Adapting to stress: The effects of hibernation and hibernacula temperature on the hepatic transcriptome of Rhinolophus pusillus.

Hibernation, a survival strategy in mammals for extreme climates, induces physiological phenomena such as ischemia-reperfusion and metabolic shifts that hold great potential for advancements in modern medicine. Despite this, the molecular mechanisms underpinning hibernation remain largely unclear. This study used RNA-seq and Iso-seq techniques to investigate the changes in liver transcriptome expression of Rhinolophus pusillus during hibernation and active periods, as well as under different microhabitat temperatures. We identified 11 457 differentially expressed genes during hibernation and active periods, of which 395 showed significant differential expression. Genes associated with fatty acid catabolism were significantly upregulated during hibernation, whereas genes related to carbohydrate metabolism and glycogen synthesis were downregulated. Conversely, immune-related genes displayed differential expression patterns: genes tied to innate immunity were significantly upregulated, while those linked to adaptive immunity and inflammatory response were downregulated. The analysis of transcriptomic data obtained from different microhabitat temperatures revealed that R. pusillus exhibited an upregulation of genes associated with lipid metabolism in lower microhabitat temperature. This upregulation facilitated an enhanced utilization rate of triglyceride, ultimately resulting in increased energy provision for the organism. Additionally, R. pusillus upregulated gluconeogenesis-related genes regardless of the microhabitat temperature, demonstrating the importance of maintaining blood glucose levels during hibernation. Our transcriptomic data reveal that these changes in liver gene expression optimize energy allocation during hibernation, suggesting that liver tissue adaptively responds to the inherent stress of its function during hibernation. This study sheds light on the role of differential gene expression in promoting more efficient energy allocation during hibernation. It contributes to our understanding of how liver tissue adapts to the stressors associated with this state.

Associations of Lower-Carbohydrate and Lower-Fat Diets with Mortality among People with Cardiovascular Disease.

BACKGROUND: Although low-carbohydrate and low-fat diets have been shown to have short-term metabolic benefits, the associations of these dietary patterns, particularly different food sources and macronutrient quality, with mortality in people with cardiovascular disease (CVD) remain unclear. OBJECTIVES: To examine the associations of different types of lower-carbohydrate diets (LCDs) and lower-fat diets (LFDs) with mortality in individuals with CVD. METHODS: This study included 3971 adults with CVD from the NHANES 1999-2014. Mortality status was linked to National Death Index mortality data through 31 December 2019. Overall, unhealthy and healthy LCD and LFD scores were determined based on the percentages of energy from total and subtypes of carbohydrate, fat, and protein. Cox proportional hazards regression models were applied to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Higher healthy LCD score was associated with favorable blood lipids and higher homeostasis model assessment of insulin resistance, whereas higher unhealthy LFD score was associated with lower high-density lipoprotein and higher C-reactive protein at baseline (all P-trend < 0.05). During 35,150 person-years of follow-up, 2163 deaths occurred. For per 20-percentile increment in dietary scores, the multivariate-adjusted HRs of all-cause mortality were 0.91 (95% CI: 0.86, 0.96) for healthy LCD score (P < 0.001), 0.94 (95% CI: 0.89, 1.00) for healthy LFD score (P = 0.04), and 1.07 (95% CI: 1.00, 1.14) for unhealthy LFD score (P = 0.04). CONCLUSIONS: Overall LCD and LFD scores are not associated with total mortality. Unhealthy LFD scores are associated with higher total mortality, whereas healthy LCD and LFD scores are associated with lower mortality in people with CVD.

Attenuation of neurovirulence of chikungunya virus by a single amino acid mutation in viral E2 envelope protein.

BACKGROUND: Chikungunya virus (CHIKV) has reemerged as a major public health concern, causing chikungunya fever with increasing cases and neurological complications. METHODS: In the present study, we investigated a low-passage human isolate of the East/ Central/South African (ECSA) lineage of CHIKV strain LK(EH)CH6708, which exhibited a mix of small and large viral plaques. The small and large plaque variants were isolated and designated as CHIKV-SP and CHIKV-BP, respectively. CHIKV-SP and CHIKV-BP were characterized in vitro and in vivo to compare their virus production and virulence. Additionally, whole viral genome analysis and reverse genetics were employed to identify genomic virulence factors. RESULTS: CHIKV-SP demonstrated lower virus production in mammalian cells and attenuated virulence in a murine model. On the other hand, CHIKV-BP induced higher pro-inflammatory cytokine levels, compromised the integrity of the blood-brain barrier, and led to astrocyte infection in mouse brains. Furthermore, the CHIKV-SP variant had limited transmission potential in Aedes albopictus mosquitoes, likely due to restricted dissemination. Whole viral genome analysis revealed multiple genetic mutations in the CHIKV-SP variant, including a Glycine (G) to Arginine (R) mutation at position 55 in the viral E2 glycoprotein. Reverse genetics experiments confirmed that the E2-G55R mutation alone was sufficient to reduce virus production in vitro and virulence in mice. CONCLUSIONS: These findings highlight the attenuating effects of the E2-G55R mutation on CHIKV pathogenicity and neurovirulence and emphasize the importance of monitoring this mutation in natural infections.

Effect of the PCSK9 R46L genetic variant on plasma insulin and glucose levels, risk of diabetes mellitus and cardiovascular disease: A meta-analysis.

BACKGROUND AND AIM: The impact of the loss-of-function (LOF) genetic variant PCSK9 R46L on glucose homeostasis and cardiovascular disease (CVD) remains uncertain, despite its established correlation with diminished blood cholesterol levels. This meta-analysis aimed at exploring the effect of the PCSK9 R46L genetic variant on plasma insulin and glucose levels, risk of diabetes mellitus and CVD. METHODS AND RESULTS: PubMed, Embase, and the Cochrane Library were searched for cohort and case-control studies published until October 1, 2023. The studies should report the association of the PCSK9 R46L genetic variant with one of the following: fasting plasma insulin, blood glucose levels, diabetes mellitus, and CVD risk. A dominant model of the PCSK9 R46L genetic variant was employed to statistical analysis. The meta-analyses were performed for continuous variables with standard mean difference (SMD), categorical variables with odds ratio (OR) using a random-effects model. A total of 17 articles with 20 studies engaging 1,186,861 population were identified and mobilized for these analyses. The overall results indicated that, compared with non-carriers of the PCSK9 R46L genetic variant, carriers of the PCSK9 R46L genetic variant did not increase or decrease the levels of fasting plasma insulin (3 studies with 7277 population; SMD, 0.08; 95% CI, -0.04 to 0.19; P = 0.270), and the levels of fasting plasma glucose (7 studies with 9331 population; SMD, 0.03; 95% CI, -0.08 to 0.13; P = 0.610). However, carriers of the PCSK9 R46L genetic variant indeed had 17% reduction in the risk of CVD (11 studies with 558,263 population; OR, 0.83; 95% CI, 0.71 to 0.98; P = 0.030), and 9% increase in the risk of diabetes mellitus (10 studies with 744,466 population; OR, 1.09; 95% CI, 1.04 to 1.14; P < 0.01). Meta-regression analyses indicated that the increased risk of diabetes mellitus and the reduced risk of CVD were positively correlated with reduction in LDL-C (P = 0.004 and 0.033, respectively). CONCLUSIONS: PCSK9 R46L genetic variant exhibited an elevated susceptibility to diabetes mellitus alongside a reduced vulnerability to CVD.

Electromagnetic field exposure monitoring of commercial 28-GHz band 5G base stations in Tokyo, Japan.

Fifth generation (5G) wireless communication is being rolled out around the world. In this work, the latest radio frequency electromagnetic field (EMF) exposure measurement results on commercial 28-GHz band 5G base stations (BSs) deployed in the urban area of Tokyo, Japan, are presented. The measurements were conducted under realistic traffic conditions with a 5G smartphone and using both omnidirectional and horn antennas. First and foremost, in all cases, the electric-field (E-field) intensity is much lower (<-38 dB) than the exposure limits. The E-field intensities for traffic-off cases do not show any significant difference between the two antennas with the maximum being 3.6 dB. For traffic-on cases, the omnidirectional antenna can undesirably capture the radio wave from the smartphone in some cases, resulting in a 7-13 dB higher E-field intensity than that using the horn antenna. We also present comparative results between 4G long term evolution BSs and sub-6-GHz band and 28-GHz band 5G BSs and provide recommendations on acquiring meaningful EMF exposure data. This work is a further step toward the standardization of the measurement method regarding quasi-millimeter/millimeter wave 5G BSs.

Epidemiology and prognostic factors for new-onset deep venous thrombosis after unicompartmental knee arthroplasty: a retrospective study.

BACKGROUND: Patients who underwent knee joint arthroplasty were at risk of venous thromboembolic events (VTEs), however, less studies were conducted to demonstrate the epidemiology and risk factors of deep venous thrombosis (DVT) following unicompartmental knee arthroplasty (UKA). Objective of this study was to explore the incidence and prognostic factors of DVT after UKA. METHODS: Patients who underwent primary UKA from December 2018 to June 2022 were recruited in this study. Demographic characteristics, operation related variables and laboratory index were extracted and analyzed. Receiver operating characteristic analysis was performed to detect the optimum cut-off value for variables of interest. Univariate and multivariate logistic analysis were performed to identify risk factors of DVT. RESULTS: 351 UKAs with a mean age of 65.4 ± 7.1 years were reviewed. After 12.9 ± 11.2 months follow-up, 35 DVTs were confirmed which indicating an incidence of 9.9%. The results showed that occupation (agricultural laborer) (P = 0.008), disease duration > 8.5 years (P = 0.035), operation time > 169 min (P = 0.003), intraoperative blood loss > 102 ml (P < 0.001), BMI > 26.8 kg/m 2 (P = 0.001), preoperative D-dimer > 0.29 mg/L (P = 0.001), prothrombin time < 10.7 s (P = 0.033) and INR < 0.98 (P = 0.032) between DVT and Non-DVT group were significantly different. Multivariate logistic regression analysis showed intraoperative blood loss > 102 ml (OR, 3.707; P, 0.001), BMI > 26.8 kg/m 2 (OR, 4.664; P, 0.004) and D-dimer > 0.29 mg/L (OR, 2.882; P, 0.009) were independent risk factors of DVT after UKA. CONCLUSION: The incidence of DVT in the present study was 9.9%, extensive intraoperative blood loss, advanced BMI and high level of D-dimer would increase the risk of lower extremity thrombosis by 2-4 times.

Structural Insights into the Mechanisms Underlying Polyaminopathies.

Polyamines are ubiquitous in almost all biological entities and involved in various crucial physiological processes. They are also closely associated with the onset and progression of many diseases. Polyaminopathies are a group of rare genetic disorders caused by alterations in the function of proteins within the polyamine metabolism network. Although the identified polyaminopathies are all rare diseases at present, they are genetically heritable, rendering high risks not only to the carriers but also to their descendants. Meanwhile, more polyaminopathic patients might be discovered with the increasing accessibility of gene sequencing. This review aims to provide a comprehensive overview of the structural variations of mutated proteins in current polyaminopathies, in addition to their causative genes, types of mutations, clinical symptoms, and therapeutic approaches. We focus on analyzing how alterations in protein structure lead to protein dysfunction, thereby facilitating the onset of diseases. We hope this review will offer valuable insights and references for the future clinical diagnosis and precision treatment of polyaminopathies.

Pancreatic duct occupation method assisted wire guide through pancreatic duct stenosis in the treatment of chronic pancreatitis.

Chronic pancreatitis is usually accompanied by pancreatic duct stenosis and pancreatic duct stones (1). Pancreatic duct stent implantation can effectively drain pancreatic fluid and relieve symptoms. However, in many cases this is not easy, because of the presence of stones or the pancreatic duct is too narrow, the guide wire may not be able to enter the distal pancreatic duct. We present a case of chronic pancreatitis with pancreatic duct stenosis in which we assisted the passage of guidewires through the pancreatic duct stenosis by means of pancreatic duct occupation.

An updated dataset and a structure-based prediction model for protein-RNA binding affinity.

Understanding the process of protein-RNA interaction is essential for structural biology. The thermodynamic process is an important part to uncover the protein-RNA interaction mechanism. The regulatory networks between protein and RNA in organisms are dominated by the binding or dissociation in the cells. Therefore, determining the binding affinity for protein-RNA complexes can help us to understand the regulation mechanism of protein-RNA interaction. Since it is time-consuming and labor-intensive to determine the binding affinity for protein-RNA complexes by experimental methods, it is necessary and urgent to develop computational methods to predict that. To develop a binding affinity prediction model, first we update the dataset of protein-RNA binding affinity benchmark (PRBAB), which includes 145 complexes now. Second, we extract the structural features based on complex structure, and then we analyze and select the representative structural features to train the regression model. Third, we random select the subset from the PRBAB2.0 to fit the protein-RNA binding affinity determined by experiment. In the end, we tested our model on the nonredundant PDBbind dataset, and the results showed that Pearson correlation coefficient r = .57 and RMSE = 2.51 kcal/mol. The Pearson correlation coefficient achieves 0.7 while removing 5 complex structures with modified residues/nucleotides and metal ions. While testing on ProNAB, the results showed that 71.60% of the prediction achieves Pearson correlation coefficient r = .61 and RMSE = 1.56 kcal/mol with experiment values.

A clinically practical model for the preoperative prediction of lymph node metastasis in bladder cancer: a multicohort study.

BACKGROUND: The aim of this study was to construct a clinically practical model to precisely predict lymph node (LN) metastasis in bladder cancer patients. METHODS: Four independent cohorts were included. The least absolute shrinkage and selection operator regression with multivariate logistic regression were applied. The diagnostic efficacy of LN score and CT/MRI was compared by accuracy, sensitivity, specificity, and area under curve (AUC). RESULTS: A total of 606 patients were included to develop a basic prediction model. After multistep gene selection, the LN metastasis prediction model was constructed with 5 genes. The model can accurately predict LN metastasis with an AUC of 0.781. For clinically practical use, we transformed the model into a Fast LN Scoring System using the SYSMH cohort (n = 105). High LN score patients exhibited a 72.2% LN metastasis rate, while low LN score patients showed a 3.4% LN metastasis rate. The LN score achieved a superior accuracy than CT/MRI (0.882 vs. 0.727). Application of LN score can correct the diagnosis of 88% (22/25) patients who were misdiagnosed by CT/MRI. DISCUSSION: The clinically practical LN score can precisely, rapidly, and conveniently predict LN status, which will assist preoperative diagnosis for LN metastasis and guide precise therapy.

Construction of Dual-Channel Water Transport in Mesoporous Silica Low Humidity Sensors to Achieve High Sensitivity.

In this paper, strong hydrophilic poly(ionic liquid)s (PILs) are selectively grafted on different positions (mesoporous channels and outer surface) of mesoporous silica via thiol-ene click chemical reaction. The purposes of selective grafting are on the one hand, to explore the differences of adsorption and transportation of water molecules in mesoporous channels and on the outer surface, and on the other hand, to combine the two approaches (intra-pore grafting and external surface grafting) to reasonably design SiO2 @PILs low humidity sensing film with synergetic function to achieve high sensitivity. The results of low relativehumidity （RH） sensing test show that the sensing performance of humidity sensor based on mesoporous silica grafted with PILs in the channels is better than that of humidity sensor based on mesoporous silica grafted with PILs on the outer surface. Compared with water molecules transport single channel, the construction of dual-channel water transport significantly improves the sensitivity of the low humidity sensor, and the response of the sensor is up to 4112% in the range of 7-33% RH. Moreover, the existence of micropores and the formation of dual-channel water transport affect the adsorption/desorption behaviors of the sensor under different humidity ranges, especially below 11% RH.

Microwave-Assisted Rational Designed CNT-Mn3 O4 /CoWO4 Hybrid Nanocomposites for High Performance Battery-Supercapacitor Hybrid Device.

Extensive research interest in hybrid battery-supercapacitor (BSH) devices have led to the development of cathode materials with excellent comprehensive electrochemical properties. In this work, carbon nanotube (CNT)-Mn3 O4 /CoWO4 triple-segment hybrid electrode is synthesized by using a two-step microwave-assisted hydrothermal route. Systematic physical characterization revealed that, with the assistance of microwave, granular Mn3 O4 and spheroid-like CoWO4 with preferred orientation, and oxygen vacancies are stacked or arranged on CNTs skeletons to construct a rational designed hybrid nanocomposite with abundant heterointerfaces and interfacial chemical bonds. Electrochemical evaluations show that the synergistic cooperation in CNT-Mn3 O4 /CoWO4 resulted in an ultra-high specific capacity (1907.5 C g-1 /529.8 mA h g-1 at 1 A g-1 ), a wide operating voltage window (1.15 V), the satisfactory rate capability (capacity maintained at 1016.5 C g-1 /282.3 mA h g-1 at 15 A g-1 ), and excellent cycling stability (117.2% initial capacity retention after 13000 cycles at 15 A g-1 ). In addition, the assembled CNT-Mn3 O4 /CoWO4 //N doped porous carbon (NC) BSH device delivered a stable working voltage of 2.05 V and superior energy density of 67.5 Wh kg-1 at power density of 1025 W kg-1 , as well as excellent stability (92.2% capacity retained at 5 A g-1 for 12600 cycles). This work provides a new and feasible tactic to develop high-performance transition metal oxide-based cathodes for advanced BSH devices.

A Bone-Penetrating Precise Controllable Drug Release System Enables Localized Treatment of Osteoporotic Fracture Prevention via Modulating Osteoblast-Osteoclast Communication.

Improving local bone mineral density (BMD) at fracture-prone sites of bone is a clinical concern for osteoporotic fracture prevention. In this study, a featured radial extracorporeal shock wave (rESW) responsive nano-drug delivery system (NDDS) is developed for local treatment. Based on a mechanic simulation, a sequence of hollow zoledronic acid (ZOL)-contained nanoparticles (HZNs) with controllable shell thickness that predicts various mechanical responsive properties is constructed by controlling the deposition time of ZOL and Ca2+ on liposome templates. Attributed to the controllable shell thickness, the fragmentation of HZNs and the release of ZOL and Ca2+ can be precisely controlled with the intervention of rESW. Furthermore, the distinct effect of HZNs with different shell thicknesses on bone metabolism after fragmentation is verified. In vitro co-culture experiments demonstrate that although HZN2 does not have the strongest osteoclasts inhibitory effect, the best pro-osteoblasts mineralization results are achieved via maintaining osteoblast-osteoclast (OB-OC) communication. In vivo, the HZN2 group also shows the strongest local BMD enhancement after rESW intervention and significantly improves bone-related parameters and mechanical properties in the ovariectomy (OVX)-induced osteoporosis (OP) rats. These findings suggest that an adjustable and precise rESW-responsive NDDS can effectively improve local BMD in OP therapy.

Tin Active Sites Confined in Zeolite Framework as a Promising Shape-Selective Catalyst for Ethylene Oxide Hydration.

Shape-selective stannosilicates have been post-synthesized for the hydration of epoxide to diols. A simple acid treatment has been employed to remove extensively the interlayer double four ring units, converting the three-dimensional (3D) UTL germanosilicate into a 2D layered IPC-1P intermediate. Isomorphous incorporation of tetrahedrally coordinated Sn active centers was realized via solid-liquid treatment of IPC-1P with diammonium hexachlorostannate aqueous solution, which was accompanied by the spontaneous condensation of neighboring silica-rich cfi layers upon calcination and structural construction of a 3D PCR structure. Sn-PCR stannosilicates with tunable Sn contents were thus prepared. With Sn-derived robust Lewis acidity confined in the intersecting 10- and 8-ring channels, the Sn-PCR (Si/Sn molar ratio of 77) catalyst served as a shape-selective nanoreactor for the hydration of ethylene oxide (EO) into ethylene glycol (EG), exhibiting a remarkable EO conversion (99.5 %) as well as a steady EG selectivity (>98.4 %) at greatly reduced H2 O/EO molar ratio and near-ambient reaction temperature.

Synergy of Two Intermolecular Hydrogen Bonds Promotes Highly Sensitive and Selective Room-Temperature Dimethyl Methylphosphonate Sensing: A Case of rGO-Based Gas Sensors.

The development of room-temperature chemiresistive gas sensors with low limit of detection, high sensitivity, and selectivity for dimethyl methylphosphonate (DMMP) detection remains a challenge. Herein, a synergy of the two intermolecular hydrogen bond-promoted approach was proposed to fabricate a room-temperature DMMP sensor with enhanced performances. As a proof of concept, ternary p-hexafluoroisopropanol phenyl (HFIP) functionalized polypyrrole-reduced graphene oxide hybrids (HFIP-PPy-rGO) were rationally designed. During the sensing process, rGO serves as a conductive carrier, ensuring that the sensors operate at room temperature, and both HFIP and PPy act as adsorption sites for DMMP through hydrogen bonding interactions. As expected, the HFIP-PPy-rGO sensor exhibits high selectivity and sensitivity to DMMP. Besides, the HFIP-PPy-rGO sensor also possesses excellent linear response to DMMP and long-term stability. Experimental results and quartz crystal microbalance measurements prove that the specific recognition of DMMP is realized by forming two intermolecular hydrogen bonds between HFIP and DMMP, as well as PPy and DMMP. Additionally, the introduction of HFIP groups also contributes to adjusting device conductivity, enhancing signal conversion function. To put the DMMP sensor into potential practical application, the obvious sensing response to different DMMP concentrations in soil was confirmed, and a wireless detection system was built to realize real-time monitoring of DMMP concentrations in the surroundings. Overall, this study provides a facile and practical solution for improving the sensing performance of room-temperature sensors based on the hydrogen bond theory.

The biogenesis, biological functions and modification of Circular RNAs.

Circular RNAs are covalently closed and non-coding in eukaryotes, which have tissue- specific and temporal-specific expression patterns whose biogenesis is regulated by transcription and splicing. Most circular RNAs are localized in the cytoplasm. The sequences and protein-binding elements of circular RNAs facilitate circular RNAs in exerting biological functions through complementary base pairing, regulating protein function or self-translation. Recent studies have revealed that N6-Methyladenosine (m6A), a prevalent post-transcriptional modification, can affect the translation, localization, and degradation of circular RNAs. Cutting-edge research into circular RNAs have benefitted from the development of high-throughput sequencing technology. Furthermore, the expansion of novel research methods has promoted progress into circular RNA research.

Hybrid manifold-deep convolutional neural network for sleep staging.

Analysis of electroencephalogram (EEG) is a crucial diagnostic criterion for many sleep disorders, of which sleep staging is an important component. Manual stage classification is a labor-intensive process and usually suffered from many subjective factors. Recently, more and more computer-aided techniques have been applied to this task, among which deep convolutional neural network has been performing well as an effective automatic classification model. Despite some comprehensive models have been developed to improve classification results, the accuracy for clinical applications has not been reached due to the lack of sufficient labeled data and the limitation of extracting latent discriminative EEG features. Therefore, we propose a novel hybrid manifold-deep convolutional neural network with hyperbolic attention. To overcome the shortage of labeled data, we update the semi-supervised training scheme as an optimal solution. In order to extract the latent feature representation, we introduce the manifold learning module and the hyperbolic module to extract more discriminative information. Eight subjects from the public dataset are utilized to evaluate our pipeline, and the model achieved 89% accuracy, 70% precision, 80% sensitivity, 72% f1-score and kappa coefficient of 78%, respectively. The proposed model demonstrates powerful ability in extracting feature representation and achieves promising results by using semi-supervised training scheme. Therefore, our approach shows strong potential for future clinical development.

Effect of Intensive Lipid-Lowering Therapy on Coronary Plaque Stabilization Derived from Optical Coherence Tomography: a Meta-analysis and Meta-regression.

PURPOSE: The definitive impacts of intensive lipid-lowering therapy (LLT) on plaque stabilization and the relationship between the key markers during LLT and plaque stability remain unquestioned. Thus, these meta-analysis and meta-regression intend to holistically evaluate the influence exerted by rigorous LLT on the minimum fibrous cap thickness (FCT) and maximum lipid arc as discerned through optical coherence tomography (OCT). This study further scrutinizes the correlation of this impact with variations in high-sensitivity C-reactive protein (hs-CRP), low-density lipoprotein cholesterol (LDL-C), or additional parameters within patients diagnosed with coronary artery disease (CAD). METHODS: Comprehensive searches were conducted on platforms including PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs) published until June 1, 2023. The search was language agnostic and targeted RCTs elaborating on the correlation between high-intensity statin therapy or statins used concomitantly with other lipid-lowering medications and the minimum FCT and maximum lipid arc as assessed by OCT. The meta-analyses were executed employing a standard mean difference (SMD) algorithm with random-effects on continuous variables. These methodologies align with the Preferred Reporting Items for Systematic and Meta-analysis (PRISMA) guidelines. RESULTS: A spectrum of 12 RCTs engaging 972 patients were identified and mobilized for these analyses. Meta-analysis outcomes depicted a conspicuous correlation between intensive LLT and an enhanced minimum FCT (12 studies with 972 participants; SMD, 0.87; 95% CI, 0.54 to 1.21; P < 0.01), reduced maximum lipid arc (9 studies with 564 participants; SMD, -0.43; 95% CI, -0.58 to -0.29; P < 0.01). Meta-regression analysis has determined an association of elevated minimum FCT with decreased LDL-C (ß, -0.0157; 95% CI, -0.0292 to -0.0023; P = 0.025), total cholesterol (TC) (ß, -0.0154; 95% CI, -0.0303 to -0.0005; P = 0.044), and apolipoprotein B (ApoB) (ß, -0.0209; 95% CI, -0.0361 to -0.0057; P = 0.022). However, no significant association was discerned relative to variations in hs-CRP/CRP (ß, -0.1518; 95% CI, -1.3766 to -1.0730; P = 0.772), triglyceride (TG) (ß, -0.0030; 95% CI, -0.0258 to -0.0318; P = 0.822), and high-density lipoprotein cholesterol (HDL-C) (ß, 0.0313; 95% CI, -0.0965 to 0.1590; P = 0.608). Subsequent subgroup meta-analysis demonstrated that high-intensity statin therapy (5 studies with 204 participants; SMD, 1.03; 95% CI, 0.67 to 1.39; P < 0.01), as well as a combinative approach including PCSK9 antibodies and statins (3 studies with 522 participants; SMD, 1.17; 95% CI, 0.62 to 1.73; P < 0.01) contributed to an increase in minimum FCT. Parallelly, high-intensity statin therapy (4 studies with 183 participants; SMD, -0.42; 95% CI, -0.65 to -0.19; P < 0.01) or the combined application of PCSK9 antibodies and statins (2 studies with 222 participants; SMD, -0.98; 95% CI, -1.26 to -0.70; P < 0.01) was evidenced to decrease the maximum lipid arc. CONCLUSIONS: Intensive LLT, mainly high-intensity statin therapy and combined PCSK9 antibody with statin, has a beneficial effect on coronary plaque stabilization derived from OCT in patients with CAD. Coronary plaque stabilization is primarily due to lipid-lowering effect, not anti-inflammatory effect. Moreover, the lipid-lowering effect has nothing to do with the changes in HDL-C and TG, but is mainly related to the reduction of LDL-C, TC, and ApoB.

Associations of serum vitamin C concentrations with risk of all-cause and cause-specific mortality among individuals with and without type 2 diabetes.

PURPOSE: Compared with people without diabetes, people with type 2 diabetes (T2D) are at higher risk of both subnormal vitamin C status and increased oxidative stress. We aimed to investigate the associations of serum vitamin C concentrations with all-cause and cause-specific mortality among adults with and without T2D. METHODS: The current analysis included 20,045 adults (2691 people with T2D and 17,354 without T2D) from the Third National Health and Nutrition Examination Survey (NHANES III) and NHANES 2003-2006. Cox proportional hazards regression models were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Restricted cubic spline analyses were used to examine the dose-response relationship. RESULTS: After a median follow-up of 17.3 years, 5211 deaths were documented. Individuals with T2D had a lower level of serum vitamin C concentrations compared with those without T2D (the median value: 40.1 vs. 44.9 µmol/L). Furthermore, the dose-response relationship between serum vitamin C and mortality showed different patterns between participants with and without T2D. In individuals without T2D, there was a nonlinear association of serum vitamin C concentrations with all-cause, cancer, and CVD mortality, with the lowest risk around a serum vitamin C concentration of 48.0 µmol/L (all Poverall < 0.05, Pnonlinearity < 0.05). In contrast, among those with T2D in the similar concentration range, higher serum vitamin C levels (ranged from 0.46 to 116.26 µmol/L) were linearly associated with lower all-cause and cancer mortality (both Poverall < 0.05, Pnonlinearity > 0.05). Significant additive interaction was observed between diabetes status and serum vitamin C levels with regard to all-cause and cancer mortality (P < 0.001). In addition, C-reactive protein, gamma-glutamyl transpeptidase, and HbA1c explained 14.08, 8.96, and 5.60% of the association between serum vitamin C and all-cause mortality among individuals with T2D, respectively. CONCLUSIONS: Higher serum vitamin C concentrations were significantly associated with lower risk of mortality in participants with T2D in a linear dose-response manner, while a nonlinear association was observed in participants without T2D, with an apparent threshold around 48.0 µmol/L. These findings suggest that the optimal vitamin C requirement may differ in individuals with and without T2D.

Molecular dynamics simulations on interactions of five antibiotics with luciferase of Vibrio Qinghaiensis sp.-Q67.

A large number of antibiotics have been used in the medical industry, agriculture, and animal husbandry industry in recent years. It may cause pollution to the aquatic environment and ultimately threaten to human health due to their prolonged exposure to the environment. We aim to study the toxicity mechanism of enrofloxacin (ENR), chlortetracycline hydrochloride (CTC), trimethoprim (TMP), chloramphenicol (CMP), and erythromycin (ETM) to luciferase of Vibrio Qinghaiensis sp.-Q67 (Q67) by using toxicity testing combined with molecular docking, molecular dynamics, and binding free energy analysis. The curve categories for ENR were different from the other four antibiotics, with ENR being J-type and the rest being S-type, and the toxicity of these five antibiotics (pEC50) followed the order of ENR (7.281) > ETM (6.814) > CMP (6.672) > CTC (6.400) > TMP (6.123), the order of toxicity value is consistent with the the magnitude of the binding free energy (ENR (-47.759 kcal/mol), ETM (-46.821 kcal/mol), CMP (-42.905 kcal/mol), CTC (-40.946 kcal/mol), TMP (-28.251 kcal/mol)). The van der Waals force provided the most important contribution to the binding free energy of the five antibiotics in the binding system with Q67 luciferase. Therefore, the dominant factor for the binding of antibiotics to luciferase was shape compensation. The face-to-face π-π stacking interaction between the diazohexane structure outside the active pocket region and the indoles structure of Phe194 and Phe250 in the molecular structure was the main reason for the highest toxicity value of antibiotic ENR. The hormesis effect of ENR has a competitive binding relationship with the α and ß subunits of luciferase. Homology modeling, molecular docking, molecular dynamics simulations and binding free energy calculations were used to derive the toxicity magnitude of different antibiotics against Q67, and insights at the molecular level. The conclusion of toxicological experiments verified the correctness of the simulation results. This study contributes to the understanding of toxicity mechanisms of five antibiotics and facilitates risk assessment of antibiotic contaminants in the aquatic environment.