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Abstract High-pressure diamond anvil cells have been widely used to create novel states of matter. Nevertheless, the lack of universal in-situ magnetic measurement techniques at megabar pressures makes it difficult to understand the underlying physics of materials’ behavior at extreme conditions, such as high-temperature superconductivity of hydrides and the formation or destruction of the local magnetic moments in magnetic systems. Here, we break through the limitations of pressure on quantum sensors by modulating the uniaxial stress along the nitrogen-vacancy axis and develop the in-situ magnetic detection technique at megabar pressures with high sensitivity ( $$\sim 1{{{\rm{\mu }}}}{{{\rm{T}}}}/\sqrt{{{{\rm{Hz}}}}}$$ ~ 1 μ T / Hz ) and sub-microscale spatial resolution. By directly imaging the magnetic field and the evolution of magnetic domains, we observe the macroscopic magnetic transition of Fe3O4 in the megabar pressure range from ferrimagnetic (α-Fe3O4) to weak ferromagnetic (β-Fe3O4) and finally to paramagnetic (γ-Fe3O4). The scenarios for magnetic changes in Fe3O4 characterized here shed light on the direct magnetic microstructure observation in bulk materials at high pressure and contribute to understanding magnetism evolution in the presence of numerous complex factors such as spin crossover, altered magnetic interactions and structural phase transitions.

In recent years, the issue of PM2.5-O3 compound pollution has become a significant global environmental concern. This study examines the spatial and temporal patterns of global PM2.5-O3 compound pollution and exposure risks, firstly at the global and urban scale, using spatial statistical regression, exposure risk assessment, and trend analyses based on the datasets of daily PM2.5 and surface O3 concentrations monitored in 120 cities around the world from 2019 to 2022. Additionally, on the basis of the common emission sources, spatial heterogeneity, interacting chemical mechanisms, and synergistic exposure risk levels between PM2.5 and O3 pollution, we proposed a synergistic PM2.5-O3 control framework for the joint control of PM2.5 and O3. The results indicated that: (1) Nearly 50% of cities worldwide were affected by PM2.5-O3 compound pollution, with China, South Korea, Japan, and India being the global hotspots for PM2.5-O3 compound pollution; (2) Cities with PM2.5-O3 compound pollution have exposure risk levels dominated by ST + ST (Stabilization) and ST + HR (High Risk). Exposure risk levels of compound pollution in developing countries are significantly higher than those in developed countries, with unequal exposure characteristics; (3) The selected cities showed significant positive spatial correlations between PM2.5 and O3 concentrations, which were consistent with the spatial distribution of the precursors NOx and VOCs; (4) During the study period, 52.5% of cities worldwide achieved synergistic reductions in annual average PM2.5 and O3 concentrations. The average PM2.5 concentration in these cities decreased by 13.97%, while the average O3 concentration decreased by 19.18%. This new solution offers the opportunity to construct intelligent and healthy cities in the upcoming low–carbon transition.

Skin-nerve interaction plays an important role in promoting wound healing. However, in diabetic ulcers (DUs), the diabetic periphery neuropathy and excessive levels of reactive oxygen species (ROS) block skin-nerve interaction and further impede the DUs healing. Herein, we developed a nanoscale metal-organic framework loaded with nerve growth factor (NGF/Ce-UiO-66, denoted NGF/CU) for the treatment of DUs. The Ce-UiO-66 (CU) was applied as an antioxidant to scavenge ROS and reduce the inflammatory response while the NGF aided in the recovery of cutaneous nerves to further promote DUs healing. Both in vitro and in vivo experiments revealed the effective ability of NGF/CU for DUs healing. Subsequent RNA sequencing analysis revealed the mechanism that NGF/CU can improve wound healing by inhibiting the NF-κB signaling pathway and recovering the neuroendocrine system of the skin. This strategy of nerve regulation will provide more ideas for the treatment of DUs and other organ injuries.

Abstract Hemangioma of infancy is the most common vascular tumor during infancy and childhood. Despite the proven efficacy of propranolol treatment, certain patients still encounter resistance or face recurrence. The need for frequent daily medication also poses challenges to patient adherence. Bleomycin (BLM) has demonstrated effectiveness against vascular anomalies, yet its use is limited by dose-related complications. Addressing this, this study proposes a novel approach for treating hemangiomas using BLM-loaded hyaluronic acid (HA)-based microneedle (MN) patches. BLM is encapsulated during the synthesis of polylactic acid (PLA) microspheres (MPs). The successful preparation of PLA MPs and MN patches is confirmed through scanning electron microscopy (SEM) images. The HA microneedles dissolve rapidly upon skin insertion, releasing BLM@PLA MPs. These MPs gradually degrade within 28 days, providing a sustained release of BLM. Comprehensive safety assessments, including cell viability, hemolysis ratio, and intradermal reactions in rabbits, validate the safety of MN patches. The BLM@PLA-MNs exhibit an effective inhibitory efficiency against hemangioma formation in a murine hemangioma model. Of significant importance, RNA-seq analysis reveals that BLM@PLA-MNs exert their inhibitory effect on hemangiomas by regulating the P53 pathway. In summary, BLM@PLA-MNs emerge as a promising clinical candidate for the effective treatment of hemangiomas. Graphical Abstract

Neurodegenerative diseases (NDDs) mostly occur in older demographics. With the average lifespan increasing over time, NDDs are becoming one of the major adverse factors affecting human health and the quality of life. Currently, there are no specific diagnostic methods for NDDs and they are usually diagnosed based on nonspecific clinical symptoms and occasionally by biomarkers, such as β-amyloid (Aβ) for Alzheimer’s disease (AD) and a-synuclein (α-syn) for Parkinson’s disease, etc. However, it is usually too late for most treatment to startr when the aforementioned criteria become detectable. Circular RNAs (circRNAs) are a type of single-stranded, covalently closed, non-coding RNAs that lack a 5′ cap structure and 3′ terminal poly-A tail. According to recent research, circRNAs may play a crucial role for the onset and progression of some NDDs. These small RNAs may be potential diagnostic and prognostic markers and therapeutic targets for these diseases. This review will provide a comprehensive overview of the recent advancements of knowledge on the functions and the possible underlying mechanism of circRNAs in the pathogenesis and treatment of NDDs.

Abstract The most common mechanical complications of acute myocardial infarction include free-wall rupture, ventricular septal rupture (VSR), papillary muscle rupture and pseudoaneurysm. It is rare for a patient to experience more than one mechanical complication simultaneously. Here, we present a case of ST-segment elevation myocardial infarction (STEMI) complicated with three mechanical complications, including ventricular apical wall rupture, ventricular aneurysm formation and ventricular septal dissection (VSD) with VSR. Cardiac auscultation revealed rhythmic S1 and S2 with a grade 3 holosystolic murmur at the left sternal border. Electrocardiogram indicated anterior ventricular STEMI. Serological tests showed a significant elevated troponin I. Bedside echocardiography revealed ventricular apical wall rupture, apical left ventricle aneurysm and VSD with VSR near the apex. This case demonstrates that several rare mechanical complications can occur simultaneously secondary to STEMI and highlights the importance of bedside echocardiography in the early diagnosis of mechanical complications.

Due to low immobilized ligand density, limited binding capacity, and severe interference from serum proteins, developing ideal peptide-based biomaterials for precise recognition and in vivo analysis of biopharmaceuticals remains a huge challenge. In this study, mimotope peptide modified pompon mum-like biomimetic magnetic microparticles (MMPs, 3.8 μm) that mimic the specific functionalities of CD20 on malignant B cells were developed for the first time. Benefit from the numerous ligand binding sites (Ni2+) on the pompon mum-like MMPs, these novel materials achieved ≥10 times higher peptide ligand densities (>2300 mg/g) and antibody binding capacities (1380 mg/g) compared to previous reported biomaterials. Leveraging the high specificity of the mimotope peptide, rituximab can be precisely recognized and enriched from cell culture media or serum samples. We also established an LC‒MS/MS method using the MMPs for tracking rituximab biotransformation in patient serum. Intriguingly, deamidation of Asn55 and Asn33, as well as oxidation of Met81 and Met34 were observed at the key complementarity determining regions of rituximab, which could potentially influence antibody function and require careful monitoring. Overall, these versatile biomimetic MMPs demonstrate superior recognition and enrichment capabilities for target antibodies, offering interesting possibilities for biotransformation analysis of biopharmaceuticals in patient serum.

Abstract Background Centromeres are critical for maintaining genomic stability in eukaryotes, and their turnover shapes genome architectures and drives karyotype evolution. However, the co-evolution of centromeres from different species in allopolyploids over millions of years remains largely unknown. Results Here, we generate three near-complete genome assemblies, a tetraploid Brachypodium hybridum and its two diploid ancestors, Brachypodium distachyon and Brachypodium stacei. We detect high degrees of sequence, structural, and epigenetic variations of centromeres at base-pair resolution between closely related Brachypodium genomes, indicating the appearance and accumulation of species-specific centromere repeats from a common origin during evolution. We also find that centromere homogenization is accompanied by local satellite repeats bursting and retrotransposon purging, and the frequency of retrotransposon invasions drives the degree of interspecies centromere diversification. We further investigate the dynamics of centromeres during alloploidization process, and find that dramatic genetics and epigenetics architecture variations are associated with the turnover of centromeres between homologous chromosomal pairs from diploid to tetraploid. Additionally, our pangenomes analysis reveals the ongoing variations of satellite repeats and stable evolutionary homeostasis within centromeres among individuals of each Brachypodium genome with different polyploidy levels. Conclusions Our results provide unprecedented information on the genomic, epigenomic, and functional diversity of highly repetitive DNA between closely related species and their allopolyploid genomes at both coarse and fine scale.

Abstract Heatwaves have significant effects on ecosystems and human health. Human habitability is impacted severely as human exposure to heatwaves is projected to increase, however, the contribution of soil moisture effects to the increased exposure is unknown. We use data from four climate models, in which two experiments are used to isolate soil moisture effects and in this way to examine projected changes of soil moisture contributions to projected increases in heatwave events. Contributions from soil moisture to future population exposure to heatwaves are also investigated. With soil moisture effects combined with global warming, the longest yearly heatwaves are found to increase by up to 20 days, intensify by up to 2°C in mean temperature, with an increasing of frequency by 15% (the percentage relative to the total number of days for a year) over most mid‐latitude land regions by 2040–2070 under the SSP585 high emissions scenario. Furthermore, soil moisture changes are found to have a significant role in projected increases of multiple heatwave characteristics regionally compared with the global land area and contribute to more global population exposed to heatwaves.

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AbstractContext Diabetic nephropathy (DN) is the main cause of end-stage renal disease. Modified Shen-Yan-Fang-Shuai formula (M-SYFSF) has excellent clinical efficacy in treating diabetic kidney disease. However, the potential mechanism of M-SYFSF remains unknown.Objective To investigate the mechanism of M-SYFSF against DN by network pharmacological analysis and biological experiments.Materials and methods Utilizing a web-based pharmacology database, the potential mechanisms of M-SYFSF against DN were identified. In vivo experiments, male SD rats were injected with streptozotocin (50 mg/kg) and got uninephrectomy to construct a model of DN. M-SYFSF (11.34 g/kg/d) was gavaged once per day for 12 weeks after model establishment. In vitro experiments, human proximal tubular cells (HK-2) were performed with advanced glycation end-products (AGEs) (100 μg/mL), then intervened with M-SYFSF freeze-dried powder. Pathological staining, WB, IHC, ELISA were conducted to explore the mechanism of M-SYFSF against DN.Results Network pharmacological analysis showed that MAPK pathway was the potential pathway. Results showed that compared with the Model group, M-SYFSF significantly reduced 24h urine albumin, UACR, and serum creatinine levels (54.90 ± 26.67 vs. 111.78 ± 4.28, 8.87 ± 1.69 vs. 53.94 ± 16.01, 11.56 ± 1.70 vs. 118.70 ± 49.57, respectively), and improved renal pathological changes. Furthermore, the intervention of M-SYFSF reduced the expression of pro-inflammatory cytokines and inhibited the activation of MAPK pathway in AGEs-treated HK-2 cells.Discussion and conclusion M-SYFSF is likely to reduce inflammation in DN by inhibiting the MAPK pathway. It provides a theoretical basis for the clinical application of M-SYFSF in the treatment of DN.

Abstract Activating cGAS‐STING pathway has great potential to achieve effective antitumor immunotherapy. However, mutant p53 (mutp53), a commonly observed genetic alteration in over 50% of human cancer, will impede the therapeutic performance of the cGAS‐STING pathway. Herein, multifunctional ZIF‐8@MnO2 nanoparticles are constructed to degrade mutp53 and facilitate the cGAS‐STING pathway. The synthesized ZIF‐8@MnO2 can release Zn2+ and Mn2+ in cancer cells to induce oxidative stress and cytoplasmic leakage of fragmented mitochondrial double‐stranded DNAs (dsDNAs). Importantly, the released Zn2+ induces variable degradation of multifarious p53 mutants through proteasome ubiquitination, which can alleviate the inhibitory effects of mutp53 on the cGAS‐STING pathway. In addition, the released Mn2+ further increases the sensitivity of cGAS to dsDNAs as immunostimulatory signals. Both in vitro and in vivo results demonstrate that ZIF‐8@MnO2 effectively promotes the cGAS‐STING pathway and synergizes with PD‐L1 checkpoint blockades, leading to remarkable regression of local tumors as well as distant metastases of breast cancer. This study proposes an inorganic metal ion‐based nanoplatform to enhance the cGAS‐STING‐mediated antitumor immunotherapy, especially to those tumors with mutp53 expression.

Abstract Diabetic kidney disease (DKD) is a prevalent complication of diabetes, often leading to end‐stage renal disease. Animal models have been widely used to study the pathogenesis of DKD and evaluate potential therapies. However, current animal models often fail to fully capture the pathological characteristics of renal injury observed in clinical patients with DKD. Additionally, modeling DKD is often a time‐consuming, costly, and labor‐intensive process. The current review aims to summarize modeling strategies in the establishment of DKD animal models by utilizing meta‐analysis related methods and to aid in the optimization of these models for future research. A total of 1215 articles were retrieved with the keywords of “diabetic kidney disease” and “animal experiment” in the past 10 years. Following screening, 84 articles were selected for inclusion in the meta‐analysis. Review manager 5.4.1 was employed to analyze the changes in blood glucose, glycosylated hemoglobin, total cholesterol, triglyceride, serum creatinine, blood urea nitrogen, and urinary albumin excretion rate in each model. Renal lesions shown in different models that were not suitable to be included in the meta‐analysis were also extensively discussed. The above analysis suggested that combining various stimuli or introducing additional renal injuries to current models would be a promising avenue to overcome existing challenges and limitations. In conclusion, our review article provides an in‐depth analysis of the limitations in current DKD animal models and proposes strategies for improving the accuracy and reliability of these models that will inspire future research efforts in the DKD research field.

Arteriovenous malformations (AVMs) are serious congenital vascular anomalies in which the arteries connect directly with veins without capillaries. This condition will continue to worsen without proper intervention and cause ulcers, repeated hemorrhages, and even cardiac insufficiency. Primary treatment options for AVMs include surgery and interventional treatment; however, they are associated with high risk and recurrence rates. Recent studies revealed that excessive activation of the Ras/MAPK pathway can induce the formation and development of peripheral AVM, whereas MEK inhibitors can effectively control nidus progression, making them a potential novel treatment for AVM. This review provides an up-to-date overview of correlated laboratory and clinical research to provide information for further research and clinical practice.

Arteriovenous malformations (AVMs) are aggressive congenital high-flow vascular anomalies, in which the feeding artery and draining vein are connected through fistulas without normal capillary networks. In severe cases, the condition may cause swelling, ulceration, bleeding, and even heart failure. Various treatment options are available for AVMs, including laser, surgical resection, embolization, and targeted drug therapy. With the development of endovascular treatment technology, absolute ethanol embolization of AVMs has become one of the first-line therapies owing to its sustained efficacy and low recurrence rate. However, administration of this therapy is challenging and may lead to serious complications if inappropriately managed. In this article, we reviewed and summarized previous clinical articles, literature reviews, and clinical trial data to comprehensively describe clinical manifestations of AVMs, the mechanism of ethanol embolotherapy, key points in treatment and management of complications, and issues that need to be addressed. We expect to provide a reliable information reference source for clinical physicians and researchers.

Previous studies have validated a close association between inflammatory factors and multiple sclerosis (MS), but their causal relationship is not fully profiled yet. This study used Mendelian randomization (MR) to investigate the causal effect of circulating inflammatory proteins on MS. Data from a large-scale genome-wide association study (GWAS) were analyzed using a two-sample MR method to explore the relationship between 91 circulating inflammatory proteins and MS. The inverse-variance-weighted (IVW) analysis was employed as the main method for evaluating exposures and outcomes. Furthermore, series of the methods of MR Egger, weighted median, simple mode, and weighted mode were used to fortify the final results. The results of the IVW method were corrected with Bonferroni (bon) and false discovery rate (fdr) for validating the robustness of results and ensuring the absence of heterogeneity and horizontal pleiotropy. The sensitivity analysis was also performed. The results of the forward MR analysis showed that higher levels of CCL25 were found to be associated with an increased risk of MS according to IVW results, OR: 1.085, 95% CI (1.011, 1.165), p = 2.42 × 10−2, adjusted p_adj_bon = 1, p_adj_fdr = 0.307. Similarly, higher levels of CXCL10 were found to be associated with an increased risk of MS, OR: 1.231, 95% CI (1.057, 1.433), p = 7.49 × 10−3, adjusted p_adj_bon = 0.682, p_adj_fdr = 0.227. In contrast, elevated levels of neurturin (NRTN) were associated with a decreased risk of MS, OR: 0.815, 95% CI (0.689, 0.964), p = 1.68 × 10−2, adjusted p_adj_bon = 1, p_adj_fdr = 0.307. Reverse MR analysis showed no causal relationship between MS and the identified circulating inflammatory cytokines. The effects of heterogeneity and level pleiotropy were further excluded by sensitivity analysis. This study provides new insights into the relationship between circulating inflammatory proteins and MS and brings up a new possibility of using these cytokines as potential biomarkers and therapeutic targets. The data in this study show that there are only weak associations between inflammatory molecules and MS risk, which did not survive bon and fdr correction, and the obtained p-values are quite low. Therefore, further studies on larger samples are needed.

Objective: To evaluate the protective effect of Yiqi Qingre Xiaozheng formula (YQQRXZF) via the regulation of autophagy in diabetic nephropathy (DN) mice induced by injection of streptozotocin (STZ) after high fat diet (HFD). Methods: The composition of YQQRXZF was analyzed by high performance liquid chromatography-electrospray ionization/mass spectrometry (HPLC-ESI/MSn). The DN model was induced by intraperitoneally injection of 50 mg/kg STZ within 5 days, followed by HFD feeding for 8 weeks in C57BL/6J mice. Mice were randomly separated into DN group, YQQRXZF group, irbesartan group, and control group. Blood glucose was calculated, and body weight was measured every 2 weeks. An enzyme-linked immunosorbent assay was used to measure the urinary albumin-to-creatinine ratio (uACR) before and after treatment, and the serum concentrations of total cholesterol (TC), low-density lipoprotein (LDL), triglycerides (TG), high-density lipoprotein (HDL), blood urea nitrogen (BUN), and serum creatinine (Scr) were measured. In addition, hematoxylin-eosin (H&E) staining, periodic acid-Schiff (PAS) staining, Masson's trichrome staining, and transmission electron microscopy (TEM) were used to observe pathological changes in renal tissue. Autophagy levels were determined by immunofluorescence staining. Results: In this study, 21 dominant chemical constituents were identified in YQQRXZF. The treatment group reduced uACR in a more significant way than the DN group (P = .018). The treatment group reduced TC, TG, and LDL concentrations after YQQRXFF treatment (P = .021, P = .014 and P = .026, respectively). H&E, PAS, and Masson staining showed that pathological damage to mice kidneys improved, the volume of renal glomeruli was reduced, and glomerular sclerosis and fibrosis were reduced. Immunofluorescence analysis revealed that expressions of LC3-Ⅱprotein increased in the treatment group (P = .013). In contrast, the protein expressions of P62 were reduced after treatment (P = .025). Conclusion: YQQRXZF effectively attenuates kidney injury in DN mice, probably by regulating autophagy.

Diabetic kidney disease (DKD) stands as the predominant cause of chronic kidney disease (CKD) on a global scale, with its incidence witnessing a consistent annual rise, thereby imposing a substantial burden on public health. The pathogenesis of DKD is primarily rooted in metabolic disorders and inflammation. Recent years have seen a surge in studies highlighting the regulatory impact of energy metabolism on innate immunity, forging a significant area of research interest. Within this context, fibroblast growth factor 21 (FGF21), recognized as an energy metabolism regulator, assumes a pivotal role. Beyond its role in maintaining glucose and lipid metabolism homeostasis, FGF21 exerts regulatory influence on innate immunity, concurrently inhibiting inflammation and fibrosis. Serving as a nexus between energy metabolism and innate immunity, FGF21 has evolved into a therapeutic target for diabetes, nonalcoholic steatohepatitis, and cardiovascular diseases. While the relationship between FGF21 and DKD has garnered increased attention in recent studies, a comprehensive exploration of this association has yet to be systematically addressed. This paper seeks to fill this gap by summarizing the mechanisms through which FGF21 operates in DKD, encompassing facets of energy metabolism and innate immunity. Additionally, we aim to assess the diagnostic and prognostic value of FGF21 in DKD and explore its potential role as a treatment modality for the condition.

Nonreciprocal elements, such as isolators and circulators, play an important role in classical and quantum information processing. Recently, strong nonreciprocal effects have been experimentally demonstrated in cavity optomechanical systems. In these approaches, the bandwidth of the nonreciprocal photon transmission is limited by the mechanical resonator linewidth, which is arguably much smaller than the linewidths of the cavity modes in most electromechanical or optomechanical devices. In this work, we demonstrate broadband nonreciprocal photon transmission in the reversed-dissipation regime, where the mechanical mode with a large decay rate can be adiabatically eliminated while mediating anti-PT-symmetric dissipative coupling with two kinds of phase factors. Adjusting the relative phases allows the observation of periodic Riemann-sheet structures with distributed exceptional points (Eps). At the Eps, destructive quantum interference breaks both the T- and P-inversion symmetry, resulting in unidirectional and chiral photon transmissions. In the reversed-dissipation regime, the nonreciprocal bandwidth is no longer limited by the mechanical mode linewidth but is improved to the linewidth of the cavity resonance. Furthermore, we find that the direction of the unidirectional and chiral energy transfer could be reversed by changing the parity of the Eps. Extending non-Hermitian couplings to a three-cavity model, the broken anti-PT-symmetry allows us to observe high-order Eps, at which a parity-dependent chiral circulator is demonstrated. The driving-phase controlled periodical Riemann sheets allow observation of the parity-dependent unidirectional and chiral energy transfer and thus provide a useful cell for building up nonreciprocal array and realizing topological, e.g., isolators, circulators, or amplifiers.

Zwitterionic sulfobetaine-based monolithic stationary phases have attracted increasing attention for their use in hydrophilic interaction chromatography. In this study, a novel hydrophilic polymeric monolith was fabricated through photo-initiated copolymerization of 3-(3-vinyl-1-imidazolio)-1-propanesulfonate (SBVI) with pentaerythritol triacrylate using methanol and tetrahydrofuran as the porogenic system. Notably, the duration for the preparation of this novel monolith was as little as 5 min, which was significantly shorter than that required for previously reported sulfobetaine-based monoliths prepared via conventional thermally initiated copolymerization. Moreover, these monoliths showed good morphology, permeability, porosity (62.4%), mechanical strength (over 15 MPa), column efficiency (51,230 plates/m), and reproducibility (relative standard deviations for all analytes were lower than 4.6%). Mechanistic studies indicated that strong hydrophilic and negative electrostatic interactions might be responsible for the retention of polar analytes on the zwitterionic SBVI-based monolith. In particular, the resulting monolith exhibited good anti-protein adhesion ability and low nonspecific protein adsorption. These excellent features seem to favor its application in bioanalysis. Therefore, the novel zwitterionic sulfobetaine-based monolith was successfully employed for the highly selective separation of small bioactive compounds and the efficient enrichment of N-glycopeptides from complex samples. In this study, we prepared a novel zwitterionic sulfobetaine-based monolith with good performance and developed a simpler and faster method for preparation of zwitterionic monoliths.

Introduction Hyperkalaemia (HK) is a potentially life-threatening electrolyte imbalance associated with several adverse clinical outcomes. The efficacy and negative effects of currently existing treatment options have made HK management questionable. Sodium zirconium cyclosilicate (SZC), a novel highly selective potassium binder, is approved for the treatment of HK. The present study will be aimed to assess the safety, effectiveness and treatment patterns of SZC in Chinese patients with HK in a real-world clinical setting as it is required by China’s drug review and approval process.Methods and analysis This is a multicentre, prospective cohort study which plans to enrol 1000 patients taking SZC or willing to take SZC from approximately 40 sites in China. Patients ≥18 years of age at the time of signing the written informed consent and with documented serum potassium levels ≥5.0 mmol/L within 1 year before study enrolment day will be included. Eligible patients will receive SZC treatment and will be followed up for 6 months from enrolment day. The primary objective will be to evaluate the safety of SZC for the management of HK in Chinese patients in terms of adverse events (AEs), serious AEs as well as discontinuation of SZC. The secondary objectives will include understanding the SZC dosage information in terms of its effectiveness and treatment patterns under real-world clinical practice and assessing effectiveness of SZC during the observational period.Ethics and dissemination This study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Dalian Medical University (approval number: YJ-JG-YW-2020). All the participating sites have received the ethics approval. Results will be disseminated through national and international presentations and peer-reviewed publications.Trial registration number NCT05271266.

Abstract Background IgA nephropathy is the most common glomerular disease and is a common cause of progression to end-stage renal disease in patients with kidney diseases. Proteinuria levels are critical for the prognosis of patients with IgA nephropathy, but many patients are still unable to effectively control their proteinuria levels after receiving RAAS blockers. Antimalarial drugs have shown good efficacy in the treatment of kidney disease in previous studies; however, there have been no strictly designed randomized controlled trials to confirm the clinical efficacy of artesunate for treating IgA nephropathy patients. Therefore, we designed this clinical trial to compare the effect of artesunate versus placebo in patients with IgA nephropathy. Methods This study is a randomized, double-blind, three-group-parallel, placebo-controlled clinical trial. One hundred and twenty eligible IgA nephropathy patients at risk of progression will be randomly divided into the artesunate 100-mg group, artesunate 50-mg group, and placebo group. Changes in proteinuria and renal function will be measured 6 months after the intervention. The levels of Gd-IgA1 and anti-Gd-IgA1 in the patient’s blood will also be tested to explore the possible immune mechanisms. Discussion Clinical evidence supporting artesunate treatment of IgA nephropathy is currently lacking, and we expect that the results of this trial will provide high-quality clinical evidence for artesunate as a treatment option for IgA nephropathy in the future. Trial registration Chinese Clinical Trial Registry ChiCTR2000038104 . Registered on 10 September 2020

PurposeTo report the design and baseline data of a 3-year cohort study in Beijing Pinggu District primary school students in China after COVID-19.MethodsNoncycloplegic and cycloplegic spherical equivalent refraction (SER) were measured, ocular biometry, including the axial length (AL), anterior chamber depth (ACD) and corneal power (CP), were collected before cycloplegia. Corneal radius (CR), AL-to-CR ratio, and lens power (LP) were calculated.ResultsAmong the 4,806 (89.1%) eligible students (51.5% male), the prevalence of emmetropia, myopia, mild hyperopia, and mild-to-high hyperopia was 12.8, 30.8, 53.0, and 3.3% after cycloplegia, respectively. Myopia increased from 2.5% in 6- to 71.6% in 12-year-old students, with 9- and 10-year-olds showing the most prominent increases. The median of cycloplegic SER was 0.50 (IQR = 1.63), and the noncycloplegic SER was −0.38 D (IQR = 1.50), which is more negative than the cycloplegic refraction. The mean AL increased with age, from 22.46 ± 0.70 mm to 24.26 ± 1.07 mm. The ACD increased from 3.38 ± 0.28 mm to 3.70 ± 0.30 mm, and the AL-to-CR ratio increased from 2.91 ± 0.08 to 3.12 ± 0.13 between 6- and 12-year-old students. AL, CR and LP explained the SER variance with R2 of 86.4% after adjusting the age and gender.Conclusions and RelevanceThe myopia prevalence since emergence of COVID-19 rapidly increased from 6- to 12-year primary school Chinese children, especially after 7 years of age. The non-cycloplegia SER overestimated the prevalence of myopia, and the cycloplegic SER is a more accurate and reliable method to assess the prevalence of refractive status.

Background: The aim of this study was to estimate the attributable risk for all-cause mortality in hypertensive adults living in Beijing, China. Methods: We conducted a prospective cohort study on the basis of the disease risk prediction model, which included 3006 hypertensive patients aged 50 and over who participated in the annual health examination from thirty-eight community health centers were randomly selected from all 53 community health centers in Dongcheng district of Beijing in China. This cohort study was conducted from January 1, 2013 to June 31, 2018 in these community health centers. Data included age, gender, education level, BMI, smoking and drinking status, renal function, diabetes mellitus (DM), coronary heart disease, levels of blood pressure, use of medications, and blood lipid levels. Results: the follow-up time was 4.90 ± 0.51 years. There were significant survival differences by gender, renal function (eGFR > 90 vs. 60–90 vs. 12 years), coronary heart disease (CHD) (CHD vs. NO CHD). In the multivariate Cox proportional hazard analysis, the prognostic factors of all-cause mortality in hypertensive patients were male [HR 1.662, 95% CI 1.110–2.489, p = 0.014], educational level

The development of thia-Baeyer-Villiger reactions has been elusive so far due to competitive oxidation of sulfoxides to sulfones. Here, the authors show a thia-Baeyer-Villiger-type oxidations converting dibenzothiophene derivatives into sulfinic esters with t-BuOOH and an iron catalyst under UV irradiation.

Gestational diabetes mellitus (GDM) is a high-risk pregnancy complication that is associated with metabolic disorder phenotypes, such as abnormal blood glucose and obesity. The link between microbiota and diet management contributes to metabolic homeostasis in GDM. Therefore, it is crucial to understand the structure of the gut microbiota in GDM and to explore the effect of dietary management on the microbiota structure. In this study, we analyzed the composition of the gut microbiota between 27 GDM and 30 healthy subjects at two time points using Illumina HiSeq 2500 platform. The taxonomy analyses suggested that the overall bacteria clustered by diabetes status, rather than diet intervention. Of particular interest, the phylum Acidobacteria in GDM was significantly increased, and positively correlated with blood glucose levels. Moreover, Partial least-squares discriminant analysis (PLS-DA) revealed that certain genera in the phyla Firmicutes, Bacteroidetes, Proteobacteria, and Lentisphaerae characterized the GDM gut microbiota. Correlation analysis indicated that blood glucose levels and BMI index were correlated with the relative abundance of SCFAS-producing genera. Through the comparison between the GDM and healthy samples with or without diet intervention, we discovered that the role of short-term diet management in GDM processes is associated with the change in the Firmicutes/Bacteroidetes ratio and some specific taxa, rather than an alternative gut microbial pattern. Our study have important implications for understanding the beneficial effects of diet intervention on the specific gut microbiota and thus possibly their metabolism in pregnant women with GDM.

The etiology and pathogenesis of rheumatoid arthritis (RA) have not yet been fully elucidated, with greater adverse drug effects in traditional treatment of RA. It is particularly necessary to develop and study Chinese herbal formula as a supplement and alternative drug for the treatment of RA. The traditional Chinese medicine compound Longteng Decoction (LTD), as an empirical prescription in the treatment of RA in Dongzhimen Hospital of Beijing University of Chinese Medicine, has been widely used in clinic. Type 2 innate lymphocytes (ILC2s) have specific transcription factors and signature cytokines that are very similar to Th cells, which have been proved to be necessary in addressing RA inflammation, and are potential targets for RA prevention and treatment. Our previous studies have confirmed that LTD can intervene in the differentiation of peripheral blood Th17 and Treg cells, reduce joint pain index and swelling degree, shorten the time of morning stiffness, reduce ESR, and inhibit joint inflammation. However, it is unclear whether LTD can promote the regression of RA synovial inflammation by regulating the immune response mechanism of ILC2s.Therefore, our team established a collagen-induced arthritis mouse model and conducted an experimental study with LTD as the intervention object. The results showed that joint swelling, synovial inflammatory infiltration, and articular cartilage destruction were alleviated in CIA mice after intervention with LTD. The proliferation and differentiation of Th17 inflammatory cells and the secretion of proinflammatory cytokines (IL-17 and IFN-γ) were inhibited. In addition, LTD can also activate ILC2s to secrete the anti-inflammatory cytokine IL-4, activate the STAT6 signaling pathway, and act synergistic with Treg cells to inhibit the infiltration of type M1 macrophages in synovial tissue and promote its transformation to M2 phenotype. Taken together, these results confirm that LTD can be used as an adjunct or alternative to RA therapy by modulating the ILC2s immune response network and slowing down the inflammatory process of synovial tissue.

Obesity and related metabolic disorders are associated with intestinal microbiota dysbiosis, disrupted intestinal barrier and chronic inflammation. Shen-Yan-Fang-Shuai formula (SYFSF) is a traditional Chinese herbal formula composed of Astragali Radix, Radix Angelicae Sinensis, Rheum Officinale Baill, and four other herbs. In this study, we identified that SYFSF treatment prevented weight gain, low-grade inflammation and insulin resistance in high-fat diet (HFD)-fed mice. SYFSF also substantially improved gut barrier function, reduced metabolic endotoxemia, as well as systemic inflammation. Sequencing of 16S rRNA genes obtained from fecal samples demonstrated that SYFSF attenuated HFD-induced gut dysbiosis, seen an decreased Firmicutes to Bacteroidetes ratios. Microbial richness and diversity were also higher in the SYFSF-treated HFD group. Furthermore, similar therapeutic effects and changes in gut microbiota profile caused by SYFSF could be replicated by fecal microbiota transfer (FMT). Taken together, our study highlights the efficacy of SYFSF in preventing obesity and related metabolic disorders. Its therapeutic effect is associated with the modulation of gut microbiota, as a prebiotic.

Quantum backaction disturbs the measurement of the position of a mechanical oscillator by introducing additional fluctuations. In a quantum backaction measurement technique, the backaction can be evaded, although at the cost of losing part of the information. In this work, we carry out such a quantum backaction measurement using a large 0.5 mm diameter silicon nitride membrane oscillator with 707 kHz frequency, via a microwave cavity readout. The measurement shows that quantum backaction noise can be evaded in the quadrature measurement of the motion of a large object.

Abstract Background Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus and the primary cause of end-stage renal disease. Existing therapies for DKD are not sufficiently effective. We report the protocol of a pragmatic randomized controlled trial of the use of traditional Chinese herbal medicine to treat patients with DKD. Methods/design This will be a multicenter randomized controlled trial. A total of 266 patients with DKD (106 with early stage, 80 with middle-stage, and 80 with advanced-stage disease) with an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m2will be included. Participants with DKD of each stage will be randomly allocated at a 1:1 ratio to either the experimental group, which will receive Xiaozhen formula and basic treatment, or the control group, which will receive basic treatment only. The study duration will be 24 weeks. The primary outcome will be urinary microalbumin excretion rate for early stage DKD, 24-h urinary protein for middle-stage DKD, and eGFR for advanced-stage DKD. Adverse events will also be evaluated. Data for all outcome indicators will be collected at baseline and weeks 4, 12, and 24. Discussion This study will provide evidence of the effectiveness and safety of traditional Chinese herbal medicine in treating patients with DKD. Trial registration Chinese Clinical Trials Registry: ChiCTR-IOR-16010072. Registered on 2 December 2016.

Over the past several decades, natural products with poly-pharmacological profiles have demonstrated promise as novel therapeutics for various complex diseases, including cancer. Berberine (PubChem CID: 2353), a soliloquies quaternary alkaloid, has been validated to exert powerful effects in many cancers. However, the underlying molecular mechanism is not yet fully elucidated. In this study, we summarized the molecular effects of berberine against multiple cancers based on current available literatures. Furthermore, a systems pharmacology infrastructure was developed to discover new cancer indications of berberine and explore their molecular mechanisms. Specifically, we incorporated 289 high-quality protein targets of berberine by integrating experimental drug–target interactions (DTIs) extracted from literatures and computationally predicted DTIs inferred by network-based inference approach. Statistical network models were developed for identification of new cancer indications of berberine through integration of DTIs and curated cancer significantly mutated genes (SMGs). High accuracy was yielded for our statistical models. We further discussed three typical cancer indications (hepatocarcinoma, lung adenocarcinoma, and bladder carcinoma) of berberine with new mechanisms of actions (MOAs) based on our systems pharmacology framework. In summary, this study systematically provides a powerful strategy to identify potential anti-cancer effects of berberine with novel mechanisms from a systems pharmacology perspective.

Backgrounds and AimsRecently, a growing number of hepatotoxicity cases aroused by Traditional Chinese Medicine (TCM) have been reported, causing increasing concern. To date, the reported predictive models for drug induced liver injury show low prediction accuracy and there are still no related reports for hepatotoxicity evaluation of TCM systematically. Additionally, the mechanism of herb induced liver injury (HILI) still remains unknown. The aim of the study was to identify potential hepatotoxic ingredients in TCM and explore the molecular mechanism of TCM against HILI.Materials and MethodsIn this study, we developed consensus models for HILI prediction by integrating the best single classifiers. The consensus model with best performance was applied to identify the potential hepatotoxic ingredients from the Traditional Chinese Medicine Systems Pharmacology database (TCMSP). Systems pharmacology analyses, including multiple network construction and KEGG pathway enrichment, were performed to further explore the hepatotoxicity mechanism of TCM.Results16 single classifiers were built by combining four machine learning methods with four different sets of fingerprints. After systematic evaluation, the best four single classifiers were selected, which achieved a Matthews correlation coefficient (MCC) value of 0.702, 0.691, 0.659, and 0.717, respectively. To improve the predictive capacity of single models, consensus prediction method was used to integrate the best four single classifiers. Results showed that the consensus model C-3 (MCC = 0.78) outperformed the four single classifiers and other consensus models. Subsequently, 5,666 potential hepatotoxic compounds were identified by C-3 model. We integrated the top 10 hepatotoxic herbs and discussed the hepatotoxicity mechanism of TCM via systems pharmacology approach. Finally, Chaihu was selected as the case study for exploring the molecular mechanism of hepatotoxicity.ConclusionOverall, this study provides a high accurate approach to predict HILI and an in silico perspective into understanding the hepatotoxicity mechanism of TCM, which might facilitate the discovery and development of new drugs.

Macroscopic mechanical systems typically respond linearly to external force, and generating nonlinearity is challenging. Here, the authors generate nonlinearity in a macroscopic mechanical resonator by linking it to a gold contact and exploiting the anharmonicity in the chemical bonding interactions.

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and satisfactory therapeutic strategies have not yet been established. The Shen-Yan-Fang-Shuai Formula (SYFSF) is a traditional Chinese formula composed of Astragali radix, Radixangelicae sinensis, Rheum officinale Baill, and four other herbs. It has been widely used as an effective treatment for DKD patients in China. However, little is known about the molecular mechanisms underlying SYFSF’s renoprotection. In this study, we compared the protective effect of SYFSF to irbesartan on the histology and renal cells in type 2 DKD rat model and high-glucose (HG) cultured mesangial cells, respectively. We found that SYFSF could significantly decrease urinary albumin, cholesterol, and triglyceride. And a decrease in serum creatinine was also found in SYFSF-treated group compared with irbesartan-treated rats. In addition, SYFSF inhibited the interstitial expansion and glomerulosclerosis in diabetic rats. Notably, SYFSF markedly downregulated the expression of MCP-1, TGF-β1, collagen IV, and fibronectin in diabetic rat models and HG-induced mesangial cell models. The renoprotection was closely associated with a reduced expression of TNF-α and phosphorylated NF-κBp65. Our study suggests that SYFSF may ameliorate diabetic kidney injury. The observed renoprotection is probably attributable to an inhibition of inflammatory response and extracellular matrix (ECM) accumulation mediated by TNF-α/NF-κBp65 signaling pathway.

The hypoalbuminuric effect of sulodexide (SDX) on diabetic kidney disease (DKD) was suggested by some clinical trials but was denied by the Collaborative Study Group. In this study, the diabetic rats were treated with SDX either from week 0 to 24 or from week 13 to 24. We found that 24-week treatment significantly decreased the urinary protein and HAVCR1 excretion, inhibited the interstitial expansion, and downregulated the renal cell apoptosis and interstitial fibrosis. Renoprotection was also associated with a reduction in renocortical/urinary oxidative activity and the normalization of renal klotho expression. However, all of these actions were not observed when SDX was administered only at the late stage of diabetic nephropathy (from week 13 to 24). In vitro, advanced glycation end products (AGEs) dose-dependently enhanced the oxidative activity but lowered the klotho expression in cultured proximal tubule epithelial cells (PTECs). Also, H2O2 could downregulate the expression of klotho in a dose-dependent manner. However, overexpression of klotho reduced the HAVCR1 production and the cellular apoptosis level induced by AGEs or H2O2. Our study suggests that SDX may prevent the progression of DKD at the early stage by upregulating renal klotho expression, which inhibits the tubulointerstitial injury induced by oxidative stress.

A derivative formula, DGBX, which is composed of three herbs (Radix astragali, Radix Angelicae sinensis, and Coptis chinensis Franch), is derived from a famous Chinese herbal formula, Danggui Buxue Tang (DBT) (Radix astragali and Radix Angelicae sinensis). We aimed to investigate the effects of DGBX on the regulation of the balance between proliferation and apoptosis of hematopoietic stem cells (HSCs) due to the aberrant immune response in a mouse model of aplastic anemia (AA). Cyclosporine (CsA), an immunosuppressor, was used as the positive control. Our results indicated that DGBX could downregulate the production of IFNγ in bone marrow cells by interfering with the binding between SLAM and SAP and the expressions of Fyn and T-bet. This herbal formula can also inhibit the activation of Fas-mediated apoptosis, interferon regulatory factor-1-induced JAK/Stat, and eukaryotic initiation factor 2 signaling pathways and thereby induce proliferation and attenuate apoptosis of HSCs. In conclusion, DGBX can relieve the immune-mediated destruction of HSCs, repair hematopoietic failure, and recover the hematopoietic function of HSCs in hematogenesis. Therefore, DGBX can be used in traditional medicine against AA as a complementary and alternative immunosuppressive therapeutic formula.

Multiway spatial join plays an important role in GIS (Geographic Information Systems) and their applications. With the increase in spatial data volumes, the performance of multiway spatial join has encountered a computation bottleneck in the context of big data. Parallel or distributed computing platforms, such as MapReduce and Spark, are promising for resolving the intensive computing issue. Previous approaches have focused on developing single-threaded join algorithms as an optimizing and partition strategy for parallel computing. In this paper, we present an effective high-performance multiway spatial join algorithm with Spark (MSJS) to overcome the multiway spatial join bottleneck. MSJS handles the problem through cascaded pairwise join. Using the power of Spark, the formerly inefficient cascaded pairwise spatial join is transformed into a high-performance approach. Experiments using massive real-world data sets prove that MSJS outperforms existing parallel approaches of multiway spatial join that have been described in the literature.

We demonstrate quantum coherent control of single electronic spins in a nitron-vacancy center in diamond by exploiting and implementing the general concept of Landau-Zener-Stückelberg interferometry at room temperature. The interferometry manipulates an effective two-level system of electronic spins which are coupled to the nearby ^{14}N nuclear spin in the nitron-vacancy center as well as the nuclear spin bath in the diamond. With a microwave field to control the energy gap between the two levels and an AC field as the time-dependent driving field in Landau-Zener-Stückelberg interferometry, the interference pattern can be generated and controlled by controlling a number of parameters in the fields, corresponding to coherent control of the state of the electronic spins. In particular, the interference pattern is observed oscillating as a function of the frequency of the microwave field. Decays in the visibility of the interference pattern are also observed and well explained by numerical simulation which takes into account the thermal fluctuations arising from the nuclear bath. Therefore, our work also demonstrates that Landau-Zener-Stückelberg interferometry can be used for probing decoherence processes of electronic spins.

BACKGROUND Cutaneous erythema is one of the most common signs of arteriovenous malformations (AVMs) in the head and neck region, influencing aesthetic appearance. Surgical resection of AVMs may lead to cicatrization of the skin or aggravation of the lesion. Laser treatment, although effective in improving superficial vascular lesions, cannot prevent deep AVMs from further development. OBJECTIVE The authors propose an absolute ethanol embolization therapy that can effectively and safely eradicate the nidus with a favorable aesthetic outcome. METHODS The authors conducted a retrospective observational study of 14 AVM patients with distinct cutaneous erythema in the head and neck region undergoing embolotherapy in a single primary care center. Symptoms before and after treatment, complications, and degree of devascularization were recorded and assessed. Changes in cutaneous redness were evaluated using a previously reported quantitative measurement. RESULTS Complete symptomatic relief was observed in 5 patients, and major improvement was observed in 9 patients. The mean Î"a* value of the color change had a significant reduction of 6.50 ± 4.04, p < .001, indicating a remarkable remission of cutaneous erythema. CONCLUSION Ethanol embolization is an effective and safe treatment for head and neck AVMs with excellent aesthetic outcomes and might become a potential treatment method for other superficial vascular anomalies. [ABSTRACT FROM AUTHOR]

How to illuminate dark matter has become the foremost open question in fundamental science nowadays, which is of great significance in understanding the laws of nature. Exploring exotic interactions beyond the standard model is one of the essential approaches to searching for dark matter particles. Although it has been explored in a variety of lab-scale and tabletop-scale setups over the past years, no such interactions have been observed, and improving the sensitivity significantly becomes of paramount importance, but challenging. Here, we formulate the conception of a spin-mechanical quantum chip compatible with scalable on-chip detectors. Utilizing the prototype chip realized by the integration of a mechanical resonator and a diamond with single nitrogen vacancy at the microscale, the constraints of spin-velocity-dependent interactions have been improved by two orders of magnitude, where there is no evidence for new bosons in the force range below 100 nm, i.e., in the rest-mass window of 2–10 electronvolts. Based on the proof-of-principle experiment, this promising chip can be scaled up to meet the requirements of searching for exotic interactions at preeminent sensitivity. Low-cost and high-yield chip-scale setups will accelerate the process of dark matter exploration, providing a path toward on-chip fundamental physics experiments. [ABSTRACT FROM AUTHOR]

Arteriovenous malformations (AVMs) are serious congenital vascular anomalies in which the arteries connect directly with veins without capillaries. This condition will continue to worsen without proper intervention and cause ulcers, repeated hemorrhages, and even cardiac insufficiency. Primary treatment options for AVMs include surgery and interventional treatment; however, they are associated with high risk and recurrence rates. Recent studies revealed that excessive activation of the Ras/MAPK pathway can induce the formation and development of peripheral AVM, whereas MEK inhibitors can effectively control nidus progression, making them a potential novel treatment for AVM. This review provides an up-to-date overview of correlated laboratory and clinical research to provide information for further research and clinical practice. [ABSTRACT FROM AUTHOR]

Diarrhea-predominant irritable bowel syndrome (IBS-D) is one of the most common chronic functional gastrointestinal diseases with limited treatments. Gut microbiota play an important role in chronic gastrointestinal diseases. In traditional Chinese medicine (TCM), Spleen–Yang deficiency (SYD) is one of the root causes of IBS-D. Fuzi-Lizhong pill (FLZP) is well known for its powerful capacity for treating SYD and has a good clinical effect on IBS-D. However, the mechanism of FLZP on the gut microbiota of IBS-D has not been fully clarified. Our present study aimed to reveal the mechanism of FLZP regulating gut microbiota of IBS-D. The body mass, CCK, MTL, and Bristol fecal character score were used to verify the establishment of the IBS-D model. IL-6, TNF, IL-1β, and IFN-γ were crucial targets screened by network pharmacology and preliminarily verified by ELISA. Eighteen gut microbiota were important for the treatment of IBS-D with FLZP. Bacteroidetes, Blautia , Turicibacter , and Ruminococcus_torques_group were the crucial gut microbiota that FLZP inhibits persistent systemic inflammation in the IBS-D model. Lactobacillus is the crucial gut microbiota that FLZP renovates intestinal immune barrier in the IBS-D model. In summary, FLZP can affect bacterial diversity and community structures in the host and regulate inflammation and immune system to treat IBS-D. [ABSTRACT FROM AUTHOR]

Valsartan has the potential to attenuate neointimal hyperplasia and to suppress the inflammatory response. This study aimed to evaluate the role of valsartan in neointimal hyperplasia and the toll-like receptor 4 (TLR4)-nitric oxide synthase (NOS) pathway in the balloon-injured rat aorta. Forty-eight Wistar rats were randomly allocated to three groups: sham control (control), balloon-injured group (surgery), and balloon-injured+valsartantreated group (valsartan). Rats were killed at 14 and 28 days after balloon-injury, and then the aortic tissues were collected for morphometric analysis as well as for measurements of the mRNA or protein expression of angiotensin II, angiotensin II type 1 (AT1) receptor, angiotensin II type 2 (AT2) receptor, TLR4, endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), serine/arginine-rich splicing factor 1(SRSF1) and extracellular signal regulated kinase (ERK). Valsartan at a dose of 20 mg/kg/day markedly decreased neointimal hyperplasia in the aorta of balloon-injured rats, and significantly reduced the mRNA or protein expression of TLR4, AT1 receptor, SRSF1 and phosphorylated-ERK (p-ERK) as well as the aortic levels of iNOS (all p<0.05). Moreover, valsartan increased the eNOS level and AT2 receptor mRNA and protein expression levels (all p<0.05). Valsartan prevented neointimal hyperplasia and inhibited SRSF1 expression and the TLR4-iNOS-ERK-AT1 receptor pathway in the balloon-injured rat aorta. [ABSTRACT FROM AUTHOR]

The Ca2(UO2)(CO3)3 complex has been shown to be the dominant species of uranyl in different aqueous environments, and thermodynamic data of the complexation have been measured accurately recently. However, a detailed understanding of the binding processes with explicit consideration of the water molecules in the presence of common salt ions such as Na+ and Cl- has been lacking. Here we use classical molecular dynamics combined with umbrella sampling to map the complete binding processes and their free-energy profiles leading to formation of the Ca2(UO2)(CO3)3 complex from UO2 2+, CO3 2-, and Ca2+ in an aqueous NaCl solution to simulate the seawater conditions. We find that the presence of Na+ ions affects the binding between UO2 2+ and CO3 2- as well as between [(UO2)(CO3)3]4- and Ca2+ by changing the coordination mode of carbonate to UO2 2+. The free energies of binding from our simulations are in good agreement with the experimental data for both pure water and the NaCl solution. Our work shows that free-energy simulations based on classical molecular dynamics simulations can be a useful tool to examine the atomistic process of the ligand binding to form the Ca2(UO2)(CO3)3 complex under different aqueous environments and that the presence of common ions can impact the complexation chemistry of uranyl. [ABSTRACT FROM AUTHOR]