Cell transcriptomic atlas of the non-human primate Macaca fascicularis.

Studying tissue composition and function in non-human primates (NHPs) is crucial to understand the nature of our own species. Here we present a large-scale cell transcriptomic atlas that encompasses over 1 million cells from 45 tissues of the adult NHP Macaca fascicularis. This dataset provides a vast annotated resource to study a species phylogenetically close to humans. To demonstrate the utility of the atlas, we have reconstructed the cell-cell interaction networks that drive Wnt signalling across the body, mapped the distribution of receptors and co-receptors for viruses causing human infectious diseases, and intersected our data with human genetic disease orthologues to establish potential clinical associations. Our M. fascicularis cell atlas constitutes an essential reference for future studies in humans and NHPs.

Self-Catalyzed, Visible-Light-Induced Selective C3-H Aroylation of Quinoxalin-2(1H)-ones with Arylaldehydes by Air as an Oxidant.

A self-catalyzed, visible-light-induced, directly selective C3-H aroylation of quinoxalin-2(1H)-ones via energy transfer and hydrogen atom transfer (HAT) catalysis has been developed. The method is highly atom-economical, eco-friendly, and easy to handle. Notably, the reaction proceeded efficiently with ambient air as the sole oxidant at room temperature.

Orf virus induces complete autophagy to promote viral replication via inhibition of AKT/mTOR and activation of the ERK1/2/mTOR signalling pathway in OFTu cells.

Orf virus (ORFV) is the causative agent of contagious ecthyma, which is an important zoonotic pathogen with a widespread distribution affecting sheep, goats and humans. Our previous research showed that autophagy can be induced in host cells by ORFV infection. However, the exact mechanism of ORFV-induced autophagy remains unknown. In this study, we investigated the underlying mechanisms of autophagy induced by ORFV in OFTu cells and the impact of autophagy on ORFV replication. By using specific autophagy inhibitors and activators, Western blotting, immunofluorescence and transmission electron microscopy imaging, we confirmed that ORFV infection triggered intracellular autophagosome accumulation and the activation of autophagic flux. Moreover, ORFV-induced autophagic activity was found to rely on an increase in the phosphorylation of tuberous sclerosis complex 2 (TSC2) and a decrease in the phosphorylation of mammalian target of rapamycin (mTOR), which is mediated by the suppression of the PI3K/AKT/mTOR signalling pathway and activation of the ERK1/2/mTOR signalling pathway. Furthermore, we investigated the role of mTOR-mediated autophagy during ORFV replication using pharmacological agents and demonstrated that ORFV-induced autophagy correlated positively with viral replication. Taken together, our data reveal the pathways of ORFV-induced autophagy and the impact of autophagy on ORFV replication, providing new insights into ORFV pathogenesis.

Effects of ambient air pollution on cause-specific hospitalizations in Wuhan during 2017-2019.

BACKGROUND: Few studies have focused on the associations between air pollutants and multiple organ system diseases in the entire hospitalized population. The present study aims to explore the short-term effects of six routinely monitored air pollutants on the broad causes of hospital admissions and estimate the resulting hospital admission burdens. METHODS: Daily hospital admission records from 2017 to 2019 were obtained from the Wuhan Information center of Health and Family Planning. Generalized additive models (GAMs) were employed to evaluate the effects of air pollutants on the percent increase in the cause-specific daily number of hospital admissions. Increased hospital admission numbers, days, and expenses were also estimated. RESULTS: A total of 2636,026 hospital admissions were identified. We found that both PM2.5 and PM10 increased the risk of hospital admissions for most disease categories. Short-term exposure to PM2.5 was positively associated with hospitalizations of several rarely studied disease categories, such as diseases of the eye and adnexa (2.83%, 95%CI: 0.96-4.73%, P < 0.01) and diseases of the musculoskeletal system and connective tissue (2.17%, 95% CI: 0.88-3.47%, P < 0.001). NO2 was observed to have a robust effect on diseases of the respiratory system (1.36%, 95%CI: 0.74-1.98%, P < 0.001). CO was significantly associated with hospital admissions for six disease categories. Furthermore, each 10-µg/m3 increase in PM2.5 was associated with an annual increase of 13,444 hospital admissions (95% CI: 6239-20,649), 124,344 admission days (95% CI: 57,705-190,983), and 166-million-yuan admission expenses (95% CI: 77-255). CONCLUSION: Our study suggested that particulate matter (PM) had a short-term effect on hospital admissions of most major disease categories and resulted in a considerable hospital admission burden. In addition, the health effects of NO2 and CO emissions require more attention in megacities.

The trade-offs and synergies of the ecological-production-living functions of grassland in the Qilian mountains by ecological priority.

Grassland degradation has caused increasingly prominent conflict between ecological environment conservation and socioeconomic development in the Qilian Mountains, China. How to effectively trade-offs and synergies to ecological and socioeconomic is essential to achieving the sustainable development of the grassland ecosystem. However, few studies have addressed the trade-offs and synergies of grassland ecosystem services in terms of coupling the natural ecosystem and the socioeconomic system. Therefore, we constructed an index of the analyzed trade-offs and synergies of grassland ecosystem services from the perspective of "ecological-production-living" functions (EPLFs) and analyzed the spatial-temporal characteristics of grassland EPLF trade-off and synergy relationships based on the data from the implementation of three conservation policies in the Qilian Mountains from 2003 to 2020. The results showed evident spatial and temporal differentiation of the grassland EPLFs. The ecological function was consistent with the production function, trending upward initially and then decreasing. The living function showed a trend of continuous increase. The spatial pattern of grassland EPLFs showed that the northwest and southeast were more active than the middle of the Qilian Mountains, and the regional gradient difference was apparent. The trade-off and synergy relationships of grassland EPLFs have obvious spatial correlations as well; spatial differences were evident under different conservation policies. With national park construction, the synergistic relationship gradually weakened and the trade-off relationship gradually strengthened. These results suggest that the policy of ecological priority increased trade-offs and reduced synergies among EPLFs was not conducive to coupling and coordinating grassland EPLFs for development in the Qilian Mountains. Our study also demonstrates that maintaining moderate grassland grazing pressure and the appropriate number of herdsmen is crucial to sustainably develop the grassland ecosystem in the Qilian Mountains, and further research into coupling mechanisms for grassland EPLFs is needed to reduce trade-offs and increase synergies with grassland ecosystem services.

Recent Advances in the Synthesis of 3,n-Fused Tricyclic Indole Skeletons via Palladium-Catalyzed Domino Reactions.

3,n-fused (n = 4-7) tricyclic indoles are pervasive motifs, embedded in a variety of biologically active molecules and natural products. Thus, numerous catalytic methods have been developed for the synthesis of these skeletons over the past few decades. In particular, palladium-catalyzed transformations have received much attention in recent years. This review summarizes recent developments in the synthesis of these tricyclic indoles with palladium-catalyzed domino reactions and their applications in the total synthesis of representative natural products.

Construction of Microporous Zincophilic Interface for Stable Zn Anode.

Aqueous zinc ion batteries (AZIBs) are promising electrochemical energy storage devices due to their high theoretical specific capacity, low cost, and environmental friendliness. However, uncontrolled dendrite growth poses a serious threat to the reversibility of Zn plating/stripping, which impacts the stability of batteries. Therefore, controlling the disordered dendrite growth remains a considerable challenge in the development of AZIBs. Herein, a ZIF-8-derived ZnO/C/N composite (ZOCC) interface layer was constructed on the surface of the Zn anode. The homogeneous distribution of zincophilic ZnO and the N element in the ZOCC facilitates directional Zn deposition on the (002) crystal plane. Moreover, the conductive skeleton with a microporous structure accelerates Zn2+ transport kinetics, resulting in a reduction in polarization. As a result, the stability and electrochemical properties of AZIBs are improved. Specifically, the ZOCC@Zn symmetric cell sustains over 1150 h at 0.5 mA cm-2 with 0.25 mA h cm-2, while the ZOCC@Zn half-cell achieves an outstanding Coulombic efficiency of 99.79% over 2000 cycles. This work provides a simple and effective strategy for improving the lifespan of AZIBs.

Percentile curves of normal echocardiographic measurements values for left heart structures in 1570 Han Chinese preterm and term infants.

OBJECTIVE: This study was designed to evaluate echocardiographic measurements in Han Chinese preterm and term infants and to build percentile curves of normal echocardiographic measurements values related to the weight. METHOD: From December 2014 to December 2021, a total of 797 male infants and 773 female infants born in * were included in the study. The echocardiographic measurements of each subject were as follows: left ventricular internal diameter at end-diastole (LVIDd), left ventricular internal diameter at end-systole (LVIDs), left ventricular posterior wall thickness at end-diastole (LVPWd), left ventricular posterior wall thickness at end-systole (LVPWs), interventricular septal thickness at end-diastole (IVSd), interventricular septal thickness at end-systole (IVSs), ascending aorta diameter (AO), left atrium (LA) dimension, left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS) and left ventricular mass (LVM). The correlations between echocardiography measurements and birth weight (BW), length (L), gestational age (GA), and body surface area (BSA) were analyzed. RESULTS: There was a good correlation between the echocardiographic measurements and birth weight and percentile curves of the echocardiographic measurements were established according to different birth weight. The echocardiographic measurements were not affected by gender. However, LVEF and LVFS did not change with BW or gender. CONCLUSIONS: The percentile curves of normal values make it possible to classify echocardiographic measurements for left heart structures and function as normal or abnormal and is helpful for the diagnosis of neonatal heart disease in preterm and term infants.

Effect of ambient fine particulates (PM2.5) on hospital admissions for respiratory and cardiovascular diseases in Wuhan, China.

BACKGROUND: Positive associations between ambient PM2.5 and cardiorespiratory disease have been well demonstrated during the past decade. However, few studies have examined the adverse effects of PM2.5 based on an entire population of a megalopolis. In addition, most studies in China have used averaged data, which results in variations between monitoring and personal exposure values, creating an inherent and unavoidable type of measurement error. METHODS: This study was conducted in Wuhan, a megacity in central China with about 10.9 million people. Daily hospital admission records, from October 2016 to December 2018, were obtained from the Wuhan Information center of Health and Family Planning, which administrates all hospitals in Wuhan. Daily air pollution concentrations and weather variables in Wuhan during the study period were collected. We developed a land use regression model (LUR) to assess individual PM2.5 exposure. Time-stratified case-crossover design and conditional logistic regression models were adopted to estimate cardiorespiratory hospitalization risks associated with short-term exposure to PM2.5. We also conducted stratification analyses by age, sex, and season. RESULTS: A total of 2,806,115 hospital admissions records were collected during the study period, from which we identified 332,090 cardiovascular disease admissions and 159,365 respiratory disease admissions. Short-term exposure to PM2.5 was associated with an increased risk of a cardiorespiratory hospital admission. A 10 µg/m3 increase in PM2.5 (lag0-2 days) was associated with an increase in hospital admissions of 1.23% (95% CI 1.01-1.45%) and 1.95% (95% CI 1.63-2.27%) for cardiovascular and respiratory diseases, respectively. The elderly were at higher PM-induced risk. The associations appeared to be more evident in the cold season than in the warm season. CONCLUSIONS: This study contributes evidence of short-term effects of PM2.5 on cardiorespiratory hospital admissions, which may be helpful for air pollution control and disease prevention in Wuhan.

SOX17 Loss-of-Function Mutation Underlying Familial Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) refers to a rare, progressive disorder that is characterized by occlusive pulmonary vascular remodeling, resulting in increased pulmonary arterial pressure, right-sided heart failure, and eventual death. Emerging evidence from genetic investigations of pediatric-onset PAH highlights the strong genetic basis underpinning PAH, and deleterious variants in multiple genes have been found to cause PAH. Nevertheless, PAH is of substantial genetic heterogeneity, and the genetic defects underlying PAH in the overwhelming majority of cases remain elusive. In this investigation, a consanguineous family suffering from PAH transmitted as an autosomal-dominant trait was identified. Through whole-exome sequencing and bioinformatic analyses as well as Sanger sequencing analyses of the PAH family, a novel heterozygous SOX17 mutation, NM_022454.4: c.379C>T; p. (Gln127*), was found to co-segregate with the disease in the family, with complete penetrance. The nonsense mutation was neither observed in 612 unrelated healthy volunteers nor retrieved in the population genetic databases encompassing the Genome Aggregation Database, the Exome Aggregation Consortium database, and the Single Nucleotide Polymorphism database. Biological analyses using a dual-luciferase reporter assay system revealed that the Gln127*-mutant SOX17 protein lost the ability to transcriptionally activate its target gene NOTCH1. Moreover, the Gln127*-mutant SOX17 protein exhibited no inhibitory effect on the function of CTNNB1-encode ß-catenin, which is a key player in vascular morphogenesis. This research firstly links SOX17 loss-of-function mutation to familial PAH, which provides novel insight into the molecular pathogenesis of PAH, suggesting potential implications for genetic and prognostic risk evaluation as well as personalized prophylaxis of the family members affected with PAH.

Comprehensive Analysis of Candidate Diagnostic and Prognostic Biomarkers Associated with Lung Adenocarcinoma.

BACKGROUND We aimed to screen and identify central genetic and molecular targets involved in advancement of lung adenocarcinoma (LUAD) and to perform an integrated analysis and clinical validation. MATERIAL AND METHODS The GEO2R technique was utilized to assess differentially expressed genes (DEGs) among the gene sets GSE75037, GSE85716, and GSE118370. Subsequently, gene Ontology (GO) analyses and Kyoto Encyclopedia of Genes and Genomes (KEGG) analytical methods were executed to determine related biofunctions and signaling pathways, which were annotated with tools from the Database for Annotation, Visualization and Integrated Discovery (DAVID) resource. Then, a protein-protein interaction (PPI) network complex consisting of all detected DEGs was built with the STRING web interface. Cytohubba and MCODE plug-ins for Cytoscape software and Gene Expression Profiling Interactive Analysis (GEPIA) were employed to identify the hub genes. Finally, the mRNA expression of the identified hub genes was quantitatively validated by The Cancer Genome Atlas (TCGA) database analysis and real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS We screened 146 upregulated DEGs and 431 downregulated DEGs with the criteria of |logFC| >1 and P<0.05, and the GO analysis indicated that DEGs were implicated in mitotic nuclear division (biological process, BP), the nucleus (cellular component, CC), and protein binding (molecular function, MF) and were associated with multiple KEGG pathways, such as the p53 signaling pathway in cancer. Then, the top 8 genes that predicted significantly different outcomes in LUAD patients were filtered from the DEGs and selected as hub genes. The TCGA database analysis and RT-qPCR results demonstrated that these genes were differentially expressed with the same trends in LUAD tissues compared with normal tissues. CONCLUSIONS Overall, we propose that 8 genes (PECAM1, CDK1, MKI67, SPP1, TOP2A, CHEK1, CCNB1, and RRM2) might be novel hub genes strongly associated with the progression and prognosis of LUAD.

[Discovery and functional analysis of a novel ISL1 variant associated with congenital heart defect].

OBJECTIVE: To analyze variation of ISL1 gene and explore its functional characteristics in relation with congenital heart defect (CHD). METHODS: Clinical data and peripheral blood samples of 194 CHD patients and 232 healthy controls were collected for the extraction of genomic DNA. The coding exons and flanking intronic regions of the ISL1 gene were sequenced. Expression plasmid for the wild-type ISL1 gene ISL1-pcDNA3.1 was constructed, and the corresponding variants were obtained by site-specific mutagenesis. The gene expression plasmid was transfected into CHO cells with liposome, and the functional characteristics of ISL1 variant were studied by double luciferase reporter gene analysis. RESULTS: A novel variant of the ISL1 gene c.499C>T (p.Q167X) was detected in a patient with sporadic CHD. Functional study showed that the variant has lost its transcriptional activation function for the MEF2C promoter. CONCLUSION: A novel variant of the ISL1 gene related to CHD has been identified. The defect of ISL1 gene may underlay the pathogenesis for a proportion of CHD.

Quercetin protects rats from catheter-related Staphylococcus aureus infections by inhibiting coagulase activity.

Coagulase (Coa) activity is essential for the virulence of Staphylococcus aureus (S aureus), one of the most important pathogenic bacteria leading to catheter-related bloodstream infections (CRBSI). We have demonstrated that the mutation of coagulase improved outcomes in disease models of S aureus CRBSI, suggesting that targeting Coa may represent a novel antiinfective strategy for CRBSI. Here, we found that quercetin, a natural compound that does not affect S aureus viability, could inhibit Coa activity. Chemical biological analysis revealed that the direct engagement of quercetin with the active site (residues Tyr187, Leu221 and His228) of Coa inhibited its activity. Furthermore, treatment with quercetin reduced the retention of bacteria on catheter surfaces, decreased the bacterial load in the kidneys and alleviated kidney abscesses in vivo. These data suggest that antiinfective therapy targeting Coa with quercetin may represent a novel strategy and provide a new leading compound with which to combat bacterial infections.

Identification and Integrated Analysis of Key Biomarkers for Diagnosis and Prognosis of Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is the main histologic form of lung cancer that affects human health, but biomarkers for therapeutic diagnosis and prognosis of the disease are currently lacking. The gene expression profile GSE18842 was downloaded from the Gene Expression Omnibus database in this prospective study, which consisted of 46 tumors and 45 controls. After screening differentially expressed genes (DEGs), we conducted functional enrichment analysis and KEGG analysis with upregulated differentially expressed genes (uDEGs) and downregulated differentially expressed genes (dDEGs), respectively. Protein-protein interaction (PPI) networks among DEGs and corresponding coding protein complexes, constructed using the STRING database, were analyzed using Cytoscape. Kaplan-Meier method was used to verify survival associated with hub genes. The GEPIA webserver was used to plot the gene expression level heat map of hub genes between NSCLC and adjacent lung tissues in the TCGA database. We identified 368 DEGs (168 uDEGs and 200 dDEGs) in NSCLC samples relative to control samples after gene integration. We established a PPI network for the DEGs, which had 249 nodes and 1472 edges protein pairs. Ten undefined hub genes with the highest connectivity degree (CDK1, UBE2C, AURKA, CCNA2, CDC20, CCNB1, TOP2A, ASPM, MAD2L1, and KIF11) were verified by survival analysis, and 9 of them were associated with poorer overall survival in NSCLC. The expression reliability of hub genes was verified by use of the GEPIA web tool. The results suggested that UBE2C, AURKA, CCNA2, CDC20, CCNB1, TOP2A, ASPM, MAD2L1, and KIF11 are inherent key biomarkers for diagnosis and prognosis, while KEGG analysis results showed the mitotic cell cycle pathway is a probable signaling pathway contributing to NSCLC progression. These genes could be promising biomarkers for diagnosis and provide a new approach for developing targeted therapeutic NSCLC drugs.

Xanthan Gum Ameliorates Osteoarthritis and Mitigates Cartilage Degradation via Regulation of the Wnt3a/ß-Catenin Signaling Pathway.

BACKGROUND Osteoarthritis (OA) is a joint disease characterized by articular cartilage degeneration and inflammation. We have previously clarified that a xanthan gum (XG) preparation exerts ameliorating effect on a rabbit OA model by regulating matrix metalloproteinase (MMP)-1 and MMP-3, which are critical proteins in the Wnt3a/ß-catenin pathway. Thus, it is reasonable to predict that the Wnt3a/ß-catenin pathway is involved in the treatment of OA with XG. MATERIAL AND METHODS The effect of XG in OA model animals were observed by hematoxylin and eosin staining (HE), Safranin O staining, and Fast Green staining. Articular cartilage degradation on the medial plateau sides was quantified using the modified Pritzker OARSI score. The levels of IL-6, TNF-alpha, and IL-1ß in synovial fluid were determined with ELISA. The protective effect of XG in rat chondrocytes was assessed by CCK8 assay. Moreover, activation of the Wnt3a/ß-catenin pathway and the expression of MMP13, ADAMTS5, aggrecan, and collagen II under the influence of XG was measured by Western blot and qRT-PCR. RESULTS Our results showed that XG reduced the OARSI score and the concentration of inflammatory cytokines in OA after intra-articular injection. XG acted on Wnt3a/ß-catenin in ATDC5 cells in a dose-dependent manner and exhibited a protective effect. XG also decreased the expression of MMP13 and ADAMTS5 and rescued the inhibition of aggrecan and collagen II expression in SNP-stimulated chondrocytes. CONCLUSIONS These results indicate that the effects of XG are related to the Wnt3a/ß-catenin pathway and XG suppresses matrix degradation by inhibiting the expression of MMPs and ADAMTS and promotes aggrecan and collagen II content in the ECM, indicating its favorable potential for use in OA therapy.

A New ISL1 Loss-of-Function Mutation Predisposes to Congenital Double Outlet Right Ventricle.

Occurring in about 1% of all live births, congenital heart defects (CHDs) represent the most frequent type of developmental abnormality and account for remarkably increased infant morbidity and mortality. Aggregating studies demonstrate that genetic components have a key role in the occurrence of CHDs. Nevertheless, due to pronounced genetic heterogeneity, the genetic causes of CHDs remain unclear in most patients. In this research, 114 unrelated patients affected with CHDs and 218 unrelated individuals without CHDs served as controls were recruited. The coding regions and splicing donors/acceptors of the ISL1 gene, which codes for a transcription factor required for proper cardiovascular development, were screened for mutations by sequencing in all study participants. The functional characteristics of an identified ISL1 mutation were delineated with a dual-luciferase reporter assay system. As a result, a new heterozygous ISL1 mutation, NM_002202.2: c.225C>G; p. (Tyr75*), was discovered in an index patient with double outlet right ventricle and ventricular septal defect. Analysis of the proband's family unveiled that the mutation co-segregated with the CHD phenotype. The nonsense mutation was absent in the 436 control chromosomes. Biological analysis showed that the mutant ISL1 protein had no transcriptional activity. Furthermore, the mutation nullified the synergistic activation between ISL1 and TBX20, another CHD-associated transcription factor. This research for the first time links an ISL1 loss-of-function mutation to double outlet right ventricle in humans, which adds insight to the molecular pathogenesis underpinning CHDs, suggesting potential implications for timely personalized management of CHD patients.

A Novel MEF2C Loss-of-Function Mutation Associated with Congenital Double Outlet Right Ventricle.

Congenital heart defect (CHD) represents the most prevalent birth defect, and accounts for substantial morbidity and mortality in humans. Aggregating evidence demonstrates the genetic basis for CHD. However, CHD is a heterogeneous disease, and the genetic determinants underlying CHD in most patients remain unknown. In the present study, a cohort of 186 unrelated cases with CHD and 300 unrelated control individuals were recruited. The coding exons and flanking introns of the MEF2C gene, which encodes a transcription factor crucial for proper cardiovascular development, were sequenced in all study participants. The functional effect of an identified MEF2C mutation was characterized using a dual-luciferase reporter assay system. As a result, a novel heterozygous MEF2C mutation, p.R15C, was detected in an index patient with congenital double outlet right ventricle (DORV) as well as ventricular septal defect. Analysis of the proband's pedigree showed that the mutation co-segregated with CHD with complete penetrance. The missense mutation, which changed the evolutionarily conserved amino acid, was absent in 300 control individuals. Functional deciphers revealed that the mutant MEF2C protein had a significantly decreased transcriptional activity. Furthermore, the mutation significantly reduced the synergistic activation between MEF2C and GATA4, another transcription factor linked to CHD. This study firstly associates MEF2C loss-of-function mutation with DORV in humans, which provides novel insight into the molecular pathogenesis of CHD, suggesting potential implications for genetic counseling and personalized treatment of CHD patients.

Inverted structural quantum dot light-emitting diodes based on Al-doped ZnO electrode.

As an indium-free transparent conducting film, Al-doped zinc oxide (AZO) was prepared by magnetron sputtering technique, exhibiting good electrical, optical and surface characteristics. UPS/XPS measurements show that AZO and zinc oxide nanoparticles (ZnO NPs) have matched energy level that can facilitate the electron injection from AZO to ZnO NPs. Inverted structural green quantum dot light-emitting diodes based on AZO cathode were fabricated, which exhibits a maximum luminance up to 178 000 cd m-2, and a maximum current efficiency of 10.1 cd A-1. Therewith, combined with the simulated space-charge-limited current (SCLC) theory, the measured current density-voltage characteristics of charge-only devices were analyzed. It demonstrated that AZO and ZnO NPs had much better electron injection efficiency than ITO, showing a electron injection efficiency close to 100%. By studying the relationship between the electric field and the current density, the measured curve of AZO-based devices nearly fits the theoretical curve of SCLC and the AZO electrode has a better ohmic contact with ZnO NPs than ITO.

MEF2C loss-of-function mutation contributes to congenital heart defects.

Congenital heart disease (CHD) is the most common type of developmental abnormality in humans, and is a leading cause for substantially increased morbidity and mortality in affected individuals. Increasing studies demonstrates a pivotal role of genetic defects in the pathogenesis of CHD, and presently mutations in more than 60 genes have been associated with CHD. Nevertheless, CHD is of pronounced genetic heterogeneity, and the genetic basis underpinning CHD in a large proportion of patients remains unclear. In the present study, the whole coding exons and splicing donors/acceptors of the MEF2C gene, which codes for a transcription factor essential for normal cardiovascular development, were sequenced in 200 unrelated patients affected with CHD, and a novel heterozygous missense mutation, p.L38P, was identified in an index patient with patent ductus arteriosus (PDA) and ventricular septal defect (VSD). Genetic scan of the mutation carrier's family members available showed that the mutation was present in all affected family members but absent in unaffected family members. Analysis of the proband's pedigree revealed that the mutation co-segregated with PDA, which was transmitted as an autosomal dominant trait with complete penetrance. The mutation changed the amino acid that was completely conserved evolutionarily, and did not exist in 300 unrelated, ethnically-matched healthy individuals used as controls. Functional deciphers by using a dual-luciferase reporter assay system unveiled that the mutant MEF2C protein had a significantly reduced transcriptional activity. Furthermore, the mutation significantly diminished the synergistic activation between MEF2C and GATA4, another cardiac core transcription factor that has been causally linked to CHD. In conclusion, this is the first report on the association of a MEF2C loss-of-function mutation with an increased vulnerability to CHD in humans, which provides novel insight into the molecular mechanisms underlying CHD, implying potential implications for early diagnosis and timely prophylaxis of CHD.

Effect of bamboo and rice straw biochars on the mobility and redistribution of heavy metals (Cd, Cu, Pb and Zn) in contaminated soil.

Biochar has emerged as an efficient tool to affect bioavailability of heavy metals in contaminated soils. Although partially understood, a carefully designed incubation experiment was performed to examine the effect of biochar on mobility and redistribution of Cd, Cu, Pb and Zn in a sandy loam soil collected from the surroundings of a copper smelter. Bamboo and rice straw biochars with different mesh sizes (<0.25 mm and <1 mm), were applied at three rates (0, 1, and 5% w/w). Heavy metal concentrations in pore water were determined after extraction with 0.01 M CaCl2. Phytoavailable metals were extracted using DTPA/TEA (pH 7.3). The European Union Bureau of Reference (EUBCR) sequential extraction procedure was adopted to determine metal partitioning and redistribution of heavy metals. Results showed that CaCl2-and DTPA-extractable Cd, Cu, Pb and Zn concentrations were significantly (p < 0.05) lower in the bamboo and rice straw biochar treated soils, especially at 5% application rate, than those in the unamended soil. Soil pH values were significantly correlated with CaCl2-extractable metal concentrations (p < 0.01). The EUBCR sequential extraction procedure revealed that the acid extractable fractions of Cd, Cu, Pb and Zn decreased significantly (p < 0.05) with biochar addition. Rice straw biochar was more effective than bamboo biochar in decreasing the acid extractable metal fractions, and the effect was more pronounced with increasing biochar application rate. The effect of biochar particle size on extractable metal concentrations was not consistent. The 5% rice straw biochar treatment reduced the DTPA-extractable metal concentrations in the order of Cd < Cu < Pb < Zn, and reduced the acid extractable pool of Cd, Cu, Pb and Zn by 11, 17, 34 and 6%, respectively, compared to the control. In the same 5% rice straw biochar treatments, the organic bound fraction increased by 37, 58, 68 and 18% for Cd, Cu, Pb and Zn, respectively, compared to the control, indicating that the immobilized metals were mainly bound in the soil organic matter fraction. The results demonstrated that the rice straw biochar can effectively immobilize heavy metals, thereby reducing their mobility and bioavailability in contaminated soils.