Clinical characteristics of heavy alcohol consumption in young and middle-aged acute cerebral infarction: A 12-month follow-up study.

Objective: To investigate the clinical characteristics and prognosis of heavy alcohol consumption among young and middle-aged patients with acute cerebral infarction (ACI). Methods: A total of 263 young and middle-aged ACI patients were included in the study from June 2018 to December 2020 and classified into heavy drinkers and non-heavy drinkers. Multivariate logistic regression analysis was conducted to assess the association between ACI and heavy alcohol consumption, considering clinical characteristics and one-year post-discharge prognosis. Results: Among the patients, 78 were heavy drinkers. Heavy drinkers were more likely to consume alcohol 24 h before ACI onset (OR 4.03, 95 % CI 2.26-7.20), especially in the form of liquor (OR 3.83, 95 % CI 1.59-9.20), and had a higher risk of diastolic blood pressure ≥90 mmHg upon admission (OR 2.02, 95 % CI 1.12-3.64). In the one-year post-discharge prognosis, heavy drinkers had a greater likelihood of poor prognosis at 3 months (OR 2.31, 95 % CI 1.01-5.25), were less likely to quit drinking after discharge (OR 0.36, 95 % CI 0.19-0.66), and had a higher risk of recurrent cerebral infarction (OR 2.79, 95 % CI 1.14-6.84). Conclusions: Over the 12-month follow-up, young and middle-aged ACI patients with heavy alcohol consumption exhibited worse short-term prognosis. Controlling alcohol consumption levels may improve the prognosis of these patients.

Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.

BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.

Neuropsychology and Neurobiology of Negative Schizotypy: A Selective Review.

Schizotypy refers to a latent personality organization that reflects liability to schizophrenia. Because schizotypy is a multidimensional construct, people with schizotypy vary in behavioral and neurobiological features. In this article, we selectively review the neuropsychological and neurobiological profiles of people with schizotypy, with a focus on negative schizotypy. Empirical evidence is presented for alterations of neuropsychological performance in negative schizotypy. We also cover the Research Domain Criteria domains of positive valence, social process, and sensorimotor systems. Moreover, we systematically summarize the neurobiological correlates of negative schizotypy at the structural, resting-state, and task-based neural levels, as well as the neurochemical level. The convergence and inconsistency of the evidence are critically reviewed. Regarding theoretical and clinical implications, we argue that negative schizotypy represents a useful organizational framework for studying neuropsychology and neurobiology across different psychiatric disorders.

This perspective paper provides empirical evidence to show that schizotypy, and especially negative schizotypy, are associated with alterations of positive valence, social process, and sensorimotor systems domains within the Research Domain Criteria (RDoC). This perspective paper also systematically summarizes the neurobiological correlates of negative schizotypy at the structural, resting-state, and task-based neural levels, as well as the neurochemical level. We argue that negative schizotypy represents a useful organizational framework for studying neuropsychology and neurobiology across different psychiatric disorders.

Logic-Based Strategy for Spatiotemporal Release of Dual Extracellular Vesicles in Osteoarthritis Treatment.

To effectively treat osteoarthritis (OA), the existing inflammation must be reduced before the cartilage damage can be repaired; this cannot be achieved with a single type of extracellular vesicles (EVs). Here, a hydrogel complex with logic-gates function is proposed that can spatiotemporally controlled release two types of EVs: interleukin 10 (IL-10)+ EVs to promote M2 polarization of macrophage, and SRY-box transcription factor 9 (SOX9)+ EVs to increase cartilage matrix synthesis. Following dose-of-action screening, the dual EVs are loaded into a matrix metalloporoteinase 13 (MMP13)-sensitive self-assembled peptide hydrogel (KM13E) and polyethylene glycol diacrylate/gelatin methacryloyl-hydrogel microspheres (PGE), respectively. These materials are mixed to form a "microspheres-in-gel" KM13E@PGE system. In vitro, KM13E@PGE abruptly released IL-10+ EVs after 3 days and slowly released SOX9+ EVs for more than 30 days. In vivo, KM13E@PGE increased the CD206+ M2 macrophage proportion in the synovial tissue and decreased the tumor necrosis factor-α and IL-1ß levels. The aggrecan and SOX9 expressions in the cartilage tissues are significantly elevated following inflammation subsidence. This performance is not achieved using anti-inflammatory or cartilage repair therapy alone. The present study provides an injectable, integrated delivery system with spatiotemporal control release of dual EVs, and may inspire logic-gates strategies for OA treatment.

Supramolecular Nanofibers Ameliorate Bleomycin-Induced Pulmonary Fibrosis by Restoring Autophagy.

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal interstitial lung disease, with limited therapeutic options available. Impaired autophagy resulting from aberrant TRB3/p62 protein-protein interactions (PPIs) contributes to the progression of IPF. Restoration of autophagy by modulating the TRB3/p62 PPIs has rarely been reported for the treatment of IPF. Herein, peptide nanofibers are developed that specifically bind to TRB3 protein and explored their potential as a therapeutic approach for IPF. By conjugating with the self-assembling fragment (Ac-GFFY), a TRB3-binding peptide motif A2 allows for the formation of nanofibers with a stable α-helix secondary structure. The resulting peptide (Ac-GFFY-A2) nanofibers exhibit specific high-affinity binding to TRB3 protein in saline buffer and better capacity of cellular uptake to A2 peptide. Furthermore, the TRB3-targeting peptide nanofibers efficiently interfere with the aberrant TRB3/p62 PPIs in activated fibroblasts and fibrotic lung tissue of mice, thereby restoring autophagy dysfunction. The TRB3-targeting peptide nanofibers inhibit myofibroblast differentiation, collagen production, and fibroblast migration in vitro is demonstrated, as well as bleomycin-induced pulmonary fibrosis in vivo. This study provides a supramolecular method to modulate PPIs and highlights a promising strategy for treating IPF diseases by restoring autophagy.

VD3/VDR attenuates bisphenol A-induced impairment in mouse Leydig cells via regulation of autophagy.

Bisphenol A (BPA) is an endocrine disruptor with reproductive toxicity. Further, 1,25-dihydroxyvitamin D3 (VD3) plays an important role in male reproduction by binding vitamin D receptor (VDR) and mediating the pleiotropic biological actions that include spermatogenesis. However, whether VD3/VDR regulates the effect of BPA on Leydig cells (LCs) injury remains unknown. This study aimed to explore the effects of VD on BPA-induced cytotoxicity in mouse LCs. Hereby, LCs treated with BPA, VD3, or both were subjected to the assays of cell apoptosis, proliferation, autophagy, and levels of target proteins. This study unveiled that cell viability was dose-dependently reduced after exposure to BPA. BPA treatment significantly inhibited LC proliferation, induced apoptosis, and also downregulated VDR expression. By jointly analyzing transcriptome data and Comparative Toxicogenomics Database (CTD) data, autophagy signaling pathways related to testicular development and male reproduction were screened out. Therefore, the autophagy phenomenon of cells was further detected. The results showed that BPA treatment could activate cell autophagy, Vdr-/- inhibits cell autophagy, and active VD3 does not have a significant effect on the autophagy of normal LCs. After VD3 and BPA were used in combination, the autophagy of cells was further enhanced, and VD3 could alleviate BPA-induced damage of LCs. In conclusion, this study found that supplementing VD3 could eliminate the inhibition of BPA on VDR expression, further enhance LCs autophagy effect, and alleviate the inhibition of LCs proliferation and induction of apoptosis by BPA, playing a protective role in cells. The research results will provide valuable strategies to alleviate BPA-induced reproductive toxicity.

Unveiling the role of hypoxia-inducible factor 2alpha in osteoporosis: Implications for bone health.

BACKGROUND: Osteoporosis (OP) has become a major public health problem worldwide. Most OP treatments are based on the inhibition of bone resorption, and it is necessary to identify additional treatments aimed at enhancing osteogenesis. In the bone marrow (BM) niche, bone mesenchymal stem cells (BMSCs) are exposed to a hypoxic environment. Recently, a few studies have demonstrated that hypoxia-inducible factor 2alpha (HIF-2α) is involved in BMSC osteogenic differentiation, but the molecular mechanism involved has not been determined. AIM: To investigate the effect of HIF-2α on the osteogenic and adipogenic differentiation of BMSCs and the hematopoietic function of hematopoietic stem cells (HSCs) in the BM niche on the progression of OP. METHODS: Mice with BMSC-specific HIF-2α knockout (Prx1-Cre;Hif-2αfl/fl mice) were used for in vivo experiments. Bone quantification was performed on mice of two genotypes with three interventions: Bilateral ovariectomy, semilethal irradiation, and dexamethasone treatment. Moreover, the hematopoietic function of HSCs in the BM niche was compared between the two mouse genotypes. In vitro, the HIF-2α agonist roxadustat and the HIF-2α inhibitor PT2399 were used to investigate the function of HIF-2α in BMSC osteogenic and adipogenic differentiation. Finally, we investigated the effect of HIF-2α on BMSCs via treatment with the mechanistic target of rapamycin (mTOR) agonist MHY1485 and the mTOR inhibitor rapamycin. RESULTS: The quantitative index determined by microcomputed tomography indicated that the femoral bone density of Prx1-Cre;Hif-2αfl/fl mice was lower than that of Hif-2αfl/fl mice under the three intervention conditions. In vitro, Hif-2αfl/fl mouse BMSCs were cultured and treated with the HIF-2α agonist roxadustat, and after 7 d of BMSC adipogenic differentiation, the oil red O staining intensity and mRNA expression levels of adipogenesis-related genes in BMSCs treated with roxadustat were decreased; in addition, after 14 d of osteogenic differentiation, BMSCs treated with roxadustat exhibited increased expression of osteogenesis-related genes. The opposite effects were shown for mouse BMSCs treated with the HIF-2α inhibitor PT2399. The mTOR inhibitor rapamycin was used to confirm that HIF-2α regulated BMSC osteogenic and adipogenic differentiation by inhibiting the mTOR pathway. Consequently, there was no significant difference in the hematopoietic function of HSCs between Prx1-Cre;Hif-2αfl/fl and Hif-2αfl/fl mice. CONCLUSION: Our study showed that inhibition of HIF-2α decreases bone mass by inhibiting the osteogenic differentiation and increasing the adipogenic differentiation of BMSCs through inhibition of mTOR signaling in the BM niche.

Discovery of a Novel and Potent Cyclin-Dependent Kinase 8/19 (CDK8/19) Inhibitor for the Treatment of Cancer.

The mediator kinases CDK8 and CDK19 control the dynamic transcription of selected genes in response to various signals and have been shown to be hijacked to sustain hyperproliferation by various solid and liquid tumors. CDK8/19 is emerging as a promising anticancer therapeutic target. Here, we report the discovery of compound 12, a novel small molecule CDK8/19 inhibitor. This molecule demonstrated not only decent enzymatic and cellular activities but also remarkable selectivity in CDK and kinome panels. Besides, compound 12 also displayed favorable ADME profiles including low CYP1A2 inhibition, acceptable clearance, and high oral bioavailability in multiple preclinical species. Robust in vivo PD and efficacy studies in mice models further demonstrated its potential use as mono- and combination therapy for the treatment of cancers.

WRKY22 Transcription Factor from Iris laevigata Regulates Flowering Time and Resistance to Salt and Drought.

Iris laevigata Fisch. is an excellent ornamental plant in cold regions due to its unique ornamental ability and strong cold resistance. However, the flowering period of the population is only about 20 days, greatly limiting its potential uses in landscaping and the cutting flower industry. In addition, I. laevigata is often challenged with various abiotic stresses including high salinity and drought in its native habitats. Thus, breeding novel cultivars with delayed flowering time and higher resistance to abiotic stress is of high importance. In this study, we utilized sequencing data from the I. laevigata transcriptome to identify WRKYs and characterized IlWRKY22, a key transcription factor that modulates flowering time and abiotic stress responses. IlWRKY22 is induced by salt and drought stress. We cloned IlWRKY22 and found that it is a Group IIe WRKY localized in the nucleus. Overexpressing IlWRKY22 in Arabidopsis thaliana (L.) Heynh. and Nicotiana tabacum L. resulted in a delayed flowering time in the transgenic plants. We created transgenic N. tabacum overexpressing IlWRKY22, which showed significantly improved resistance to both salt and drought compared to the control plants. Thus, our study revealed a unique dual function of IlWRKY22, an excellent candidate gene for breeding novel Iris cultivars of desirable traits.

Unraveling the genetic basis of the causal association between inflammatory cytokines and osteonecrosis.

Background: Previous studies have reported that the occurrence and development of osteonecrosis is closely associated with immune-inflammatory responses. Mendelian randomization was performed to further assess the causal correlation between 41 inflammatory cytokines and osteonecrosis. Methods: Two-sample Mendelian randomization utilized genetic variants for osteonecrosis from a large genome-wide association study (GWAS) with 606 cases and 209,575 controls of European ancestry. Another analysis included drug-induced osteonecrosis with 101 cases and 218,691 controls of European ancestry. Inflammatory cytokines were sourced from a GWAS abstract involving 8,293 healthy participants. The causal relationship between exposure and outcome was primarily explored using an inverse variance weighting approach. Multiple sensitivity analyses, including MR-Egger, weighted median, simple model, weighted model, and MR-PRESSO, were concurrently applied to bolster the final results. Results: The results showed that bFGF, IL-2 and IL2-RA were clinically causally associated with the risk of osteonecrosis (OR=1.942, 95% CI=1.13-3.35, p=0.017; OR=0.688, 95% CI=0.50-0.94, p=0.021; OR=1.386, 95% CI=1.04-1.85, p = 0.026). there was a causal relationship between SCF and drug-related osteonecrosis (OR=3.356, 95% CI=1.09-10.30, p=0.034). Conclusion: This pioneering Mendelian randomization study is the first to explore the causal link between osteonecrosis and 41 inflammatory cytokines. It conclusively establishes a causal association between osteonecrosis and bFGF, IL-2, and IL-2RA. These findings offer valuable insights into osteonecrosis pathogenesis, paving the way for effective clinical management. The study suggests bFGF, IL-2, and IL-2RA as potential therapeutic targets for osteonecrosis treatment.

Protector-free, non-plasmonic silver quantum clusters by femtosecond pulse laser irradiation: in situ binding on nanocellulose filaments for improved catalytic activity and cycling performance.

This study introduces a new, facile method to synthesize silver clusters from aqueous silver ion solution by using high intensity femtosecond pulse laser irradiation. The particles obtained in the absence of reducing or capping agents are 1-17 nm in size and presented quantum properties, as characterized by fluorescence, but did not exhibit plasmon signals, which is not a common characteristic of conventional silver nanoparticles. In a further development, small silver quantum clusters (∼1 nm) were bound in situ to wet-spun filaments of cellulose nanofibrils by pulsed laser irradiation. The obtained hybrid filaments as well as free silver quantum clusters revealed a catalytic activity remarkably higher than that of free gold quantum clusters; moreover, the hybrid filaments were found to show improved stability and cycling performance for silver-based catalysis. The present results indicate the potential of femtosecond laser irradiation to generate clusters as well as hybrid systems with excellent performance and reactivity.

Correlation Between Early Serum Myoglobin Levels and the Incidence and Prognosis of Intensive Care Unit-Acquired Weakness (ICU-AW) in Septic Shock Patients: A Comparative Study.

Intensive Care Unit-acquired weakness (ICU-AW) is a common complication that significantly impedes patient recovery. In the study, we investigated the correlation between early serum myoglobin levels in patients with septic shock due to pneumonia, and the incidence of ICU-AW, duration of mechanical ventilation, and prognosis. Patients were classified based on the development of ICU-AW within the first 10 days of ICU admission. We measured serum myoglobin levels upon ICU entry, and analyzed demographic data, APACHE II scores, use of mechanical ventilation, and clinical outcomes, including mortality and duration of mechanical ventilation. The results indicated significantly elevated serum myoglobin levels in the ICU-AW group, correlated with prolonged mechanical ventilation and increased mortality. ROC analysis revealed myoglobin as a promising biomarker for predicting ICU-AW, with an area under the curve of 0.843 (95% CI: 0.819~0.867), demonstrating a sensitivity of 76.00% and specificity of 82.30%. These findings underscored serum myoglobin as a predictive biomarker for early ICU-AW in septic shock patients, highlighting its potential to guide clinical decision-making.

Efficacy and safety of high-frequency repetitive transcranial magnetic stimulation (rTMS) for migraine: a meta-analysis of randomized controlled trials.

OBJECTIVE: To assess the efficacy and safety of high-frequency repetitive transcranial magnetic stimulation in the prevention or treatment of migraine by conducting a pooled analysis of relevant randomized controlled trials. METHODS: The PubMed, Embase, Cochrane, OVID, SCOPUS, Web of Science, and clinicaltrials.gov databases were systematically searched for randomized controlled trials (RCTs) comparing high-frequency rTMS and sham stimulation for the prevention or treatment of migraine. A meta-analysis of relevant outcome measures was performed using RevMan 5.3 software. RESULTS: Eight RCTs with a total of 384 patients were included. A total of 23 patients dropped out, and thus, 361 patients were ultimately included for analysis. The high-frequency rTMS group had a lower frequency of attacks than the sham group (MD = - 5.10; 95% CI: - 8.10, - 2.09; P = 0.0009). The rTMS group has less intense headaches than the sham group (SMD = - 0.74; 95% CI - 1.04, - 0.44; P < 0.00001). High-frequency rTMS improved patient disability (SMD = - 0.45; 95% CI - 0.75, - 0.16; P = 0.003). High-frequency rTMS led to no advantage in reducing the number of abortive medications (MD = - 1.10; 95% CI - 3.28, 1.08; P = 0.32), but it increased the occurrence of adverse events (RR = 1.69; 95% CI 1.09, 2.64; P = 0.02). CONCLUSIONS: High-frequency rTMS reduces the frequency of attacks and headache intensity in migraine patients and improves the patient's disability, but it also increases adverse events.

An Expert-Knowledge-based Graph Convolutional Network for Skeleton-based Physical Rehabilitation Exercises Assessment.

Physical therapists play a crucial role in guiding patients through effective and safe rehabilitation processes according to medical guidelines. However, due to the therapist-patient imbalance, it is neither economical nor feasible for therapists to provide guidance to every patient during recovery sessions. Automated assessment of physical rehabilitation can help with this problem, but accurately quantifying patients' training movements and providing meaningful feedback poses a challenge. In this paper, an Expert-knowledge-based Graph Convolutional approach is proposed to automate the assessment of the quality of physical rehabilitation exercises. This approach utilizes experts' knowledge to improve the spatial feature extraction ability of the Graph Convolutional module and a Gated pooling module for feature aggregation. Additionally, a Transformer module is employed to capture long-range temporal dependencies in the movements. The attention scores and weight matrix obtained through this approach can serve as interpretability tools to help therapists understand the assessment model and assist patients in improving their exercises. The effectiveness of the proposed method is verified on the KIMORE dataset, achieving state-of-the-art performance compared to existing models. Experimental results also illustrate the interpretability of the method in both spatial and temporal dimensions.

GELT: A graph embeddings based lite-transformer for knowledge tracing.

The development of intelligent education has led to the emergence of knowledge tracing as a fundamental task in the learning process. Traditionally, the knowledge state of each student has been determined by assessing their performance in previous learning activities. In recent years, Deep Learning approaches have shown promising results in capturing complex representations of human learning activities. However, the interpretability of these models is often compromised due to the end-to-end training strategy they employ. To address this challenge, we draw inspiration from advancements in graph neural networks and propose a novel model called GELT (Graph Embeddings based Lite-Transformer). The purpose of this model is to uncover and understand the relationships between skills and questions. Additionally, we introduce an energy-saving attention mechanism for predicting knowledge states that is both simple and effective. This approach maintains high prediction accuracy while significantly reducing computational costs compared to conventional attention mechanisms. Extensive experimental results demonstrate the superior performance of our proposed model compared to other state-of-the-art baselines on three publicly available real-world datasets for knowledge tracking.

Bifonazole caffeate: The first molecular salt of bifonazole with enhanced biopharmaceutical property based on experiments and quantum chemistry research.

In order to make novel breakthroughs in molecular salt studies of BCS class-IV antifungal medication bifonazole (BIF), a salification-driven strategy towards ameliorating attributes and aiding augment efficiency is raised. This strategy fully harnesses structural characters together attributes and benefits of caffeic acid (CAF) to concurrently enhance dissolvability and permeability of BIF by introducing the two ingredients into the identical molecular salt lattice through the salification reaction, which, coupled with the aroused potential activity of CAF significantly amplifies the antifungal efficacy of BIF. Guided by this route, the first BIF-organic molecular salt, BIF-CAF, is directionally designed and synthesized with satisfactorily structural characterizations and integrated theoretical and experimental explorations on the pharmaceutical properties. Single-crystal X-ray diffraction resolving confirms that there is a lipid-water amphiphilic sandwich structure constructed by robust charge-assistant hydrogen bonds in the salt crystal, endowing the molecular salt with the potential to enhance both dissolvability and permeability relative to the parent drug, which is validated by experimental evaluations. Remarkably, the comprehensive DFT-based theoretical investigations covering frontier molecular orbital, molecular electrostatic potential, Hirshfeld surface analysis, reduced density gradient, topology, sphericity and planarity analysis strongly support these observations, thereby allowing some positive relationships between macroscopic properties and microstructures of the molecular salt can be made. Intriguingly, the optimal properties, together with the stimulated activity of CAF markedly augment in vitro antifungal ability of the molecular salt, with magnifying inhibition zones and reducing minimum inhibitory concentrations. These findings fill in the gaps on researches of BIF-organic molecular salt, and adequately exemplify the feasibility and validity by integrating theoretical and experimental approaches to resolve BIF's problems via the salification-driven tactic.

miR-449a disturbs atherosclerotic plaque stability in streptozotocin and high-fat diet-induced diabetic mice by targeting CEACAM1.

BACKGROUND: Emerging evidence indicates carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is involved in the development of atherosclerosis (AS). However, the roles and functions of CEACAM1 in AS remain unknown. Therefore, this study aims to investigate the roles and molecular functions of CEACAM1 in AS. METHODS: We constructed a diabetes mellitus (DM) + high-fat diet (HFD) mouse model based on the streptozotocin (STZ)-induced apolipoprotein E-knockdown (ApopE-/-) mouse to investigate the roles and regulatory mechanism of miR-449a/CEACAM1 axis. The mRNA expression and protein levels in this study were examined using quantity PCR, western blot, immunofluorescence (IF), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry (IHC), respectively. And the lipid deposition and collagen content were detected using Oil Red O and Sirius Red staining. Cell apoptosis, migration, invasion, and tuber formation were detected by Annexin-V FITC/PI, wound healing, transwell, and tuber formation assays, respectively. The relationship between miR-449a and CEACAM1 was determined by a dual-luciferase reporter gene assay. RESULTS: miR-449a and MMP-9 were upregulated, and CEACAM1 was downregulated in the DM + HFD MOUSE model. Upregulation of CEACAM1 promoted atherosclerotic plaque stability and inhibited inflammation in the DM + HFD mouse model. And miR-449a directly targeted CEACAM1. Besides, miR-449a interacted with CEACAM1 to regulate atherosclerotic plaque stability and inflammation in DM-associated AS mice. In vitro, the rescue experiments showed miR-449a interacted with CEACAM1 to affect apoptosis, migration, invasion, and tuber formation ability in high glucose (HG)-induced HUVECs. CONCLUSION: These results demonstrated that miR-449a promoted plaque instability and inflammation in DM and HFD-induced mice by targeting CEACAM1.

Battling Salmonella enteritidis infections: integrating proteomics and in vivo assessment of Galla Chinensis tannic acid.

Salmonella infections pose a significant threat to animal and human health. Phytochemicals present a potential alternative treatment. Galla chinensis tannic acid (GCTA), a hydrolyzable polyphenolic compound, inhibits bacterial growth and demonstrates potential as an alternative or supplement to antibiotics to prevent Salmonella infections. However, little is known about the antimicrobial mechanism of GCTA against Salmonella. Here, we revealed 456 differentially expressed proteins upon GCTA treatment, impacting pathways related to DNA replication, repair, genomic stability, cell wall biogenesis, and lipid metabolism using TMT-labeled proteomic analysis. TEM analysis suggested altered bacterial morphology and structure post-treatment. A Salmonella-infected-mouse model indicated that GCTA administration improved inflammatory markers, alleviated intestinal histopathological alterations, and reduced Salmonella enterica serovar Enteritidis (S. Enteritidis) colonization in the liver and spleen of Salmonella-infected mice. The LD50 of GCTA was 4100 mg/kg with an oral single dose, vastly exceeding the therapeutic dose. Thus, GCTA exhibited antibacterial and anti-infective activity against S. Enteritidis. Our results provided insight into the molecular mechanisms of these antibacterial effects, and highlights the potential of GCTA as an alternative to antibiotics.

Evaluation of tubal patency based on peak injection pressure in four-dimensional hysterosalpingo-contrast sonography among infertile females: a preliminary study.

Background: Although the application of four-dimensional hysterosalpingo-contrast sonography (4D-HyCoSy) has relatively good diagnostic accuracy for assessing the patency of the fallopian tubes, the evaluation process mainly relies on morphological findings of the fallopian tubes and pelvic cavity. The purpose of this study was to explore the relationship of peak injection pressure during 4D-HyCoSy and tubal patency to provide a quantitative indicator for the evaluation of fallopian tube patency. Methods: This study included infertile patients who underwent 4D-HyCoSy and laparoscopic chromopertubation (LC) between 2020 and 2022, with LC serving as the reference test for assessing tubal patency. For the HyCoSy procedure, the ultrasound contrast agent was injected automatically using a liquid injection machine, and real-time pressure values were recorded. Patients were classified based on tubal patency status in LC as bilaterally patent, unilaterally patent, or bilaterally nonpatent. The average peak injection pressure and contrast agent volume of different groups were compared. Receiver operating characteristic (ROC) curve analysis was employed to determine the cutoff value. Results: A total of 268 infertile patients were enrolled in the study. With LC as the standard examination, the sensitivity and specificity of 4D-HyCoSy in diagnosing nonpatent fallopian tubes were 91.1% and 95.1%, respectively. In general, peak injection pressure was observed to gradually increase as tubal patency decreased (P<0.001), with average peak injection pressures of 233.5±66.3, 338.8±99.8, and 469.6±63.1 mmHg in the bilaterally patent, unilaterally patent, and bilaterally nonpatent groups, respectively. The volume of contrast agent used in patients in the bilaterally nonpatent group was significantly lower than that in the other two groups (P<0.01), with average volumes of 22.7±6.3, 24.3±9.3, and 18.9±9.2 mL, respectively. When one fallopian tube was patent, the area under the curve (AUC) for distinguishing obstruction from patency of the other fallopian tube was 0.827, with a sensitivity of 79.8% and a specificity of 74.3% (cutoff value: 254.3 mmHg). Similarly, when one fallopian tube was nonpatent, the AUC was 0.866, with a sensitivity of 90.6% and a specificity of 78.3% (cutoff value: 401.3 mmHg). Conclusions: Peak injection pressure during 4D-HyCoSy demonstrates promising diagnostic performance in evaluating fallopian tube patency in infertile patients.