Age-related decline in melatonin contributes to enhanced osteoclastogenesis via disruption of redox homeostasis.

BACKGROUND: Increased oxidative stress contributes to enhanced osteoclastogenesis and age-related bone loss. Melatonin (MT) is an endogenous antioxidant and declines with aging. However, it was unclear whether the decline of MT was involved in the enhanced osteoclastogenesis during the aging process. METHODS: The plasma level of MT, oxidative stress status, bone mass, the number of bone marrow-derived monocytes (BMMs) and its osteoclastogenesis were analyzed in young (3-month old) and old (18-month old) mice (n = 6 per group). In vitro, BMMs isolated from aged mice were treated with or without MT, followed by detecting the change of osteoclastogenesis and intracellular reactive oxygen species (ROS) level. Furthermore, old mice were treated with MT for 2 months to investigate the therapeutic effect. RESULTS: The plasma level of MT was markedly lower in aged mice compared with young mice. Age-related decline in MT was accompanied by enhanced oxidative stress, osteoclastogenic potential and bone loss. MT intervention significantly suppressed the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis, decreased intracellular ROS and enhanced antioxidant capacity of BMMs from aged mice. MT supplementation significantly attenuated oxidative stress, osteoclastogenesis, bone loss and deterioration of bone microstructure in aged mice. CONCLUSIONS: These results suggest that age-related decline of MT enhanced osteoclastogenesis via disruption of redox homeostasis. MT may serve as a key regulator in osteoclastogenesis and bone homeostasis, thereby highlighting its potential as a preventive agent for age-related bone loss.

Identification and characterization of two O-methyltransferases involved in biosynthesis of methylated 2-(2-phenethyl)chromones in agarwood.

The 2-(2-phenethyl)chromones (PECs) are the signature constituents responsible for the fragrance and pharmacological properties of agarwood. O-Methyltransferases (OMTs) are necessary for the biosynthesis of methylated PECs, but there is little known about OMTs in Aquilaria sinensis. In this study, we identified 29 OMT genes from the A. sinensis genome. Expression analysis showed they were differentially expressed in different tissues and responded to drill wounding. Comprehensive analysis of the gene expression and methylated PEC content revealed that AsOMT2, AsOMT8, AsOMT11, AsOMT16, and AsOMT28 could potentially be involved in methylated PECs biosynthesis. In vitro enzyme assays and functional analysis in Nicotiana benthamiana demonstrated that AsOMT11 and AsOMT16 could methylate 6-hydroxy-2-(2-phenylethyl)chromone to form 6-methoxy-2-(2-phenylethyl)chromone. A transient overexpression experiment in the variety 'Qi-Nan' revealed that AsOMT11 and AsOMT16 could significantly promote the accumulation of three major methylated PECs. Our results provide candidate genes for the mass production of methylated PECs using synthetic biology.

Tanshinone IIA attenuates osteoarthritis via inhibiting aberrant angiogenesis in subchondral bone.

Excessive angiogenesis in subchondral bone is a pathological feature of osteoarthritis (OA). Tanshinone IIA (TIIA), an active compound found in Salvia miltiorrhiza, demonstrates significant anti-angiogenic properties. However, the effect of TIIA on abnormal subchondral angiogenesis in OA is still unclear. This study aims to investigate the mechanism of TIIA in modulating subchondral bone angiogenesis during OA and assess its therapeutic potential in OA. Our findings demonstrate that TIIA attenuated articular cartilage degeneration, normalized subchondral bone remodeling, and effectively suppressed aberrant angiogenesis within subchondral bone in monosodium iodoacetate (MIA)-induced OA mice. Additionally, the angiogenesis capacity of primary CD31hiEmcnhi endothelial cells was observed to be significantly reduced after treatment with TIIA in vitro. Mechanically, TIIA diminished the proportion of hypertrophic chondrocytes, ultimately leading to a substantial reduction in the secretion of vascular endothelial growth factor A (VEGFA). The supernatant of hypertrophic chondrocytes promoted the tube formation of CD31hiEMCNhi endothelial cells, whereas TIIA inhibited this process. Furthermore, TIIA effectively suppressed the expression of vascular endothelial growth factor receptor 2 (VEGFR2) along with its downstream MAPK pathway in CD31hiEmcnhi endothelial cells. In conclusion, our data indicated that TIIA could effectively inhibit the abnormal angiogenesis in subchondral bone during the progression of OA by suppressing the VEGFA/VEFGR2/MAPK pathway. These findings significantly contribute to our understanding of the abnormal angiogenesis in OA and offer a promising therapeutic target for OA treatment.

Mendelian randomization analysis reveals the impact of physical and occupational activities on the risk of gastroesophageal reflux disease and Barrett's esophagus.

BACKGROUND: Recent studies have indicated that participating in physical activity may provide a safeguard against gastroesophageal reflux disease (GERD). Nevertheless, the precise links between physical and occupational activity and the occurrence of GERD and Barrett's esophagus (BE) are still uncertain. METHODS: Conducting univariate and multivariate Mendelian randomization investigations to examine the causal relationship between exposures and outcomes. Genetic variation simulation was used in randomized experiments. Data on physical and occupational activity were obtained from the UK Biobank and GWAS catalog. In the meantime, data on GERD and BE were extracted from a high quality meta-analysis. RESULTS: The results of univariate Mendelian randomization analysis using multiple methods suggest a causal relationship between strenuous sports or other forms of exercise (as a protective factor) and GERD/BE. At the same time, three types of occupational related physical activities, including heavy manual or physical work, shift work and walking or standing work, are risk factors for GERD/BE and have a causal relationship with them. These results were reconfirmed through multivariate Mendelian randomization analysis, which excluding the influence of other potential confounding factors. CONCLUSIONS: The findings indicated that strenuous sports or other forms of exercise could lower the likelihood of GERD/BE, while excessive physical strain in the workplace, prolonged periods of standing or walking, and shift work could raise the risk of GERD/BE. Acknowledging this risk and implementing suitable measures can contribute to the prevention of GERD and BE, thus mitigating the associated health burden.

Performant automatic differentiation of local coupled cluster theories: Response properties and ab initio molecular dynamics.

In this work, we introduce a differentiable implementation of the local natural orbital coupled cluster (LNO-CC) method within the automatic differentiation framework of the PySCFAD package. The implementation is comprehensively tuned for enhanced performance, which enables the calculation of first-order static response properties on medium-sized molecular systems using coupled cluster theory with single, double, and perturbative triple excitations [CCSD(T)]. We evaluate the accuracy of our method by benchmarking it against the canonical CCSD(T) reference for nuclear gradients, dipole moments, and geometry optimizations. In addition, we demonstrate the possibility of property calculations for chemically interesting systems through the computation of bond orders and Mössbauer spectroscopy parameters for a [NiFe]-hydrogenase active site model, along with the simulation of infrared spectra via ab initio LNO-CC molecular dynamics for a protonated water hexamer.

Machine learning in risk prediction of continuous renal replacement therapy after coronary artery bypass grafting surgery in patients.

OBJECTIVES: This study aimed to develop machine learning models for risk prediction of continuous renal replacement therapy (CRRT) following coronary artery bypass grafting (CABG) surgery in intensive care unit (ICU) patients. METHODS: We extracted CABG patients from the electronic medical record system of the hospital. The endpoint of this study was the requirement for CRRT after CABG surgery. The Boruta method was used for feature selection. Seven machine learning algorithms were developed to train models and validated using 10 fold cross-validation (CV). Model discrimination and calibration were estimated using the area under the receiver operating characteristic curve (AUC) and calibration plot, respectively. We used the SHapley Additive exPlanations (SHAP) method to illustrate the effects of the features attributed to the model and analyze the effects of individual features on the output of the mode. RESULTS: In this study, 72 (37.89%) patients underwent CRRT, with a higher mortality compared to those patients without CRRT. The Gaussian Naïve Bayes (GNB) model with the highest AUC were considered as the final predictive model and performed best in predicting postoperative CRRT. The analysis of importance revealed that cardiac troponin T, creatine kinase isoenzyme, albumin, low-density lipoprotein cholesterol, NYHA, serum creatinine, and age were the top seven features of the GNB model. The SHAP force analysis illustrated how created model visualized individualized prediction of CRRT. CONCLUSIONS: Machine learning models were developed to predict CRRT. This contributes to the identification of risk variables for CRRT following CABG surgery in ICU patients and enables the optimization of perioperative managements for patients.

Effects of Lianhuaqingwen Capsules in adults with mild-to-moderate coronavirus disease 2019: an international, multicenter, double-blind, randomized controlled trial.

BACKGROUND: In a randomized trial, Lianhuaqingwen (LHQW) capsule was effective for accelerating symptom recovery among patients with coronavirus disease 2019 (COVID-19). However, the lack of blinding and limited sample sizes decreased the level of clinical evidence. OBJECTIVES: To evaluate the efficacy and safety of LHQW capsule in adults with mild-to-moderate COVID-19. METHODS: We conducted a double-blind randomized controlled trial in adults with mild-to-moderate COVID-19 (17 sites from China, Thailand, Philippine and Vietnam). Patients received standard-of-care alone or plus LHQW capsules (4 capsules, thrice daily) for 14 days. The primary endpoint was the median time to sustained clinical improvement or resolution of nine major symptoms. RESULTS: The full-analysis set consisted of 410 patients in LHQW capsules and 405 in placebo group. LHQW significantly shortened the primary endpoint in the full-analysis set (4.0 vs. 6.7 days, hazards ratio: 1.63, 95% confidence interval: 1.39-1.90). LHQW capsules shortened the median time to sustained clinical improvement or resolution of stuffy or runny nose (2.8 vs. 3.7 days), sore throat (2.0 vs. 2.6 days), cough (3.2 vs. 4.9 days), feeling hot or feverish (1.0 vs. 1.3 days), low energy or tiredness (1.3 vs. 1.9 days), and myalgia (1.5 vs. 2.0 days). The duration to sustained clinical improvement or resolution of shortness of breath, headache, and chills or shivering did not differ significantly between the two groups. Safety was comparable between the two groups. No serious adverse events were reported. INTERPRETATION: LHQW capsules promote recovery of mild-to-moderate COVID-19 via accelerating symptom resolution and were well tolerated. Trial registration ChiCTR2200056727 .

Efficacy and Safety of Finerenone for Prevention of Cardiovascular Events in Type 2 Diabetes Mellitus With Chronic Kidney Disease: A Meta-analysis of Randomized Controlled Trials.

ABSTRACT: Only a few meta-analyses evaluated the effect of finerenone on cardiovascular events in type 2 diabetes mellitus with chronic kidney disease. The main aim of this meta-analysis was to gain more reliable assessments of the efficacy and safety of finerenone for prevention of cardiovascular events in diabetic kidney disease. We searched for finerenone in the treatment of diabetic kidney disease from database (PubMed, Embase, and ClinicalTrials.gov ) until December 30, 2021. Relative risks (RRs) with 95% confidence intervals (CIs) calculated by the Mantel-Haenszel random-effects model were used as summary statistics for the categorical data. We included 4 studies that met the inclusion criteria with 13,943 participants. The finerenone group demonstrated a great benefit in reducing the incidence of major adverse cardiac events (RR: 0.88; 95% CI 0.80-0.96; P = 0.003), all-cause mortality (RR: 0.89; 95% CI 0.80-0.99; P = 0.04), myocardial infarction (RR: 0.79; 95% CI 0.67-0.92; P = 0.003), and new-onset hypertension (RR: 0.71; 95% CI 0.62-0.81; P < 0.00001). No difference was found in adverse events between the finerenone and placebo groups (RR: 1.00; 95% CI [0.98-1.01], P = 0.59), whereas a higher risk of hyperkalemia was observed in the finerenone group than in the placebo group (RR = 2.04, 95% CI 1.80-2.32; P < 0.00001). Besides, cerebrovascular events and new-onset atrial fibrillation did not increase in patients taking finerenone. Overall, finerenone treatment showed a great benefit of reducing the risk of major adverse cardiac events, all-cause mortality, myocardial infarction, and new-onset hypertension events in patients with type 2 diabetes mellitus and chronic kidney disease.

Effect of PCSK9 Monoclonal Antibody Versus Placebo/Ezetimibe on Atrial Fibrillation in Patients at High Cardiovascular Risk: A Meta-Analysis of 26 Randomized Controlled Trials.

BACKGROUND: Patients at high cardiovascular risk are closely associated with an increased risk of atrial fibrillation (AF). Whether proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9 mAbs) can attenuate AF progression remains unknown. METHODS: To compare PCSK9 mAbs with placebo or ezetimibe to explore the effect of PCSK9 mAbs therapy on the end-point of incidence of AF, we searched PubMed, Embase, and ClinicalTrials.gov for articles. We used Mantel-Haenszel risk ratio (RR) with corresponding 95% CI for the categorical data, including the incidence of AF and predefined other outcomes of interest. RESULTS: We included 21 articles consisting of 26 randomized controlled trials with a total of 95,635 participants. Quantitative synthesis revealed that PCSK9 mAbs significantly reduce the incidence of AF events (RR 0.84; 95% CI 0.72-0.98; p = 0.03), whereas no obvious differences were seen between the PCSK9 mAbs group and the ezetimibe group (RR 0.90; 95% CI 0.29-2.76; p = 0.85). PCSK9 mAbs also markedly decreased the incidence of cerebrovascular events (RR 0.75; 95% CI 0.66-0.85; p < 0.0001) and new-onset hypertension (RR 0.92; 95% CI 0.87-0.97; p = 0.003), but not the risk of cardiovascular death (RR 0.95; 95% CI 0.85-1.07; p = 0.40) and new-onset diabetes mellitus (RR 1.01; 95% CI 0.95-1.08; p = 0.67). CONCLUSIONS: Overall, the PCSK9 mAbs therapy reduced AF and presented certain cardiovascular benefits in patients at high cardiovascular risk. Further big-scale and long follow-up duration randomized controlled trials that compare PCSK9 mAbs with ezetimibe are required to evaluate the effect of PCSK9 mAbs versus ezetimibe on AF.

Comparative study of first-principles approaches for effective Coulomb interaction strength Ueff between localized f-electrons: Lanthanide metals as an example.

As correlation strength has a key influence on the simulation of strongly correlated materials, many approaches have been proposed to obtain the parameter using first-principles calculations. However, a comparison of the different Coulomb strengths obtained using these approaches and an investigation of the mechanisms behind them are still needed. Taking lanthanide metals as an example, we research the factors that affect the effective Coulomb interaction strength, Ueff, by local screened Coulomb correction (LSCC), linear response (LR), and constrained random-phase approximation (cRPA) in the Vienna Ab initio Simulation Package. The Ueff LSCC value increases from 4.75 to 7.78 eV, Ueff LR is almost stable at about 6.0 eV (except for Eu, Er, and Yb), and Ueff cRPA shows a two-stage decreasing trend in both light and heavy lanthanides. To investigate these differences, we establish a scheme to analyze the coexistence and competition between the orbital localization and the screening effect. We find that LSCC and cRPA are dominated by the orbital localization and the screening effect, respectively, whereas LR shows the balance of the competition between the two factors. Additionally, the performance of these approaches is influenced by different starting points from the Perdew-Burke-Ernzerhof (PBE) and PBE + U, especially for cRPA. Our results provide useful knowledge for understanding the Ueff of lanthanide materials, and similar analyses can also be used in the research of other correlation strength simulation approaches.

Structural Characterization and Anticomplement Activity of an Acidic Heteropolysaccharide from Lysimachia christinae Hance.

A novel acidic heteropolysaccharide (LCP-90-1) was isolated and purified from a traditional "heat-clearing" Chinese medicine, Lysimachia christinae Hance. LCP-90-1 (Mw, 20.65 kDa) was composed of Man, Rha, GlcA, Glc, Gal, and Ara, with relative molar ratios of 1.00: 3.00: 11.62: 1.31: 1.64: 5.24. The backbone consisted of 1,4-α-D-GlcpA, 1,4-α-D-Glcp, 1,4-ß-L-Rhap, and 1,3,5-α-L-Araf, with three branches of ß-D-Galp-(1 → 4)-ß-L-Rhap-(1→, α-L-Araf-(1→ and α-D-Manp-(1→ attached to the C-5 position of 1,3,5-α-L-Araf. LCP-90-1 exhibited potent anticomplement activity (CH50: 135.01 ± 0.68 µg/mL) in vitro, which was significantly enhanced with increased glucuronic acid (GlcA) content in its degradation production (LCP-90-1-A, CH50: 28.26 ± 0.39 µg/mL). However, both LCP-90-1 and LCP90-1-A were inactivated after reduction or complete acid hydrolysis. These observations indicated the important role of GlcA in LCP-90-1 and associated derivatives with respect to anticomplement activity. Similarly, compared with LCP-90-1, the antioxidant activity of LCP-90-1-A was also enhanced. Thus, polysaccharides with a high content of GlcA might be important and effective substances of L. christinae.

Structural Characterization and Anti-inflammatory Activities of Anticomplementary Polysaccharides from Rhododendron principis.

Rhododendron principis leaves have been used as "Dama", a Traditional Tibetan Medicine for treating inflammatory diseases. R. principis crude polysaccharides with anticomplementary activity demonstrated promising anti-inflammatory effects on acute lung injury induced by lipopolysaccharide. R. principis crude polysaccharides significantly decreased the levels of TNF-α and interleukin-6 in both serum and blood and bronchoalveolar lavage fluid in lipopolysaccharide-induced acute lung injury mice by intragastric administration (100 mg/kg). A heteropolysaccharide, ZNDHP, was obtained from R. principis crude polysaccharides with successive anticomplementary activity-guided separation. ZNDHP was characterized as a branched neutral polysaccharide with a backbone composed of → 2)-ß-Glcp-(1→, → 2,6)-α-Glcp-(1→, → 6,3)-ß-Galp-(1→, → 2,6)-α-Galp-(1→, → 6,2)-ß-Glcp-(1→, → 4)-α-Glcp-(1→, → 5)-ß-Araf-(1→, → 3,5)-α-Araf-(1→, and → 4,6)-ß-Manp-(1→, and the backbone structure was further confirmed by partial acid hydrolysis. In addition to anticomplementary and antioxidant activities, ZNDHP exhibited potent anti-inflammatory activity by significantly inhibiting the secretion of nitric oxide, TNF-α, interleukin-6, and interleukin-1ß of lipopolysaccharide-treated RAW 264.7 cells. However, all of these activities decreased greatly after partially hydrolyzing, indicating the importance of the multibranched structure for its bioactivity. Therefore, ZNDHP might be an important component of R. principis for treating inflammation.

Antinociceptive diterpenoid alkaloids from the roots of Aconitum austroyunnanense.

A phytochemical investigation on the roots of Aconitum austroyunnanense afforded three undescribed aconitine-type C19-diterpenoid alkaloids, austroyunnanines A-C (1-3). Structural elucidation of all the compounds were performed by spectral methods such as 1 D and 2 D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy. The isolated alkaloids were tested in vivo for their antinociceptive properties. Consequently, austroyunnanine B (2) exhibited significant antinociceptive effect and its ID50 value (48.0 µmol/kg) was 2-fold less than those of the positive control drugs aspirin and acetaminophen.

[Effects of Rehmanniae Radix and Rehmanniae Radix Praeparata on proteomics and autophagy in mice with type 2 diabetes mellitus induced by high-fat diet coupled with streptozotocin].

To compare the pancreatic proteomics and autophagy between Rehmanniae Radix-and Rehmanniae Radix Praeparata-treated mice with type 2 diabetes mellitus(T2DM). The T2DM mouse model was established by high-fat diet coupled with streptozotocin(STZ, intraperitoneal injection, 100 mg·kg~(-1), once a day for three consecutive days). The mice were then randomly assigned into a control group, low-(5 g·kg~(-1)) and high-dose(15 g·kg~(-1)) Rehmanniae Radix groups, low-(150 mg·kg~(-1)) and high-dose(300 mg·kg~(-1)) catalpol groups, low-(5 g·kg~(-1)) and high-dose(15 g·kg~(-1)) Rehmanniae Radix Praeparata groups, low-(150 mg·kg~(-1)) and high-dose(300 mg·kg~(-1)) 5-hydroxymethyl furfuraldehyde(5-HMF) groups, and a metformin(250 mg·kg~(-1)) group. In addition, a normal group was also set and each group included 8 mice. The pancreas was collected after four weeks of administration and proteomics tools were employed to study the effects of Rehmanniae Radix and Rehmanniae Radix Praeparata on protein expression in the pancreas of T2DM mice. The expression levels of proteins involved in autophagy, inflammation, and oxidative stress response in the pancreatic tissues of T2DM mice were determined by western blotting, immunohistochemical assay, and transmission electron microscopy. The results showed that the differential proteins between the model group and Rehmanniae Radix/Rehmanniae Radix Prae-parata group were enriched in 7 KEGG pathways, such as autophagy-animal, which indicated that the 7 pathways may be associated with T2DM. Compared with the control group, drug administration significantly up-regulated the expression levels of beclin1 and phosphorylated mammalian target of rapamycin(p-mTOR)/mTOR and down-regulated those of the inflammation indicators, Toll-like receptor-4(TLR4) and Nod-like receptor protein 3(NLRP3), in the pancreas of T2DM mice, and Rehmanniae Radix showed better performance. In addition, the expression levels of inducible nitric oxide synthase(iNOS), nuclear factor erythroid 2-related factor 2(Nrf2), and heine oxygenase-1(HO-1) in the pancreas of T2DM mice were down-regulated after drug administration, and Rehmanniae Radix Praeparata demonstrated better performance. The results indicate that both Rehmanniae Radix and Rehmanniae Radix Praeparata can alleviate the inflammatory symptoms, reduce oxidative stress response, and increase the autophagy level in the pancreas of T2DM mice, while they exert the effect on different autophagy pathways.

Converting Commodity Polyolefins to Electronic Materials through Borane-Catalyzed Alkene Isomerization.

Novel approaches to the functionalization of commodity polymers could provide avenues for the synthesis of materials for next-generation electronic devices. Herein, we present a catalytic method for the conversion of common unsaturated polymers such as polybutadiene, polyisoprene, and styrene-butadiene copolymers [e.g., polystyrene-block-polybutadiene-block-polystyrene and poly(styrene-stat-butadiene)] to poly(acetylene) (PA)-based multiblock copolymers with conjugation lengths of up to ∼20, making them potentially suitable for electronics applications. Additionally, we demonstrate the application of this method to the formal conversion of polyethylene─the most widely produced thermoplastic─into PA-containing multiblock materials.

The bidirectional association of C-peptide with cardiovascular risk in nondiabetic adults and patients with newly diagnosed type 2 diabetes mellitus: a retrospective cohort study.

BACKGROUND: Recent literature reported the biological role of C-peptide, but this role is still controversial and unclear. The primary aim of this study was to investigate associations between C-peptide and cardiovascular biomarkers as well as events. METHODS: A total of 55636 participants who had a health examination from 2017 to 2021 were included. Of them, 6727 participants visited the hospital at least twice. Cardiovascular biomarkers like high-sensitivity C-reactive protein (hs-CRP) and high-sensitivity cardiac troponin T (hs-cTnT) were measured and their relationships with fasting C-peptide were evaluated for all participants. Cardiovascular events were obtained during the last visit and their associations with C-peptide were evaluated for those participants who visited the hospital at least twice. RESULTS: Among the included participants, 11.1% had a previous type 2 diabetes mellitus (T2DM). In the participants without previous T2DM, the relationships between fasting C-peptide and hs-CRP and hs-cTnT were negative if the value of fasting C-peptide was < 1.4 ng/mL and positive if the value was ≥ 1.4 ng/mL. These relationships remained significant after adjusting for hemoglobin A1c, insulin resistance index, and its interaction with C-peptide, even if the participants were stratified by glucose metabolism status or levels of insulin resistance index. Hazard ratios of cardiovascular events were first decreased and then increased with the increasing of baseline C-peptide levels, though these associations became unsignificant using the multivariate Cox regression model. Unlike the participants without previous T2DM, the associations of C-peptide with cardiovascular biomarkers and events were not significant in the patients with previous T2DM. CONCLUSIONS: The associations of C-peptide with cardiovascular biomarkers and events were different between the participants without previous T2DM and those with previous T2DM. The effect of C-peptide on cardiovascular risk may be bidirectional, play a benefit role at a low level, and play a harmful role at a high level in the nondiabetic adults and the patients with newly diagnosed T2DM.

Downregulation of MicroRNA-145-5p in Activated Microglial Exosomes Promotes Astrocyte Proliferation by Removal of Smad3 Inhibition.

In spinal cord injury, microglial activation plays an important role during the inflammatory process. Specifically, the cellular and molecular interactions between microglia and astrocytes are of critical importance. Cells can communicate with each other through the substances carried by exosomes, and overproliferated astrocytes would create a physical and chemical barrier that prevents neurite regeneration, thereby interfering with functional recovery. On the other hand, Smad3 is an important factor in the proliferation, migration, and apoptosis of astrocytes. In this study, supernatant and purified exosomes were collected from LPS-treated microglia and co-cultured with astrocytes. The results showed that astrocytic proliferation was promoted with higher levels of Smad3. Furthermore, miRNA sequencing analysis was performed on microglial exosomes after inflammation. The results revealed a differential expression of miR-145-5p in the exosomes. The Dual-Luciferase assay showed that miR-145-5p could bind to Smad3 mRNA and regulate the levels of Smad3 protein at the post-transcriptional level. Subsequently, exosomes were transfected with miR-145-5p mimics, and astrocytes after mechanical injury were cultured with these exosomes for 24 h. The levels of Smad3 and phosphor-Smad3 proteins were analyzed by western blot and qRT-PCR. CCK8 and flow cytometry showed lower proliferation of astrocytes after co-culturing with the exosomes transfected with the miR-145-5p mimic. This study finds that miR-145-5p was found to be a negative regulator of astrocyte proliferation, and that its downregulation promotes smad3 activity and thus astrocyte proliferation.

Diabatic Valence-Hole States in the C2 Molecule: "Putting Humpty Dumpty Together Again".

Despite the long history of spectroscopic studies of the C2 molecule, fundamental questions about its chemical bonding are still being hotly debated. The complex electronic structure of C2 is a consequence of its dense manifold of near-degenerate, low-lying electronic states. A global multi-state diabatic model is proposed here to disentangle the numerous configuration interactions that occur within four symmetry manifolds of excited states of C2 (1Πg, 3Πg, 1Σu+ , and 3Σu+ ). The key concept of our model is the existence of two "valence-hole" configurations, 2σg22σu11πu33σg2 for 1,3Πg states and 2σg22σu11πu43σg1 for 1,3Σu+ states, that are derived from 3σg ← 2σu electron promotion. The lowest-energy state from each of the four C2 symmetry species is dominated by this type of valence-hole configuration at its equilibrium internuclear separation. As a result of their large binding energy (nominal bond order of 3) and correlation with the 2s22p2 + 2s2p3 separated-atom configurations, the presence of these valence-hole configurations has a profound impact on the global electronic structure and unimolecular dynamics of C2.

Serum complement C1q level is associated with left ventricular hypertrophy induced by coarctation of the aorta: A retrospective observational study.

BACKGROUND: The complement system plays an important role in the development of left ventricular hypertrophy. Complement C1q is an initial component of the classical complement pathway and is related to many inflammatory diseases. We aimed to determine whether there was an association between serum complement C1q and left ventricular hypertrophy induced by coarctation of the aorta (CoA). METHODS: Based on whether CoA was combined with a large ventricular septal defect (VSD) or patent ductus arteriosus (PDA), the patients were divided into a simple CoA group (n = 15) and a complex CoA group (n = 13). Meanwhile, we selected simple large VSD (n = 14) patients and normal children (n = 28) as the control group. The serum complement C1q level was compared using immunity transmission turbidity among different groups. RESULTS: The preoperative content of C1q in the simple CoA group was significantly lower than that in the complex CoA group and normal group (96.97 ± 20.66 vs. 130.73 ± 35.78, 96.97 ± 20.66 vs. 156.21 ± 29.14, P < 0.05). There was no significant difference in the preoperative content of C1q between the complex CoA group and the large VSD group (P > 0.05). There was a negative correlation between the preoperative complement C1q content and the interventricular septal thickness and left ventricular posterior wall thickness (r = - 0.035, r = - 0.288, P < 0.05). The percentage of postoperative decrease in C1q in children with simple CoA or complex CoA was positively correlated with the time of cardiopulmonary bypass and aortic cross clamp, respectively (r = 0.797, r = 0.622, r = 0.898, r = 0.920, P < 0.05). There was no significant difference in the content of preoperative triglycerides (TG), total cholesterol (TCHO), high-density lipoprotein cholesterol (HDL-C) or low-density lipoprotein cholesterol (LDL-C) among the different groups (P > 0.05). In the simple CoA group and complex CoA group, the preoperative complement C1q, TG, TCHO, HDL-C and LDL-C levels were significantly higher than those after the operation (P < 0.05). There was no significant correlation between preoperative complement C1q and TG, TCHO, HDL-C or LDL-C (P > 0.05). CONCLUSIONS: Complement C1q has an inhibitory effect on the formation of left ventricular hypertrophy, which may not be mediated by regulating lipid metabolism. During cardiac surgery, complement C1q may have a protective effect against myocardial injury.

Accurate thermochemistry of covalent and ionic solids from spin-component-scaled MP2.

We study the performance of spin-component-scaled second-order Møller-Plesset perturbation theory (SCS-MP2) for the prediction of the lattice constant, bulk modulus, and cohesive energy of 12 simple, three-dimensional covalent and ionic semiconductors and insulators. We find that SCS-MP2 and the simpler scaled opposite-spin MP2 (SOS-MP2) yield predictions that are significantly improved over the already good performance of MP2. Specifically, when compared to experimental values with zero-point vibrational corrections, SCS-MP2 (SOS-MP2) yields mean absolute errors of 0.015 (0.017) Å for the lattice constant, 3.8 (3.7) GPa for the bulk modulus, and 0.06 (0.08) eV for the cohesive energy, which are smaller than those of leading density functionals by about a factor of two or more. We consider a reparameterization of the spin-scaling parameters and find that the optimal parameters for these solids are very similar to those already in common use in molecular quantum chemistry, suggesting good transferability and reliable future applications to surface chemistry on insulators.