Modeling of phosphate speciation on goethite surface: Effects of humic acid.

Iron (hydr)oxides and humic acid (HA) are important active components in soils and usually coexist in the environment. The effects of HA on the adsorption and subsequent immobilization of phosphate on iron (hydr)oxide surface are of great importance in studies of soil fertility and eutrophication. In this study, two types of goethite with different particle sizes were prepared to investigate the phosphate adsorption behaviors and complexation mechanisms in the absence or presence of HA by combining multiple characterization and modeling studies. The adsorption capacity of micro- (M-Goe) and nano-sized goethite (N-Goe) for phosphate was 2.02 and 2.04 µmol/m2, which decreased by ∼25% and ∼45% in the presence of 100 and 200 mg/L HA, respectively. Moreover, an increase in equilibrium phosphate concentration significantly decreased the adsorption amount of goethite for HA. Charge distribution-multisite surface complexation (CD-MUSIC) and natural organic matter-charge distribution (NOM-CD) modeling identified five phosphate complexes and their corresponding affinity constants (logKP). Among these phosphate complexes, FeOPO2OH, (FeO)2PO2, and (FeO)2POOH species were predominant complexes on the surface of both M-Goe and N-Goe across a wide range of pH and initial phosphate concentrations. The presence of HA had little effect on the coordination mode and logKP of phosphate on goethite surface. These results and the obtained model parameters shed new lights on the interfacial reactivity of phosphate at the goethite-water interface in the presence of HA, and may facilitate further prediction of the environmental fate of phosphate in soils and sediments.

[Corrigendum] MicroRNA­222­3p promotes tumor cell migration and invasion and inhibits apoptosis, and is correlated with an unfavorable prognosis of patients with renal cell carcinoma.

Following the publication of the above article, an interested reader drew to the attention of the Editorial Office that, in Fig. 3A on p. 530, two pairs of data panels were overlapping, such that certain of the panels appeared to have been derived from the same original sources where the results from differently performed experiments were intended to have been portrayed. The authors have examined their original data, and realize that errors associated with data handling/labelling during the preparation of the representative images in Fig. 3A had occurred. The revised version of Fig. 3, showing the correct data for the 'NC/ACHN/Invasion and Migration' data panels, the 'Inhibitor NC/786­O' panel and the 'Inhibitor NC/ACHN/Invasion' panel, is shown on the next page. The authors can confirm that the errors associated with this figure did not have any significant impact on either the results or the conclusions reported in this study, and all the authors agree with the publication of this Corrigendum. The authors are grateful to the Editor of International Journal of Molecular Medicine for giving them the opportunity to publish this Corrigendum; furthermore, they apologize to the readership of the Journal for any inconvenience caused. [International Journal of Molecular Medicine 43: 525­534, 2019; DOI: 10.3892/ijmm.2018.3931].

Erratum: [Corrigendum] miR­216a­5p acts as an oncogene in renal cell carcinoma.

[This corrects the article DOI: 10.3892/etm.2018.5881.].

[Corrigendum] microRNA­181a­5p functions as an oncogene in renal cell carcinoma.

Following the publication of the above article and a corrigendum in 2018 that corrected details of the correspondence information for authors, errors made in Fig. 5 and the funding details (doi: 10.3892/mmr.2018.9117), an interested reader drew to the authors' attention that, in Fig. 6 on p. 8515 showing the results of cell migration and invasion assay experiments, a pair of data panels were overlapping, such that data which were intended to show the results from differently performed experiments appeared to have been derived from the same original source. After having consulted their original data, the authors have realized that Fig. 6 was assembled incorrectly, The revised version of Fig. 6, now showing the correct data for the 'ACHN/migratory/NC' experiment, is shown on the next page. Note that all the authors approve of the publication of this corrigendum, and the authors are grateful to the Editor of Molecular Medicine Reports for granting them the opportunity to publish this. The authors regret their oversight in allowing this error to be included in the paper, and also apologize to the readership for any inconvenience caused. [Molecular Medicine Reports 17: 8510­8517, 2018; DOI: 10.3892/mmr.2018.8899].

Erratum: [Corrigendum] miR­199b­5p serves as a tumor suppressor in renal cell carcinoma.

[This corrects the article DOI: 10.3892/etm.2018.6151.].

Myeloid-derived growth factor and its effects on cardiovascular and metabolic diseases.

Myeloid-derived growth factor (MYDGF) is a paracrine protein produced by bone marrow-derived monocytes and macrophages. Current research shows that it has protective effects on the cardiovascular system, such as repairing heart tissue after myocardial infarction, enhancing cardiomyocyte proliferation, improving cardiac regeneration after myocardial injury, regulating proliferation and survival of endothelial cells, reducing endothelial cell damage, resisting pressure overload-induced heart failure, as well as protecting against atherosclerosis. Furthermore, regarding the metabolic diseases, MYDGF has effects of improving type 2 diabetes mellitus, relieving non-alcoholic fatty liver disease, alleviating glomerular diseases, and resisting osteoporosis. Herein, we will discuss the biology of MYDGF and its effects on cardiovascular and metabolic diseases.

Selective uneven enrichment of soil organic carbon among different-sized sediments under a rain-induced overland flow: 13C stable isotope evidence.

Soil organic carbon (SOC) enrichment varies among sediments of different sizes during rain-induced overland flow erosion. This selective transport of SOC is complex in conjunction with the exposure of labile and stable organic carbon (OC), accompanied by heterogeneous aggregate disintegration under raindrop effects. Utilizing the variations in δ13C values of SOC fractions, we traced this selective transport, linking it to aggregate-wrapped SOC changes during erosion. A modified soil pan facilitated the simultaneous monitoring of splash and sheet erosion via artificially simulated rainfall, with control over the intensity and slope. Aggregate composition, SOC distribution, and δ13C values in the erosion samples were analyzed. The results indicated that distinct sorting existed within the aggregate fragments. Along with SOC variation among different sediment sizes, the proportions of clay and fine silt within sediment aggregates increased as a function of slope and rainfall intensity, whereas particulate OC within aggregates decreased. The SOC enrichment ratios (ERocs) and δ13C values in splash-eroded sediments were positively correlated with those in sheet-eroded sediments. The ERocs in splash-eroded sediments were lower than those in sheet-eroded sediments, but δ13C values were the opposite. Moreover, δ13C values of SOC enriched in sediment particles of all sizes from aggregate stripping were lower than those of the original soil. This indicates that raindrop hits promote heavy C loss during sheet erosion, which is different for mineral-associated and particulate OC. As the slope and rainfall intensity increased, δ13C values for all sediment sizes decreased over the course of erosion. Interestingly, the highest δ13C values were observed under a rainfall intensity of 60 mm h-1, whereas the highest SOC concentrations were noted on a 5° slope. These observations suggest divergent mechanisms affect δ13C values and SOC concentrations in eroded sediments. All these results verified that selective sorting existed for the light SOC fraction. Finally, the internal selective transport of one SOC fraction may explain the enhanced mineralization and reaggregation capacity of the deposited sediments.

Continuous intrafemoral artery infusion of urokinase improves diabetic foot ulcers healing and decreases cardiovascular events in a long-term follow-up study.

INTRODUCTION: Diabetic foot ulcer (DFU) is a disabling complication of diabetes mellitus. Here, we attempted to assess whether long-term intrafemoral artery infusion of low-dose urokinase therapy improved DFUs and decreased cardiovascular events in patients with DFUs. RESEARCH DESIGN AND METHODS: This trial was a single-center, randomized, parallel study. A total of 195 patients with DFU were randomized to continuous intrafemoral thrombolysis or conventional therapy groups. The continuous intrafemoral thrombolysis group received continuous intrafemoral urokinase injection for 7 days, and conventional therapy just received wound debridement and dressing change. Then, a follow-up of average 6.5 years was performed. RESULTS: Compared with conventional therapy, at the first 1 month of intervention stage, the ulcers achieved a significant improvement in continuous intrafemoral thrombolysis group including a complete closure (72.4% vs 17.5%), an improved ulcer (27.6% vs 25.8%), unchanged or impaired ulcer (0% vs 56.7%). During the 6.5-year follow-up, for the primary outcome of ulcer closure rate, continuous intrafemoral thrombolysis therapy obtained a better complete healing rate (HR 3.42 (95% CI 2.35 to 4.98, p<0.0001)). For the secondary outcome of cardiovascular disease events, continuous intrafemoral thrombolysis therapy had a lower incidence of cardiovascular events (HR 0.50 (95% CI 0.34 to 0.74, p<0.0001)). Importantly, intrafemoral thrombolysis therapy decreased the incidence of cardiovascular death (HR 0.42 (95%CI 0.20 to 0.89, p=0.0241)). Additionally, continuous intrafemoral thrombolysis therapy improved local skin oxygenation and peripheral neuropathy as well as glycolipid metabolic profiles when compared with conventional therapy group (p<0.05). CONCLUSIONS: Continuous intrafemoral thrombolysis therapy has a better therapeutic efficacy to improve DFUs and decrease cardiovascular events. TRIAL REGISTRATION NUMBER: NCT01108120.

Face-dependent phosphate speciation on goethite: CD-MUSIC modeling and ATR-FTIR/2D-COS study.

Understanding the face-dependent phosphate adsorption mechanisms and their variations with environmental conditions is of great significance for revealing phosphate adsorption mechanisms on various goethites and predicting phosphorus speciation in iron-rich soils. In this study, micro- (MicroGoe) and nano-sized goethite (NanoGoe) were synthesized and used to investigate the face-dependent adsorption behaviors of proton and phosphate on goethite by combining the charge distribution-multisite surface complexation (CD-MUSIC) model and attenuated total reflectance Fourier transform infrared (ATR-FTIR). The results demonstrated that MicroGoe had a higher charge density and phosphate adsorption capacity than NanoGoe, which could be attributed to the higher site density of ≡FeOH-0.5 and inner-layer capacitance arising from a higher proportion of capping face and rougher surface of MicroGoe. The logKH of ≡FeOH-0.5 on the main and capping face was 8.2 and 8.9, respectively. Three types of monodentate mononuclear phosphate complexes in different protonated states were identified, along with the non-protonated bidentate complex. Protonated monodentate complexes were formed at relatively low pH and high surface loadings, whereas non-protonated complexes were the predominant species at intermediate to high pH. MicroGoe had a higher percentage of monodentate complexes than NanoGoe, and both goethites had considerably lower phosphate adsorption on the capping face than on the main face. The results provide valuable insights into the interfacial reactivity of goethite prepared with various methods and facilitate further prediction of phosphorus speciation and availability in iron-rich soils.

Cytokeratin 7 Expression and Mismatch Repair Status for Survival Prediction in Patients With Low Rectal Cancer After Neoadjuvant Therapy.

BACKGROUND: More than half of the patients with locally advanced low rectal cancer exhibit no or minor response to nCRT. It is important to investigate the predictive and prognostic values of potential biomarkers in patients with locally advanced low rectal cancer receiving nCRT. MATERIALS AND METHODS: This retrospective study included 162 patients with locally advanced low rectal cancer who underwent nCRT, followed by total mesorectal excision (TME) between 2016 and 2019. Cytokeratin 7 (CK7) expression and mismatch repair (MMR) status were determined by immunohistochemistry (IHC). Categorical variables were compared using the chi-square test. Overall survival (OS) and disease-free survival (DFS) curves were estimated using the Kaplan-Meier and Cox methods. RESULTS: There were predominance significant differences in distance from anus margin (P < .0001) and circumferential extent of the tumor (P < .0001).CK7 positive expression was detected in 21 of the 162 patients (13%). The univariate and multivariate analysis revealed that patients whose tumors had CK7 positive expression had significantly shorter OS (HR = 3.878, P = .038; HR = 1.677, P = .035) and DFS (HR = 3.055, P = .027;HR = 3.569, P = .038) than those with CK7 negative expression. While patients with CK7 positive expression had a higher proportion of worse TRG compared with CK7 negative patients (P = .001). Patients with deficient mismatch repair (dMMR) just occupied a small proportion (8.6%), but there was still a close connection between the MMR status and recurrence after TME (P = .045). MMR status was an independent risk factor affecting the OS (HR = .307, P < .0001; HR = .123, P < .0001) and DFS (HR = .288, P < .0001; HR = .286, P < .0001) by univariate and multivariate analysis. But no significant difference in the proportion of TRG was observed between patients with dMMR and pMMR (P = .920). CONCLUSIONS: The result confirms negative prognostic role of CK7-positive and dMMR statuses, which have potential predictive value for neoadjuvant chemoradiotherapy response. This provides opportunity to modify individualized treatment strategies for patients with different CK7 expression levels and dMMR statuses.

Inflammatory Cell-Derived MYDGF Attenuates Endothelial LDL Transcytosis to Protect Against Atherogenesis.

BACKGROUND: Inflammation contributes to the pathogenesis of atherosclerosis. But little is known about the potential benefits of inflammatory cells to atherosclerosis. The aim of this study was to investigate the function of inflammatory cells/endothelium axis and determine whether and how inflammatory cell-derived MYDGF (myeloid-derived growth factor) inhibited endothelial LDL (low-density lipoprotein) transcytosis. METHODS: In in vivo experiments, both loss- and gain-of-function strategies were used to evaluate the effect of inflammatory cell-derived MYDGF on LDL transcytosis. We generated monocyte/macrophage-targeted MYDGF-null mice on an Ldlr (LDL receptor)-/- background in the loss-of-function strategy and restored the inflammatory cell-derived MYDGF by bone marrow transplantation and inflammatory cell-specific overexpression of MYDGF mice model in the gain-of-function strategy. In in vitro experiments, coculture experiments between primary mouse aortic endothelial cells and macrophages and mouse aortic endothelial cells supplemented with or without recombinant MYDGF were conducted. RESULTS: Inflammatory cell-derived MYDGF deficiency aggravated endothelial LDL transcytosis, drove LDL uptake by artery wall, and thus exacerbated atherosclerosis in vivo. Inflammatory cell-derived MYDGF restoration by bone marrow transplantation and inflammatory cell MYDGF overexpression alleviated LDL transport across the endothelium, prevented LDL accumulation in the subendothelial space, and subsequently ameliorated atherosclerosis in vivo. Furthermore, in the in vitro study, macrophages isolated from MYDGF+/+ mice and recombinant MYDGF attenuated LDL transcytosis and uptake in mouse aortic endothelial cells. Mechanistically, MYDGF inhibited MAP4K4 (mitogen-activated protein kinase kinase kinase kinase isoform 4) phosphorylation, enhanced activation of Akt (protein kinase B)-1, and diminished the FoxO (forkhead box O) 3a signaling cascade to exert protective effects of MYDGF on LDL transcytosis and atherosclerosis. CONCLUSIONS: The findings support a role for inflammatory cell-derived MYDGF served as a cross talk factor between inflammatory cells and endothelial cells that inhibits LDL transcytosis across endothelium. MYDGF may become a novel therapeutic drug for atherosclerosis, and the beneficial effects of inflammatory cell in atherosclerosis deserve further attention.

Anti-PD-1/Her2 Bispecific Antibody IBI315 Enhances the Treatment Effect of Her2-Positive Gastric Cancer through Gasdermin B-Cleavage Induced Pyroptosis.

The majority of patients with human epidermal growth factor receptor 2 (Her2)-positive gastric cancer develop refractory to Her2-targeted therapy, where upregulation of immune checkpoints plays an essential role. Herein, a recombinant fully human IgG1 bispecific antibody IBI315 targeting both PD-1 and Her2 is developed  and its antitumor efficacy as well as the underlying mechanism is investigated. IBI315 crosslinks the physical interaction between Her2-positive tumor cells and PD-1-positive T cells, resulting in significantly enhanced antitumor effects compared to each parent antibody or their combination, both in vitro and in vivo mouse tumor models reconstituted with human immune cells using patient-derived xenografts and organoids. Moreover, IBI315 treatment also induces the recruitment and activation of immune cells in tumors. Mechanistically, IBI315 triggers gasdermin B (GSDMB)-mediated pyroptosis in tumor cells, leading to the activation and recruiments of T cells. The activated T cells secret IFNγ, enhancing GSDMB expression and establishing a positive feedback loop of T cell activation and tumor cell killing. Notably, GSDMB is found to be elevated in Her2-positive gastric cancer cells, providing a rationale for IBI315's efficacy. IBI315 is supported here as a promising bispecific antibody-based immunotherapy approach for Her2-positive gastric cancer in preclinical studies, broadening the therapeutic landscape of this patient population.

IL-2Rα-biased agonist enhances antitumor immunity by invigorating tumor-infiltrating CD25+CD8+ T cells.

To avoid regulatory T cell promotion and vascular toxicity, the interleukin-2 receptor-ß/interleukin-2 receptor-γ (IL-2Rßγ)-biased approach is used by most IL-2 analogs in immuno-oncology. However, recent clinical disappointments in these IL-2 agonists have questioned this strategy. Here we show that both wild-type (IL-2wt) and IL-2Rßγ-attenuated (IL-2α-bias) agonists that preserve IL-2Rα (CD25) activities can effectively expand tumor-specific CD8+ T cells (TSTs) and exhibit better antitumor efficacy and safety than the 'non-α' counterpart (IL-2nα). Mechanistically, TSTs coexpress elevated CD25 and PD-1 and are more susceptible to stimulation by IL-2Rα-proficient agonists. Moreover, the antitumor efficacy of anti-PD-1 depends on activation of PD-1+CD25+ TSTs through autocrine IL-2-CD25 signaling. In individuals with cancer, a low IL-2 signature correlates with non-responsiveness to anti-PD-1 treatment. In mouse models, IL-2α-bias, but not IL-2nα, restores the IL-2 signature and synergizes with anti-PD-1 to eradicate large established tumors. These findings underscore the indispensable function of CD25 in IL-2-based immunotherapy and provide rationales for evaluating IL-2Rα-biased agonists in individuals with cancer.

Adsorption behavior of soil fulvic acid on crystal faces of kaolinite and goethite: Described by CD-MUSIC model.

The interaction between organic matter (OM) and minerals has significant impacts on the mineralization process and rate of OM, and can protect part of organic carbon in soils. In this study, the complex species of fulvic acid (FA) on the surface of minerals (kaolinite and goethite) and the corresponding thermodynamic characteristics were investigated with the CD-MUSIC model and isothermal titration calorimetry. With increasing pH, the adsorption of kaolinite for FA increased at pH < 5.5 and decreased at pH > 5.5, which might be due to the binding of carboxyl groups of FA onto the positively charged sites of O-face and edge-face. However, that of goethite consistently decreased with increasing pH from 3.5 to 9.0 due to an increase in electrostatic repulsion. The fraction of FA was mainly adsorbed on the edge-face and O-face to form inner sphere complexes on kaolinite and outer sphere complexes on goethite. Molar adsorption enthalpies indicated that FA was adsorbed through two site types on kaolinite, while that was one site type on goethite. In addition, the molar enthalpy was more closely associated with inner sphere complexation for kaolinite, while with outer sphere complexation for goethite. The findings shed new light on the adsorption behavior and complexation mechanism of OM on the crystal faces of mineral-water interface.

Best-corrected visual acuity results facilitate molecular diagnosis of infantile nystagmus patients harboring FRMD7 mutations.

The visual function of patients with infantile nystagmus (IN) can be significantly decreased owing to constant eye movement. While, reaching a definitive diagnosis becomes a challenge due to genetic heterozygous of this disease. To address it, we investigated whether best-corrected visual acuity (BCVA) results can facilitate the molecular diagnosis of IN patients harboring FRMD7 mutations. 200 patients with IN from 55 families and 133 sporadic cases were enrolled. Mutations were comprehensively screened by direct sequencing using gene-specific primers for FRMD7. We also retrieved related literature to verify the results based on our data. We found that the BCVA of patients with IN harboring FRMD7 mutations was between 0.5 and 0.7, which was confirmed by data retrieved from the literature. Our results showed that BCVA results facilitate the molecular diagnosis of patients with IN harboring FRMD7 mutations. In addition, we identified 31 FRMD7 mutations from the patients, including six novel mutations, namely, frameshift mutation c.1492_1493insT (p.Y498LfsTer14), splice-site mutation c.353C > G, three missense mutations [c.208C > G (p.P70A), c.234G > A (p.M78I), and c.1109G > A (p.H370R)], and nonsense mutation c.1195G > T (p.E399Ter). This study demonstrates that BCVA results may facilitate the molecular diagnosis of IN patients harboring FRMD7 mutations.

Contamination and source apportionment of metals in urban road dust (Jinan, China) integrating the enrichment factor, receptor models (FA-NNC and PMF), local Moran's index, Pb isotopes and source-oriented health risk.

Contamination and source identifications of metals in urban road dust are critical for remediation and health protection. Receptor models are commonly used for metal source identification, whereas the results are usually subjective and not verified by other indicators. Here we present and discuss a comprehensive approach to study metal contamination and sources in urban road dust (Jinan) in spring and winter by integrating the enrichment factor (EF), receptor models (positive matrix factorization (PMF) and factor analysis with nonnegative constraints (FA-NNC)), local Moran's index, traffic factors and Pb isotopes. Cadmium, Cr, Cu, Pb, Sb, Sn and Zn were the main contaminants, with mean EFs of 2.0-7.1. The EFs were 1.0-1.6 times higher in winter than in spring but exhibited similar spatial trends. Chromium contamination hotspots occurred in the northern area, with other metal contamination hotspots in the central, southeastern and eastern areas. The FA-NNC results indicated Cr contamination primarily resulting from industrial sources and other metal contamination primarily originating from traffic emissions during the two seasons. Coal burning emissions also contributed to Cd, Pb and Zn contamination in winter. FA-NNC model-identified metal sources were verified via traffic factors, atmospheric monitoring and Pb isotopes. The PMF model failed to differentiate Cr contamination from other detrital metals and the above anthropogenic sources, largely due to the model grouping metals by emphasizing hotspots. Considering the FA-NNC results, industrial and traffic sources accounted for 28.5 % (23.3 %) and 44.7 % (28.4 %), respectively, of the metal concentrations in spring (winter), and coal burning emissions contributed 34.3 % in winter. Industrial emissions primarily contributed to the health risks of metals due to the high Cr loading factor, but traffic emissions dominated metal contamination. Through Monte Carlo simulations, Cr had 4.8 % and 0.4 % possibilities posing noncarcinogenic and 18.8 % and 8.2 % possibilities posing carcinogenic risks for children in spring and winter, respectively.

Diagnostic Value of the Combined Measurement of Serum HCY and NRG4 in Type 2 Diabetes Mellitus with Early Complicating Diabetic Nephropathy.

PURPOSE: This study aimed to investigate the value of combined detection of HCY and NRG4 in the diagnosis of early diabetic kidney disease (DKD) and to explore the association between the ratio of HCY/NRG4 and DKD. METHODS: A total of 140 diabetic patients and 43 healthy people were prospectively enrolled. The plasma HCY level, NRG4 level and HCY/NRG4 of them were measured to compare their differences and analyze the correlation with DKD. The independent influencing factors of patients with DKD were screened, and the nomograph of DKD occurrence was constructed. RESULTS: The levels of HCY and HCY/NRG4 in diabetic patients were significantly increased, while the level of NRG4 was significantly decreased (p < 0.01). The AUCs of HCY/NRG4 predicted for DKD were 0.961. HCY/NRG4 and the course of DM were independent risk factors for DKD. A predictive nomograph of DKD was constructed, and decision curve analysis (DCA) showed good clinical application value. HCY/NRG4 was positively correlated with Scr, UACR, TG, UA, BUN, TCHOL and LDL and negatively correlated with eGFR and HDL (p < 0.05). CONCLUSIONS: The level of HCY and NRG4 is closely related to the severity of DM, and combined detection of HCY/NRG4 can identify patients with DKD at an early stage.

Identification of RPGR ORF15 mutation for X-linked retinitis pigmentosa in a large Chinese family and in vitro correction with prime editor.

X-linked retinitis pigmentosa (XLRP) is the most severe form of Retinitis Pigmentosa (RP) and one of the leading causes of blindness in the world. Currently, there is no effective treatment for RP. In the present study, we recruited a XLRP family and identified a 4 bp deletion mutation (c. 2234_2237del) in RPGR ORF15 with Sanger sequencing, which was located in the exact same region as the missing XES (X chromosome exome sequencing) coverage. Then, we generated cell lines harboring the identified mutation and corrected it via enhanced prime editing system (ePE). Collectively, Sanger sequencing identified a pathogenic mutation in RPGR ORF15 for XLRP which was corrected with ePE. This study provides a valuable insight for genetic counseling of the afflicted family members and prenatal diagnosis, also paves a way for applying prime editing based gene therapy in those patients.