GSTO1 aggravates EGFR-TKIs resistance and tumor metastasis via deglutathionylation of NPM1 in lung adenocarcinoma.

Despite significantly improved clinical outcomes in EGFR-mutant lung adenocarcinoma, all patients develop acquired resistance and malignancy on the treatment of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Understanding the resistance mechanisms is crucial to uncover novel therapeutic targets to improve the efficacy of EGFR-TKI treatment. Here, integrated analysis using RNA-Seq and shRNAs metabolic screening reveals glutathione S-transferase omega 1 (GSTO1) as one of the key metabolic enzymes that is required for EGFR-TKIs resistance in lung adenocarcinoma cells. Aberrant upregulation of GSTO1 confers EGFR-TKIs resistance and tumor metastasis in vitro and in vivo dependent on its active-site cysteine 32 (C32). Pharmacological inhibition or knockdown of GSTO1 restores sensitivity to EGFR-TKIs and synergistically enhances tumoricidal effects. Importantly, nucleophosmin 1 (NPM1) cysteine 104 is deglutathionylated by GSTO1 through its active C32 site, which leads to activation of the AKT/NF-κB signaling pathway. In addition, clinical data illustrates that GSTO1 level is positively correlated with NPM1 level, NF-κB-mediated transcriptions and progression of human lung adenocarcinoma. Overall, our study highlights a novel mechanism of GSTO1 mediating EGFR-TKIs resistance and malignant progression via protein deglutathionylation, and GSTO1/NPM1/AKT/NF-κB axis as a potential therapeutic vulnerability in lung adenocarcinoma.

X-ray Structure-Guided Discovery of a Potent Benzimidazole Glutaminyl Cyclase Inhibitor That Shows Activity in a Parkinson's Disease Mouse Model.

The secretory glutaminyl cyclase (sQC) and Golgi-resident glutaminyl cyclase (gQC) are responsible for N-terminal protein pyroglutamation and associated with various human diseases. Although several sQC/gQC inhibitors have been reported, only one inhibitor, PQ912, is currently undergoing clinic trials for the treatment of Alzheimer's disease. We report an X-ray crystal structure of sQC complexed with PQ912, revealing that the benzimidazole makes "anchor" interactions with the active site zinc ion and catalytic triad. Structure-guided design and optimization led to a series of new benzimidazole derivatives exhibiting nanomolar inhibition for both sQC and gQC. In a MPTP-induced Parkinson's disease (PD) mouse model, BI-43 manifested efficacy in mitigating locomotor deficits through reversing dopaminergic neuronal loss, reducing microglia, and decreasing levels of the sQC/gQC substrates, α-synuclein, and CCL2. This study not only offers structural basis and new leads for drug discovery targeting sQC/gQC but also provides evidence supporting sQC/gQC as potential targets for PD treatment.

Sacubitril/valsartan reversal of left ventricular remodeling is associated with improved hemodynamics in resistant hypertension.

BACKGROUND: Sacubitril/valsartan (S/V) has been shown to be an effective antihypertensive drug combination. However, its therapeutic effects on blood pressure (BP), hemodynamics, and left ventricular (LV) remodeling in resistant hypertension (RHTN) remain unclear. METHODS: Eighty-six patients completed this self-control study, during which olmesartan was administered within the first 8 weeks (phase 1), followed by S/V within the second 8 weeks (phase 2), with nifedipine and hydrochlorothiazide taken as background medications. Office BP, echocardiography, and hemodynamics assessment using impedance cardiography were performed at baseline and at the eighth and sixteenth weeks. RESULTS: The reduction in office BP was larger in phase 2 than in phase 1 (19.59/11.66 mmHg vs. 2.88/1.15 mmHg). Furthermore, the treatment in phase 2 provided greater reductions in systemic vascular resistance index (SVRI) and thoracic blood saturation ratio (TBR), with differences between the two phases of -226.59 (-1212.80 to 509.55) dyn·s/cm5/m2 and -0.02 (-0.04 to 0.02). Switching from olmesartan to S/V also significantly reduced E/E', LV mass index, LV end-diastolic volume index, and LV end-systolic volume index (all P < 0.05). Decreases in arterial stiffness, SVRI, and TBR were correlated with changes in indicators of LV remodeling (all P < 0.05). This correlation persisted even after adjusting for confounders including changes in BP. CONCLUSIONS: Switching from olmesartan to S/V effectively lowered BP and reversed ventricular remodeling in RHTN. In addition, hemodynamic improvement was also observed. Changes in hemodynamics played an important role in reversing LV remodeling of S/V, and were independent of its antihypertensive effect.

Vertical distribution of arsenic and bacterial communities in calcareous farmland amending by organic fertilizer and iron-oxidizing bacteria: Field experiment on concomitant remediation.

The migration and transformation mechanisms of arsenic (As) in soil environments necessitate an understanding of its influencing processes. Here, we investigate the subsurface biogeochemical transformation of As and iron (Fe) through amended in the top 20 cm with iron oxidizing bacteria (FeOB) and organic fertilizer (OF). Our comprehensive 400-day field study, conducted in a calcareous soil profile sectioned into 20 cm increments, involved analysis by sequential extraction and assessment of microbial properties. The results reveal that the introduction of additional OF increased the release ratio of As/Fe from the non-specific adsorption fraction (136.47 %) at the subsoil depth (40-60 cm), underscoring the importance of sampling at various depths and time points to accurately elucidate the form, instability, and migration of As within the profile. Examination of bacterial interaction networks indicated a disrupted initial niche in the bottom layer, resulting in a novel cooperative symbiosis. While the addition of FeOB did not lead to the dominance of specific bacterial species, it did enhance the relative abundance of As-tolerant Acidobacteria and Gemmatimonadetes in both surface (39.2 % and 38.76 %) and deeper soils (44.29 % and 23.73 %) compared to the control. Consequently, the amendment of FeOB in conjunction with OF facilitated the formation of poorly amorphous Fe (hydr)oxides in the soil, achieved through abiotic and biotic sequestration processes. Throughout the long-term remediation process, the migration coefficient of bioavailable As within the soil profile decreased, indicating that these practices did not exacerbate As mobilization. This study carries significant implications for enhancing biogeochemical cycling in As-contaminated Sierozem soils and exploring potential bioremediation strategies. ENVIRONMENTAL IMPLICATION: The long-term exposure of sewage irrigation has potential adverse effects on the local ecosystem, causing serious environmental problems. Microorganisms play a vital role in the migration and transformation of arsenic in calcareous soil in arid areas, which highlights the necessity of understanding its dynamics. The vertical distribution, microbial community and fate of arsenic in calcareous farmland soil profile in northwest China were studied through field experiments. The results of this work have certain significance for the remediation of arsenic-contaminated soil in arid areas, and provide new insights for the migration, transformation and remediation of arsenic in this kind of soil.

Arsenic and cadmium simultaneous immobilization in arid calcareous soil amended with iron-oxidizing bacteria and organic fertilizer.

Immobilization stands as the most widely adopted remediation technology for addressing heavy metal(loid) contamination in soil. However, it is crucial to acknowledge that this process does not eliminate pollutants; instead, it confines them, potentially leaving room for future mobilization. Presently, our comprehension of the temporal variations in the efficacy of immobilization, particularly in the context of its applicability to arid farmland, remains severely limited. To address this knowledge gap, our research delves deep into the roles of iron-oxidizing bacteria (FeOB) and organic fertilizer (OF) in the simultaneous immobilization of arsenic (As) and cadmium (Cd) in soils. We conducted laboratory incubation and field experiments to investigate these phenomena. When OF was combined with FeOB, a noteworthy transformation of available As and Cd into stable species, such as the residual state and combinations with Fe-Mn/Al oxides, was observed. This transformation coincided with changes in soil properties, including pH, Eh, soluble Fe, and dissolved organic carbon (DOC). Furthermore, we observed synergistic effects between available As and Cd when treated with bacteria and OF individually. The stabilization efficiency of As and Cd, as determined by the Toxicity Characteristic Leaching Procedure, reached its highest values at 33.39 % and 24.67 %, respectively, after 120 days. Nevertheless, the formation of iron­calcium complexes was disrupted due to pH fluctuations. Hence, long-term monitoring and model development are essential to enhance our understanding of the remediation process. The application of organic fertilizer and the use of FeOB in calcareous soil hold promise for the restoration of polluted soil and the maintenance of soil health by mitigating the instability of heavy metals(loid).

Response of trace elements in urban deposition to emissions in a northwestern river valley type city: 2010-2021.

Anthropogenic activities release significant quantities of trace elements into the atmosphere, which can infiltrate ecosystems through both wet and dry deposition, resulting in ecological harm. Although the current study focuses on the emission inventory and deposition of trace elements, their complex interactions remain insufficiently explored. In this study, we employ emission inventories and deposition data for eight TEs (Cr, Mn, Ni, Cu, Zn, As, Cd, Pb) in Lanzhou City to unveil the relationship between these two aspects. Emissions in Lanzhou can be roughly divided into two periods centered around 2017. Preceding 2017, industrial production constituted the primary source of TEs emissions except for As; coal combustion was the primary contributor to Cr, Mn, and As emissions; waste incineration played a significant role in As, Zn, and Cd emissions; biomass combustion influenced Cr and Cd emissions; and transportation sources were the predominant contributors to Pb and Cu emissions. With the establishment of waste-to-energy plants and the implementation of ultra-low emission retrofits, emissions from these sources decreased substantially after 2017. Consequently, emissions from industrial production emerged as the main source of TEs. The deposition concentrations of Cr, Mn, Ni, Cu, and Pb followed a similar trend to the emissions. However, Cd and As exhibited lower emissions and a less pronounced response relationship. Moreover, Zn concentrations fluctuated within a narrow range and showed a weaker response to emissions. The consistent changes in emissions and TEs deposition concentrations signify a shift in deposition pollution in Lanzhou city from Coal-fired pollution to that driven by transportation and industrial activities. Within this transition, the industrial production process offers significant potential for emission reduction. This insight provides a crucial foundation for managing TEs pollution and implementing strategies to prevent ecological risks.

Spatial distribution and migration of lead and zinc and the influence of parent materials in typical paddy soils of Hunan Province, China.

This study aimed to investigate the distribution and migration characteristics of lead (Pb) and zinc (Zn) in paddy soils in Hunan Province, China. A total of 343 soil samples from 63 profiles were collected from typical regions. The concentration, spatial distribution, and migration behaviors of Pb and Zn in the paddy soils were examined. The results showed that (1) the concentration ranges of Pb and Zn in the surface layer were 17.62-114.07 mg/kg and 44.98-146.84 mg/kg, respectively. (2) The content was higher in the middle and lower reaches of the Xiangjiang River basin horizontally and exhibited shallow enrichment characteristics vertically. (3) Pb migration was weaker than Zn migration, and the parent material had the most significant influence on Pb and Zn content in the bottom soil layer. The research results will clarify the characteristics of Pb and Zn contents in paddy soils in Hunan Province, further understand the horizontal distribution and vertical migration and transformation characteristics of Pb and Zn contents in paddy soils, and provide basic data for scientific rice cultivation and safe food production.

Hypertension and cystatin C account for sex differences in serum homocysteine levels in acute coronary syndrome subjects with normal serum creatinine.

BACKGROUND: Hyperhomocysteinemia is one of cardiovascular disease risk factors and fasting homocysteine levels are significantly elevated in male compared to female acute coronary syndrome (ACS) patients with normal renal function. However, it is not known the sex related determinants of plasma homocysteine levels in ACS subjects without renal dysfunction. METHODS: A total of 165 ACS participants with normal plasma creatinine who underwent coronary angiography were included in the present study. Clinical parameters, homocysteine, fasting glucose and lipid profile, hemoglobin, white blood cell, platelets, creatinine, cystatin C, blood urea nitrogen, uric acid (UA), and albumin were measured. Multivariate linear regression analyses were used to recognize the predictive factors for homocysteine. RESULTS: The levels of plasma homocysteine were significantly higher in men than in women (P < 0.0001). In males, homocysteine (log10) was positively associated with hypertension (r = 0.569, P < 0.001), creatinine (r = 0.367, P < 0.001) and cystatin C (log10) (r = 0.333, P = 0.001). In females, homocysteine (log10) was positively correlated with age (r = 0.307, P = 0.107), hypertension (r = 0.456, P < 0.001), creatinine (r = 0.341, P = 0.008), cystatin C (log10) (r = 0.429, P = 0.001) and UA (r = 0.569, P < 0.001) whereas was negatively associated with LDL-C (r = - 0.298, P = 0.021) and ApoB (r = - 0.273, P = 0.033). Parameters up to statistical significance in males or females were incorporated into the stepwise linear regression models. In men, hypertension (P < 0.001) and creatinine (P = 0.031) were independently related to homocysteine. Most of the variability of homocysteine levels in males were only determined by hypertension. In women, cystatin C (log10) (P = 0.004) and hypertension (P = 0.005) were independently related to homocysteine (log10). Plasma cystatin C had a higher explanatory value than hypertension in females. CONCLUSIONS: Hypertension and cystatin C could explain most of the sex differences in serum homocysteine levels in ACS subjects with normal serum creatinine. This finding suggested the importance of making different strategies in males and females to manage hyperhomocysteinemia effectively in ACS subjects without renal dysfunction.

Fine control for the preparation of ceria nanorods (111).

The morphologies and exposed surfaces of ceria nanocrystals are important factors in determining their performance. In order to establish a structure-property relationship for ceria nanomaterials, it is essential to have materials with well-defined morphologies and specific exposed facets. This is also crucial for acquiring high resolution 17O solid-state NMR spectra. In this study, we explore the synthesis conditions for preparing CeO2 nanorods with exposed (111) facets. The effects of alkali concentration, hydrothermal temperature and time, cerium source and oxidation agent are investigated and optimal synthesis conditions are found. The resulting CeO2 nanorods show very narrow 17O NMR peaks for the oxygen ions in the first, second and third layers, providing a foundation for future research on mechanisms involving ceria materials using 17O solid-state NMR spectroscopy.

A novel risk model of three SUMOylation genes based on RNA expression for potential prognosis and treatment sensitivity prediction in kidney cancer.

Introduction: Kidney cancer is one of the most common and lethal urological malignancies. Discovering a biomarker that can predict prognosis and potential drug treatment sensitivity is necessary for managing patients with kidney cancer. SUMOylation is a type of posttranslational modification that could impact many tumor-related pathways through the mediation of SUMOylation substrates. In addition, enzymes that participate in the process of SUMOylation can also influence tumorigenesis and development. Methods: We analyzed the clinical and molecular data which were obtanied from three databases, The Cancer Genome Atlas (TCGA), the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC), and ArrayExpress. Results: Through analysis of differentially expressed RNA based on the total TCGA-KIRC cohort, it was found that 29 SUMOylation genes were abnormally expressed, of which 17 genes were upregulated and 12 genes were downregulated in kidney cancer tissues. A SUMOylation risk model was built based on the discovery TCGA cohort and then validated successfully in the validation TCGA cohort, total TCGA cohort, CPTAC cohort, and E-TMAB-1980 cohort. Furthermore, the SUMOylation risk score was analyzed as an independent risk factor in all five cohorts, and a nomogram was constructed. Tumor tissues in different SUMOylation risk groups showed different immune statuses and varying sensitivity to the targeted drug treatment. Discussion: In conclusion, we examined the RNA expression status of SUMOylation genes in kidney cancer tissues and developed and validated a prognostic model for predicting kidney cancer outcomes using three databases and five cohorts. Furthermore, the SUMOylation model can serve as a biomarker for selecting appropriate therapeutic drugs for kidney cancer patients based on their RNA expression.

Remediation of arsenic-contaminated calcareous agricultural soils by iron-oxidizing bacteria combined with organic fertilizer.

In arid soil with low-iron and high-calcium carbonate contents, the fate of arsenic (As) is mainly controlled by the contents of calcium and organic matter in the soil. However, there is still a lack of knowledge about their interaction and that effect on their absorption by maize. The purpose of this study was to explore the long-term immobilization and repair mechanism of in situ As-contaminated farmland. We designed three treatments: iron-oxidizing bacteria (FeOB), organic fertilizer, FeOB and organic fertilizer added in combination. After 140-day field farmland remediation trial, the results showed that the FeOB can effectively immobilize the water-soluble As (FS1) in soil, and the organic fertilizer promoted the remediation of FeOB. In addition, the content of As in maize grains was reduced after treatment by FeOB and organic fertilizer. The XRD and XPS analysis of the topsoil showed that the combined treatment of FeOB and organic fertilizer promoted the formation of calcium arsenate mineral with low solubility and high stability; As(III) would gradually transform into As(V). The biological iron (hydr)oxide can increase the contents of Fe and As in the rhizosphere and form iron plaques on the surface of the roots by SEM-EDS analysis of maize root. Collectively, these results clarify the main biogeochemical ways to control the fate of As in calcareous soils with low-iron and low-organic matter contents and provide a basis for in situ remediation of As.

A phosphoglycerate mutase 1 allosteric inhibitor overcomes drug resistance to EGFR-targeted therapy via disrupting IL-6/JAK2/STAT3 signaling pathway in lung adenocarcinoma.

Resistance to epidermal growth factor receptor (EGFR) inhibitors, from the first-generation erlotinib to the third generation osimertinib, is a clinical challenge in the treatment of patients with EGFR-mutant lung adenocarcinoma. Our previous work found that a novel allosteric inhibitor of phosphoglycerate mutase 1 (PGAM1), HKB99, restrains erlotinib resistance in lung adenocarcinoma cells. However, the role of HKB99 in osimertinib resistance and its underlying molecular mechanism remains to be elucidated. Herein, we found that IL-6/JAK2/STAT3 signaling pathway is aberrantly activated in both erlotinib and osimertinib resistant cells. Importantly, HKB99 significantly blocks the interaction of PGAM1 with JAK2 and STAT3 via the allosteric sites of PGAM1, which leads to inactivation of JAK2/STAT3 and thereby disrupts IL-6/JAK2/STAT3 signaling pathway. Consequently, HKB99 remarkably restores EGFR inhibitor sensitivity and exerts synergistic tumoricidal effect. Additionally, HKB99 alone or in combination with osimertinib down-regulated the level of p-STAT3 in xenograft tumor models. Collectively, this study identifies PGAM1 as a key regulator in IL-6/JAK2/STAT3 axis in the development of resistance to EGFR inhibitors, which could serve as a therapeutic target in lung adenocarcinoma with acquired resistance to EGFR inhibitors.

New ε-N-thioglutaryl-lysine derivatives as SIRT5 inhibitors: Chemical synthesis, kinetic and crystallographic studies.

SIRT5 has been implicated in various physiological processes and human diseases, including cancer. Development of new highly potent, selective SIRT5 inhibitors is still needed to investigate disease-related mechanisms and therapeutic potentials. We here report new ε-N-thioglutaryllysine derivatives, which were designed according to SIRT5-catalysed deacylation reactions. These ε-N-thioglutaryllysine derivatives displayed potent SIRT5 inhibition, of which the potential photo-crosslinking derivative 8 manifested most potent inhibition with an IC50 value of 120 nM to SIRT5, and low inhibition to SIRT1-3 and SIRT6. The enzyme kinetic assays revealed that the ε-N-thioglutaryllysine derivatives inhibit SIRT5 by lysine-substrate competitive manner. Co-crystallographic analyses demonstrated that 8 binds to occupy the lysine-substate binding site by making hydrogen-bonding and electrostatic interactions with SIRT5-specific residues, and is likely positioned to react with NAD+ and form stable thio-intermediates. Compound 8 was observed to have low photo-crosslinking probability to SIRT5, possibly due to inappropriate position of the diazirine group as observed in SIRT5:8 crystal structure. This study provides useful information for developing drug-like inhibitors and cross-linking chemical probes for SIRT5-related studies.

Temporal distribution and accumulation pattern of cadmium and arsenic in the actual field calcareous soil-maize system, northwest China.

The contrasting chemical behaviors of two toxic elements, arsenic (As) and cadmium (Cd) in co-contamination calcareous soil and its absorption by crops have not been thoroughly explored, especially in the implementation of the measure of prohibiting the use of wastewater to irrigate farmland. We propose that the present environmental characteristics of ecologically fragile areas and appropriate restoration measures are critical determinant of soil remediation. In this study, the typical field farmland irrigated by industrial and domestic wastewater in the Chinese Loess Plateau for >50 years was selected. The results showed that after the sewage irrigation was stopped, the mean contents of Cd (7.09 mg/kg) and As (13.47 mg/kg) in the soil were still rising, which might be a potential input source. The average values of soil risk indices such as the potential ecological risk (PERI = 2394), pollution load index (PLI > 4 for 60 % of studied samples), and degree of contamination (Dc = 86.6) showed severe soil pollution in the study area. The decrease of soil pH, the loss of soil texture and calcium carbonate were found to be the reasons for the high chemical activity of Cd. The bioconcentration factors (< 0.2) and translocation factor (> 1.0) of Cd indicate that corn is an excluder plant and an ideal phytoremediation method. Thus, 20 % of studied samples were higher than maximum permitted levels of Cd in grain, indicating potential related health hazards. On the contrary, As was mainly adsorbed in calcareous soil, and its bioavailability was lower compared with Cd. The difference between DTPA extraction and sequential extraction may be due to the transformation of chemical forms, resulting in unstable fractions increased the bioavailability of toxic elements. Overall, the findings provide new insights for solutions to manage and repair farmlands under the post-wastewater irrigation period.

Molecular Dynamics Simulation Analysis of Damage and Expansion Process of Nanoindentation Single-Crystal 3C-SiC Carbide Specimens at Different Temperature.

The molecular dynamics method was used to analyze the influence of simulated temperature on the damage expansion process of the 3C-SiC sample under nano-indentation loading in order to study the influence of temperature on the internal damage and expansion mechanism of the 3C-SiC single crystal sample further during the nano-indentation loading process. A simulation test platform for diamond indenter indentation was established. The process of stress and strain distribution, dislocation evolution, dislocation expansion and potential energy change were analyzed, combined with the radial distribution function and load displacement curve. The influence of temperature on the 3C-SiC material was discussed. The variation trend of the potential energy-step curve is basically the same at the temperatures of 0 K, 300 K, 600 K and 900 K. The difference in strain distribution was characterized by the influence of temperature on stress intensity, expansion direction and type. The microcosmic manifestation is the significant difference in the dislocation slip at low temperature. In the process of dislocation evolution and expansion, dislocation climbs at room temperature and increases at high temperature, which is closely related to energy release. This study has certain guiding significance for investigating the internal damage difference and temperature effect of the 3C-SiC sample.

Enhanced external counterpulsation ameliorates endothelial dysfunction and elevates exercise tolerance in patients with coronary artery disease.

Purpose: Enhanced external counterpulsation (EECP) is a new non-drug treatment for coronary artery disease (CAD). However, the long-term effect of EECP on endothelial dysfunction and exercise tolerance, and the relationship between the changes in the endothelial dysfunction and exercise tolerance in the patients with coronary heart disease are still unclear. Methods: A total of 240 patients with CAD were randomly divided into EECP group (n = 120) and control group (n = 120). All patients received routine treatment of CAD as the basic therapy. Patients in the EECP group received 35 1-h daily sessions of EECP during 7 consecutive weeks while the control group received the same treatment course, but the cuff inflation pressure was 0-10 mmHg. Peak systolic velocity (PSV), end diastolic velocity (EDV), resistance index (RI), and inner diameter (ID) of the right carotid artery were examined using a Color Doppler Ultrasound and used to calculate the fluid shear stress (FSS). Serum levels of human vascular endothelial cell growth factor (VEGF), vascular endothelial cell growth factor receptor 2 (VEGFR2), and human angiotensin 2 (Ang2) were determined by enzyme-linked immunosorbent assay (ELISA). Exercise load time, maximal oxygen uptake (VO2max ), metabolic equivalent (METs), anaerobic threshold (AT), peak oxygen pulse (VO2max/HR) were assessed using cardiopulmonary exercise tests. Results: After 1 year follow-up, the EDV, PSV, ID, and FSS were significantly increased in the EECP group (P < 0.05 and 0.01, respectively), whereas there were no significant changes in these parameters in the control group. The serum levels of VEGF and VEGFR2 were elevated in the EECP and control groups (all P < 0.05). However, the changes in VEGF and VEGFR2 were significantly higher in the EECP group than in the control group (P < 0.01). The serum level of Ang2 was decreased in the EECP group (P < 0.05) and no obvious changes in the control group. As for exercise tolerance of patients, there were significant increases in the exercise load time, VO2max, VO2max/HR, AT and METs in the EECP group (all P < 0.05) and VO2max and METs in the control group (all P < 0.05). Correlation analyses showed a significant and positive correlations of VEGF and VEGFR2 levels with the changes in FSS (all P < 0.001). The correlations were still remained even after adjustment for confounders (all Padjustment < 0.001). Linear regression displays the age, the medication of ACEI (angiotensin-converting enzyme inhibitors) or ARB (angiotensin receptor blockers), the diabetes and the changes in VEGF and VEGFR2 were positively and independently associated with the changes in METs after adjustment for confounders (all Padjustment < 0.05). Conclusion: The data of our study suggested that EECP is a useful therapeutic measurement for amelioration of endothelial dysfunction and long-term elevation of exercise tolerance for patients with coronary heart disease. Clinical trial registration: [http://www.chictr.org.cn/], identifier [ChiCTR1800020102].

Unveiling the Surface Structure of ZnO Nanorods and H2 Activation Mechanisms with 17O NMR Spectroscopy.

ZnO plays a very important role in many catalytic processes involving H2, yet the details on their interactions and H2 activation mechanism are still missing, owing to the lack of a characterization method that provides resolution at the atomic scale and follows the fate of oxide surface species. Here, we apply 17O solid-state NMR spectroscopy in combination with DFT calculations to unravel the surface structure of ZnO nanorods and explore the H2 activation process. We show that six different types of oxygen ions in the surface and subsurface of ZnO can be distinguished. H2 undergoes heterolytic dissociation on three-coordinated surface zinc and oxygen ions, while the formed hydride species migrate to nearby oxygen species, generating a second hydroxyl site. When oxygen vacancies are present, homolytic dissociation of H2 occurs and zinc hydride species form from the vacancies. Reaction mechanisms on oxide surfaces can be explored in a similar manner.

Insights into memory effect mechanisms of layered double hydroxides with solid-state NMR spectroscopy.

Layered double oxides (LDOs) can restore the parent layered double hydroxides (LDHs) structure under hydrous conditions, and this "memory effect" plays a critical role in the applications of LDHs, yet the detailed mechanism is still under debate. Here, we apply a strategy based on ex situ and in situ solid-state NMR spectroscopy to monitor the Mg/Al-LDO structure changes during recovery at the atomic scale. Despite the common belief that aqueous solution is required, we discover that the structure recovery can occur in a virtually solid-state process. Local structural information obtained with NMR spectroscopy shows that the recovery in aqueous solution follows dissolution-recrystallization mechanism, while the solid-state recovery is retro-topotactic, indicating a true "memory effect". The amount of water is key in determining the interactions of water with oxides, thus the memory effect mechanism. The results also provide a more environmentally friendly and economically feasible LDHs preparation route.

Metabolic and Nonmetabolic Functions of PSAT1 Coordinate Signaling Cascades to Confer EGFR Inhibitor Resistance and Drive Progression in Lung Adenocarcinoma.

Emerging evidence demonstrates that the dysregulated metabolic enzymes can accelerate tumorigenesis and progression via both metabolic and nonmetabolic functions. Further elucidation of the role of metabolic enzymes in EGFR inhibitor resistance and metastasis, two of the leading causes of death in lung adenocarcinoma, could help improve patient outcomes. Here, we found that aberrant upregulation of phosphoserine aminotransferase 1 (PSAT1) confers erlotinib resistance and tumor metastasis in lung adenocarcinoma. Depletion of PSAT1 restored sensitivity to erlotinib and synergistically augmented the tumoricidal effect. Mechanistically, inhibition of PSAT1 activated the ROS-dependent JNK/c-Jun pathway to induce cell apoptosis. In addition, PSAT1 interacted with IQGAP1, subsequently activating STAT3-mediated cell migration independent of its metabolic activity. Clinical analyses showed that PSAT1 expression positively correlated with the progression of human lung adenocarcinoma. Collectively, these findings reveal the multifunctionality of PSAT1 in promoting tumor malignancy through its metabolic and nonmetabolic activities. SIGNIFICANCE: Metabolic and nonmetabolic functions of PSAT1 confer EGFR inhibitor resistance and promote metastasis in lung adenocarcinoma, suggesting therapeutic targeting of PSAT1 may attenuate the malignant features of lung cancer.

The role of Fe-oxidizing bacteria (FeOB) and organic matters in As removal in the heavy-polluted arid soil.

The bio-remediation of As-polluted farmlands in the arid area is seldomly reported. This study aimed at understanding the impact of DOM, Fe-oxides, and FeOB biogeochemical processes on As remediation. The approaches used included: FeOB strain Pseudomonas flavescens LZU-3; Batch-experiment. Our results showed that all FeOB tested effectively immobilized As (>95%) during microbial mineralization; DOM play an important role in the reduction of Fe(III)(hydr)oxides and As(V); Less-crystallized ferrihydrite transform to more-crystallized goethite and secondary minerals; Under the reaction of FeOB and DOM, the As-Fe-OM ternary compound were formed, containing N, S, C and O functional group; The addition of OM can clearly reduce soil Eh, promoting dissolution of As in bound to iron oxides, co-precipitation of the amorphous iron oxide in Fe(III)-OM-FeOB, closely related to As in bound to insoluble organics and sulfides and mineral residues, which plays an important role in controlling the mobilization of As. This study provides controlling of As transportation and transformation in the As-DOM-Bio-Fe ternary system as As-remediation technology in the arid soil.