Modular click chemistry libraries for functional screens using a diazotizing reagent.

Click chemistry is a concept in which modular synthesis is used to rapidly find new molecules with desirable properties1. Copper(I)-catalysed azide-alkyne cycloaddition (CuAAC) triazole annulation and sulfur(VI) fluoride exchange (SuFEx) catalysis are widely regarded as click reactions2-4, providing rapid access to their products in yields approaching 100% while being largely orthogonal to other reactions. However, in the case of CuAAC reactions, the availability of azide reagents is limited owing to their potential toxicity and the risk of explosion involved in their preparation. Here we report another reaction to add to the click reaction family: the formation of azides from primary amines, one of the most abundant functional groups5. The reaction uses just one equivalent of a simple diazotizing species, fluorosulfuryl azide6-11 (FSO2N3), and enables the preparation of over 1,200 azides on 96-well plates in a safe and practical manner. This reliable transformation is a powerful tool for the CuAAC triazole annulation, the most widely used click reaction at present. This method greatly expands the number of accessible azides and 1,2,3-triazoles and, given the ubiquity of the CuAAC reaction, it should find application in organic synthesis, medicinal chemistry, chemical biology and materials science.

Unveiling the role of GAS41 in cancer progression.

GAS41, a member of the human YEATS domain family, plays a pivotal role in human cancer development. It serves as a highly promising epigenetic reader, facilitating precise regulation of cell growth and development by recognizing essential histone modifications, including histone acetylation, benzoylation, succinylation, and crotonylation. Functional readouts of these histone modifications often coincide with cancer progression. In addition, GAS41 functions as a novel oncogene, participating in numerous signaling pathways. Here, we summarize the epigenetic functions of GAS41 and its role in the carcinoma progression. Moving forward, elucidating the downstream target oncogenes regulated by GAS41 and the developing small molecule inhibitors based on the distinctive YEATS recognition properties will be pivotal in advancing this research field.

LINC01089 suppresses lung adenocarcinoma cell proliferation and migration via miR-301b-3p/STARD13 axis.

BACKGROUND: Lung adenocarcinoma (LUAD) is one of the most common cancers with high morbidity and mortality worldwide. Long non-coding RNAs (lncRNAs) serve as tumor promoters or suppressors in the development of various human malignancies, including LUAD. Although long intergenic non-protein coding RNA 1089 (LINC01089) suppresses the progression of breast cancer, its mechanism in LUAD requires further exploration. Thus, we aimed to investigate the underlying function and mechanism of LINC01089 in LUAD. METHODS: The expression of LINC01089 in LUAD and normal cell lines was detected. Functional assays were applied to measure cell proliferation, apoptosis and migration. Besides, mechanism experiments were employed for assessing the interplay among LINC01089, miR-301b-3p and StAR related lipid transfer domain containing 13 (STARD13). Data achieved in this study was statistically analyzed with Student's t test or one-way analysis of variance. RESULTS: LINC01089 expression was significantly down-regulated in LUAD tissues and cells and its overexpression could reduce cell proliferation and migration. Moreover, LINC01089 could regulate STARD13 expression through competitively binding to miR-301b-3p in LUAD. Additionally, rescue assays uncovered that STARD13 depletion or miR-301b-3p overexpression could countervail the restraining effect of LINC01089 knockdown on the phenotypes of LUAD cells. CONCLUSION: LINC01089 served as a tumor-inhibitor in LUAD by targeting miR-301b-3p/STARD13 axis, providing an innovative insight into LUAD therapies. Trial registration Not applicable.

Alteration of oncogenic IGF-II gene methylation status associates with hepatocyte malignant transformation.

BACKGROUND: Oncogenic insulin-like growth factor-II (IGF-II) is overexpressed in hepatocellular carcinoma (HCC). The present study aimed to analyze the dynamic alteration of IGF-II CpG site methylation status and its molecular mechanism in HCC progression. METHODS: IGF-II alterations were observed in rat hepatocarcinogenesis models induced by 2-acetylaminofluorene. Liver IGF-II expression was compared by immunohistochemistry or tissue IGF-II specific concentration (nmol/mg protein). Status of human IGF-II promoter 3 (P3) or rat IGF-II P2 CpG site methylation was amplified by methylation-specific polymerase chain reaction (MSP). Serum IGF-II levels were quantitatively detected by an enzyme-linked immunosorbent assay. RESULTS: The levels of hepatic IGF-II expression were significantly elevated in the HCC group (P < 0.001). The unmethylation rate of IGF-II P3 CpG sites was 100% in the HCC-, 52.5% in the paracancerous-, and none (0%) in the distal noncancerous-tissues. Abnormal IGF-II expression was related to differentiation degree, tumor invasion, and positive HBV-DNA (all P < 0.001), with a negative correlation between P3 methylation degree and IGF-II expression. There was a positive correlation between liver IGF-II specific concentration and circulating IGF-II level (r = 0.97, P < 0.001). Significantly negative correlation was found between IGF-II P2 CpG site methylation and circulating IGF-II (rs = -0.89, P < 0.001) or liver IGF-II level (rs = -0.84, P < 0.001). CONCLUSIONS: The increase of serum IGF-II and the alteration of oncogenic gene IGF-II methylation may be biomarkers for HCC diagnosis and DNA methylation may be the therapeutic target of HCC.

Reversal effect of ouabain on multidrug resistance in esophageal carcinoma EC109/CDDP cells by inhibiting the translocation of Wnt/ß-catenin into the nucleus.

The incidence of esophageal carcinoma is increasing throughout the world. A major obstacle to its treatment is acquired multidrug resistance (MDR) which results in the failure of chemotherapy and patient relapse. Here, we identified that ouabain is capable of reversing MDR to cisplatin (CDDP) in EC109/CDDP cells and explore the possible mechanisms of action. The parental and the MDR cell lines were both sensitive to ouabain with 50 % inhibitory concentration (IC50) values of 258.11 and 710.63 nM, respectively. Cisplatin cytotoxicity increased in the EC109/CDDP cells by the addition of ouabain which helps promote CDDP-induced apoptosis. Ouabain at 20 nM effectively reduced the IC50 of CDDP in EC109/CDDP cells from 36.54 to 3.39 µM. This represents a 10.78-fold increase in sensitization to CDDP. We also found that ouabain was capable of down regulating the expression of P-glycoprotein (P-gp) and Bcl-2 in a dose- and time-dependent manner. Finally, the results indicated that ouabain suppressed Wnt luciferase report (TOPFlash) activity obviously in EC109/CDDP and depressed the translocation of ß-catenin into the nucleus. Moreover, ouabain showed reversal effect of MDR to CDDP in nude mouse xenograft model, and reduced the protein level of ß-catenin (Y333) in tumor tissue of CDDP plus ouabain group. All data proved that ouabain has a potent ß-catenin-dependent anti-MDR effect.

Regulation of endoplasmic reticulum stress on autophagy and apoptosis of nucleus pulposus cells in intervertebral disc degeneration and its related mechanisms.

Intervertebral disc degeneration (IVDD) is a common and frequent disease in orthopedics, which seriously affects the quality of life of patients. Endoplasmic reticulum stress (ERS)-regulated autophagy and apoptosis play an important role in nucleus pulposus (NP) cells in IVDD. Hypoxia and serum deprivation were used to induce NP cells. Cell counting kit-8 (CCK-8) assay was used to detect cell activity and immunofluorescence (IF) was applied for the appraisement of glucose regulated protein 78 (GRP78) and green fluorescent protein (GFP)-light chain 3 (LC3). Cell apoptosis was detected by flow cytometry and the expression of LC3II/I was detected by western blot. NP cells under hypoxia and serum deprivation were induced by lipopolysaccharide (LPS), and intervened by ERS inhibitor (4-phenylbutyric acid, 4-PBA) and activator (Thapsigargin, TP). Then, above functional experiments were conducted again and western blot was employed for the evaluation of autophagy-, apoptosis and ERS-related proteins. Finally, NP cells under hypoxia and serum deprivation were stimulated by LPS and intervened using apoptosis inhibitor z-Val-Ala-DL-Asp-fluoromethyl ketone (Z-VAD-FMK) and autophagy inhibitor 3-methyladenine (3-MA). CCK-8 assay, IF, flow cytometry and western blot were performed again. Besides, the levels of inflammatory cytokines were measured with enzyme-linked immunosorbent assay (ELISA) and the protein expressions of programmed death markers were estimated with western blot. It showed that serum deprivation induces autophagy and apoptosis. ERS was significantly activated by LPS in hypoxic and serum deprivation environment, and autophagy and apoptosis were significantly promoted. Overall, ERS affects the occurrence and development of IVDD by regulating autophagy, apoptosis and other programmed death.

Effect of caffeine intake on self-reported and genetic prediction of osteoarthritis: an epidemiological study and Mendelian randomization analysis.

Background: Osteoarthritis (OA) holds the distinction of being the most widespread musculoskeletal disorder. Any disruptions in the integrity of the articular cartilage can result in joint malfunction, discomfort, and impaired physical functioning. Increasing evidence indicates the negative impacts of caffeine intake on hyaline cartilage. The primary objective of this study was to delve deeper into understanding the potential link between the consumption of caffeine and the risk of developing OA. Methods: In this study, we constructed logistic regression models to evaluate the correlation between caffeine consumption and the risk of osteoarthritis using data from the National Health and Nutrition Examination Survey. Following that, we utilized genome-wide association studies to conduct a Mendelian randomization (MR) analysis investigating the association between coffee consumption and the likelihood of developing knee OA. We employed various statistical methods, including inverse variance weighting (IVW), weighted median, weighted mode, simple mode, and MR-Egger regression, to ensure comprehensive analysis and robust conclusions. To evaluate heterogeneity and the potential impact of pleiotropy, we conducted several statistical tests, including Cochran's Q test, MR-Egger intercept test, MR Pleiotropy RESidual Sum and Outlier test (MR-PRESSO), and MR Steiger test. Results: The weighted multivariate logistic regression analysis showed that the relationship between high caffeine intake (95-206 and ≥206 mg/day) and OA prevalence remained significantly high even after adjusting for covariates using the lowest caffeine intake (< 11 mg/day) as reference: Model 1-OR (95% Cl) = 1.365 (1.18-1.58) and 1.59 (1.38-1.83); Model 2-OR (95% Cl) = 1.21 (1.04-1.42) and 1.44 (1.23-1.68); and Model 3-OR (95% Cl) = 1.19 (1.01-1.40) and 1.30 (1.10-1.52), respectively (p < 0.05). The findings from the fixed effects inverse variance weighted (IVW) analysis revealed a statistically significant link between coffee intake and the likelihood of developing knee osteoarthritis: OR = 1.94; 95% confidence interval (Cl) =1.471-2.517; (p < 0.001). Consistent findings were obtained across various other methods, including MR-Egger regression, weighted median, weighted mode, and simple mode analyses. Conclusion: Our study showed a positive correlation between OA prevalence and high caffeine intake (≥95 mg/day).

Quantitative assessment of pneumothorax by using Shannon entropy of lung ultrasound M-mode image and diaphragmatic excursion based on automated measurement.

Background: Lung ultrasound (LUS) and diaphragm ultrasound (DUS) are the appropriate modalities for conservative observation to those patients who are with stable pneumothorax, as well as for the timely detection of life-threatening pneumothorax at any location, due to they are portable, real-time, relatively cost effective, and most important, without radiation exposure. The absence of lung sliding on LUS M-mode images and the abnormality of diaphragmatic excursion (DE) on DUS M-mode images are the most common and novel diagnostic criteria for pneumothorax, respectively. However, visual inspection of M-mode images remains subjective and quantitative analysis of LUS and DUS M-mode images are required. Methods: Shannon entropy of LUS M-mode image (ShanEnLM) and DE based on the automated measurement (DEAM) are adapted to the objective pneumothorax diagnoses and the severity quantifications in this study. Mild, moderate, and severe pneumothoraces were induced in 24 male New Zealand rabbits through insufflation of room air (5, 10 and 15, and 25 and 40 mL/kg, respectively) into their pleural cavities. In vivo intercostal LUS and subcostal DUS M-mode images were acquired using a point-of-care system for estimating ShanEnLM and DEAM. Results: ShanEnLM and DEAM as functions of air insufflation volumes exhibited U-shaped curves and were exponentially decreasing, respectively. Either ShanEnLM or DEAM had areas under the receiver operating characteristic curves [95% confidence interval (CI)] of 1.0000 (95% CI: 1.0000-1.0000), 0.9833 (95% CI: 0.9214-1.0000), and 0.9407 (95% CI: 0.8511-1.0000) for differentiating between normal and mild pneumothorax, mild and moderate pneumothoraces, and moderate and severe pneumothoraces, respectively. Conclusions: Our findings imply that the combination of ShanEnLM and DEAM give the promising potential for pneumothorax quantitative diagnosis.

Pattern classification of interstitial lung diseases from computed tomography images using a ResNet-based network with a split-transform-merge strategy and split attention.

In patients with interstitial lung disease (ILD), accurate pattern assessment from their computed tomography (CT) images could help track lung abnormalities and evaluate treatment efficacy. Based on excellent image classification performance, convolutional neural networks (CNNs) have been massively investigated for classifying and labeling pathological patterns in the CT images of ILD patients. However, previous studies rarely considered the three-dimensional (3D) structure of the pathological patterns of ILD and used two-dimensional network input. In addition, ResNet-based networks such as SE-ResNet and ResNeXt with high classification performance have not been used for pattern classification of ILD. This study proposed a SE-ResNeXt-SA-18 for classifying pathological patterns of ILD. The SE-ResNeXt-SA-18 integrated the multipath design of the ResNeXt and the feature weighting of the squeeze-and-excitation network with split attention. The classification performance of the SE-ResNeXt-SA-18 was compared with the ResNet-18 and SE-ResNeXt-18. The influence of the input patch size on classification performance was also evaluated. Results show that the classification accuracy was increased with the increase of the patch size. With a 32 × 32 × 16 input, the SE-ResNeXt-SA-18 presented the highest performance with average accuracy, sensitivity, and specificity of 0.991, 0.979, and 0.994. High-weight regions in the class activation maps of the SE-ResNeXt-SA-18 also matched the specific pattern features. In comparison, the performance of the SE-ResNeXt-SA-18 is superior to the previously reported CNNs in classifying the ILD patterns. We concluded that the SE-ResNeXt-SA-18 could help track or monitor the progress of ILD through accuracy pattern classification.

Recent understanding of the mechanisms of the biological activities of hesperidin and hesperetin and their therapeutic effects on diseases.

Flavonoids are natural phytochemicals that have therapeutic effects and act in the prevention of several pathologies. These phytochemicals can be found in lemon, sweet orange, bitter orange, clementine. Hesperidin and hesperetin are citrus flavonoids from the flavanones subclass that have anti-inflammatory, antioxidant, antitumor and antibacterial potential. Preclinical studies and clinical trials demonstrated therapeutical effects of hesperidin and its aglycone hesperetin in various diseases, such as bone diseases, cardiovascular diseases, neurological diseases, respiratory diseases, digestive diseases, urinary tract diseases. This review provides a comprehensive overview of the biological activities of hesperidin and hesperetin, their therapeutic potential in various diseases and their associated molecular mechanisms. This article also discusses future considerations for the clinical applications of hesperidin and hesperetin.

The landscape of enhancer RNA identify prognosis-related molecular subtypes in gastric cancer.

BACKGROUND: Enhancer RNAs (eRNAs), the transcriptional products of active enhancers, are of great significance in the initial progression of cancers. However, the biological function and bioinformatics profiles of eRNA in gastric cancer remains largely enigmatic. METHODS: Firstly, STAD were clustered into three subtypes with the data of eRNA expression from TCeA. Then we explored the difference of the tumor immune microenvironment, transcription levels, and transcription regulation among the three clusters. Finally, samples collected from 12 patients diagnosed with STAD were used to conduct qRT-PCR, verifying the conclusion based on network database. RESULTS: The three clusters were detected to have different tumor microenvironments: Cluster A has an immune "cold" microenvironment. While cluster B features as more infiltration of immune cells, accompanied with higher expression of immune checkpoints such as PDCD1, LAG3, and TIGIT. Besides, Cluster C shows a higher stromal feature with B lineage, neutrophils, and fibroblasts. Further analyses indicated that CpG island methylation level of Cluster B is different from the other two clusters. Meanwhile, Cluster A and B showed significant enrichment of TP53 and KRAS mutation respectively while Cluster C has higher tumor mutation burden (TMB) and microsatellite instability (MSI). With the elaboration of transcriptional regulation of epigenetic clustering, we detected that Cluster A enriched in epithelial phenotype pathways. Cluster B enriched in cell-cell adhesion. Cluster C enriched in fibroblast proliferation. The clinical cohort show that Cluster B patients have lower interstitial cell characteristics and CAF infiltration. CONCLUSION: We identified three unique epigenetic clusters of STAD through the differential activation of super-enhancers, and identified Cluster B with a higher immune infiltrating and a better prognosis, which provides a novel understanding of eRNAs and potential clinical applicability of eRNA-based molecular subtypes in gastric cancer.

Correction: d-sp orbital hybridization: a strategy for activity improvement of transition metal catalysts.

Correction for 'd-sp orbital hybridization: a strategy for activity improvement of transition metal catalysts' by Hui Chen et al., Chem. Commun., 2022, 58, 7730-7740, https://doi.org/10.1039/D2CC02299K.

Micron-confined microcapturer-triggered Fenton as efficient and environmentally-friendly method for simultaneously capturing bloom-forming cyanobacteria, inhibiting cell-regrowth and degrading microcystins.

The frequent outbreak and continuous expansion of harmful cyanobacteria blooms (HCBs) have become important environmental concerns and public health issues globally. In this study, the "micron-confined Fe(II)-modified-microcapturer (FMC)-triggered Fenton" technology was established as advanced process adaptable to the HCB treatment. Results show that 95.7-99.4% of cyanobacteria cells were captured and separated from the HCB water at the optimum doses of Fe(II) and H2O2 within only 30 s. The chain-like cyanobacteria of A. flos-aquae were easier to be collected by FMCs compared with the unicellular M. aeruginosa. It was confirmed by scanning electron microscopic observation and fluorescence staining flow cytometry measurement that the FMC-carrying Fe(II) played the roles of both cell-gripper and Fenton catalyst. During the one-step process, the FMC-triggered Fenton effectively inhibited the cyanobacteria regrowth via inactivating the cells, and meanwhile, the microcystins of LR and RR were removed. The analyses by continuous flow chemiluminescence and X-ray photoelectron spectroscopy denote that FMCs performed efficiently in capture and Fe(II)-catalytic oxidation through increasing mass transfer, exposing sufficient active reactive oxygen species active-sites on the FMC surface and accelerating electron transfer. The micron-field-confined cascade processes retained the robust performance of Fenton against the high pH of bulk HCB water. This novel interface-dependent Fenton method is a promising tool for HCB treatment owing to its great efficiency, versatility, rapidness and eco-environmental friendliness.

Nano-metal diborides-supported anode catalyst with strongly coupled TaOx/IrO2 catalytic layer for low-iridium-loading proton exchange membrane electrolyzer.

The sluggish kinetics of oxygen evolution reaction (OER) and high iridium loading in catalyst coated membrane (CCM) are the key challenges for practical proton exchange membrane water electrolyzer (PEMWE). Herein, we demonstrate high-surface-area nano-metal diborides as promising supports of iridium-based OER nanocatalysts for realizing efficient, low-iridium-loading PEMWE. Nano-metal diborides are prepared by a novel disulphide-to-diboride transition route, in which the entropy contribution to the Gibbs free energy by generation of gaseous sulfur-containing products plays a crucial role. The nano-metal diborides, TaB2 in particular, are investigated as the support of IrO2 nanocatalysts, which finally forms a TaOx/IrO2 heterojunction catalytic layer on TaB2 surface. Multiple advantageous properties are achieved simultaneously by the resulting composite material (denoted as IrO2@TaB2), including high electrical conductivity, improved iridium mass activity and enhanced corrosion resistance. As a consequence, the IrO2@TaB2 can be used to fabricate the membrane electrode with a low iridium loading of 0.15 mg cm-2, and to give an excellent catalytic performance (3.06 A cm-2@2.0 V@80 oC) in PEMWE-the one that is usually inaccessible by unsupported Ir-based nanocatalysts and the vast majority of existing supported Ir-based catalysts at such a low iridium loading.

Quantification of Cerebral Vascular Autoregulation Immediately Following Resuscitation from Cardiac Arrest.

Cerebral vascular autoregulation is impaired following resuscitation from cardiac arrest (CA), and its quantification may allow assessing CA-induced brain injury. However, hyperemia occurring immediately post-resuscitation limits the application of most metrics that quantify autoregulation. Therefore, to characterize autoregulation during this critical period, we developed three novel metrics based on how the cerebrovascular resistance (CVR) covaries with changes in cerebral perfusion pressure (CPP): (i) Î¸CVR, which quantifies the CVR vs CPP gradient, (ii) a CVR-based transfer function analysis, and (iii) CVRx, the correlation coefficient between CPP and CVR. We tested these metrics in a model of asphyxia induced CA and resuscitation using seven adult male Wistar rats. Mean arterial pressure (MAP) and cortical blood flow recorded for 30 min post-resuscitation via arterial cannulation and laser speckle contrast imaging, were used as surrogates of CPP and cerebral blood flow (CBF), while CVR was computed as the CPP/CBF ratio. Using our metrics, we found that the status of cerebral vascular autoregulation altered substantially during hyperemia, with changes spread throughout the 0-0.05 Hz frequency band. Our metrics push the boundary of how soon autoregulation can be assessed, and if validated against outcome markers, may help develop a reliable metric of brain injury post-resuscitation.

Highly Mimetic Ex Vivo Lung-Cancer Spheroid-Based Physiological Model for Clinical Precision Therapeutics.

Lung cancer remains a major health problem despite the considerable research into prevention and treatment methods. Through a deeper understanding of tumors, patient-specific ex vivo spheroid models with high specificity can be used to accurately investigate the cause, metastasis, and treatment strategies for lung cancer. Biofabricate lung tumors are presented, consisting of patient-derived tumor spheroids, endothelial cells, and lung decellularized extracellular matrix, which maintain a radial oxygen gradient, as well as biophysicochemical behaviors of the native tumors for precision medicine. It is also demonstrated that the developed lung-cancer spheroid model reproduces patient responses to chemotherapeutics and targeted therapy in a co-clinical trial, with 85% accuracy, 86.7% sensitivity, and 80% specificity. RNA sequencing analysis validates that the gene expression in the spheroids replicates that in the patient's primary tumor. This model can be used as an ex vivo predictive model for personalized cancer therapy and to improve the quality of clinical care.

A pan­cancer analysis of RCC2 and its interaction with HMGA2 protein in an in vitro model of colorectal cancer cells.

Regulator of chromosome condensation 2 (RCC2) is highly involved in the development of tumor malignancies. The underlying mechanisms remain to be elucidated. The present study aimed to explore the role of RCC2 in the development of tumor malignancies and explore the underlying mechanisms in colorectal cancer (CRC). RCC2 expression and survival analysis were performed in human pan-cancer. The results of searching its mRNA expression in The Cancer Genome Atlas (TCGA) database showed that RCC2 was highly expressed in different types of cancer. High RCC2 expression levels were significantly correlated with poor survival outcomes by the Kaplan-Meier analysis in the TCGA database. Immunohistochemistry revealed that RCC2 was higher expressed in 36 CRC tissues than in adjacent normal tissues. Co-immunoprecipitation revealed that RCC2 bound to high mobility group A2 (HMGA2). Ectopic expression of RCC2 promoted cell proliferation, migration and invasion, whereas knockdown of HMGA2 exerted the opposite effects. Collectively, the data provided a novel biomarker of RCC2 in various types of cancer. High RCC2 expression levels were correlated with poor prognosis in different types of cancer. In addition, RCC2 may combine with HMGA2 to promote CRC malignancy.

Effect of regulating macrophage polarization phenotype on intervertebral disc degeneration.

BACKGROUND: Macrophages are the only inflammatory cells that can penetrate the closed nucleus pulposus and their polarization plays an important role in intervertebral disc degeneration (IVDD). This paper attempted to investigate the pathogenesis of IVDD by altering the polarization state of macrophages. METHODS: Macrophage RAW264.7 cells were induced by interferonγ (IFN-γ) and lipopolysaccharide (LPS). The polarization of RAW264.7 cells was estimated by western blot and immunofluorescence. The expressions of inflammatory factors were detected by ELISA. Subsequently, RAW264.7 cells were treated with different concentrations of minocycline (Mino) and sinomenine (Sino), followed by the assessment of cell viability with cell counting kit-8 kit. Then, RAW264.7 cell culture medium was collected for the culture of human nucleus pulposus cells (NPCs). Toluidine blue staining and type II collagen staining were applied to assay the level of type II collagen. The cell apoptosis, oxidative stress, and nitric oxide (NO) level were appraised by TUNEL, oxidative stress kits and NO kit, respectively. Western blot was employed to test the levels of apoptosis- and oxidative stress-related proteins. RESULTS: IFN-γ and LPS could induce M1 polarization of RAW264.7 cells. Mino and Sino could reduce the polarization of RAW264.7 cells toward M1. M1-polarized medium inhibited LPS-induced activity, inflammation, and damage of NPCs, which were enhanced by Mino and Sino in medium. CONCLUSION: M1 polarization of macrophages promoted LPS-induced inflammation and damage of NPCs.

d-sp orbital hybridization: a strategy for activity improvement of transition metal catalysts.

Orbital hybridization to regulate the electronic structures and surface chemisorption properties of transition metals has been extensively investigated for searching high-performance catalysts toward various reactions. Unlike conventional d-d hybridization, the d-sp hybridization interaction between transition metals and p-block elements could result in surprising electronic properties and catalytic activities. This feature article highlights the recent progress in the development of high-performance transition metal-based catalysts through the extraordinary d-sp hybridization strategy, particularly for energy-related electrocatalytic applications. We start by giving an introduction of fundamental concepts associated with electronic structures of transition metal catalysts, including the Sabatier principle, d-band theory, electronic descriptor, as well as the comparison of d-d hybridization and d-sp hybridization strategies. Then, we summarize the theoretical and experimental advances in d-sp hybridization catalysts, including p-block element-doped metal catalysts, intermetallic catalysts and supported metal catalysts, with emphasis on the important roles of d-sp hybridization in tuning catalytic performances. Finally, we present existing challenges and future development prospects for the rational design of advanced d-sp hybridization catalysts.

Wnt5a/ROR1 activates DAAM1 and promotes the migration in osteosarcoma cells.

Receptor tyrosine kinase like orphan receptor 2 (ROR2) regulates Wnt5a-induced cell migration by phosphorylating PI3K/Akt and activating RhoA in osteosarcoma. However, the role of Wnt5a signaling and its corresponding receptors in the regulation of osteosarcoma metastasis remains poorly understood. ROR1 monoclonal antibody (mAb) and short hairpin (sh)RNA targeting ROR2 markedly inhibited the activity of dishevelled associated activator of morphogenesis 1 (DAAM1) and RhoA and retarded cell migration in osteosarcoma. ROR1 mAb and ROR2 shRNA destroyed the microfilament formation of osteosarcoma cells. Silencing of DAAM1 (with DAAM1 shRNA) downregulated RhoA activity and inhibited cell migration. The decrease of cell migration caused by DAAM1 shRNA was rescued by wild-type DAAM1 overexpression. DAAM1 and PI3Kα/Akt were parallel signaling pathways mediating osteosarcoma cell migration in response to Wnt5a. It was concluded that Wnt5a promotes osteosarcoma cell migration via ROR1/2 receptors, and then activates DAAM1 and RhoA.