Use of medical exome sequencing for identification of underlying genetic defects in NICU: Experience in a cohort of 2303 neonates in China.

Emerging evidence demonstrates the clinical utility of genomic applications in newborn intensive care unit (NICU) patients with strong indications of Mendelian etiology. However, such applications' diagnostic yield and utility remain unclear for NICU cohorts with minimal phenotype selection. In this study, focused medical exome sequencing was used as a first-tier, singleton-focused diagnostic tool for 2303 unrelated sick neonates. Integrated analysis of single nucleotide variants (SNVs), small insertions and deletions (Indels), and large copy number variants (CNVs) was performed. The diagnostic rate in this NICU cohort is 12.3% (284/2303), with 190 probands with molecular diagnoses made from SNV/Indel analyses (66.9%), 93 patients with diagnostic aneuploidy/CNVs findings (32.8%), and 1 patient with both SNV and CNV (0.4%). In addition, 54 (2.3%) of patients had a reportable incidental finding. Multiple organ involvements, craniofacial abnormalities, and dermatologic abnormalities were the strongest positive predictors for a molecular diagnosis. Among the 190 cases with SNV/Indel defects, direct impacts on medical management were observed in 46.8% of patients after the results were reported. In this study, we demonstrate that focused medical exome sequencing is a powerful first-line diagnostic tool for NICU patients. Significant number of diagnosed NICU patients can benefit from more focused medical management and long-term care.

Investigation of α-Fe2O3 catalyst structure for efficient photocatalytic fenton oxidation removal of antibiotics: preparation, performance, and mechanism.

Currently, the surface structure modification of photocatalysts is one of the effective means of enhancing their photocatalytic efficiency. Therefore, it is critically important to gain a deeper understanding of how the surface of α-Fe2O3 photocatalysts influences catalytic activity at the nanoscale. In this work, α-Fe2O3 catalysts were prepared using the solvothermal method, and four distinct morphologies were investigated: hexagonal bipyramid (THB), cube (CB), hexagonal plate (HS), and spherical (RC). The results indicate that the hexagonal bipyramid (THB) exhibits the highest degradation activity towards tetracycline (TC), with a reaction rate constant of k = 0.0969 min-1. The apparent reaction rate constants for the cube (CB), hexagonal plate (HS), and spherical (RC) morphologies are 0.0824, 0.0726, and 0.0585 min-1, respectively. In addition, it has been observed that the enhancement of photocatalytic activity is closely related to the increase in surface area, which provides more opportunities for interactions between Fe2+ and holes. The quenching experiments and electron paramagnetic resonance (EPR) results indicate that the ˙O2, ˙OH and h+ contribute mainly to the degradation of TC in the system. This research contributes to a more comprehensive understanding of catalyst surface alterations and their impact on catalytic performance.

[Pollution Characteristics and Risk Assessment of Heavy Metals in the Bioretention Systems of Sponge Cities].

As an important water purification and seepage measure for sponge cities, biofiltration systems have been widely used in their construction in China. In order to identify the heavy metal accumulation, pollution, and its potential environmental risk in the biofiltration systems, this study examined the heavy metal contents and spatial distribution characteristics by taking the biofiltration systems of Yuelai new town, Chongqing, the first demonstration area of sponge city construction in China, as the research object, and conducted a risk evaluation of the pollution level and ecological environment in this new town using the contamination factor (CF), geo-accumulation Index (Igeo), and potential ecological risk coefficient (PERC). The results showed that, except for Mn, the average contents of Cu, Zn, Pb, Ni, and Cd in the biofiltration systems of Yuelai new town were 4.14, 1.77, 4.98, 1.23, and 6.51 times higher than the soil background values of Chongqing. In terms of spatial distribution, the contents of heavy metals in biofiltration systems along the roads in different functional areas showed great differences. The contents of Cu, Zn, Mn, Pb, Ni, and Cd in the industrial area were significantly higher than those of the same types of heavy metals in the biofiltration systems in other areas (P<0.05). The CF and Igeo showed that the pollution level of heavy metals was ranked as follows:Mn

SKAP2, a novel target of HSF4b, associates with NCK2/F-actin at membrane ruffles and regulates actin reorganization in lens cell.

In addition to roles in stress response, heat shock factors (HSFs) play crucial roles in differentiation and development. Heat shock transcription factor 4 (HSF4) deficiency leads to defect in lens epithelial cell (LEC) differentiation and cataract formation. However, the mechanism remains obscure. Here, we identified Src kinase-associated phosphoprotein 2 (SKAP2) as a downstream target of HSF4b and it was highly expressed at the anterior tip of lens elongating fibre cells in vivo. The HSF4-deficient lenses showed reduced SKAP2 expression and defects in actin reorganization. The disassembly of stress fibres and formation of cortical actin fibres are critical for the initiation of LEC differentiation. SKAP2 localized at actin-rich ruffles in human LECs (SRA01/04 cells) and knockdown SKAP2 using RNA interference impaired the disassembly of cellular stress fibres in response to fibroblast growth factor (FGF)-b. Overexpression of SKAP2, but not the N-terminal deletion mutant of SKAP2, induced the actin remodelling. We further found that SKAP2 interacted with the SH2 domain of non-catalytic region of tyrosine kinase adaptor protein 2 (NCK2) via its N-terminus. The complex of SKAP2-NCK2-F-actin accumulated at the leading edge of the lamellipodium, where FGF receptors and focal adhesion were also recruited. These results revealed an essential role for HSF4-mediated SKAP2 expression in the regulation of actin reorganization during lens differentiation, likely through a mechanism that SKAP2 anchors the complex of NCK2/focal adhesion to FGF receptors at the lamellipodium in lens epithelial cells.

Simultaneous Desalination and Removal of Recalcitrant Organics from Reverse Osmosis Leachate Concentrate by Electrochemical Oxidation.

Reverse osmosis (RO) concentrate produced in the municipal solid waste (MSW) leachate treatment process is extremely hard to be treated because of its high color, high salt content, and high concentration of recalcitrant organic compounds. A new multichannel flow reactor with electrode gaps of 5 mm was designed to desalinate and remove organics simultaneously from the RO leachate concentrate (ROLC) by electrochemical oxidation process using the RuO2/IrO2-coated titanium plate (RuO2/IrO2-Ti) as the anodes. The effects of the process parameters of current density (I A), superficial circulating velocity (U L), etc. on the removal efficiency (RE) of the chemical oxygen demand (COD) and average energy consumption () were investigated. The results illustrated that after 3 h of treatment, the RE of COD, Cl-, and color could reach as high as 96.5, 96.7, and 99.6%, respectively. Besides, the of the electrochemical oxidation treatment process is as low as 40.98 kWh/(kg COD), and a new mechanism of the simultaneous removal of COD and desalination has been proposed. This work provides an alternative technology for the treatment of MSW leachate RO concentrate.

Screening of Kozak-motif-located SNPs and analysis of their association with human diseases.

The Kozak motif, which is located near the translational start codon, often regulates the protein translation. Moreover, it is believed that the conserved positions -3 and +4 contribute the most. Since changes that occur in this motif have a great impact on protein yield and in some cases are associated with disease, we screened the human SNP database for all Kozak-motif-located SNPs (kSNPs) and focused on the strong-changed kSNPs (sckSNPs). Many intron-located and synonymous SNPs are reported to be associated with disease, though the mechanisms underlying these associations are poorly understood. Here, we performed haplotype analysis on sckSNP-containing genes and found that there are some sckSNPs that exist in the same haplotype blocks of reported intron-located and synonymous disease-associated SNPs, indicating that those kSNPs could be a true risk factor for disease-association by affecting the efficiency of protein expression. Our findings provide a candidate explanation for how diseases are associated with intron-located and synonymous SNPs.

Genome-Wide Association Studies of HIV-1 Host Control in Ethnically Diverse Chinese Populations.

Genome-wide association studies (GWASs) have revealed several genetic loci associated with HIV-1 outcome following infection (e.g., HLA-C at 6p21.33) in multi-ethnic populations with genetic heterogeneity and racial/ethnic differences among Caucasians, African-Americans, and Hispanics. To systematically investigate the inherited predisposition to modulate HIV-1 infection in Chinese populations, we performed GWASs in three ethnically diverse HIV-infected patients groups (i.e., HAN, YUN, and XIN, N = 538). The reported loci at 6p21.33 was validated in HAN (e.g., rs9264942, P = 0.0018). An independent association signal (rs2442719, P = 7.85 × 10(-7), HAN group) in the same region was observed. Imputation results suggest that haplotype HLA-B*13:02/C*06:02, which can partially account for the GWAS signal, is associated with lower viral load in Han Chinese. Moreover, several novel loci were identified using GWAS approach including the top association signals at 6q13 (KCNQ5, rs947612, P = 2.15 × 10(-6)), 6p24.1 (PHACTR1, rs202072, P = 3.8 × 10(-6)), and 11q12.3 (SCGB1D4, rs11231017, P = 7.39 × 10(-7)) in HAN, YUN, and XIN groups, respectively. Our findings imply shared or specific mechanisms for host control of HIV-1 in ethnically diverse Chinese populations, which may shed new light on individualized HIV/AIDS therapy in China.

Combined analysis with copy number variation identifies risk loci in lung cancer.

BACKGROUND: Lung cancer is the most important cause of cancer mortality worldwide, but the underlying mechanisms of this disease are not fully understood. Copy number variations (CNVs) are promising genetic variations to study because of their potential effects on cancer. METHODOLOGY/PRINCIPAL FINDINGS: Here we conducted a pilot study in which we systematically analyzed the association of CNVs in two lung cancer datasets: the Environment And Genetics in Lung cancer Etiology (EAGLE) and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial datasets. We used a preestablished association method to test the datasets separately and conducted a combined analysis to test the association accordance between the two datasets. Finally, we identified 167 risk SNP loci and 22 CNVs associated with lung cancer and linked them with recombination hotspots. Functional annotation and biological relevance analyses implied that some of our predicted risk loci were supported by other studies and might be potential candidate loci for lung cancer studies. CONCLUSIONS/SIGNIFICANCE: Our results further emphasized the importance of copy number variations in cancer and might be a valuable complement to current genome-wide association studies on cancer.

Identifying chemicals with potential therapy of HIV based on protein-protein and protein-chemical interaction network.

Acquired immune deficiency syndrome (AIDS) is a severe infectious disease that causes a large number of deaths every year. Traditional anti-AIDS drugs directly targeting the HIV-1 encoded enzymes including reverse transcriptase (RT), protease (PR) and integrase (IN) usually suffer from drug resistance after a period of treatment and serious side effects. In recent years, the emergence of numerous useful information of protein-protein interactions (PPI) in the HIV life cycle and related inhibitors makes PPI a new way for antiviral drug intervention. In this study, we identified 26 core human proteins involved in PPI between HIV-1 and host, that have great potential for HIV therapy. In addition, 280 chemicals that interact with three HIV drugs targeting human proteins can also interact with these 26 core proteins. All these indicate that our method as presented in this paper is quite promising. The method may become a useful tool, or at least plays a complementary role to the existing method, for identifying novel anti-HIV drugs.

[Effect of the subsurface constructed wetland evolution into free surface flow constructed wetland on the removal of organic matter, nitrogen, and phosphor in wastewater].

Many previous studies demonstrated that the performance of the subsurface constructed wetlands (SSCW) for wastewater treatment was superior to that of the free flow surface constructed wetlands (FFSCW). However, our results indicated that the performance of FFSCW derived from the evolution of SSCW due to clogging for COD, TOC, total nitrogen (TN), and total phosphor (TP) removal was higher than those of SSCW with the same substrate and plant. The laboratory culture experiments were adopted to evaluate the effect of the constructed wetland evolution on the organic matter mineralization, nitrification/denitrification as well as removal of nitrogen and phosphor. It was shown that, after evolution of SSCW into FFSCW, the mineralization rate for organic matter (as TOC) was 1.82 mg x h(-1), and it was 1.49 mg x h(-1) for SSCW. The removal efficiency for NO3(-) was 96.8%, and it was 58.1% for SSCW. The abiotic denitrification removal efficiency was 40%, and it was 28.2% for SSCW. In addition, the maximum equilibrium adsorption capacity of the substrate after evolution for phosphor (as P) was 160 mg x kg(-1), and it was 140 mg x kg(-1) for SSCW substrate. The organic coverage of the substrate was found to be beneficial to phosphor removal. The nitrification ability decreased after evolution. These results suggest the important effect of constructed wetland evolution on its performance.

Length of the ORF, position of the first AUG and the Kozak motif are important factors in potential dual-coding transcripts.

A single mammalian transcript normally encodes one protein, but the transcript of GNAS (G-protein alpha-subunit) contains two reading frames and produces two structurally unrelated proteins, XLalphas and ALEX. No other confirmed GNAS-like dual-coding transcripts have been reported to date, even though many such candidate genes have been predicted by bioinformatics analysis. In this study, we constructed a series of vectors to test how two protein products were translated from a single transcript in vitro. The length of the ORF (open reading frame), position of the first AUG and the Kozak motif were found to be important factors. These factors, as well as 55-bp NMD (nonsense-mediated mRNA decay) rule, were used in a bioinformatics search for candidate dual-coding transcripts. A total of 1307, 750 and 474 two-ORF-containing transcripts were found in human, mouse and rat, respectively, of which 170, 89 and 70, respectively, were found to be potential dual-coding transcripts. Most transcripts showed low conservation among species. Interestingly, dual-coding transcripts were significantly enriched for transcripts from the zinc-finger protein family, which are usually DNA-binding proteins involved in regulation of the transcription process.