable clinical performance with nanofilled resin composite and etch-and-rinse adhesive system over the observation period of eight years.

A novel approach to exploit Small-Molecule glucagon-like Peptide-1 receptor agonists with high potency.

Small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonists are recognized as promising therapeutics for type 2 diabetes mellitus (T2DM) and obesity. Danuglipron, an investigational small-molecule agonist, has demonstrated high efficacy in clinical trials. However, further development of danuglipron is challenged by a high rate of gastrointestinal adverse events. While these effects may be target-related, it is plausible that the carboxylic acid group present in danuglipron may also play a role in these outcomes by affecting the pharmacokinetic properties and dosing regimen of danuglipron, as well as by exerting direct gastrointestinal irritation. Therefore, this study aims to replace the problematic carboxylic acid group by exploring the internal binding cavity of danuglipron bound to GLP-1R using a water molecule displacement strategy. A series of novel triazole-containing compounds have been designed and synthesized during the structure-activity relationship (SAR) study. These efforts resulted in the discovery of compound 2j with high potency (EC50 = 0.065 nM). Moreover, docking simulations revealed that compound 2j directly interacts with the residue Glu387 within the internal cavity of GLP-1R, effectively displacing the structural water previously bound to Glu387. Subsequent in vitro and in vivo experiments demonstrated that compound 2j had comparable efficacy to danuglipron in enhancing insulin secretion and improving glycemic control. Collectively, this study offers a practicable approach for the discovery of novel small-molecule GLP-1R agonists based on danuglipron, and compound 2j may serve as a lead compound to further exploit the unoccupied internal cavity of danuglipron's binding pocket.

Effects of OSA-starch-fatty acid interactions on the structural, digestibility and release characteristics of high amylose corn starch.

This study investigated the effects of octenyl succinic anhydride (OSA)-starch-fatty acid (FA) interactions on the structural, digestibility and release characteristics of high amylose corn starch (HAS). FTIR and XRD analysis showed that the hydrophobic interaction between HAS and FA promoted the covalent binding between OSA and HAS. With the increasing of the FA chain length, the complex index, degree of substitution, R1047/1022 and relative crystallinity of OSA-HAS-FA increased first and then decreased, whereas the first-order rate coefficient and percentage of digested in infinite time showed an opposite trend. Structural changes and the molecular interactions of OSA-HAS-FA with 12­carbon FA resulted in highest resistant starch content (45.43%) and encapsulation efficiency of curcumin (Cur) (47.98%). In vitro release test revealed that Cur could be gradually released from OSA-HAS-FA in simulated gastric, intestinal and colonic fluids. Results provided novel insights into HAS-FA complex grafted with OSA as carrier for colon-specific of functional materials.

SEETrials: Leveraging Large Language Models for Safety and Efficacy Extraction in Oncology Clinical Trials.

Background: Initial insights into oncology clinical trial outcomes are often gleaned manually from conference abstracts. We aimed to develop an automated system to extract safety and efficacy information from study abstracts with high precision and fine granularity, transforming them into computable data for timely clinical decision-making. Methods: We collected clinical trial abstracts from key conferences and PubMed (2012-2023). The SEETrials system was developed with four modules: preprocessing, prompt modeling, knowledge ingestion and postprocessing. We evaluated the system's performance qualitatively and quantitatively and assessed its generalizability across different cancer types- multiple myeloma (MM), breast, lung, lymphoma, and leukemia. Furthermore, the efficacy and safety of innovative therapies, including CAR-T, bispecific antibodies, and antibody-drug conjugates (ADC), in MM were analyzed across a large scale of clinical trial studies. Results: SEETrials achieved high precision (0.958), recall (sensitivity) (0.944), and F1 score (0.951) across 70 data elements present in the MM trial studies Generalizability tests on four additional cancers yielded precision, recall, and F1 scores within the 0.966-0.986 range. Variation in the distribution of safety and efficacy-related entities was observed across diverse therapies, with certain adverse events more common in specific treatments. Comparative performance analysis using overall response rate (ORR) and complete response (CR) highlighted differences among therapies: CAR-T (ORR: 88%, 95% CI: 84-92%; CR: 95%, 95% CI: 53-66%), bispecific antibodies (ORR: 64%, 95% CI: 55-73%; CR: 27%, 95% CI: 16-37%), and ADC (ORR: 51%, 95% CI: 37-65%; CR: 26%, 95% CI: 1-51%). Notable study heterogeneity was identified (>75% I 2 heterogeneity index scores) across several outcome entities analyzed within therapy subgroups. Conclusion: SEETrials demonstrated highly accurate data extraction and versatility across different therapeutics and various cancer domains. Its automated processing of large datasets facilitates nuanced data comparisons, promoting the swift and effective dissemination of clinical insights.

Clinical influencing factors of vital pulp therapy on pulpitis permanent teeth with 2 calcium silicate-based materials: A randomized clinical trial.

BACKGROUND: Compared with traditional root canal therapy (RCT), vital pulp therapy (VPT) is a personalized and minimally invasive method for the treatment of pulpitis caused by dental caries. However, there are still no clear guidelines for VPT because high-quality randomized clinical trials are scarce. This prospective cohort study evaluated the clinical efficacy of VPT with the light-curable calcium silicate-based material TheraCal LC (TH) and bioceramic material iRoot BP Plus (BP) in reversible and irreversible pulpitis permanent teeth with carious exposures. METHODS: 115 teeth with reversible or irreversible pulpitis caused by deep care were randomly divided into 2 groups. TheraCal LC and iRoot BP Plus were used for the pulp capping. Direct pulp capping (DPC), partial pulpotomy (PP) and full pulpotomy (FP) were performed based on observation of the exposed pulp. Postoperative discomforts were enquired and recorded via follow-up phone calls. Clinical and radiographic evaluations were performed 3, 6, and 12 months postoperatively. RESULTS: The overall clinical success rate in the first year was 90.4% (47/52) in both groups. The TH group required less operating time, showed lower levels of pain, and had shorter pain duration post-operative (P < .001). According to the binary logistic regression model, preoperative pain duration was significantly correlated with the prognosis of VPT (P = .011). CONCLUSION: VPT with TheraCal LC and iRoot BP Plus in pulpitis permanent carious teeth both achieved good clinical outcomes, and TheraCal LC can be easily operated for clinical use. Preoperative pain duration of the affected tooth might have a significant correlation with the prognosis of VPT.

Development and interpretation of a pathomics-driven ensemble model for predicting the response to immunotherapy in gastric cancer.

BACKGROUND: Only a subset of patients with gastric cancer experience long-term benefits from immune checkpoint inhibitors (ICIs). Currently, there is a deficiency in precise predictive biomarkers for ICI efficacy. The aim of this study was to develop and validate a pathomics-driven ensemble model for predicting the response to ICIs in gastric cancer, using H&E-stained whole slide images (WSI). METHODS: This multicenter study retrospectively collected and analyzed H&E-stained WSIs and clinical data from 584 patients with gastric cancer. An ensemble model, integrating four classifiers: least absolute shrinkage and selection operator, k-nearest neighbors, decision trees, and random forests, was developed and validated using pathomics features, with the objective of predicting the therapeutic efficacy of immune checkpoint inhibition. Model performance was evaluated using metrics including the area under the curve (AUC), sensitivity, and specificity. Additionally, SHAP (SHapley Additive exPlanations) analysis was used to explain the model's predicted values as the sum of the attribution values for each input feature. Pathogenomics analysis was employed to explain the molecular mechanisms underlying the model's predictions. RESULTS: Our pathomics-driven ensemble model effectively stratified the response to ICIs in training cohort (AUC 0.985 (95% CI 0.971 to 0.999)), which was further validated in internal validation cohort (AUC 0.921 (95% CI 0.839 to 0.999)), as well as in external validation cohort 1 (AUC 0.914 (95% CI 0.837 to 0.990)), and external validation cohort 2 (0.927 (95% CI 0.802 to 0.999)). The univariate Cox regression analysis revealed that the prediction signature of pathomics-driven ensemble model was a prognostic factor for progression-free survival in patients with gastric cancer who underwent immunotherapy (p<0.001, HR 0.35 (95% CI 0.24 to 0.50)), and remained an independent predictor after multivariable Cox regression adjusted for clinicopathological variables, (including sex, age, carcinoembryonic antigen, carbohydrate antigen 19-9, therapy regime, line of therapy, differentiation, location and programmed death ligand 1 (PD-L1) expression in all patients (p<0.001, HR 0.34 (95% CI 0.24 to 0.50)). Pathogenomics analysis suggested that the ensemble model is driven by molecular-level immune, cancer, metabolism-related pathways, and was correlated with the immune-related characteristics, including immune score, Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data score, and tumor purity. CONCLUSIONS: Our pathomics-driven ensemble model exhibited high accuracy and robustness in predicting the response to ICIs using WSIs. Therefore, it could serve as a novel and valuable tool to facilitate precision immunotherapy.

Percutaneous Coronary Intervention as a Non-Surgical Treatment for Ischemic Mitral Regurgitation in Patients with Multi-Vessel Coronary Artery Disease.

BACKGROUND Multi-vessel coronary artery disease (MVD) represents a severe type of coronary artery disease (CAD). Ischemic mitral regurgitation (IMR) is a common mechanical complication in patients with CAD. This study aimed to retrospectively investigate the efficacy of percutaneous coronary intervention (PCI) on moderate/severe IMR in patients with MVD. MATERIAL AND METHODS Clinical data were collected from 15 patients who underwent successful treatment for MVD combined with moderate/severe IMR through the PCI procedure and achieved complete revascularization between January 2014 and December 2022. Cardiac structural and functional parameters were assessed through echocardiographic evaluations. Color flow recordings of MR jets were obtained through an enlarged view of the 4-chamber cut, and the diagnosis of MR was categorized into mild (<4 cm²), moderate (4-8 cm²), and severe (>8 cm²), based on the MR area. RESULTS The common features of the selected cases were advanced age, low body weight, and renal insufficiency. Cardiac echocardiography revealed an augmentation in the left atrial anteroposterior diameter and left ventricular internal diameter at end-systole after PCI, while the left ventricle internal diameter in diastole, left ventricular ejection fraction, and left ventricular fractional shortening were comparable to preoperative values. All patients had moderate/severe MR preoperatively, and MR improved at 1 month (2.73±0.69) and 12 months (2.26±0.58) after PCI. CONCLUSIONS In cases of MVD accompanied by moderate/severe IMR, undergoing PCI can spare certain elderly patients with low body weight and renal insufficiency from high-risk surgery, alleviating the severity of MR without undergoing mitral valve intervention.

The impact of 5-aminosalicylates on the efficacy of mesenchymal stem cell therapy in a murine model of ulcerative colitis.

Inflammatory bowel disease (IBD) is distinguished by persistent immune-mediated inflammation of the gastrointestinal tract. Previous experimental investigations have shown encouraging outcomes for the use of mesenchymal stem cell (MSC)-based therapy in the treatment of IBD. However, as a primary medication for IBD patients, there is limited information regarding the potential interaction between 5-aminosalicylates (5-ASA) and MSCs. In this present study, we employed the dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mouse model to examine the influence of a combination of MSCs and 5-ASA on the development of UC. The mice were subjected to weight measurement, DAI scoring, assessment of calprotectin expression, and collection of colons for histological examination. The findings revealed that both 5-ASA and MSCs have demonstrated efficacy in the treatment of UC. However, it is noteworthy that 5-ASA exhibits a quicker onset of action, while MSCs demonstrate more advantageous and enduring therapeutic effects. Additionally, the combination of 5-ASA and MSC treatment shows a less favorable efficacy compared to the MSCs alone group. Moreover, our study conducted in vitro revealed that 5-ASA could promote MSC migration, but it could also inhibit MSC proliferation, induce apoptosis, overexpress inflammatory factors (IL-2, IL-12P70, and TNF-α), and reduce the expression of PD-L1 and PD-L2. Furthermore, a significant decrease in the viability of MSCs within the colon was observed as a result of 5-ASA induction. These findings collectively indicate that the use of 5-ASA has the potential to interfere with the therapeutic efficacy of MSC transplantation for the treatment of IBD.

A ternary correlation multi-symptom network strategy based on in vivo chemical profile identification and metabolomics to explore the molecular basis of Ephedra herb against viral pneumonia.

Ephedra herb (EH), an important medicine prescribed in herbal formulas by Traditional Chinese Medicine practitioners, has been widely used in the treatment of viral pneumonia in China. However, the molecular basis of EH in viral pneumonia remains unclear. In this study, a ternary correlation multi-symptom network strategy was established based on in vivo chemical profile identification and metabolomics to explore the molecular basis of EH against viral pneumonia. Results showed that 143 compounds of EH and 70 prototype components were identified in vivo. EH could reduce alveolar-capillary barrier disruption in rats with viral pneumonia and significantly downregulate the expression of inflammatory factors and bronchoalveolar lavage fluid. Plasma metabolomics revealed that EH may be involved in the regulation of arachidonic acid, tryptophan, tyrosine, nicotinate, and nicotinamide metabolism. The multi-symptom network showed that 12 compounds have an integral function in the treatment of viral pneumonia by intervening in many pathways related to viruses, immunity and inflammation, and lung injury. Further verification demonstrated that sinapic acid and frambinone can regulate the expression of related genes. It has been shown to be a promising representative of the pharmacological constituents of ephedra.

An integrated signature of clinical metrics and immune-related genes as a prognostic indicator for ST-segment elevation myocardial infarction patient survival.

Background: The immune-inflammatory pathway plays a critical role in myocardial infarction development. However, few studies have systematically explored immune-related genes in relation to myocardial infarction prognosis using bioinformatic analysis. Our study aims to identify differentially expressed immune-related genes(DEIRGs) in ST-segment elevation myocardial infarction (STEMI) patients and investigate their association with clinical outcomes. Materials and methods: We conducted a systematic review of Gene Expression Omnibus datasets, selecting GSE49925, GSE60993, and GSE61144 for analysis. DEIRGs were identified using GEO2R and overlapped across the chosen datasets. Functional enrichment analysis elucidated the DEIRGs' biological functions and pathways. We established an optimal prognostic prediction model using LASSO penalized Cox proportional hazards regression. The signature's clinical utility was evaluated through survival analysis, ROC curve assessment, and decision curve analysis. Additionally, we constructed a prognostic nomogram for survival rate prediction. External validation was performed using our own plasma samples. Results: The resulting prognostic signature integrated two dysregulated DEIRGs (S100A12 and IL2RB) and two clinical variables (serum creatinine level and Gensini score). This signature effectively stratified patients into low- and high-risk groups. Survival analysis, ROC curve analysis, and decision curve analysis demonstrated its robust predictive performance and clinical utility within the first two years post-disease onset. External validation confirmed significant outcome differences between risk groups. Conclusions: Our study establishes a prognostic signature that combines DEIRGs and clinical variables for STEMI patients. The signature exhibits promising predictive capabilities for patient stratification and survival risk assessment.

Development of a Cell Culture Model for Inducible SARS-CoV-2 Replication.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces direct cytopathic effects, complicating the establishment of low-cytotoxicity cell culture models for studying its replication. We initially developed a DNA vector-based replicon system utilizing the CMV promoter to generate a recombinant viral genome bearing reporter genes. However, this system frequently resulted in drug resistance and cytotoxicity, impeding model establishment. Herein, we present a novel cell culture model with SARS-CoV-2 replication induced by Cre/LoxP-mediated DNA recombination. An engineered SARS-CoV-2 transcription unit was subcloned into a bacterial artificial chromosome (BAC) vector. To enhance biosafety, the viral spike protein gene was deleted, and the nucleocapsid gene was replaced with a reporter gene. An exogenous sequence was inserted within NSP1 as a modulatory cassette that is removable after Cre/LoxP-mediated DNA recombination and subsequent RNA splicing. Using the PiggyBac transposon strategy, the transcription unit was integrated into host cell chromatin, yielding a stable cell line capable of inducing recombinant SARS-CoV-2 RNA replication. The model exhibited sensitivity to the potential antivirals forsythoside A and verteporfin. An innovative inducible SARS-CoV-2 replicon cell model was introduced to further explore the replication and pathogenesis of the virus and facilitate screening and assessment of anti-SARS-CoV-2 therapeutics.