Urinary concentrations of bisphenol A and its alternatives: Potential predictors of and associations with antral follicle count among women from an infertility clinic in Northern China.

BACKGROUND: Experimental studies have suggested exposure to bisphenol A (BPA) and its alternatives, such as bisphenol F (BPF) and bisphenol S (BPS), may exert adverse effects on ovarian reserve, but human evidence is limited. Moreover, the potential predictors of exposure to bisphenols among women seeking infertility treatment have not been reported. OBJECTIVE: To explore whether individual or mixture of BPA, BPF, and BPS were related to antral follicle count (AFC), and further identify the predictors of exposure to bisphenols among women seeking assisted reproductive treatment. METHODS: A total of 111 women from a reproductive center in Shenyang, China were enrolled in this study from September 2020 to February 2021. The concentrations of urinary BPA, BPF, and BPS were measured using ultra-high-performance liquid chromatography-triple quadruple mass spectrometry (UHPLC-MS/MS). AFC was measured by two infertility physicians through transvaginal ultrasonography on the 2-5 days of a natural cycle. Demographic characteristics, dietary habits, and lifestyles were obtained by questionnaires. The associations between individual and mixture of urinary bisphenols concentrations (BPA, BPF, and BPS) and AFC were assessed by the Poisson regression models and the quantile-based g-computation (QGC) model, respectively. The potential predictors of exposure to bisphenols were identified by the multivariate linear regression models. RESULTS: After adjusting for confounders, elevated urinary concentrations of BPA, BPF and BPS were associated with reduced AFC (ß = -0.016; 95%CI: -0.025, -0.006 in BPA; ß = -0.017; 95%CI: -0.029, -0.004 in BPF; ß = -0.128; 95%CI: -0.197, -0.060 in BPS). A quantile increase in the bisphenols mixture was negatively associated with AFC (ß = -0.101; 95%CI: -0.173, -0.030). Intake of fried food had higher urinary concentrations of BPF, BPS, and total bisphenols (∑BPs) than women who did not eat, and age was related to increased urinary BPF concentrations. CONCLUSION: Our findings indicated that exposure to individual BPA, BPF, BPS and bisphenol mixtures were associated with impaired ovarian reserve. Furthermore, the intake of fried food, as identified in this study, could serve as an important bisphenols exposure route for reproductive-aged women.

Pathogenic sphingosine 1-phosphate pathway in psoriasis: a critical review of its pathogenic significance and potential as a therapeutic target.

Sphingosine-1-phosphate (S1P) is a sphingolipid mediator that exerts a variety of biological functions, including immune, cardiovascular, and neurological regulation as well as tumor promotion, through high-affinity G protein-coupled receptors (S1P1-5). It has been reported that circulating S1P levels remain higher in patients with psoriasis than in healthy individuals and that circulating S1P levels do not decrease after anti-TNF-α treatment in those patients. The S1P-S1PR signaling system plays an important role in inhibiting keratinocyte proliferation, regulating lymphocyte migration, and promoting angiogenesis, thus contributing to the regulation of psoriasis pathogenesis. Here, we review the mechanisms by which S1P-S1PR signaling affects the development of psoriasis and the available clinical/preclinical evidence for targeting S1P-S1PR in psoriasis. S1P-S1PR signaling mechanisms may partially explain the link between psoriasis and its comorbidities. Although the detailed mechanisms remain to be elucidated, S1P may be a new target for future psoriasis remission.

Urinary bisphenol A and S are associated with diminished ovarian reserve in women from an infertility clinic in Northern China.

Bisphenol A (BPA) has been demonstrated to cause ovarian toxicity including disruption of steroidogenesis and inhibition of follicle growth. Still, human evidence is lacking on its analogs such as bisphenol F (BPF) and bisphenol S (BPS). In this study, we aimed to investigate the associations between exposure to BPA, BPF, and BPS with ovarian reserve in women of childbearing age. We recruited 111 women from an infertility clinic in Shenyang, North China between September 2020 and February 2021. Anti-müllerian hormone (AMH), follicle-stimulating hormone (FSH), and estradiol (E2) were measured as indicators of ovarian reserve. Urinary BPA, BPF, and BPS concentrations were quantified by ultra-high-performance liquid chromatography-triple quadruple mass spectrometry (UHPLC-MS/MS). Linear and logistic regression models were applied to assess the associations between urinary BPA, BPF, and BPS levels and indicators of ovarian reserve and DOR, respectively. Restricted cubic spline (RCS) models were further utilized to explore potential non-linear associations. Our results showed that urinary BPS concentrations were negatively associated with AMH (ß = - 0.287, 95 %CI: - 0.505, - 0.070, P = 0.010) and this inverse relationship was further confirmed in the RCS model. In addition, higher levels of BPA and BPS exposure were associated with increased DOR risk (BPA: OR = 7.112, 95 %CI: 1.247, 40.588, P = 0.027; BPS: OR = 6.851, 95 %CI: 1.241, 37.818, P = 0.027). No significant associations of BPF exposure with ovarian reserve. Our findings implied that higher BPA and BPS exposure may be related to decreased ovarian reserve.

Scutellarin protects the kidney from ischemia/reperfusion injury by targeting Nrf2.

BACKGROUND: Acute kidney injury (AKI) results in high morbidity and mortality among inpatients, while effective treatment and intervention are still absent. Therefore, this study aims to explore the effects of Scutellarin (Scu) in experimental models in vivo and in vitro. METHODS: In vivo experiment, we employed a total of 30 Wistar rats, which further were modelled by a bilateral renal pedicle clip for 45 min, then received 50 mg/kg/day Scu. In vitro, HK-2 cells were administered with 20µΜ Scu and then incubated in hypoxia/reoxygenation (H/R) conditions for 24 h. The knockdown of Nrf2 expression was conducted by small interfering RNA (siRNA) transfection. RESULTS: As a result, the AKI model was well established with an increased SCr, BUN, KIM-1 level, and histological injury score, while Scu treatment reduced the levels above and increased the antioxidative enzyme HO-1. H/R induced an increase of ROS in HK-2 cells, while Scu decreased the ROS level. Bioinformatics results showed the transcription factor Nrf2 was a hub protein during the AKI, which also bound to Scu with low binding energy, indicating that the downstream effect of Scu might be mediated by Nrf2. To verify the suppose above, we employed siRNA against Nrf2, which shows a significant increase in ROS after Nrf2 was blocked. Meanwhile, the HO-1 showed similar expression compared with the 'H/R + Nrf2 siRNA' and 'H/R + Nrf2 siRNA + Scu' group, implying the protective effect of Scu was mediated by the Nrf2/HO-1 pathway. CONCLUSION: Scu led to up-regulation of HO-1 through activating the Nrf2 signalling pathway, protecting the kidneys from ischemia/reperfusion (I/R)-induced oxidative damage.

Host Tissue Environment Directs Activities of an Epichloë Endophyte, While It Induces Systemic Hormone and Defense Responses in Its Native Perennial Ryegrass Host.

Increased resilience of pasture grasses mediated by fungal Epichloë endophytes is crucial to pastoral industries. The underlying mechanisms are only partially understood and likely involve very different activities of the endophyte in different plant tissues and responses of the plant to these. We analyzed the transcriptomes of Epichloë festucae and its host, Lolium perenne, in host tissues of different function and developmental stages. The endophyte contributed approximately 10× more to the transcriptomes than to the biomass of infected tissues. Proliferating mycelium in growing host tissues highly expressed genes involved in hyphal growth. Nonproliferating mycelium in mature plant tissues, transcriptionally equally active, highly expressed genes involved in synthesizing antiherbivore compounds. Transcripts from the latter accounted for 4% of fungal transcripts. Endophyte infection systemically but moderately increased transcription of L. perenne genes with roles in hormone biosynthesis and perception as well as stress and pathogen resistance while reducing expression of genes involved in photosynthesis. There was a good correlation between transcriptome-based observations and physiological observations. Our data indicate that the fitness-enhancing effects of the endophyte are based both on its biosynthetic activities, predominantly in mature host tissues, and also on systemic alteration of the host's hormonal responses and induction of stress response genes. [Formula: see text] Copyright © 2017 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .

Last hope for the doomed? Thoughts on the importance of a parasexual cycle for the yeast Candida albicans.

The yeast Candida albicans, a commensal colonizer and occasional pathogen of humans, has a rudimentary mating ability. However, mating is a cumbersome process that has never been observed outside the laboratory, and the population structure of the species is predominantly clonal. Here we discuss recent findings that indicate that mating ability is under selection in C. albicans, i.e. that it is a biologically relevant process. C. albicans strains can only mate after they have sustained genetic damage. We propose that the rescue of such damaged strains by mating may be the primary reason why mating ability is under selection.

Vaporization phosphorization-mediated synthesis of phosphorus-doped TiO2 nanocomposites for combined photodynamic and photothermal therapy of renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a disease with high incidence and poor prognosis. The conventional treatment involves radiotherapy and chemotherapy, but chemotherapeutic agents are often associated with side effects, i.e., cytotoxicity to nontumor cells. Therefore, there is an urgent need for the development of novel therapeutic strategies for ccRCC. We synthesized spherical P/TiO2 nanoparticles (P/TiO2 NPs) by vaporization phosphorization (VP). X-ray photoelectron spectroscopy (XPS) and ultraviolet-visible diffuse reflectance spectroscopy (UV-Vis DRS) analyses confirmed that the anatase TiO2 surface was successfully doped with phosphorus and produced a large number of oxygen vacancies (OV). Serving as a photosensitizer, P/TiO2 NPs not only extended the photoresponse range to the near-infrared II region (NIR II) but also introduced a donor energy level lower than the TiO2 conduction band, narrowing the band gap, which could facilitate the migration of photogenerated charges and trigger the synergistic treatment of photodynamic therapy (PDT) and photothermal therapy (PTT). During NIR irradiation in vitro, the P/TiO2 NPs generated local heat and various oxygen radicals, including 1O2, ˙O2-, H2O2, and ˙OH, which damaged the ccRCC cells. In vivo, administration of the P/TiO2 NPs + NIR reduced the tumor volume by 80%, and had the potential to inhibit tumor metastasis by suppressing intratumor neoangiogenesis. The P/TiO2 NPs showed superior safety and efficacy relative to the conventional chemotherapeutic agent used in ccRCC treatment. This study introduced an innovative paradigm for renal cancer treatment, highlighting the potential of P/TiO2 NPs as safe and effective nanomaterials and presenting a compelling new option for clinical applications in anticancer therapy.

COX6C expression driven by copy amplification of 8q22.2 regulates cell proliferation via mediation of mitosis by ROS-AMPK signaling in lung adenocarcinoma.

Copy number variations (CNVs) play a vital role in regulating genes expression and tumorigenesis. We explored the copy number alterations in early-stage lung adenocarcinoma using high-throughput sequencing and nucleic acid flight mass spectrometry technology, and found that 8q22.1-22.2 is frequently amplified in lung adenocarcinoma tissues. COX6C localizes on the region and its expression is notably enhanced that driven by amplification in lung adenocarcinoma. Knockdown of COX6C significantly inhibits the cell proliferation, and induces S-G2/M cell cycle arrest, mitosis deficiency and apoptosis. Moreover, COX6C depletion causes a deficiency in mitochondrial fusion, and impairment of oxidative phosphorylation. Mechanistically, COX6C-induced mitochondrial deficiency stimulates ROS accumulation and activates AMPK pathway, then leading to abnormality in spindle formation and chromosome segregation, activating spindle assemble checkpoint, causing mitotic arrest, and ultimately inducing cell apoptosis. Collectively, we suggested that copy amplification-mediated COX6C upregulation might serves as a prospective biomarker for prognosis and targeting therapy in patients with lung adenocarcinoma.

Facile synthesis of MoS2@red phosphorus heterojunction for synergistically photodynamic and photothermal therapy of renal cell carcinoma.

The therapy of the clear cell renal cell carcinoma (ccRCC) is crucial for the human healthcare due to its easy metastasis and recurrence, as well as resistance to radiotherapy and chemotherapy. In this work, we propose the synthesis of MoS2@red phosphorus (MoS2@RP) heterojunction to induce synergistic photodynamic and photothermal therapy (PDT/PTT) of ccRCC. The MoS2@RP heterojunction exhibits enhanced spectra absorption in the NIR range and produce local heat-increasing under the NIR laser irradiation compared with pure MoS2 and RP. The high photocatalytic activity of the MoS2@RP heterojunction contributes to effective transferring of the photo-excited electrons from the RP to MoS2, which promotes the production of various types of radical oxygen species (ROS) to kill the ccRCC cells. After the NIR irradiation, the MoS2@RP can effectively induce the apoptosis in the ccRCC cells through localized hyperthermia and the generation of ROS, while exhibiting low cytotoxicity towards normal kidney cells. In comparison to MoS2, the MoS2@RP heterojunction shows an approximate increase of 22 % in the lethality rate of the ccRCC cells and no significant change in toxicity towards normal cells. Furthermore, the PDT/PTT treatment using the MoS2@RP heterojunction effectively eradicates a substantial number of deep-tissue ccRCC cells in vivo without causing significant damage to major organs. This study presents promising effect of the MoS2@RP heterojunction-based photo-responsive therapy for effective ccRCC treatment.

Personalized prediction of mortality in patients with acute ischemic stroke using explainable artificial intelligence.

BACKGROUND: Research into the acute kidney disease (AKD) after acute ischemic stroke (AIS) is rare, and how clinical features influence its prognosis remain unknown. We aim to employ interpretable machine learning (ML) models to study AIS and clarify its decision-making process in identifying the risk of mortality. METHODS: We conducted a retrospective cohort study involving AIS patients from January 2020 to June 2021. Patient data were randomly divided into training and test sets. Eight ML algorithms were employed to construct predictive models for mortality. The performance of the best model was evaluated using various metrics. Furthermore, we created an artificial intelligence (AI)-driven web application that leveraged the top ten most crucial features for mortality prediction. RESULTS: The study cohort consisted of 1633 AIS patients, among whom 257 (15.74%) developed subacute AKD, 173 (10.59%) experienced AKI recovery, and 65 (3.98%) met criteria for both AKI and AKD. The mortality rate stood at 4.84%. The LightGBM model displayed superior performance, boasting an AUROC of 0.96 for mortality prediction. The top five features linked to mortality were ACEI/ARE, renal function trajectories, neutrophil count, diuretics, and serum creatinine. Moreover, we designed a web application using the LightGBM model to estimate mortality risk. CONCLUSIONS: Complete renal function trajectories, including AKI and AKD, are vital for fitting mortality in AIS patients. An interpretable ML model effectively clarified its decision-making process for identifying AIS patients at risk of mortality. The AI-driven web application has the potential to contribute to the development of personalized early mortality prevention.

Rational Optimization of Cathode Composites for Sulfide-Based All-Solid-State Batteries.

All-solid-state lithium-ion batteries with argyrodite solid electrolytes have been developed to attain high conductivities of 10-3 S cm-1 in studies aiming at fast ionic conductivity of electrolytes. However, no matter how high the ionic conductivity of the electrolyte, the design of the cathode composite is often the bottleneck for high performance. Thus, optimization of the composite cathode formulation is of utmost importance. Unfortunately, many reports limit their studies to only a few parameters of the whole electrode formulation. In addition, different measurement setups and testing conditions employed for all-solid-state batteries make a comparison of results from mutually independent studies quite difficult. Therefore, a detailed investigation on different key parameters for preparation of cathodes employed in all-solid-state batteries is presented here. Employing a rational approach for optimization of composite cathodes using solid sulfide electrolytes elucidated the influence of different parameters on the cycling performance. First, powder electrodes made without binders are investigated to optimize several parameters, including the active materials' particle morphology, the nature and amount of the conductive additive, the particle size of the solid electrolyte, as well as the active material-to-solid electrolyte ratio. Finally, cast electrodes are examined to determine the influence of a binder on cycling performance.

Zeolitic imidazolate framework/aptamer-based fluorescence assay for the facile and high-sensitivity detection of acetamiprid.

Accurate monitoring of trace pesticides in complex matrix remains a challenge in food safety supervision. Herein, we designed a facile zeolitic imidazolate framework (ZIF)-8/aptamer-based assay for the sensitive detection of acetamiprid. ZIF-8 efficiently adsorbs 6-carboxyfluorescein-labeled complementary DNA (cDNA-FAM) via electrostatic interaction, hydrogen bonding and Zn2+ coordination, which contributed to resistance to cDNA-FAM displacement by biological ligands. ZIF-8 serves as an "ion pump" that contains lots of Zn2+ who boosts cDNA-FAM adsorption and triggers the photoinduced electron transfer (PET) effect from FAM to ZIF-8, improving the sensing sensitivity. Acetamiprid could trigger the change in the adsorption state of cDNA-FAM, further tuning the PET effect and causing fluorescence conversion. The fluorescence assay showed a high sensitivity for monitoring acetamiprid with a detection limit of 0.05 ng mL-1 in the apple sample. This ZIF/DNA-based analytical platform provides a powerful tool for facile and low-cost screening of pesticide residues, with promising applications in food safety monitoring.

Downregulation of MDM2 by small interference RNA induces apoptosis and sensitizes MCF-7 breast cells to resveratrol.

Recent studies have demonstrated the mouse double minute gene (MDM2), a main oncogene, as a novel and interesting therapeutic target for cancer therapy. The aim of this study was to investigate the involvement of MDM2 in antiproliferative and antimetastatic effects of resveratrol in breast cancer cells. MCF-7 cells were transfected with siRNA against MDM2 and resveratrol. Proliferation and apoptosis were evaluated by MTT assay and cell death ELISA assay, respectively. MDM2, p53, Bax, Bcl-2, caspase-3, MMP-2, and MMP9 expressions were determined by qRT-PCR and Western blotting. Transfection with si-MDM2 significantly suppressed the expression of MDM2 expression, resulting in MCF-7 cell growth inhibition and spontaneous apoptosis. Pretreatment with Si-MDM2 synergically increased antiproliferation and antimetatstatic effects of resveratrol. No significant anticancer effects were detected with negative control siRNA treatment. Our findings suggest that silencing of MDM2 by specific siRNA effectively induce apoptosis and also enhanced anticancer effects of resveratrol. Therefore, siMDM2 may be a potent combination in breast therapy.

Hospitalized patients received furosemide undergoing acute kidney injury: the risk and prediction tool.

PURPOSE: Furosemide, a frequently prescribed diuretic for managing congestive heart failure and edema, remains a topic of debate regarding its potential risk of inducing acute kidney injury (AKI) in patients. Consequently, this study aims to examine the occurrence of hospital-acquired AKI (HA-AKI) in hospitalized patients who are administered furosemide and to investigate potential risk factors associated with this outcome. METHODS: This study encompassed a cohort of 22374 hospitalized patients who either received furosemide treatment or not from June 1, 2012, to December 31, 2017. Propensity score matching was employed to establish comparability between the two groups regarding covariates. Subsequently, a nomogram was constructed to predict the probability of AKI occurrence among patients who underwent furosemide treatment. RESULTS: The regression analysis identified the single-day total dose of furosemide as the most significant factor for AKI, followed by ICU administration, estimated glomerular filtration rate, antibiotic, statin, NSAIDs, ß-blockers, proton pump inhibitor, chronic kidney disease, and 7 other indicators. Subgroup analysis revealed a synergistic effect of furosemide with surgical operation, previous treatment with ß-blockers, ACEI/ARB and antibiotics, leading to an increased risk of AKI when used in combination. Subsequently, a visually represented prognostic nomogram was developed to predict AKI occurrence in furosemide users. The predictive accuracy of the nomogram was assessed through calibration analyses, demonstrating an excellent agreement between the nomogram predictions and the actual likelihood of AKI, with a probability of 77.40%. CONCLUSIONS: Careful consideration of factors such as dosage, concurrent medication use, and renal function of the patient is necessary for clinical practice when using furosemide. Our practical prognostic model for HA-AKI associated with furosemide use can be utilized to assist clinicians in making informed decisions about patient care and treatment.

Hexarelin alleviates apoptosis on ischemic acute kidney injury via MDM2/p53 pathway.

INTRODUCTION: Hexarelin exhibits significant protection against organ injury in models of ischemia/reperfusion (I/R)-induced injury (IRI). Nevertheless, the impact of Hexarelin on acute kidney injury (AKI) and its underlying mechanism remains unclear. In this study, we investigated the therapeutic potential of Hexarelin in I/R-induced AKI and elucidated its molecular mechanisms. METHODS: We assessed the protective effects of Hexarelin through both in vivo and in vitro experiments. In the I/R-induced AKI model, rats were pretreated with Hexarelin at 100 µg/kg/d for 7 days before being sacrificed 24 h post-IRI. Subsequently, kidney function, histology, and apoptosis were assessed. In vitro, hypoxia/reoxygenation (H/R)-induced HK-2 cell model was used to investigate the impact of Hexarelin on apoptosis in HK-2 cells. Then, we employed molecular docking using a pharmmapper server and autodock software to identify potential target proteins of Hexarelin. RESULTS: In this study, rats subjected to I/R developed severe kidney injury characterized by tubular necrosis, tubular dilatation, increased serum creatinine levels, and cell apoptosis. However, pretreatment with Hexarelin exhibited a protective effect by mitigating post-ischemic kidney pathological changes, improving renal function, and inhibiting apoptosis. This was achieved through the downregulation of conventional apoptosis-related genes, such as Caspase-3, Bax and Bad, and the upregulation of the anti-apoptotic protein Bcl-2. Consistent with the in vivo results, Hexarelin also reduced cell apoptosis in post-H/R HK-2 cells. Furthermore, our analysis using GSEA confirmed the essential role of the apoptosis pathway in I/R-induced AKI. Molecular docking revealed a strong binding affinity between Hexarelin and MDM2, suggesting the potential mechanism of Hexarelin's anti-apoptosis effect at least partially through its interaction with MDM2, a well-known negative regulator of apoptosis-related protein that of p53. To validate these findings, we evaluated the relative expression of MDM2 and p53 in I/R-induced AKI with or without Hexarelin pre-administration and observed a significant suppression of MDM2 and p53 by Hexarelin in both in vivo and in vitro experiments. CONCLUSION: Collectively, Hexarelin was identified as a promising medication in protecting apoptosis against I/R-induced AKI.

Tilianin Reduces Apoptosis via the ERK/EGR1/BCL2L1 Pathway in Ischemia/Reperfusion-Induced Acute Kidney Injury Mice.

Background: Acute kidney injury (AKI) is a common syndrome impacting about 13.3 million patients per year. Tilianin has been reported to alleviate myocardial ischemia/reperfusion (I/R) injury, while its effect on AKI is unknown; thus, this study aimed to explore if tilianin protects I/R-induced AKI and the underlying mechanisms. Methods: The microarray dataset GSE52004 was downloaded from GEO DataSets (Gene Expression Omnibus). Differential expression analysis and gene-set enrichment analysis (GSEA) were performed by R software to identify apoptosis pathway-related genes. Then, RcisTarget was applied to identify the transcription factor (TF) related to apoptosis. The STRING database was used to construct a protein-protein interaction (PPI) network. Cytoscape software visualized PPI networks, and hub TFs were selected via cytoHubba. AutoDock was used for molecular docking of tilianin and hub gene-encoded proteins. The expression levels of hub genes were assayed and visualized by quantitative real-time PCR, Western blotting, and immunohistochemistry by establishing I/R-induced AKI mouse models. Results: Bioinformatics analysis showed that 34 genes, including FOS, ATF4, and Gadd45g, were involved in the apoptosis pathway. In total, seven hub TFs might play important roles in tilianin-regulating apoptosis pathways. In in vivo, tilianin improved kidney function and reduced the number of TUNEL-positive renal tubular epithelial cells (RTECs) after I/R-induced AKI. Tilianin reduced the activation of the ERK pathway and then downregulated the expression of EGR1. This further ameliorated the expression of anti-apoptotic genes such as BCL2L1 and BCL2, reduced pro-apoptotic genes such as BAD, BAX, and caspase-3, and reduced the release of cytochrome c. Conclusion: Tilianin reduced apoptosis after I/R-induced AKI by the ERK/EGR1/BCL2L1 pathway. Our findings provided novel insights for the first time into the protective effect and underlying molecular mechanisms of tilianin on I/R-induced AKI.

Identification a novel de novo RUNX2 frameshift mutation associated with cleidocranial dysplasia.

BACKGROUND: Cleidocranial dysplasia (CCD) is a rare genetic disorder affecting bone and cartilage development. Clinical features of CCD comprise short stature, delayed ossification of craniofacial structures with numerous Wormian bones, underdeveloped or aplastic clavicles and multiple dental anomalies. Several studies have revealed that CCD development is strongly linked with different mutations in runt-related transcription factor 2 (RUNX2) gene. OBJECTIVE: Identification and functional characterization of RUNX2 mutation associated with CCD. METHODS: We performed genetic testing of a patient with CCD using whole exome sequencing and found a novel RUNX2 frameshift mutation: c.1550delT in a sporadic case. We also compared the functional activity of the mutant and wild-type RUNX2 through immunofluorescence microscopy and osteocalcin promoter luciferase assay. RESULTS: We found a novel RUNX2 frameshift mutation, c.1550delT (p.Trp518Glyfs*60). Both mutant RUNX2 and wild-type RUNX2 protein were similarly confined in the nuclei. The novel mutation caused abrogative transactivation activity of RUNX2 on osteocalcin promoter. CONCLUSIONS: We explored a novel RUNX2 deletion/frameshift mutation in a sporadic CCD patient. This finding suggests that the VWRPY domain may play a key role in RUNX2 transactivation ability.

Ratiometric fluorescent hydrogel for point-of-care monitoring of organophosphorus pesticide degradation.

The residues of organophosphorus pesticides have caused the potential risk in environment and human health, arousing worldwidely great concern. Herein, we fabricated a robust gold nanoclusters/MnO2 composites-based hydrogel portable kit for accurate monitoring of paraoxon residues and degradation in Chinese cabbages. With the immobilization of gold nanoclusters/MnO2 composites into a hydrogel, a ratiometric fluorescent signal is generated by catalyzing the oxidation of o-phenylenediamine, which possesses a built-in correction with low background interference. Coupling with acetylcholinesterase catalytic reactions and pesticide inhibition effect, the portable kit can sensitively detect paraoxon residues with a detection limit of 5.0 ng mL-1. For on-site quantification, the fluorescent color variations of portable kit are converted into digital information that exhibits applicative linear range toward pesticide. Notably, the hydrogel portable kit was successfully applied for precisely monitoring the residue and degradation of paraoxon in Chinese cabbage, providing a potential pathway toward practical point-of-care testing in food safety monitoring.

Calycosin attenuates renal ischemia/reperfusion injury by suppressing NF-κB mediated inflammation via PPARγ/EGR1 pathway.

Renal ischemia reperfusion injury (IRI) is a leading and common cause of acute kidney injury (AKI), and inflammation is a critical factor in ischemic AKI progression. Calycosin (CAL), a major active component of Radix astragali, has been reported to have anti-inflammatory effect in multiple organs. However, whether CAL can alleviate renal IRI and its mechanism remain uncertain. In the present study, a renal IRI model is established by bilateral renal pedicles occlusion for 35 min in male C57BL/6 mice, and the effect of CAL on renal IRI is measured by serum creatinine and pathohistological assay. Hypoxia/reoxygenation (H/R) stimulated human renal tubular epithelial cells HK-2 were applied to explore the regulatory mechanisms of CAL. Luciferase reporter assay and molecular docking were applied to identify the CAL's target protein and pathway. In the mice with renal IRI, CAL dose dependently alleviated the renal injury and decreased nuclear factor kappa B (NF-κB) mediated inflammatory response. Bioinformatics analysis and experiments showed that early growth response 1 (EGR1) increased in mice with renal IRI and promoted NF-κB mediated inflammatory processes, and CAL dose-dependably reduced EGR1. Through JASPAR database and luciferase reporter assay, peroxisome proliferator-activated receptor γ (PPARγ) was predicted to be a transcription factor of EGR1 and repressed the expression of EGR1 in renal tubular epithelial cells. CAL could increase PPARγ in a dose dependent manner in mice with renal IRI and molecular docking predicted CAL could bind stably to PPARγ. In HK-2 cells after H/R, CAL increased PPARγ, decreased EGR1, and inhibited NF-κB mediated inflammatory response. However, PPARγ knockdown by siRNA transfection abrogated the anti-inflammation therapeutic effect of CAL. CAL produced a protective effect on renal IRI by attenuating NF-κB mediated inflammatory response via PPARγ/EGR1 pathway.

High levels of a fungal superoxide dismutase and increased concentration of a PR-10 plant protein in associations between the endophytic fungus Neotyphodium lolii and ryegrass.

Neotyphodium lolii is a fungal endosymbiont of the ryegrass Lolium perenne. Its growth is tightly controlled and synchronized with that of the plant. How the symbionts communicate is largely unknown but failure of the endophyte to elicit a defense response is considered crucial for successful symbiosis. In silver-stained two-dimensional gels of protein extracts from endophyte-infected ryegrass, a fungal Cu/Zn superoxide dismutase was detectable, even though the fungus accounts for only <¹/500 of the biomass, indicating that it is an abundant fungal protein and that the fungus needs protection against reactive oxygen species. The plant increased levels of a pathogenesis-related class 10 (PR-10) protein; when equal amounts of protein from infected and uninfected plants were loaded, PR-10 was only detectable in extracts from infected plants. Presence of the endophyte did not lead to a significant increase in PR10 transcript levels. In protein extracts from a symbiosis containing an N. lolii variant with an abnormal in planta growth pattern, the fungal Cu/Zn superoxide dismutase but not PR-10 protein was detectable. The correlation between increased PR-10 levels and presence of a normally growing endophyte is suggestive of a role of a very limited host defense in the interaction between grass and endophyte.