Damage-Free Silica Coating for Colloidal Nanocrystals Through a Proactively Water-Generating Amidation Reaction at High Temperature.

Silica is a promising shell coating material for colloidal nanoparticles due to its excellent chemical inertness and optical transparency. To encapsulate high-quality colloidal nanocrystals with silica shells, the silane coupling hydrolysis is currently the most effective approach. However, this reaction requires water, which often adversely affects the intrinsic physicochemical properties of nanocrystals. Achieving a damage-free silica encapsulation process to nanocrystals by hydrolysis is a huge challenge. Here, a novel strategy is developed to coat colloidal nanocrystals with a denser silica shell via a proactively water-generating reaction at high temperature. In this work, water molecules are continuously and proactively released into the reaction system through the amidation reaction, followed by in situ hydrolysis of silane, completely avoiding the impacts of water on nanocrystals during the silica coating process. In this work, water sensitive perovskite nanocrystals (CsPbBr3 ) are selected as the typical colloidal nanocrystals for silica coating. Notably, this high-temperature in situ encapsulation technology greatly improves the optical properties of nanocrystals, and the silica shells exhibit a denser structure, providing nanocrystals with better protection. This method overcomes the challenge of the influence of water on nanocrystals during the hydrolysis process, and provides an important reference for the non-destructive encapsulation of colloidal nanocrystals.

Fluorine Passivation Inhibits "Particle Talking" Behaviors under Thermal and Electrical Conditions of Pure Blue Mixed Halide Perovskite Nanocrystals.

Owing to outstanding optoelectronic properties, lead halide perovskite nanocrystals (PNCs) are considered promising emitters for next-generation displays. However, the development of pure blue (460-470 nm) perovskite nanocrystal light-emitting diodes (PNC-LEDs), which correspond to the requirements of Rec. 2020 standard, lag far behind that of their green and red counterparts. Here, pure blue CsPb(Br/Cl)3 nanocrystals with remarkable optical performance are demonstrated by a facile fluorine passivation strategy. Prominently, the fluorine passivation on halide vacancies and strong bonding of Pb-F intensely enhance crystal structure stability and inhibit "particle talking" behaviors under both thermal and electrical conditions. Fluorine-based PNCs with high resistance of luminescence thermal quenching retain 70% of photoluminescent intensity when heated to 343 K, which can be attributed to the elevated activation energy for carrier trapping and unchanged grain size. Fluorine-based PNC-LEDs also exhibit stable pure blue electroluminescence (EL) emission with sevenfold promoted luminance and external quantum efficiencies (EQEs), where the suppression of ion migration is further evidenced by a lateral structure device with applied polarizing potential.

Serum Human Epididymis Protein 4 as a Prognostic Predictor of New-Onset Heart Failure among Women after Acute Coronary Syndrome: A Single-Center Retrospective Study.

INTRODUCTION: Little is known about the prognostic factors among women with acute coronary syndrome (ACS), partly due to the small number of women included in heart failure (HF) clinical trials. Human epididymis protein 4 (HE4) has been proven to be a new biomarker for acute and chronic HF over the years. We hypothesize that HE4 could be a promising predictor. METHODS: This retrospective study analyzed data from Zhejiang Provincial People's Hospital. This study included 302 female patients with ACS between January 1, 2021, and December 1, 2021. The primary outcome was new-onset HF after ACS during the 12-month follow-up period. We used a logistic regression model to evaluate the association between serum HE4 levels and the incidence of HF. Serum HE4 levels were measured at baseline (within 24 h after admission). RESULTS: Of the 302 female patients, 70 (23.2%) developed new-onset HF within 12 months. Serum HE4 levels in patients with adverse events were significantly higher than those in patients without events (8.9 [7.3-11.5] pmol/dL versus 5.9 [5.0-6.8] pmol/dL, p < 0.001). The levels of HE4, troponin I peak, left ventricular ejection fraction (LVEF), and estimated glomerular filtration rate (eGFR) were validated as independent predictors, with HE4 being the best laboratory predictor (area under the curve, 0.863; 95% confidence interval, 0.817-0.909). Serum HE4 concentrations of >6.93 pmol/dL distinguished patients at risk of HF with 82.9% sensitivity and 78.0% specificity (maximum Youden index J, 0.609). Moreover, HE4 levels were associated with an increased risk of HF. DISCUSSION: We found a strong relationship between HE4 and the occurrence of HF after ACS among women, which might help identify patients at high risk of HF for whom close or intense management should be mandatory.

Molecular insights and optimization strategies for the competitive binding of engineered ACE2 proteins: a multiple replica molecular dynamics study.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to spread globally, and rapid viral evolution and the emergence of new variants pose challenges to pandemic control. During infection, the spike protein of SARS-CoV-2 interacts with the human ACE2 protein via its receptor binding domain (RBD), and it is known that engineered forms of ACE2 can compete with wild-type (WT) ACE2 for binding to inhibit infection. Here, we conducted multiple replica molecular dynamics (MRMD) simulations to study the mechanisms of the engineered ACE2 variants 3N39 and 3N94 and provide directions for optimization. Our findings reveal that engineered ACE2 is notably more efficacious in systems that show weaker binding to WT ACE2 (i.e., WT and BA.1 RBD), but also faces immune escape as the virus evolves. Moreover, by modifying residue types near the binding interface, engineered ACE2 alters the electrostatic potential distribution and reconfigures the hydrogen bonding network, which results in modified binding to the RBD. However, this structural rearrangement does not occur in all RBD variants. In addition, we identified potentially engineerable beneficial residues and potentially engineerable detrimental residues in both ACE2 and RBD. Functional conservation can thus enable the optimization of these residues and improve the binding competitiveness of engineered ACE2, which therefore provides additional immune escape prevention. Finally, we conclude that these findings have implications for understanding the mechanisms responsible for engineered ACE2 and can help us to develop engineered ACE2 proteins that show superior performance.

Binding mechanism of inhibitors to SARS-CoV-2 main protease deciphered by multiple replica molecular dynamics simulations.

The outbreak caused by SARS-CoV-2 has received extensive worldwide attention. As the main protease (Mpro) in SARS-CoV-2 has no human homologues, it is feasible to reduce the possibility of targeting the host protein by accidental drugs. Thus, Mpro has been an attractive target of efficient drug design for anti-SARS-CoV-2 treatment. In this work, multiple replica molecular dynamics (MRMD) simulations, principal component analysis (PCA), free energy landscapes (FELs), and the molecular mechanics-generalized Born surface area (MM-GBSA) method were integrated together to decipher the binding mechanism of four inhibitors masitinib, O6K, FJC and GQU to Mpro. The results indicate that the binding of four inhibitors clearly affects the structural flexibility and internal dynamics of Mpro along with dihedral angle changes of key residues. The analysis of FELs unveils that the stability in the relative orientation and geometric position of inhibitors to Mpro is favorable for inhibitor binding. Residue-based free energy decomposition reveals that the inhibitor-Mpro interaction networks involving hydrogen bonding interactions and hydrophobic interactions provide significant information for the design of potent inhibitors against Mpro. The hot spot residues including H41, M49, F140, N142, G143, C145, H163, H164, M165, E166 and Q189 identified by computational alanine scanning are considered as reliable targets of clinically available inhibitors inhibiting the activities of Mpro.

Deciphering the binding mechanism of inhibitors of the SARS-CoV-2 main protease through multiple replica accelerated molecular dynamics simulations and free energy landscapes.

The pneumonia outbreak caused by the SARS-CoV-2 virus poses a serious threat to human health and the world economy. The development of safe and highly effective antiviral drugs is of great significance for the treatment of COVID-19. The main protease (Mpro) of SARS-CoV-2 is a key enzyme for viral replication and transcription and has no homolog in humans. Therefore, the Mpro is an ideal target for the design of drugs against COVID-19. Insights into the inhibitor-Mpro binding mechanism and conformational changes of the Mpro are essential for the design of potent drugs that target the Mpro. In this study, we analyzed the conformational changes of the Mpro that are induced by the binding of three inhibitors, YTV, YSP and YU4, using multiple replica accelerated molecular dynamics (MR-aMD) simulations, dynamic cross-correlation map (DCCM) calculations, principal component analysis (PCA), and free energy landscape (FEL) analysis. The results from DCCM calculations and PCA show that the binding of inhibitors significantly affects the kinetic behavior of the Mpro and induces a conformational rearrangement of the Mpro. The binding ability and binding mechanism of YTV, YSP and YU4 to the Mpro were investigated using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method. The results indicate that substitution of the tert-butanol group by methylbenzene and trifluoromethyl groups enhances the binding ability of YSP and YU4 to the Mpro compared with YTV; moreover, massive hydrophobic interactions are detected between the inhibitors and the Mpro. Meanwhile, T25, L27, H41, M49, N142, G143, C145, M165, E166 and Q189 are identified as the key residues for inhibitor-Mpro interactions using residue-based free energy decomposition calculations, which can be employed as efficient targets in the design of drugs that inhibit the activity of the Mpro.

Stable Lead-Free Tin Halide Perovskite with Operational Stability >1200 h by Suppressing Tin(II) Oxidation.

Sn-based perovskites are the most promising alternative materials for Pb-based perovskites to address the toxicity problem of lead. However, the development of SnII -based perovskites has been hindered by their extreme instability. Here, we synthesized efficient and stable lead-free Cs4 SnBr6 perovskite by using SnF2 as tin source instead of easily oxidized SnBr2 . The SnF2 configures a fluorine-rich environment, which can not only suppress the oxidation of Sn2+ in the synthesis, but also construct chemically stable Sn-F coordination to hinder the electron transfer from Sn2+ to oxygen within the long-term operation process. The SnF2 -derived Cs4 SnBr6 perovskite shows a high photoluminescence quantum yield of 62.8 %, and excellent stability against oxygen, moisture, and light radiation for 1200 h, representing one of the most stable lead-free perovskites. The results pave a new pathway to enhance the optical properties and stability of lead-free perovskite for high-performance light emitters.

Mutation-Induced Impacts on the Switch Transformations of the GDP- and GTP-Bound K-Ras: Insights from Multiple Replica Gaussian Accelerated Molecular Dynamics and Free Energy Analysis.

Mutations yield significant effect on the structural flexibility of two switch domains, SW1 and SW2, in K-Ras, which is considered as an important target of anticancer drug design. To unveil a molecular mechanism with regard to mutation-mediated tuning on the activity of K-Ras, multiple replica Gaussian accelerated molecular dynamics (MR-GaMD) simulations followed by analysis of free energy landscapes (FELs) are performed on the GDP- and GTP-bound wild-type (WT), G12V, and D33E K-Ras. The results suggest that G12V and D33E not only evidently change the flexibility of SW1 and SW2 but also greatly affect correlated motions of SW1 and SW2 separately relative to the P-loop and SW1, which exerts a certain tuning on the activity of K-Ras. The information stemming from the analyses of FELs reveals that the conformations of SW1 and SW2 are in high disorders in the GDP- and GTP-associated WT and mutated K-Ras, possibly producing significant effect on binding of guanine nucleotide exchange factors or effectors to K-Ras. The interaction networks of GDP and GTP with K-Ras are identified and the results uncover that the instability in hydrogen-bonding interactions of SW1 with GDP and GTP is mostly responsible for conformational disorder of SW1 and SW2 as well as tunes the activity of oncogenic K-Ras.

Protection of Sacubitril/Valsartan against Pathological Cardiac Remodeling by Inhibiting the NLRP3 Inflammasome after Relief of Pressure Overload in Mice.

BACKGROUND/AIMS: The persistent existence of pathological cardiac remodeling, resulting from aortic stenosis, is related to poor clinical prognosis after successful transcatheter aortic valve replacement (TAVR). Sacubitril/valsartan (Sac/Val), comprising an angiotensin receptor blocker and a neprilysin inhibitor, has been demonstrated to have a beneficial effect against pathological cardiac remodeling, including cardiac fibrosis and inflammation in heart failure. The aim of this study was to determine whether Sac/Val exerts a cardioprotective effect after pressure unloading in mice. METHODS AND RESULTS: Male C57BL/6 J mice were subjected to debanding (DB) surgery after 8 weeks (wk) of aortic banding (AB). Cardiac function was assessed by echocardiography, which indicated a protective effect of Sac/Val after DB. After treatment with Sac/Val post DB, decreased heart weight and myocardial cell size were observed in mouse hearts. In addition, histological analysis, immunofluorescence, and western blot results showed that Sac/Val attenuated cardiac fibrosis and inflammation after DB. Finally, our data indicated that Sac/Val treatment could significantly suppress NF-κB signaling and NLRP3 inflammasome activation in mice after relief of pressure overload. CONCLUSION: Sac/Val exerted its beneficial effects to prevent maladaptive cardiac fibrosis and dysfunction in mice following pressure unloading, which was at least partly due to the inhibition of NLRP3 inflammasome activation.

Molecular mechanism with regard to the binding selectivity of inhibitors toward FABP5 and FABP7 explored by multiple short molecular dynamics simulations and free energy analyses.

Recently, fatty acid binding proteins 5 and 7 (FABP5 and FABP7) have been regarded as the prospective targets for clinically treating multiple diseases related to FABPs. In this work, multiple short molecular dynamics (MSMD) simulations followed by binding free energy calculations were performed to investigate the binding selectivity of three inhibitors, namely, 65X, 8KS, and 5M8 toward FABP5 and FABP7. The RMSF analysis suggests that the structural flexibility of FABP5 is stronger than that of FABP7; moreover, the calculated molecular surface area of FABP5 is also larger than that of FABP7. Meanwhile, the results from the cross-correlation analysis show that the inhibitor bindings exert different impacts on the internal dynamics of FABP5 and FABP7. Binding free energies predicted by the molecular mechanics/generalized Born surface area (MM-GBSA) method indicate that the increase in the enthalpy changes caused by the bindings of inhibitors toward FABP7 relative to FABP5 mostly drives the binding selectivity of the inhibitors toward FABP5 versus FABP7. Hierarchical clustering analysis based on the energy contributions of separate residues and calculations of residue-based free energy decompositions were carried out by using the equilibrated MSMD trajectories. The obtained results not only recognize the hot interaction spots of inhibitors with FABP5 and FABP7, but also display that several common residues, namely, (T56, T54), (L60, F58), (E75, E73), (A76, A78), (D79, D77), (R81, R79), (R107, R109), (C120, L118), and (R129, R127) belonging to (FABP5, FABP7) induce obvious binding differences in the inhibitors toward FABP5 and FABP7. Therefore, these residues play significant roles in the binding selectivities of inhibitors toward FABP5 and FABP7.

Molecular Dynamics Exploration of Selectivity of Dual Inhibitors 5M7, 65X, and 65Z toward Fatty Acid Binding Proteins 4 and 5.

Designing highly selective inhibitors of fatty acid binding proteins 4 and 5 (FABP4 and FABP5) is of importance for treatment of some diseases related with inflammation, metabolism, and tumor growth. In this study, molecular dynamics (MD) simulations combined with molecular mechanics generalized Born surface area (MM-GBSA) method were performed to probe binding selectivity of three inhibitors (5M7, 65X, and 65Z) to FABP4/FABP5 with Ki values of 0.022/0.50 µM, 0.011/0.086 µM, and 0.016/0.12 µM, respectively. The results not only suggest that all inhibitors associate more tightly with FABP4 than FABP5, but also prove that the main forces driving the selective bindings of inhibitors to FABP4 and FABP5 stem from the difference in the van der Waals interactions and polar interactions of inhibitors with two proteins. Meanwhile, a residue-based free energy decomposition method was applied to reveal molecular basis that inhibitors selectively interact with individual residues of two different proteins. The calculated results show that the binding difference of inhibitors to the residues (Phe16, Phe19), (Ala33, Gly36), (Phe57, Leu60), (Ala75, Ala78), (Arg126, Arg129), and (Tyr128, Tyr131) in (FABP4, FABP5) drive the selectivity of inhibitors toward FABP4 and FABP5. This study will provide great help for further design of effective drugs to protect against a series of metabolic diseases, arteriosclerosis, and inflammation.

Effect of electrostatic polarization and bridging water on CDK2-ligand binding affinities calculated using a highly efficient interaction entropy method.

A new highly efficient interaction entropy (IE) method combined with the polarized protein-specific charge (PPC) force field is employed to investigate the interaction mechanism of CDK2-ligand binding and the effect of the bridging water. Our result shows that the computed binding free energies for five CDK2-ligand complexes using the IE method have a significantly linear correlation with the experimentally measured values with a correlation coefficient of 0.98 in consideration of the bridging water under the PPC force field. And the correlation coefficient is found to be slightly weaker with a value of 0.95 using the traditional normal mode (Nmode) method for calculation of entropy change. Importantly, the rank of the predicted binding free energies is significantly consistent with the experimental rank based on the IE method calculated entropy change using the PPC force field. However, without including the bridging water under PPC simulation, the correlation coefficient is below 0.83. For comparison, the result obtained from the simulation using the nonpolarized AMBER force field gives a much weaker correlation with the correlation coefficients of 0.44 and 0.45 using the Nmode method and IE method, due to the lack of electrostatic polarization. Furthermore, hydrogen bond analysis indicates that the bridging water makes a significant contribution to mediating the hydrogen bond network of protein-ligand binding and stabilizing the complex structure. The current study demonstrates that the new IE method is superior to the standard Nmode method in computing the binding free energy. And our results also emphasize the importance of electronic polarization and bridging water in MD simulations and free energy calculations.

Direct folding simulation of helical proteins using an effective polarizable bond force field.

We report a direct folding study of seven helical proteins (, Trpcage, , C34, N36, , ) ranging from 17 to 53 amino acids through standard molecular dynamics simulations using a recently developed polarizable force field-Effective Polarizable Bond (EPB) method. The backbone RMSDs, radius of gyrations, native contacts and native helix content are in good agreement with the experimental results. Cluster analysis has also verified that these folded structures with the highest population are in good agreement with their corresponding native structures for these proteins. In addition, the free energy landscape of seven proteins in the two dimensional space comprised of RMSD and radius of gyration proved that these folded structures are indeed of the lowest energy conformations. However, when the corresponding simulations were performed using the standard (nonpolarizable) AMBER force fields, no stable folded structures were observed for these proteins. Comparison of the simulation results based on a polarizable EPB force field and a nonpolarizable AMBER force field clearly demonstrates the importance of polarization in the folding of stable helical structures.

A Comparative Insight into Amprenavir Resistance of Mutations V32I, G48V, I50V, I54V, and I84V in HIV-1 Protease Based on Thermodynamic Integration and MM-PBSA Methods.

Drug resistance of mutations V32I, G48V, I50V, I54V, and I84V in HIV-1 protease (PR) was found in clinical treatment of HIV patients with the drug amprenavir (APV). In order to elucidate the molecular mechanism of drug resistance associated with these mutations, the thermodynamic integration (TI) and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) methods were applied to calculate binding free energies of APV to wild-type PR and these mutated PRs. The relative binding free energy differences from the TI calculations reveal that the decrease in van der Waals interactions of APV with mutated PRs relative to the wild-type PR mainly drives the drug resistance. This result is in good agreement with the previous experimental results and is also consistent with the results from MM-PBSA calculations. Analyses based on molecular dynamics trajectories show that these mutations can adjust the shape and conformation of the binding pocket, which provides main contributions to the decrease in the van der Waals interactions of APV with mutated PRs. The present study could provide important guidance for the design of new potent inhibitors that could alleviate drug resistance of PR due to mutations.

Perovskite Nanocrystals In Situ Encapsulated in TiO2 Microspheres for Stable CO2 Photoreduction in Water.

Photoreduction of carbon dioxide (CO2) into fuels presents a promising approach to mitigate global warming and energy crises. Halide perovskite nanocrystals (NCs) with prominent optoelectronic properties have triggered substantial attention as photocatalysts but are limited by the charge recombination and instability. Here, we develop stable CsPbBr3/titania microspheres (TMs) by in situ growth of CsPbBr3 NCs inside mesoporous TMs through solid-state sintering, which significantly improves the stability of perovskite NCs, making them applicable in water with efficient CO2 photoreduction performance. Notably, the CsPbBr3/TMs demonstrates a 6.73- and 9.23-fold increase in the rate of CH4 production compared to TMs and CsPbBr3, respectively. The internal electric field facilitates S-scheme charge transfer, enhancing the separation of electron-hole pairs, as evidenced by X-ray photoelectron spectroscopy and electron paramagnetic resonance analysis, which is pivotal for the selective photoreduction of CO2. These insights pave the way for the design of CsPbBr3-based photocatalysts with superior efficiency and stability.

Association of Hemoglobin to Red Blood Cell Distribution Width-Standard Deviation (RDW-SD) Ratio and 3-Month Readmission in Elderly Chinese Patients with Heart Failure: A Retrospective Cohort Study.

Purpose: Hemoglobin (Hb) and red blood cell distribution width-standard deviation (RDW-SD) have clinical significance in the prognosis of heart failure (HF). Little is known regarding the prognostic value of the Hb/RDW-SD ratio in patients with HF. This study sought to investigate the association between Hb/RDW-SD ratio and HF 3-month readmission in Chinese elderly patients. Patients and Methods: The present study was a retrospective cohort study. A total of 1816 HF patients were extracted from the Chinese HF database. A generalized linear model was used to explore the association between Hb/RDW-SD and 3-month readmission in HF. The generalized additive model was used to explore the nonlinear relationship, and a two-piecewise linear regression model was used to find the inflection point. Subgroup analysis explored interactions and whether each subgroup was consistent with the primary outcome direction. Results: Result showed Hb/RDW-SD was negatively associated with HF 3-month readmission (OR = 0.70, 95% CI: 0.55 to 0.89, P = 0.0031). A non-linear relationship was detected between Hb/RDW-SD and HF 3-month readmission with two inflection points (1.78 and 2.17). Both Hb/RDW-SD < 1.78 and Hb/RDW-SD > 2.17 showed a significant correlation between them, with corresponding effect values of (OR = 0.38, 95% CI: 0.17 to 0.87, P = 0.0209) and (OR = 0.44, 95% CI: 0.27 to 0.71, P = 0.0007), respectively. Conclusion: Hb/RDW-SD is negatively associated with HF 3-month readmission. The relationship between Hb/RDW-SD and HF 3-month readmission is also non-linear. Both Hb/RDW-SD < 1.78 and Hb/RDW-SD > 2.17 were strong negatively associated with HF 3-month readmission.

Nomogram to predict the incidence of new-onset heart failure after acute coronary syndrome among women.

Background: Although great progress has been made in caring for patients with acute coronary syndrome (ACS), the incidence of heart failure (HF) after discharge remains high after ACS. Aims: We aimed to investigate the risk predictors for new-onset HF and build a simple nomogram to optimize the clinical management of female patients. Methods: The clinical data of 319 female patients with ACS between January 1, 2021 and January 1, 2022, were obtained from the Zhejiang Provincial People's Hospital. Multivariate logistic regression analysis was carried out to build the prediction model among all participants and then verified by 10-fold cross-validation. The discrimination, calibration, and clinical usefulness of the prediction model were assessed using receiver operating characteristic curve, calibration curve, and decision curve analyses. Results: This study analyzed 15 potential independent risk predictors of new-onset HF in 319 female patients with ACS. The incidence of HF onset was 23.2%. The following 5 independent risk predictors were filtered out as most relevant for predicting 12-month HF onset: left ventricular ejection fraction ≤ 60.5%, high-density lipoprotein ≤ 1.055 mmol/L, human epididymal protein 4 > 69.6 pmol/L, creatinine > 71.95 µmol/L, and diagnosis of myocardial infarction (MI). Conclusion: Our nomogram, which used five easily obtained clinical variables, could be a useful tool to help identify female individuals with ACS who are at high risk of developing HF after discharge and facilitate communication between female patients and physicians.

Electroacupuncture combined with extracorporeal shock wave therapy improves pain symptoms and inflammatory factor levels in knee osteoarthritis patients.

Objective: To compare the clinical efficacy and safety of electroacupuncture combined with extracorporeal shock wave therapy (EESWT) and extracorporeal shock wave therapy (ESWT) in the treatment of knee osteoarthritis (KOA). Methods: A total of 135 KOA patients who received EESWT treatment were selected as the EESWT group, and 135 KOA patients who received extracorporeal shock wave therapy (ESWT) were selected as the ESWT group. The clinical efficacy, inflammatory factors in joint synovial fluid and adverse events during treatment were compared before and after treatment. Results: The clinical effective rate of patients in the EESWT group (89.63 %) after treatment was significantly higher than that of the ESWT group (74.81 %) (p < 0.01). The lysholm kness (LKSS) score and range of motion (ROM) of the patients in the EESWT group after treatment were higher than those of the ESWT group, while Lequesne index score, visual analogue scale (VAS) score and Western Ontario and McMaster Universities Arthritis Index (WOMAC) were lower than those of the ESWT group (p < 0.01). Compared with ESWT group, the changes in the expression levels of nitric oxide (NO), superoxide dismutase (SOD), interleukin 1ß (IL-1ß), tumor necrosis factor-α (TNF-α), matrix metalloproteinase-3 (MMP-3), and transforming growth factor ß1 (TGF-ß1) in the synovial fluid of the EESWT group after treatment were significantly greater than those of the ESWT group (p < 0.01). No significant difference in the incidence of adverse events between the EESWT group and the ESWT group (p > 0.05). Conclusion: EESWT significantly improves pain symptoms and inflammatory factor levels in KOA patients and is an optional KOA treatment option worthy of clinical attention.

Insights into the selectivity of a brain-penetrant CDK4/6 vs CDK1/2 inhibitor for glioblastoma used in multiple replica molecular dynamics simulations.

Cyclin dependent kinases (CDKs) play an important role in cell cycle regulation and their dysfunction is associated with many cancers. That is why CDKs have been attractive targets for the treatment of cancer. Glioblastoma is a cancer caused by the aberrant expression of CDK4/6, so exploring the mechanism of the selection of CDK4/6 toward inhibitors relative to the other family members CDK1/2 is essential. In this work, multiple replica molecular dynamics (MRMD) simulations, principal component analysis (PCA), free energy landscapes (FELs), molecular mechanics Poisson-Boltzmann/Generalized Born surface area (MM-PB/GBSA) and other methods were integrated to decipher the selectively binding mechanism of the inhibitor N1J to CDK4/6 and CDK1/2. Molecular electrostatic potential (MESP) analysis provides an explanation for the N1J selectivity. Residue-based free energy decomposition reveals that most of the hot residues are located at the same location of CDKs proteins, but the different types of residues in different proteins cause changes in binding energy, which is considered as a potential developmental direction to improve the selectivity of inhibitors to CDK4/6. These results provide insights into the source of inhibitor and CDK4/6 selectivity for the future development of more selective inhibitors.Communicated by Ramaswamy H. Sarma.