A novel inherited CARD9 deficiency in an otherwise healthy woman with CNS candidiasis.

Patients with caspase-associated recruitment domain-9 (CARD9) deficiency are more likely to develop invasive fungal disease that affect CNS. However, the understanding of how Candida invades and persists in CNS is still limited. We here reported a 24-year-old woman who were previously immunocompetent and diagnosed with CNS candidiasis. A novel autosomal recessive homozygous CARD9 mutation (c.184 + 5G > T) from this patient was identified using whole genomic sequencing. Furthermore, we extensively characterized the impact of this CARD9 mutation on the host immune response in monocytes, neutrophils and CD4 + T cells, using single cell sequencing and in vitro experiments. Decreased pro-inflammatory cytokine productions of CD14 + monocyte, impaired Th17 cell differentiation, and defective neutrophil accumulation in CNS were found in this patient. In conclusion, this study proposed a novel mechanism of CNS candidiasis development. Patients with CNS candidiasis in absence of known immunodeficiencies should be analyzed for CARD9 gene mutation as the cause of invasive fungal infection predisposition.

Influence of radiotherapy interruption on esophageal cancer with intensity-modulated radiotherapy: a retrospective study.

BACKGROUND: Radiotherapy interruption (RTI) prolongs the overall total treatment time and leads to local control loss in many cancers, but it is unclear in esophageal cancer. We aimed to evaluate the influence of RTI on the overall survival (OS), progression-free survival (PFS), and local-regional recurrence-free survival (LRFS) of patients with esophageal cancer undergoing chemoradiotherapy. METHODS: A total of 299 patients with esophageal squamous cell carcinoma from 2017 to 2019 were retrospectively analyzed to investigate the effect of RTI on OS, PFS, and LRFS. The delayed time of radiotherapy interruption was calculated as the actual radiation treatment time minus the scheduled time. The univariate and multivariate analyses were performed by the COX proportional hazards regression models, and the survival analysis was performed through the Kaplan‒Meier method, and compared with the log-rank test. RESULTS: The 3-year OS, PFS, and LRFS rates were 53.0%, 42.0%, and 48.0%, respectively. The univariate and multivariate analyses showed that the delayed time > 3 days was an independent adverse prognostic factor for OS (HR = 1.68, 95% CI 1.10-2.55, p = 0.016), and LRFS (HR = 1.74, 95% CI 1.18-2.57, p = 0.006). The patient with a delayed time of > 3 days had poorer survival rates of OS, and LRFS than patients with a delayed time of ≤ 3 days (OS, p = 0.047; LRFS, p = 0.013), and the survival outcomes of patients with shorter delayed time (1-3 days) were slightly different from the patients without interruptions. The impact of delay time on PFS is not statistically significant, but the survival outcomes of the two groups were slightly different. CONCLUSION: There was a significant correlation between delayed time and local control of esophageal cancer. The delayed time for more than 3 days might decrease the survival outcome, and increase the local recurrence risk.

Synthesis and Study of Photothermal Properties of a Mixed-Valence Nanocluster CuI/CuII with Strong near-Infrared Optical Absorption Supported by 4-tert-Butylcalix[4]arene Ligand.

The first mixed-valence nanocluster CuI/CuII with the highest percentage of CuII ions was synthesized by using 4-tert-butylcalix[4]arene (Calix4), with the formula DMF2⊂[(CO3)2-@CuII6CuI3(Calix4)3Cl2(DMF)5(H3O)]•DMF (1), as a photothermal nanocluster. Its structure was characterized using single-crystal X-ray diffraction, Fourier-transform infrared spectroscopy, and powder X-ray diffraction. In addition, the charge state and chemical composition of the nanocluster were determined using electrospray ionization spectrometry and X-ray photoelectron spectroscopy (XPS) spectrum. The results of the XPS and X-ray crystallography revealed that there are two independent CuII and CuI centers in nanocluster 1 with the relative abundances of 66.6 and 33.3% for CuII and CuI, respectively. The nanocluster contains three four-coordinated CuI ions with a square-planar geometry and six five-coordinated CuII ions with a square pyramid geometry. The nanocluster shows strong near-infrared optical absorption in the solid state and excellent photothermal conversion ability (the equilibrium temperature ∼78.2 °C) with the light absorption centers in 286-917 nm over previous reported pentanucleus CuI4CuII clusters and CuII compounds.

Synthesis of Two Neutral Silver Alkynyl Nanoclusters by a Single Divalent Tetrahedral Anion Template and a Study of Their Optical Features.

The synthesis of nanoclusters from simple structural units is usually a challenging process because of the complexity and unpredictability of the self-assembly process of these types of compounds. Herein, two new neutral 19-nuclearity silver nanoclusters based on alkynyl ligands with the formulas [(CrO4)@Ag19(C≡CtBu)8(Ph2PO2)6(tfa)3(CH3OH)2] (1) and [(SO4)@Ag19(C≡CtBu)8(Ph2PO2)6(tfa)3(CH3OH)2] (2), in which tfa = trifluoroacetate, were synthesized, and their structures were investigated by single-crystal and powder X-ray diffraction, electrospray ionization mass spectrometry, elemental analyses, and Fourier transform infrared spectroscopy. The surface ligands of Ph2PO2H and trifluoroacetate were assembled through hydrogen bonding, metal-aromatic interactions, and coordination bonding around 19 silver atoms as the metal skeletons of the nanoclusters. Sulfate and chromate anions, as a template within the metal skeleton of clusters through bonding with silver atoms, stabilized the structure. In addition, the UV-vis absorption spectroscopy, luminescence properties, and thermal stability of the nanoclusters were investigated.

Strain Effect in Palladium Nanostructures as Nanozymes.

While various effects of physicochemical parameters (e.g., size, facet, composition, and internal structure) on the catalytic efficiency of nanozymes (i.e., nanoscale enzyme mimics) have been studied, the strain effect has never been reported and understood before. Herein, we demonstrate the strain effect in nanozymes by using Pd octahedra and icosahedra with peroxidase-like activities as a model system. Strained Pd icosahedra were found to display 2-fold higher peroxidase-like catalytic efficiency than unstrained Pd octahedra. Theoretical analysis suggests that tensile strain is more beneficial to OH radical (a key intermediate for the catalysis) generation than compressive strain. Pd icosahedra are more active than Pd octahedra because icosahedra amplify the surface strain field. As a proof-of-concept demonstration, the strained Pd icosahedra were applied to an immunoassay of biomarkers, outperforming both unstrained Pd octahedra and natural peroxidases. The findings in this research may serve as a strong foundation to guide the design of high-performance nanozymes.

Road traffic injury mortality and morbidity by country development status, 2011-2017.

PURPOSE: This research examined road traffic injury mortality and morbidity disparities across of country development status, and discussed the possibility of reducing country disparities by various actions to accelerate the pace of achieving Sustainable Development Goals target 3.6 - to halve the number of global deaths and injuries from road traffic accidents by 2020. METHODS: Data for road traffic mortality, morbidity, and socio-demographic index (SDI) were extracted by country from the estimates of the Global Burden of Disease study, and the implementation of the three types of national actions (legislation, prioritized vehicle safety standards, and trauma-related post-crash care service) were extracted from the Global Status Report on Road Safety by World Health Organization. We fitted joinpoint regression analysis to identify and quantify the significant rate changes from 2011 to 2017. RESULTS: Age-adjusted road traffic mortality decreased substantially for all the five SDI categories from 2011 to 2017 (by 7.52%-16.08%). Age-adjusted road traffic mortality decreased significantly as SDI increased in the study time period, while age-adjusted morbidity generally increased as SDI increased. Subgroup analysis by road user yielded similar results, but with two major differences during the study period of 2011 to 2017: (1) pedestrians in the high SDI countries experienced the lowest mortality (1.68-1.90 per 100,000 population) and morbidity (110.45-112.72 per 100,000 population for incidence and 487.48-491.24 per 100,000 population for prevalence), and (2) motor vehicle occupants in the high SDI countries had the lowest mortality (4.07-4.50 per 100,000 population) but the highest morbidity (428.74-467.78 per 100,000 population for incidence and 1025.70-1116.60 per 100,000 population for prevalence). Implementation of the three types of national actions remained nearly unchanged in all five SDI categories from 2011 to 2017 and was consistently stronger in the higher SDI countries than in the lower SDI countries. Lower income nations comprise the heaviest burden of global road traffic injuries and deaths. CONCLUSION: Global road traffic deaths would decrease substantially if the large mortality disparities across country development status were reduced through full implementation of proven national actions including legislation and law enforcement, prioritized vehicle safety standards and trauma-related post-crash care services.

Neferine suppresses osteoclast differentiation through suppressing NF-κB signal pathway but not MAPKs and promote osteogenesis.

Osteoporosis is an ageing disease characterized by elevated osteoclastic bone resorption resulting in bone loss, decrease bone strength, and elevated incidence of fractures. Neferine, a natural compound isolated from the traditional Chinese medicine Nelumbo nucifera (Lotus), has been reported exhibit anti-inflammatory, antioxidant, and anticancer properties. However, its effect on bone remains to be determined. Here we showed that Neferine inhibits RANKL-induced osteoclast formation in a dose- and time-dependent manner. Furthermore, Neferine also demonstrated antiresorptive properties by effectively ameliorating the bone resorptive activity of mature osteoclasts. Mechanistically, Neferine suppressed RANKL-induced activation of NF-κB signaling pathway. This in turn hindered the induction and activation of NFATc1 resulting in downregulation of osteoclast marker genes closely related to differentiation, fusion as well as bone resorption. Interestingly, we found Neferine enhanced the differentiation and bone mineralization activity of MC3T3-E1 preosteoblast cells. Finally, mice treated with Neferine was protected against ovariectomy (OVX)-induced bone loss. The Neferine treatment improved bone volume following ovariectomy and also exhibited less TRAP-positive osteoclasts on bone surface. Collectively our data provide promising evidence that Neferine could be a potential therapeutic application for against osteolytic bone conditions such as osteoporosis.

Genome-Wide Temporal Profiling of Transcriptome and Open Chromatin of Early Cardiomyocyte Differentiation Derived From hiPSCs and hESCs.

RATIONALE: Recent advances have improved our ability to generate cardiomyocytes from human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs). However, our understanding of the transcriptional regulatory networks underlying early stages (ie, from mesoderm to cardiac mesoderm) of cardiomyocyte differentiation remains limited. OBJECTIVE: To characterize transcriptome and chromatin accessibility during early cardiomyocyte differentiation from hiPSCs and hESCs. METHODS AND RESULTS: We profiled the temporal changes in transcriptome and chromatin accessibility at genome-wide levels during cardiomyocyte differentiation derived from 2 hiPSC lines and 2 hESC lines at 4 stages: pluripotent stem cells, mesoderm, cardiac mesoderm, and differentiated cardiomyocytes. Overall, RNA sequencing analysis revealed that transcriptomes during early cardiomyocyte differentiation were highly concordant between hiPSCs and hESCs, and clustering of 4 cell lines within each time point demonstrated that changes in genome-wide chromatin accessibility were similar across hiPSC and hESC cell lines. Weighted gene co-expression network analysis (WGCNA) identified several modules that were strongly correlated with different stages of cardiomyocyte differentiation. Several novel genes were identified with high weighted connectivity within modules and exhibited coexpression patterns with other genes, including noncoding RNA LINC01124 and uncharacterized RNA AK127400 in the module related to the mesoderm stage; E-box-binding homeobox 1 (ZEB1) in the module correlated with postcardiac mesoderm. We further demonstrated that ZEB1 is required for early cardiomyocyte differentiation. In addition, based on integrative analysis of both WGCNA and transcription factor motif enrichment analysis, we determined numerous transcription factors likely to play important roles at different stages during cardiomyocyte differentiation, such as T and eomesodermin (EOMES; mesoderm), lymphoid enhancer-binding factor 1 (LEF1) and mesoderm posterior BHLH transcription factor 1 (MESP1; from mesoderm to cardiac mesoderm), meis homeobox 1 (MEIS1) and GATA-binding protein 4 (GATA4) (postcardiac mesoderm), JUN and FOS families, and MEIS2 (cardiomyocyte). CONCLUSIONS: Both hiPSCs and hESCs share similar transcriptional regulatory mechanisms underlying early cardiac differentiation, and our results have revealed transcriptional regulatory networks and new factors (eg, ZEB1) controlling early stages of cardiomyocyte differentiation.

An experimental and theoretical study of adenine adsorption on Au(111).

A model study of adenine adsorption on the Au(111) surface is reported for molecular adlayers prepared by evaporation in vacuum and deposition from saturated aqueous solution. The electronic structure and adsorption geometry of the molecular films were studied experimentally by X-ray photoelectron spectroscopy and near edge X-ray absorption fine structure spectroscopy. Adsorption models are proposed for the adlayers arising from the different preparation methods. Density functional theory calculations were used to examine both parallel and upright adenine adsorption geometries, supply additional information on the bond strength, and identify which atom is involved in bonding to Au(111). In the case of deposition in vacuum, the adenine molecule is bound via van der Waals forces to Au(111) with the molecular plane parallel to the surface, consistent with the published scanning tunneling microscopy data on this system. The most stable parallel adenine configuration was found to have an adsorption energy of ca. -1.1 eV using the optB86b-vdW functional. For adenine deposition from aqueous solution, the adlayer is disordered, with molecules in an upright geometry, and with an adsorption energy of ca. -1.0 eV, coordinated via the imino N3 nitrogen atom. The present study contributes to the substantial literature of model studies of adenine on Au(111), complementing the existing knowledge with information on electronic structure, bonding geometry and adsorption energy of this system.

Comparative studies of aerobic and anaerobic biodegradation of methylparaben and propylparaben in activated sludge.

The biodegradability of two typical parabens (methylparaben and propylparaben) in activated sludge, at initial concentrations of 1mgL-1 or 10mgL-1, was investigated under aerobic and anaerobic conditions. The results showed that microorganisms played a key role in degradation of parabens in WWTPs, especially in aerobic systems. The half-lives of methylparaben and propylparaben under aerobic conditions have been estimated to range between 15.8 and 19.8min, and benzoic acid was found to be one of the major biodegradation products. The calculated biodegradation efficiency of methylparaben and propylparaben in activated sludge under aerobic conditions was significantly higher than that observed under anaerobic (nitrate, sulfate, and Fe (III) reducing) conditions, as methylparaben and propylparaben exhibited comparatively higher persistence in anaerobic systems, with half-lives ≥43.3h and ≥8.6h, respectively. Overall, the results of this study imply that the majority of these parabens can be eliminated by aerobic biodegradation during conventional wastewater treatment processes, whereas minor removal is possible in anaerobic systems if an insufficient hydraulic retention time was maintained.

Docetaxel-Loaded Lecithoid Nanoparticles with Enhanced Lung Targeting Efficiency and Reduced Systemic Toxicity: Developed by Solid Dispersion and Effervescent Techniques.

The application of chemotherapeutics with chemical drugs is always challenged by their high toxicities throughout the body in clinical trials. Here, we reported a smart formulation of docetaxel developed by solid dispersion and effervescent techniques for efficient and safe delivery of chemical drug to lung tissue. To achieve a high delivery to lung with reduced systemic toxicity, docetaxel was loaded into a kind of lecithoid nanoparticles (DTX-LN) which were prepared by a solid dispersion and effervescent method. After intravenous administration of DTX-LN to rabbit, the docetaxel level in lung was approximately 37-fold higher than that of docetaxel injection (DTX-INJ, a commercial injection preparation of DTX/polysorbate 80 micelles) group at 0.5 h and showed the highest tissue distribution among all the organs. Besides, the targeting parameter Re value of total increased amount of DTX in lung (AUC0-t) ratio (DTX-LN to DTX-INJ) is about 16.69, indicating a significantly enhanced lung targeting ability of DTX-LN. In subacute toxicity study, DTX-LN displayed a reduced hematotoxicity, especially for the negative impacts on white blood cells, lymphocyte and granulocyte when compared with DTX-INJ during both weekly and 3-weekly schedules administration. In addition, histopathological analysis demonstrated that DTX-LN showed less tissue damages on rabbit heart and kidney compared to DTX-INJ. Hence, this work would provide an insight for improving lung delivery efficacy of drugs with reduced systemic toxicity.

Spectroscopic Identification of the Au-C Bond Formation upon Electroreduction of an Aryl Diazonium Salt on Gold.

Electroreduction of aryl diazonium salts on gold can produce organic films that are more robust than their analogous self-assembled monolayers formed from chemical adsorption of organic thiols on gold. However, whether the enhanced stability is due to the Au-C bond formation remains debated. In this work, we report the electroreduction of an aryl diazonium salt of 4,4'-disulfanediyldibenzenediazonium on gold forming a multilayer of Au-(Ar-S-S-Ar)n, which can be further degraded to a monolayer of Au-Ar-S- by electrochemical cleavage of the S-S moieties within the multilayer. By conducting an in situ surface-enhanced Raman spectroscopic study of both the multilayer formation/degradation and the monolayer reduction/oxidation processes, coupled to density functional theory calculations, we provide compelling evidence that an Au-C bond does form upon electroreduction of aryl diazonium salts on gold and that the enhanced stability of the electrografted organic films is due to the Au-C bond being intrinsically stronger than the Au-S bond for a given phenylthiolate compound by ca. 0.4 eV.

Astragaloside I Stimulates Osteoblast Differentiation Through the Wnt/ß-catenin Signaling Pathway.

Astragaloside I (As-I), one of the main active ingredients in Astragalus membranaceus, is believed to have osteogenic properties, but this hypothesis has not been investigated in detail. In the present work, the As-I-induced osteogenic effects and its underlying mechanism were studied in MC3T3-E1 cells. The results indicated that the cellular levels of ALP and extracellular matrix calcium increased in a dose-dependent manner by As-I. To clarify the mechanisms involved in this process, the effect of As-I on the key osteogenic-related genes was investigated. We found that As-I stimulated the expression of ß-catenin and Runx2 in MC3T3-E1 cells, which play central roles in the Wnt/ß-catenin signaling pathway, suggesting that As-I could promote osteoblastic differentiation by regulating the Wnt/ß-catenin signaling pathway. Moreover, the osteogenic effect of As-I could be inhibited by DKK-1, which is the classical inhibitor of Wnt/ß-catenin-signaling pathway. Furthermore, As-I also increased BMP-2, BGP and OPG/RANKL expression, which are also activated by Wnt/ß-catenin signaling pathway. Taken together, our findings show that As-I stimulates osteoblast differentiation through the Wnt/ß-catenin signaling pathway, which also activates the BMP pathway and RANK pathway, thus highlighting the As-I for pharmaceutical and medicinal applications such as treating bone disease. Copyright © 2016 John Wiley & Sons, Ltd.

Cetuximab inhibits colorectal cancer development through inactivating the Wnt/ß-catenin pathway and modulating PLCB3 expression.

Colorectal cancer (CRC) often necessitates cetuximab (an EGFR-targeting monoclonal antibody) for treatment. Despite its clinical utility, the specific operative mechanism of cetuximab remains elusive. This research investigated the influence of PLCB3, a potential CRC oncogene, on cetuximab treatment. We extracted differentially expressed genes from the GSE140973, the overlapping genes combined with 151 Wnt/ß-Catenin signaling pathway-related genes were identified. Then, we conducted bioinformatics analysis to pinpoint the hub gene. Subsequently, we investigated the clinical expression characteristics of this hub gene, through cell experimental, scrutinized the impact of cetuximab and PLCB3 on CRC cellular progression. The study identified 26 overlapping genes. High expression of PLCB3, correlated with poorer prognosis. PLCB3 emerged as a significant oncogene associated with patient prognosis. In vitro tests revealed that cetuximab exerted a cytotoxic effect on CRC cells, with PLCB3 knockdown inhibiting CRC cell progression. Furthermore, cetuximab treatment led to a reduction in both ß-catenin and PLCB3 expression, while simultaneously augmenting E-cadherin expression. These findings revealed PLCB3 promoted cetuximab inhibition on Wnt/ß-catenin signaling. Finally, simultaneous application of cetuximab with a Wnt activator (IM12) and PLCB3 demonstrated inhibited CRC proliferation, migration, and invasion. The study emphasized the pivotal role of PLCB3 in CRC and its potential to enhance the efficacy of cetuximab treatment. Furthermore, cetuximab suppressed Wnt/ß-catenin pathway to modulate PLCB3 expression, thus inhibiting colorectal cancer progression. This study offered fresh perspectives on cetuximab mechanism in CRC.

Hai-Honghua medicinal liquor is a reliable remedy for fracture by promotion of osteogenic differentiation via activation of PI3K/Akt pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Hai-Honghua medicinal liquor (HHML), an external Chinese herbal formula preparation, is often applied to treat freshly closed tibia/fibular fractures, ankle fractures, and other bone-related disorders, but the related molecular mechanism is unclear. AIM OF THE STUDY: To evaluate the therapeutic effect of HHML in patients with tibial/fibular and ankle fractures, and to explore its related possible mechanism. METHODS AND MATERIALS: A total of 182 patients with tibia/fibular fractures and 183 patients with ankle fractures were enrolled in this study. A randomized, controlled, unblinded clinical trial was designed to evaluate the therapeutic effect of HHML on tibial/fibular and ankle fractures. The chemical compositions of HHML were analyzed by the HPLC-Q-Extractive MS/MS. Furthermore, a rat tibial fracture model was established to evaluate the therapeutic effects of HHML in promoting fracture healing, and the mouse embryonic osteoblasts cell line of MC3T3-E1 was further carried out to explore the mechanisms of HHML on osteoblast differentiation. RESULTS: In the clinical evaluation, HHML treatment significantly shortened the time for pain and swelling in patients with tibial/fibular fractures (P < 0.01) and ankle fractures (P < 0.01), and the incidence of complications was significantly reduced as well. Subsequently, 116 constituents were identified from HHML via HPLC-Q-TOF-MS/MS analysis. In vivo, no obvious changes in weight were observed in HHML-treated rats. Moreover, the levels of bone formation markers (including osteocalcin (OCN), N-terminal propeptide of type I procollagen (PINP), alkaline phosphatase (ALP), calcium (Ca) and substance P) in rat serum were significantly increased in HHML-treated rats compared with model rats (P < 0.05). Micro-CT analysis showed bone mineral density (BMD), bone volume fraction (BV/TV), trabecular thickness (Tb.Th) of the HHML-treated rats were significantly increased (P < 0.05, vs. Model) while trabecular separation (Tb.Sp) and structure model index (SMI) values were significantly reduced (P < 0.05, vs. Model). Histological analysis showed that HHML treatment promoted the healing of fractures and cartilage repair, and increased the osteoblasts and collagen fibers. Furthermore, our results also revealed HHML could promote MC3T3-E1 cells proliferation and osteoblast differentiation via regulation of the runt-related transcription factor 2 (RUNX2), bone alkaline phosphatase (BALP), and OCN by activating phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway, which confirmed by adding PI3K chemical inhibitor of LY294002. CONCLUSION: HHML treatment is a reliable remedy for fractures in tibial and ankle by promotion of osteogenic differentiation via activation of PI3K/Akt pathway.

Personalized transcriptome signatures in a cardiomyopathy stem cell biobank.

BACKGROUND: There is growing evidence that pathogenic mutations do not fully explain hypertrophic (HCM) or dilated (DCM) cardiomyopathy phenotypes. We hypothesized that if a patient's genetic background was influencing cardiomyopathy this should be detectable as signatures in gene expression. We built a cardiomyopathy biobank resource for interrogating personalized genotype phenotype relationships in human cell lines. METHODS: We recruited 308 diseased and control patients for our cardiomyopathy stem cell biobank. We successfully reprogrammed PBMCs (peripheral blood mononuclear cells) into induced pluripotent stem cells (iPSCs) for 300 donors. These iPSCs underwent whole genome sequencing and were differentiated into cardiomyocytes for RNA-seq. In addition to annotating pathogenic variants, mutation burden in a panel of cardiomyopathy genes was assessed for correlation with echocardiogram measurements. Line-specific co-expression networks were inferred to evaluate transcriptomic subtypes. Drug treatment targeted the sarcomere, either by activation with omecamtiv mecarbil or inhibition with mavacamten, to alter contractility. RESULTS: We generated an iPSC biobank from 300 donors, which included 101 individuals with HCM and 88 with DCM. Whole genome sequencing of 299 iPSC lines identified 78 unique pathogenic or likely pathogenic mutations in the diseased lines. Notably, only DCM lines lacking a known pathogenic or likely pathogenic mutation replicated a finding in the literature for greater nonsynonymous SNV mutation burden in 102 cardiomyopathy genes to correlate with lower left ventricular ejection fraction in DCM. We analyzed RNA-sequencing data from iPSC-derived cardiomyocytes for 102 donors. Inferred personalized co-expression networks revealed two transcriptional subtypes of HCM. The first subtype exhibited concerted activation of the co-expression network, with the degree of activation reflective of the disease severity of the donor. In contrast, the second HCM subtype and the entire DCM cohort exhibited partial activation of the respective disease network, with the strength of specific gene by gene relationships dependent on the iPSC-derived cardiomyocyte line. ADCY5 was the largest hubnode in both the HCM and DCM networks and partially corrected in response to drug treatment. CONCLUSIONS: We have a established a stem cell biobank for studying cardiomyopathy. Our analysis supports the hypothesis the genetic background influences pathologic gene expression programs and support a role for ADCY5 in cardiomyopathy.

Determinants of brachial-ankle pulse wave velocity in Chinese patients with rheumatoid arthritis.

OBJECTIVE: To investigate the relationship between Brachial-ankle pulse wave velocity (baPWV), and its associated risk factors in Chinese patients with RA. METHODS: 138 Chinese RA patients and 150 healthy subjects were included. baPWV of all the participants was measured. RA related factors were determined, as well as traditional cardiovascular risk factors. RESULTS: baPWV was significant higher in RA group (1705.44 ± 429.20 cm/s) compared to the healthy control group (1386.23 ± 411.09 cm/s) (P < 0.001). Compared with low baPWV group, high baPWV group patients were significantly older (P = 0.008) and taller (P = 0.033). Serum cholesterol (P = 0.035), triglycerides (P = 0.004), and LDL level (P = 0.006) were significantly higher in high baPWV group patients compared with low baPWV group patients. The baPWV of RA patients was positively correlated with age (r = 0.439, P < 0.001), and serum cholesterol level (r = 0.231, P = 0.035), serum triglycerides level (r = 0.293, P < 0.001), serum LDL level (r = 0.323, P = 0.003). Meanwhile, baPWV negatively correlated with the height of RA patients (r = -0.253, P = 0.043). Multivariate regression analysis showed that baPWV of RA group was independently associated with age and serum triglycerides level. CONCLUSIONS: The old age and high level of serum triglycerides may be the major determinants of arterial stiffness in Chinese RA patients.

Downregulation of cancer-associated fibroblast exosome-derived miR-29b-1-5p restrains vasculogenic mimicry and apoptosis while accelerating migration and invasion of gastric cancer cells via immunoglobulin domain-containing 1/zonula occluden-1 axis.

Background: Cancer-associated fibroblast (CAF) exosomal miRNAs have gradually a hot spot in cancer therapy. This study mainly explores the effect of CAF-derived exosomal miR-29b-1-5p on gastric cancer (GC) cells.Methods: CAFs and exosomes were identified by Western blot and transmission electron microscopy. CAF-derived exosomes-GC cells co-culture systems were constructed. Effects of CAF-derived exosomal miR-29b-1-5p on GC cells were determined by cell counting kit-8, flow cytometry, wound healing, Transwell assays and Western blot. The relationship between miR-29b-1-5p and immunoglobulin domain-containing 1 (VSIG1) was assessed by TargetScan, dual-luciferase reporter and RNA immunoprecipitation (RIP) experiments. The interaction between VSIG1 and zonula occluden-1 (ZO-1) was detected by co-immunoprecipitation. Expressions of miR-29b-1-5p, VSIG1 and ZO-1 were determined by quantitative real-time PCR. Vascular mimicry (VM) was detected using immunohistochemistry and tube formation assays. Rescue experiments and xenograft tumor assays were used to further determine the effect of CAF-derived exosomal miR-29b-1-5p/VSIG1 on GC.Results: VM structure, upregulation of miR-29b-1-5p, and downregulation of VSIG1 and ZO-1 were shown in GC tissues. MiR-29b-1-5p targeted VSIG1, which interacted with ZO-1. CAF-derived exosomal miR-29b-1-5p inhibitor suppressed the viability, migration, invasion and VM formation, but promoted the apoptosis of GC cells. MiR-29b-1-5p inhibitor increased levels of VSIG1, ZO-1 and E-cadherin, whilst decreasing levels of VE-cadherin, N-cadherin and Vimentin in vitro and in vivo, which however was partially reversed by shVSIG1. Downregulation of CAF-derived exosomal miR-29b-1-5p impeded GC tumorigenesis and VM structure in vivo by upregulating VSIG1/ZO-1 expression.Conclusion: Downregulation of CAF-derived exosomal miR-29b-1-5p inhibits GC progression via VSIG1/ZO-1 axis.

Hydroxy-α-sanshool from the fruits of Zanthoxylum bungeanum Maxim. promotes browning of white fat by activating TRPV1 to induce PPAR-γ deacetylation.

BACKGROUND: Accumulating evidence suggested increasing energy expenditure is a feasible strategy for combating obesity, and browning of white adipose tissue (WAT) to promote thermogenesis might be one of the attractive ways. Hydroxy-α-sanshool (HAS), a natural amide alkaloid extracted from the fruits of Zanthoxylum bungeanum Maxim, possesses lots of benefits in lipid metabolism regulation. METHODS: The anti-obesity effect of HAS was investigated by establishing an animal model of obesity and a 3T3-L1 differentiation cell model. Effects of HAS on the whole-body fat and liver of obese mice, and the role of HAS in inducing browning of white fat were studied by Micro CT, Metabolic cage detection, Cell mitochondrial pressure detection, transmission electron microscopy and cold exposure assays. Furthermore, the Real-time PCR (qPCR), digital PCR (dPCR), western blot, Co-immunoprecipitation (Co-IP), molecular docking, drug affinity responsive target stability (DARTS), Cellular thermal shift assay (CETSA) and other methods were used to investigate the target and mechanisms of HAS. RESULTS: We found that treatment with HAS helped mice combat obesity caused by a high fat diet (HFD) and improve metabolic characteristics. In addition, our results suggested that the anti-obesity effect of HAS is related to increase energy consumption and thermogenesis via induction of browning of WAT. The further investigations uncovered that HAS can up-regulate UCP-1 expression, increase mitochondria number, and elevate the cellular oxygen consumption rates (OCRs) of white adipocytes. Importantly, the results indicated that browning effects of HAS is closely associated with SIRT1-dependent PPAR-γ deacetylation through activating the TRPV1/AMPK pathway, and TRPV1 is the potential drug target of HAS for the browning effects of WAT. CONCLUSIONS: Our results suggested the HAS can promote browning of WAT via regulating AMPK/SIRT-1/PPARγ signaling, and the potential drug target of HAS is the membrane receptor of TRPV1.

Synthesis of gold nanowire networks and nanoparticles by tyrosine reduction of chloroaurate.

A simple and facile synthesis of gold nanowire networks and sol particles at room temperature is presented using L-tyrosine (Tyr) as both the reducing and capping agent. The synthesis conditions with varying the gold precursor concentration ([HAuCl4], 0.1-2.5 mM) and concentration ratio of tyrosine to gold precursor R ([Tyr]/[HAuCl4], 0.05-10) were identified for the preparation of network-like nanowires and sol nanoparticles. Gold sol particles with sizes between 10 and 18 nm were mostly obtained at R > or = 0.2. Network-like gold nanowires with average diameters as thin as 8 nm can be reproducibly synthesized at R < or = 0.1. The experimental data revealed that the phenolic and carboxyl group of Tyr were oxidized to form quinone and alcohol, respectively. The growth process was examined to elucidate the influence of the synthesis conditions on different morphologies, showing marked difference in isotropic and anisotropic growth of gold nanostructures at different synthesis conditions. The study showed that tyrosine possesses excellent reducing capability with short nucleation period and long growth period as compared with other amino acids.