QM/CG-MM: Systematic Embedding of Quantum Mechanical Systems in a Coarse-Grained Environment with Accurate Electrostatics.

Quantum Mechanics/Molecular Mechanics (QM/MM) can describe chemical reactions in molecular dynamics (MD) simulations at a much lower cost than ab initio MD. Still, it is prohibitively expensive for many systems of interest because such systems usually require long simulations for sufficient statistical sampling. Additional MM degrees of freedom are often slow and numerous but secondary in interest. Coarse-graining (CG) is well-known to be able to speed up sampling through both reduction in simulation cost and the ability to accelerate the dynamics. Therefore, embedding a QM system in a CG environment can be a promising way of expediting sampling without compromising the information about the QM subsystem. Sinitskiy and Voth first proposed the theory of Quantum Mechanics/Coarse-grained Molecular Mechanics (QM/CG-MM) with a bottom-up CG mapping. Mironenko and Voth subsequently introduced the DFT-QM/CG-MM formalism to couple a Density Functional Theory (DFT) treated QM system and to an apolar environment. Here, we present a more complete theory that addresses MM environments with significant polarity by explicitly accounting for the electrostatic coupling. We demonstrate our QM/CG-MM method with a chloride-methyl chloride SN2 reaction system in acetone, which is sensitive to solvent polarity. The method accurately recapitulates the potential of mean force for the substitution reaction, and the reaction barrier from the best model agrees with the atomistic simulations within sampling error. These models also have generalizability. In two other reactive systems that they have not been trained on, the QM/CG-MM model still achieves the same level of agreement with the atomistic QM/MM models. Finally, we show that in these examples the speed-up in the sampling is proportional to the acceleration of the rotational dynamics of the solvent in the CG system.

Enhanced Fluorescence Based on Slow Light Effect of ZIF-8 Photonic Crystals for Trace 2,4,6-Trinitrophenol Detection.

In response to growing concerns about public safety and environmental conservation, it is essential to develop a precise identification method for trace explosives. To improve the stability and detection sensitivity of perovskite quantum dots (PQDs) and address the issue of low porosity in traditional polymer-based photonic crystals (PhCs), this study proposed a PQD photoluminescence (PL) enhancement strategy based on the slow light effect of ZIF-8 PhCs for highly sensitive, selective, and convenient detection of 2,4,6-trinitrophenol (TNP). The slow light effect at the photonic band gap edge is the basis of amplifying the PL signal. PhCs were fabricated by the evaporation-induced self-assembly method. The diffraction wavelength overlapping the whole visible region was designed to match the emission wavelength of PQDs. Results showed that PhCs matching the PBG edge with PQDs' emission peak amplified the PL signal 11.3 times, significantly improving sensitivity for trace TNP detection with a limit as low as 2.52 nM. Moreover, there was a 13.3-fold enhancement of PQDs' fluorescence lifetime when the emission wavelength fell in the PBG range. The hydrophobic surface of ZIF-8 PhCs enhanced the PQDs' stability and moisture resistance. Furthermore, the selective quenching mechanism of TNP by the sensor was photoinduced electron transfer (PET) verified by DFT calculations and time-resolved PL decay dynamics measurements. This study demonstrated great potential for manipulating light emission enhancement by PhCs in developing efficient fluorescent sensors for trace environmental pollutant detection.

Effects of disc overhang diameter on the uplift bearing capacity of new-type concrete expanded-plate pile groups.

The disc overhang diameter can significantly affect the uplift bearing capacity of new concrete expanded-plate pile groups, affecting their design and practical applications. Accordingly, this effect was investigated considering the failure laws of the soil surrounding various pile types and groups. Based on the uplift bearing capacities of single and double piles, a finite element simulation was adopted to establish models for the four-, six-, and nine-pile groups. The relationship between the disc overhang diameter and uplift-bearing capacity of each pile group was explored: as the disk overhang diameter increased, the uplift-bearing capacities of the pile groups increased; however, this relationship is nonlinear. The optimal disc overhang diameter was determined as 1.5-1.75 times the pile diameter. For a constant disc overhang diameter, corner piles have a greater uplift bearing capacity than side piles in the six-pile group, and a greater uplift bearing capacity than the side and center piles in the nine-pile group. Thus, the pile-group effect depends on the pile position. The uplift bearing capacity did not increase linearly with the number of piles, and the average uplift bearing capacity of a pile in a pile group was less than that of a single pile. Therefore, the uplift bearing capacity of the pile groups decreased as the number of piles increased. The reliability of the simulation was verified via visual testing of a small-scale half-cut pile model.

Assessing and Optimizing Large Language Models on Spondyloarthritis Multi-Choice Question Answering: Protocol for Enhancement and Assessment.

BACKGROUND: Spondyloarthritis (SpA), a chronic inflammatory disorder, predominantly impacts the sacroiliac joints and spine, significantly escalating the risk of disability. SpA's complexity, as evidenced by its diverse clinical presentations and symptoms that often mimic other diseases, presents substantial challenges in its accurate diagnosis and differentiation. This complexity becomes even more pronounced in nonspecialist health care environments due to limited resources, resulting in delayed referrals, increased misdiagnosis rates, and exacerbated disability outcomes for patients with SpA. The emergence of large language models (LLMs) in medical diagnostics introduces a revolutionary potential to overcome these diagnostic hurdles. Despite recent advancements in artificial intelligence and LLMs demonstrating effectiveness in diagnosing and treating various diseases, their application in SpA remains underdeveloped. Currently, there is a notable absence of SpA-specific LLMs and an established benchmark for assessing the performance of such models in this particular field. OBJECTIVE: Our objective is to develop a foundational medical model, creating a comprehensive evaluation benchmark tailored to the essential medical knowledge of SpA and its unique diagnostic and treatment protocols. The model, post-pretraining, will be subject to further enhancement through supervised fine-tuning. It is projected to significantly aid physicians in SpA diagnosis and treatment, especially in settings with limited access to specialized care. Furthermore, this initiative is poised to promote early and accurate SpA detection at the primary care level, thereby diminishing the risks associated with delayed or incorrect diagnoses. METHODS: A rigorous benchmark, comprising 222 meticulously formulated multiple-choice questions on SpA, will be established and developed. These questions will be extensively revised to ensure their suitability for accurately evaluating LLMs' performance in real-world diagnostic and therapeutic scenarios. Our methodology involves selecting and refining top foundational models using public data sets. The best-performing model in our benchmark will undergo further training. Subsequently, more than 80,000 real-world inpatient and outpatient cases from hospitals will enhance LLM training, incorporating techniques such as supervised fine-tuning and low-rank adaptation. We will rigorously assess the models' generated responses for accuracy and evaluate their reasoning processes using the metrics of fluency, relevance, completeness, and medical proficiency. RESULTS: Development of the model is progressing, with significant enhancements anticipated by early 2024. The benchmark, along with the results of evaluations, is expected to be released in the second quarter of 2024. CONCLUSIONS: Our trained model aims to capitalize on the capabilities of LLMs in analyzing complex clinical data, thereby enabling precise detection, diagnosis, and treatment of SpA. This innovation is anticipated to play a vital role in diminishing the disabilities arising from delayed or incorrect SpA diagnoses. By promoting this model across diverse health care settings, we anticipate a significant improvement in SpA management, culminating in enhanced patient outcomes and a reduced overall burden of the disease. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/57001.

Molecular Dynamics Simulation of Complex Reactivity with the Rapid Approach for Proton Transport and Other Reactions (RAPTOR) Software Package.

Simulating chemically reactive phenomena such as proton transport on nanosecond to microsecond and beyond time scales is a challenging task. Ab initio methods are unable to currently access these time scales routinely, and traditional molecular dynamics methods feature fixed bonding arrangements that cannot account for changes in the system's bonding topology. The Multiscale Reactive Molecular Dynamics (MS-RMD) method, as implemented in the Rapid Approach for Proton Transport and Other Reactions (RAPTOR) software package for the LAMMPS molecular dynamics code, offers a method to routinely sample longer time scale reactive simulation data with statistical precision. RAPTOR may also be interfaced with enhanced sampling methods to drive simulations toward the analysis of reactive rare events, and a number of collective variables (CVs) have been developed to facilitate this. Key advances to this methodology, including GPU acceleration efforts and novel CVs to model water wire formation are reviewed, along with recent applications of the method which demonstrate its versatility and robustness.

Creation of memory-memory entanglement in a metropolitan quantum network.

Towards realizing the future quantum internet1,2, a pivotal milestone entails the transition from two-node proof-of-principle experiments conducted in laboratories to comprehensive multi-node set-ups on large scales. Here we report the creation of memory-memory entanglement in a multi-node quantum network over a metropolitan area. We use three independent memory nodes, each of which is equipped with an atomic ensemble quantum memory3 that has telecom conversion, together with a photonic server where detection of a single photon heralds the success of entanglement generation. The memory nodes are maximally separated apart for 12.5 kilometres. We actively stabilize the phase variance owing to fibre links and control lasers. We demonstrate concurrent entanglement generation between any two memory nodes. The memory lifetime is longer than the round-trip communication time. Our work provides a metropolitan-scale testbed for the evaluation and exploration of multi-node quantum network protocols and starts a stage of quantum internet research.

What are the important factors influencing the physical activity level of junior high school students: a cross-sectional survey.

Background: Engaging in regular physical activity has been consistently linked to improved physical health and academic performance. Despite its known benefits, there is a concerning trend of decreased physical activity among children globally. The study primarily aims to investigate the level of physical activity among junior high school students in Taiyuan and analyse the main affecting factors from a socio-ecological perspective. Methods: A cross-sectional study was conducted, involving 650 junior high school students from 7 schools in Taiyuan, and 648 valid questionnaires were ultimately collected. The data on students' physical activity levels were collected through the Children's Leisure Activities Study Survey Questionnaire, and the data on factors affecting students' physical activity were collected through the Student Perceived Factors Affecting Physical Activity Questionnaire. Results: In this study, students from the 7th, 8th, and 9th grades participated in physical activities, averaging 214.500 min per week in moderate-intensity and 25.000 min in high-intensity activities, cumulatively averaging 280.000 min weekly. Notably, a significant disparity (p = 0.012) was observed in the combined duration of moderate and high-intensity activities, with male students engaging more time compared to their female counterparts (307.500 vs. 255.000 min). This variance extended across different grades, particularly evident in 8th graders who recorded the highest weekly high-intensity activity duration (31.000 min) and overall physical activity time (320.500 min), surpassing the 7th graders(p = 0.007 for high-intensity activities). Furthermore, an exploratory factor analysis of a 32-item questionnaire, designed to identify determinants of physical activity, revealed six principal components. These components were found to positively correlate with both moderate and high-intensity physical activities. Conclusion: Results emphasize that educational institutions and community programs should collaborate to offer engaging weekend physical activity programs. Schools should develop and implement tailored physical education curricula addressing gender and grade differences. Furthermore, schools and local governments should invest in high-quality sports equipment and facilities.

Interaction between Dietary Lactoferrin and Gut Microbiota in Host Health.

The gut microbiota are known to play an important role in host health and disease. Alterations in the gut microbiota composition can disrupt the stability of the gut ecosystem, which may result in noncommunicable chronic diseases (NCCDs). Remodeling the gut microbiota through personalized nutrition is a novel therapeutic avenue for both disease control and prevention. However, whether there are commonly used gut microbiota-targeted diets and how gut microbiota-diet interactions combat NCCDs and improve health remain questions to be addressed. Lactoferrin (LF), which is broadly used in dietary supplements, acts not only as an antimicrobial in the defense against enteropathogenic bacteria but also as a prebiotic to propagate certain probiotics. Thus, LF-induced gut microbiota alterations can be harnessed to induce changes in host physiology, and the underpinnings of their relationships and mechanisms are beginning to unravel in studies involving humans and animal models.

Effect of structural support size and position on depressed tibial plateau fractures: A finite element analysis.

Objective: Structural support for depressed tibial plateau fractures is receiving increasing attention. Currently, there has been little biomechanical evaluation of structural support. This work aimed to investigate the effect of structural support size and position on fracture fixation stability. Methods: A split-depressed tibial plateau fracture model was created according to the fracture map. Cortical screws combined with structural filler were used for fracture fixation. The filler diameter was set to small, medium and large, and the filler position was set to the center and offset by 1, 2 and 3 mm to study the effect of position and size on stability. Results: The maximum stress on the implant in all scenarios occurs at the lower contact surface between the anterior screw and the filler. Increased support size resulted in increased mean maximum screw stress, depressed fragment axial displacement and separated fragment transverse displacement (screw stress: 266.6 ± 37.7 MPa vs. 266.7 ± 51.0 MPa vs. 273.8 ± 41.5 MPa; depressed displacement: 0.123 ± 0.036 mm vs. 0.133 ± 0.049 mm vs. 0.158 ± 0.050 mm; separated displacement: 0.402 ± 0.031 mm VS 0.412 ± 0.047 mm VS 0.437 ± 0.049 mm). The larger the offset of the support position was, the larger the peak screw stress and the larger the reduction loss of depressed and separated fragment reduction, regardless of the support size. The medium support combined with the central position presented the minimum of peak stress and reduction loss. Cortical bone was below 2 % and trabecular strain was below 10 % for all scenarios. Conclusion: Central placement of structural support provides superior stability for the treatment of depressed tibial plateau fractures compared to the eccentric placement. When a support is placed centrally, optimal stability is achieved when the diameter matches the diameter of the depressed region. Thus, the utilization of equal-diameter fillers to provide central support appears to be an ideal selection for depressed tibial plateau fractures.

In Vitro/Vivo Mechanisms of Antibacterial Peptide NZ2114 against Staphylococcus pseudintermedius and Its Biofilms.

Staphylococcus pseudintermedius is an opportunistic pathogen commonly found in canines, and has garnered escalating interest due to its potential for zoonotic transmission and increasing antimicrobial resistance. However, the excessive use of antibiotics and the characteristic of S. pseudintermedius forming biofilms make treatment challenging. In this study, the in vivo and in vitro antimicrobial activity and mechanisms of action of NZ2114, a plectasin-derived peptide, against S. pseudintermedius were investigated. NZ2114 exhibited potent antibacterial activity towards S. pseudintermedius (minimum inhibitory concentration, MIC = 0.23 µM) with a lower probability of inducing drug-resistant mutations and efficient bactericidal action, which was superior to those of mopirucin (MIC = 0.25-0.5 µM) and lincomycin (MIC = 4.34-69.41 µM). The results of electron microscopy and flow cytometry showed that NZ2114 disrupted S. pseudintermedius' cell membrane, resulting in cellular content leakage, cytoplasmic membrane shrinkage, and, eventually, cell death. The intracellular ROS activity and Alamar Blue detection showed that NZ2114 interferes with intracellular metabolic processes. In addition, NZ2114 effectively inhibits biofilm formation, and confocal laser scanning microscopy further revealed its antibacterial and anti-biofilm activity (biofilm thickness reduced to 6.90-17.70 µm). The in vivo therapy of NZ2114 in a mouse pyoderma model showed that it was better than lincomycin in effectively decreasing the number of skin bacteria, alleviating histological damage, and reducing the skin damage area. These results demonstrated that NZ2114 may be a promising antibacterial candidate against S. pseudintermedius infections.

PLD2 deletion ameliorates sepsis-induced cardiomyopathy by suppressing cardiomyocyte pyroptosis via the NLRP3/caspase 1/GSDMD pathway.

OBJECTIVE: Sepsis-induced cardiomyopathy (SICM) is a life-threatening complication. Phospholipase D2 (PLD2) is crucial in mediating inflammatory reactions and is associated with the prognosis of patients with sepsis. Whether PLD2 is involved in the pathophysiology of SICM remains unknown. This study aimed to investigate the effect of PLD2 knockout on SICM and to explore potential mechanisms. METHODS: The SICM model was established using cecal ligation and puncture in wild-type and PLD2-knockout mice and lipopolysaccharide (LPS)-induced H9C2 cardiomyocytes. Transfection with PLD2-shRNA lentivirus and a PLD2 overexpression plasmid were used to interfere with PLD2 expression in H9C2 cells. Cardiac pathological alterations, cardiac function, markers of myocardial injury, and inflammatory factors were used to evaluate the SICM model. The expression of pyroptosis-related proteins (NLRP3, cleaved caspase 1, and GSDMD-N) was assessed using western blotting, immunofluorescence, and immunohistochemistry. RESULTS: SICM mice had myocardial tissue damage, increased inflammatory response, and impaired heart function, accompanied by elevated PLD2 expression. PLD2 deletion improved cardiac histological changes, mitigated cTNI production, and enhanced the survival of the SICM mice. Compared with controls, PLD2-knockdown H9C2 exhibits a decrease in inflammatory markers and lactate dehydrogenase production, and scanning electron microscopy results suggest that pyroptosis may be involved. The overexpression of PLD2 increased the expression of NLRP3 in cardiomyocytes. In addition, PLD2 deletion decreased the expression of pyroptosis-related proteins in SICM mice and LPS-induced H9C2 cells. CONCLUSION: PLD2 deletion is involved in SICM pathogenesis and is associated with the inhibition of the myocardial inflammatory response and pyroptosis through the NLRP3/caspase 1/GSDMD pathway.

Pharmacokinetics and pharmacodynamics of antibacterial peptide NZX in Staphylococcus aureus mastitis mouse model.

Staphylococcus aureus is associated with dairy mastitis, which causes serious economic losses to dairy farming industry. Antibacterial peptide NZX showed good antibacterial activity against S. aureus. This study aimed to evaluate pharmacokinetics and pharmacodynamics of NZX against S. aureus-induced mouse mastitis. NZX exhibited potent in vitro antibacterial activity against the test S. aureus strains (minimal inhibitory concentration (MIC): 0.23-0.46 µM), low mutant prevention concentration (MPC: 1.18-3.68 µM), and a long post antibiotic effect (PAE: 2.20-8.84 h), which was superior to those of lincomycin and ceftiofur. Antibacterial mechanisms showed that NZX could penetrate the cell membrane, resulting in obvious cell membrane perforation and morphological changes, and bind to intracellular DNA. Furthermore, NZX had a good stability in milk environment (retention rate: 85.36%, 24 h) than that in mammary homogenate (47.90%, 24 h). In mouse mastitis model, NZX (25-400 µg/gland) could significantly reduce the bacterial load of mammary tissue in a dose-dependent manner. In addition, NZX (100 µg/gland) could relieve the inflammatory symptoms of mammary tissue, and significantly decreased its pathological scores. The concentration-time curve of NZX (100 µg/gland) in the mammary tissue was plotted and the corresponding pharmacokinetic parameters were obtained by non-compartment model calculation. Those parameters of Tmax, T1/2, Cmax and AUC were 0.5 h, 35.11 h, 32.49 µg/g and 391 µg·h/g, respectively. Therefore, these results suggest that NZX could act as a promising candidate for treating dairy mastitis disease caused by S. aureus. KEY POINTS: • NZX could kill S. aureus by dual mechanism involved in membrane and DNA disruption • NZX could relieve S. aureus-induced mouse mastitis • Pharmacokinetic parameters of NZX in mouse mammary gland were obtained.

Polylactic Glycolic Acid-Mediated Delivery of Plectasin Derivative NZ2114 in Staphylococcus epidermidis Biofilms.

Antimicrobial peptides (AMPs) are antibiotic candidates; however, their instability and protease susceptibility limit clinical applications. In this study, the polylactic acid-glycolic acid (PLGA)-polyvinyl alcohol (PVA) drug delivery system was screened by orthogonal design using the double emulsion-solvent evaporation method. NZ2114 nanoparticles (NZ2114-NPs) displayed favorable physicochemical properties with a particle size of 178.11 ± 5.23 nm, polydispersity index (PDI) of 0.108 ± 0.10, ζ potential of 4.78 ± 0.67 mV, actual drug-loading rate of 4.07 ± 0.37%, encapsulation rate of 81.46 ± 7.42% and cumulative release rate of 67.75% (120 h) in PBS. The results showed that PLGA encapsulation increased HaCaT cell viability by 20%, peptide retention in 50% serum by 24.12%, and trypsin tolerance by 4.24-fold. Meanwhile, in vitro antimicrobial assays showed that NZ2114-NPs had high inhibitory activity against Staphylococcus epidermidis (S. epidermidis) (4-8 µg/mL). Colony counting and confocal laser scanning microscopy (CLSM) confirmed that NZ2114-NPs were effective in reducing the biofilm thickness and bacterial population of S. epidermidis G4 with a 99% bactericidal rate of persister bacteria, which was significantly better than that of free NZ2114. In conclusion, the results demonstrated that PLGA nanoparticles can be used as a reliable NZ2114 delivery system for the treatment of biofilm infections caused by S. epidermidis.

Influence of centroid acceleration acquisition and filtering class on head injury criterion evaluation.

BACKGROUND: Although the Head Injury Criteria (HIC) has been widely applied to assess head impact injuries, it faces two outstanding problems: 1) HIC is affected strongly by the cut-off frequency when processing acceleration signals. And these cut-off frequencies are experiential and lack unified guidelines; 2) If the head was impacted on a different part, should the corresponding HIC threshold be the same? If these problems are not resolved, it could potentially lead to a critical misinterpretation of the safety assessment. METHODS: Finite element method was used to reconstruct head impacts. The head model includes tissues like skull, brainstem, cerebrospinal fluid, etc. The head model was impacted in the frontal, occipital, parietal or lateral direction with different impact velocities. Acceleration signals of the head model were extracted directly from the skull and the head centroid node. To obtain a robust HIC, the filtering class of acceleration signals were analyzed carefully. Then, the relation between rigid body HIC and the centroid node HIC were studied systematically. RESULTS: When the filtering class of rigid body acceleration and centroid node acceleration reached the cut-off frequency, the corresponding derivative of HIC tended to change smoothly. Using these cut-off frequencies, robust HICs were obtained. The rigid body HIC far exceeded that of centroid node HIC, such as 8, 9, 14 and 31 times exceeded in the frontal, occipital, parietal and lateral impact conditions, respectively. Moreover, approximate linear relations were found between the rigid body HIC and the centroid node HIC in different impact directions, respectively. From these relations, the injury thresholds of rigid body HIC of various directions were given quantitatively. CONCLUSIONS: The rational filtering class like CFC 800 and CFC 700 were given for rigid body HIC and centroid node HIC, respectively. The rigid body HIC had a significant discrepancy from the centroid node HIC. Linear relations between the rigid body HIC and centroid node HIC were found, and their slopes changed with impact directions. From these relations, we can adjust the injury thresholds reasonably if the head receives different impacts. These findings can effectively enhance the applicability of HIC.

Causality of the gut microbiome and atherosclerosis-related lipids: a bidirectional Mendelian Randomization study.

AIMS: Recent studies have indicated an association between intestinal flora and lipids. However, observational studies cannot indicate causality. In this study, we aimed to investigate the potentially causal relationships between the intestinal flora and blood lipids. METHODS: We performed a bidirectional two-sample Mendelian Randomization (MR) analysis to investigate the causal relationship between intestinal flora and blood lipids. Summary statistics of genome-wide association studies (GWASs) for the 211 intestinal flora and blood lipid traits (n = 5) were obtained from public datasets. Five recognized MR methods were applied to assess the causal relationship with lipids, among which, the inverse-variance weighted (IVW) regression was used as the primary MR method. A series of sensitivity analyses were performed to test the robustness of the causal estimates. RESULTS: The results indicated a potential causal association between 19 intestinal flora and dyslipidemia in humans. Genus Ruminococcaceae, Christensenellaceae, Parasutterella, Terrisporobacter, Parabacteroides, Class Erysipelotrichia, Family Erysipelotrichaceae, and order Erysipelotrichales were associated with higher dyslipidemia, whereas genus Oscillospira, Peptococcus, Ruminococcaceae UCG010, Ruminococcaceae UCG011, Dorea, and Family Desulfovibrionaceae were associated with lower dyslipidemia. After using the Bonferroni method for multiple testing correction, Only Desulfovibrionaceae [Estimate = -0.0418, 95% confidence interval [CI]: 0.9362-0.9826, P = 0.0007] exhibited stable and significant negative associations with ApoB levels. The inverse MR analysis did not find a significant causal effect of lipids on the intestinal flora. Additionally, no significant heterogeneity or horizontal pleiotropy for IVs was observed in the analysis. CONCLUSION: The study suggested a causal relationship between intestinal flora and dyslipidemia. These findings will provide a meaningful reference to discover dyslipidemia for intervention to address the problems in the clinic.

Efficiency of NZ2114 on Superficial Pyoderma Infected with Staphylococcus pseudintermedius.

Staphylococcus pseudintermedius (S. pseudintermedius) is the main pathogen causing pyoderma of canines. With the emergence of drug-resistant bacteria, traditional antibiotic treatments are limited. As a potential antibacterial agent, NZ2114 was effective against S. pseudintermedius, including drug-resistant strains. Its bactericidal efficacy was superior to mupiroxacin, ofloxacin and lincomycin. To facilitate the transcutaneous delivery of NZ2114 for the treatment of superficial pyoderma, chemical permeation enhancers were added since water-soluble NZ2114 does not easily penetrate the skin lipid layer. Two different NZ2114 sprays were prepared by combining 1% Azone + 10% propylene glycol (PG) or 5% N-methylpyrrolidone (NMP) + 10% PG with NZ2114 after screening. The cumulative permeability of NZ2114 sprays were 244.149 and 405.245 µg/cm2 at 24 h with an in vitro percutaneous assay of mice skin, which showed a 244% and 405% increase in skin permeability than NZ2114, respectively. In addition, the efficacy of NZ2114 sprays in reducing skin bacteria colonisation was demonstrated in a mouse model of superficial pyoderma (24 mice, 3 mice/group) induced by S. pseudintermedius, and the 5% NMP + 10% PG + NZ2114 group had the best therapeutic effect compared to the other groups. This preparation did not cause any skin irritation, laying the foundation for the development of an effective and non-toxic topical product.

Microcystin-RR promote lipid accumulation through CD36 mediated signal pathway and fatty acid uptake in HepG2 cells.

Microcystins (MC)-RR is a significant analogue of MC-LR, which has been identified as a hepatotoxin capable of influencing lipid metabolism and promoting the progression of liver-related metabolic diseases. However, the toxicity and biological function of MC-RR are still not well understood. In this study, the toxic effects and its role in lipid metabolism of MC-RR were investigated in hepatoblastoma cells (HepG2cells). The results demonstrated that MC-RR dose-dependently reduced cell viability and induced apoptosis. Additionally, even at low concentrations, MC-RR promoted lipid accumulation through up-regulating levels of triglyceride, total cholesterol, phosphatidylcholines and phosphatidylethaolamine in HepG2 cells, with no impact on cell viability. Proteomics and transcriptomics analysis further revealed significant alterations in the protein and gene expression profiles in HepG2 cells treated with MC-RR. Bioinformatic analysis, along with subsequent validation, indicated the upregulation of CD36 and activation of the AMPK and PI3K/AKT/mTOR in response to MC-RR exposure. Finally, knockdown of CD36 markedly ameliorated MC-RR-induced lipid accumulation in HepG2 cells. These findings collectively suggest that MC-RR promotes lipid accumulation in HepG2 cells through CD36-mediated signal pathway and fatty acid uptake. Our findings provide new insights into the hepatotoxic mechanism of MC-RR.

A mendelian randomization study investigates the causal relationship between immune cell phenotypes and cerebral aneurysm.

Background: Cerebral aneurysms (CAs) are a significant cerebrovascular ailment with a multifaceted etiology influenced by various factors including heredity and environment. This study aimed to explore the possible link between different types of immune cells and the occurrence of CAs. Methods: We analyzed the connection between 731 immune cell signatures and the risk of CAs by using publicly available genetic data. The analysis included four immune features, specifically median brightness levels (MBL), proportionate cell (PC), definite cell (DC), and morphological attributes (MA). Mendelian randomization (MR) analysis was conducted using the instrumental variables (IVs) derived from the genetic variation linked to CAs. Results: After multiple test adjustment based on the FDR method, the inverse variance weighted (IVW) method revealed that 3 immune cell phenotypes were linked to the risk of CAs. These included CD45 on HLA DR+NK (odds ratio (OR), 1.116; 95% confidence interval (CI), 1.001-1.244; p = 0.0489), CX3CR1 on CD14- CD16- (OR, 0.973; 95% CI, 0.948-0.999; p = 0.0447). An immune cell phenotype CD16- CD56 on NK was found to have a significant association with the risk of CAs in reverse MR study (OR, 0.950; 95% CI, 0.911-0.990; p = 0.0156). Conclusion: Our investigation has yielded findings that support a substantial genetic link between immune cells and CAs, thereby suggesting possible implications for future clinical interventions.