A multiscale functional map of somatic mutations in cancer integrating protein structure and network topology.

A major goal of cancer biology is to understand the mechanisms underlying tumorigenesis driven by somatically acquired mutations. Existing computational approaches focus on either scoring the pathogenicity of mutations or characterizing their effects at specific scales. Here, we established a unified computational framework, NetFlow3D, that systematically maps the multiscale mechanistic effects of somatic mutations in cancer. The establishment of NetFlow3D hinges upon the Human Protein Structurome, a complete repository we first compiled that incorporates the 3D structures of every single protein as well as the binding interfaces for all known PPIs in humans. The vast majority of 3D structural information was resolved by recent deep learning algorithms. By applying NetFlow3D to 415,017 somatic protein-altering mutations in 5,950 TCGA tumors across 19 cancer types, we identified 1,656 intra- and 3,343 inter-protein 3D clusters of mutations throughout the Human Protein Structurome, of which ~50% would not have been found if using only experimentally-determined protein structures. These 3D clusters have converging effects on 377 cellular subnetworks. Compared to canonical PPI network analyses, NetFlow3D achieved a 5.5-fold higher statistical power for identifying significantly dysregulated subnetworks. The majority of identified subnetworks were previously obscured by the overwhelming background noise of non-clustered passenger mutations, including portions of non-canonical PRC1, mediator complex, MCM2-7 complex, neddylation of cullins, complement system, TRiC, etc. NetFlow3D and our pan-cancer results can be accessed from http://netflow3d.yulab.org. This work shows that mapping how individual mutations act across scales requires the integration of their local spatial organization on protein structures and their global topological organization in the PPI network.

Retraction Notice to: LINC00472 Acts as a Tumor Suppressor in NSCLC through KLLN-Mediated p53-Signaling Pathway via MicroRNA-149-3p and MicroRNA-4270.

[This retracts the article DOI: 10.1016/j.omtn.2019.06.003.].

Bioremediation of stainless steel pickling sludge through microbially induced carbonate precipitation.

In this study, microbial induce carbonate precipitation (MICP) was introduced to immobilize chromium (Cr) in stainless steel pickling sludge (SSPS). Two methods were utilized to conduct the MICP process - Bacteria lysis liquor (BLL)-based MICP and bacteria-based MICP. BLL was obtained by breaking the cell walls with ultrasonic treatment. The urea hydrolyzation test illustrated that the BLL was better than bacteria solution. Both the treatments of bacteria lysis liquor-based MICP and bacteria-based MICP process can effectively entrap the Cr into mineral lattices, that reduce the potential environmental risk of SSPS. With 30 g/L urea and 7 days' treatment, BLL-based MICP presented better immobilization performance than bacteria-based MICP by lowering the bacteria concentration (OD600) from 0.8 to 0.7. The excellent biosorption of BLL contributed to Cr removal. Nevertheless, the addition of calcium (Ca) significantly enhanced the immobilization performance of bacteria-based MICP process rather than BLL-based MICP process. pH-dependent leaching tests illustrated the leaching of Cr followed an amphoteric pattern, while the leaching of Ni and Ca followed the cation pattern. Geochemical modeling revealed that the leaching of Cr from bio-mineralized products was solubility-controlled by Cr(OH)3 and Cr2O3.

Environmental investigation of bio-modification of steel slag through microbially induced carbonate precipitation.

Steel slag (SS) is one of byproduct of steel manufacture industry. The environmental concerns of SS may limit their re-use in different applications. The goal of this study was to investigate the leaching behavior of metals from SS before and after treated by microbially induced carbonate precipitation (MICP). Toxicity characteristic leaching procedure, synthetic precipitation leaching procedure and water leaching tests were performed to evaluate the leaching behavior of major elements (Fe, Mg and Ca) and trace elements (Ba, Cu and Mn) in three scenarios. The concentrations of leaching metals increased with the content of SS. After it reached the peak concentration, the leaching concentration decreased with the content of SS. The leachability of all elements concerned in this study was below 0.5%. The carbonate generated from the MICP process contributed to the low leachability of metals. After bio-modified by MICP process, the leaching concentrations of Ba from TCLP, SPLP and WLT tests were below 2.0 mg/L, which was the limit in drinking water regulated by U.S. EPA. The concentrations of Cu leached out from MICP-treated SS-sand samples were below 1.3 mg/L which is the limit regulated by national secondary drinking water. Compared with the regulations of U.S.EPA and Mississippi Department of Environment Quality (MDEQ), MICP-treated samples were classified as non-hazardous materials with respects to the leaching of metals. Meanwhile, maximum contaminant limits regulated by U.S.EPA states that MICP-treated SS are eco-friendly materials that can be reused as construction materials.

Chemical fixation of toxic metals in stainless steel pickling residue by Na2S∙xH2O, FeSO4∙6H2O and phosphoric acid for beneficial uses.

The leaching concentrations of different metals in stainless steel pickling residue (SSPR) were determined and the toxic metals were treated using Na2S∙xH2O, FeSO4∙6H2O, and phosphoric acid. A modified European Community Bureau of Reference (BCR) sequential extraction was used to identify the speciation of the concerned metals. Results showed that SSPR contains a large amount of Ca (58.41%), Fe (29.44%), Cr (3.83%), Ni (2.94%), Mn (2.82%) and some of Al, Cu, Mg, Zn. Among them, Cr and Ni were the most toxic metals in SSPR, thus the raw SSPR falls into hazardous waste category due to the leaching amount of Cr. In addition, the leached Cr was identified as Cr6+ (MgCrO4) in the waste. BCR test revealed that risk assessment code (RAC) of Cr and Ni were 33.29% and 61.7%, indicating they posed "high" and "very high" risk to the environment, respectively. After fixing by Na2S∙xH2O and FeSO4∙6H2O, the leaching concentrations of Cr and Ni were less than 1.5 and 0.5 mg/L, respectively. After fixing by Na2S∙xH2O and FeSO4∙6H2O the treated SSPR can be safely reused as roadbed materials, concrete and cement aggregates. This study provides a useful implication in treatment and beneficial reuse of heavy metal-containing hazardous wastes.

Transcriptional regulatory model of fibrosis progression in the human lung.

To develop a systems biology model of fibrosis progression within the human lung we performed RNA sequencing and microRNA analysis on 95 samples obtained from 10 idiopathic pulmonary fibrosis (IPF) and 6 control lungs. Extent of fibrosis in each sample was assessed by microCT-measured alveolar surface density (ASD) and confirmed by histology. Regulatory gene expression networks were identified using linear mixed-effect models and dynamic regulatory events miner (DREM). Differential gene expression analysis identified a core set of genes increased or decreased before fibrosis was histologically evident that continued to change with advanced fibrosis. DREM generated a systems biology model (www.sb.cs.cmu.edu/IPFReg) that identified progressively divergent gene expression tracks with microRNAs and transcription factors that specifically regulate mild or advanced fibrosis. We confirmed model predictions by demonstrating that expression of POU2AF1, previously unassociated with lung fibrosis but proposed by the model as regulator, is increased in B lymphocytes in IPF lungs and that POU2AF1-knockout mice were protected from bleomycin-induced lung fibrosis. Our results reveal distinct regulation of gene expression changes in IPF tissue that remained structurally normal compared with moderate or advanced fibrosis and suggest distinct regulatory mechanisms for each stage.

LINC00472 Acts as a Tumor Suppressor in NSCLC through KLLN-Mediated p53-Signaling Pathway via MicroRNA-149-3p and MicroRNA-4270.

Long non-coding RNAs and microRNAs (miRNAs) have been reported to participate in the progression of non-small-cell lung cancer (NSCLC). Long intergenic non-protein-coding RNA 472 (LINC00472), miR-149-3p, and miR-4270 were found to be involved in tumor activities, suggesting potential roles in NSCLC. Thus, this study aimed to examine the ability of LINC00472 to influence the progression of NSCLC with the involvement of miR-149-3p and miR-4270. Initially, differentially expressed long non-coding RNAs (lncRNAs), downstream regulatory miRNAs, and genes related to NSCLC were identified. Next, the interaction among LINC00472, miR-149-3p and miR-4270, and KLLN and the p53-signaling pathway was determined. The effect of LINC00472 on the expression of E-cadherin, N-cadherin, and Vimentin was examined through gain-of-function and loss-of-function experiments. Lastly, the effects of LINC00472 on NSCLC tumor growth were assessed in vivo. LINC00472 and KLLN were found to exhibit low levels, while miR-149-3p and miR-4270 were highly expressed in NSCLC. In addition, the overexpression of LINC00472 was observed to upregulate KLLN and activate the p53-signaling pathway, which ultimately inhibited the invasion, migration, and EMT of NSCLC cells via miR-149-3p and miR-4270, corresponding to decreased N-cadherin and Vimentin and increased E-cadherin. The overexpression of LINC00472 exerted an inhibitory effect on tumor growth in vivo. Taken together, the key evidence suggests that the overexpression of LINC00472 can downregulate miR-149-3p and miR-4270 to upregulate KLLN and activate the p53-signaling pathway, thus inhibiting the development of NSCLC. This study highlights the potential of LINC00472 as a promising therapeutic target for NSCLC treatment.

Enhancing the taste of raw soy sauce using low intensity ultrasound treatment during moromi fermentation.

Sonication can significantly enhance amino acids (AAs) release to accelerate maturation during short-term and low-salt soy sauce fermentation. Here, sonication was applied at 68 kHz (60 W/L/10 min/8 circles) to determine its effects on the taste during long-term and high-salt soy sauce fermentation. The possible mechanisms were explored by analyzing differences in enzymes profile, proximate indices, molecular weight distribution of peptides, AAs composition and microstructures of sonicated moromis and their controls. Sonication greatly elevated levels of organic taste compounds ranging from 8.4% to 22.2%, but lowered levels of NaCl (6.0%), peptides ≤ 1 kDa (5.2%), histidine (20.5%) and glutamic acid (3.4%). Compared to its controls, sonicated raw soy sauces also had a more harmonious and palatable taste. Increased enzymes' activities and formation of more surface area and reaction sites in sonicated moromis might be the possible mechanisms for sonication to elevate levels of taste compounds and sensory quality of soy sauce.

Characterization and chemical fixation of stainless steel pickling residue using sodium sulfide hydrate.

The stainless steel pickling residue (SSPR) produced from the stainless steel industries in China contains large amounts of heavy metals such as chromium (Cr) and nickel (Ni). The study found that the hexavalent chromium Cr (VI) was the primary contributor to the leaching of Cr in the toxicity character leaching test. A chemical fixation with sodium sulfide was used to treat the SSPR, and the response surface methodology (RSM) was employed to optimize the process. The results revealed that the sodium sulfide dose and curing time had significant effects on the fixation of Cr. The higher was the sodium sulfide dose, and the longer the curing time, the lower the leaching concentration of Cr would be. The water addition amount had insignificant effect when it was higher than 70%. A dose of 1.2% sodium sulfide on dry mass basis, a water addition of 90-100%, and a curing time of longer than 10 days in the open air could reduce the leaching of Cr to below the beneficial use threshold. The low chemical dose and simple procedures established in this study make this treatment method cost-effective for rendering the SSPR into a nonhazardous and useful material.

Characterization of taste and aroma compounds in Tianyou, a traditional fermented wheat flour condiment.

Taste and aroma compounds in Tianyou were determined using HPLC and GC-MS/GC-olfactometry. By comparison with light soy sauce (control), the contents of salt, sugar, total nitrogen and total acid in Tianyou were higher, while the contents of umami, sweet and bitter free amino acids, and the percentage of 1-5kDa peptides in Tianyou were lower. Thirty-one aroma-active compounds were identified in both Tianyou and the control (30 compounds in common). Aroma extraction dilution analysis indicated that most flavor dilution factors of aroma-active compounds were lower in Tianyou than the control. Quantitative descriptive analysis showed that Tianyou had significantly stronger salty and sweet tastes, weaker umami taste and weaker malty, caramel-like and smoky notes when compared to the control (p<0.05), which were in agreement with the analyses of taste and aroma compounds. This confirms that Tianyou has a distinctively different flavor from light soy sauce.

Dynamic transcription profiles of "Qinguan" apple (Malus × domestica) leaves in response to Marssonina coronaria inoculation.

Marssonina apple blotch, caused by the fungus Marssonina coronaria, is one of the most destructive apple diseases in China and East Asia. A better understanding of the plant's response to fungi during pathogenesis is urgently needed to improve plant resistance and to breed resistant cultivars. To address this, the transcriptomes of "Qinguan" (a cultivar with high resistance to M. coronaria) apple leaves were sequenced at 12, 24, 48, and 72 h post-inoculation (hpi) with Marssonina coronaria. The comparative results showed that a total of 1956 genes were differentially expressed between the inoculated and control samples at the 4 time points. Gene ontology (GO) term enrichment analysis of differentially expressed genes (DEGs) revealed changes in cellular component, secondary metabolism including chalcone isomerase activity, phytoalexin biosynthetic process, anthocyanin-containing compound biosynthetic process, lignin biosynthetic process, positive regulation of flavonoid biosynthetic process; and molecular functions or biological processes related to the defense response, biotic stimulus response, wounding response and fungus response. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that DEGs were significantly enriched in flavonoid biosynthesis, vitamin B6 metabolism, phenylpropanoid biosynthesis, and the stilbenoid, diarylheptanoid and gingerol biosynthesis pathways. Furthermore, the importance of changes in cellular components and partial polyphenol compounds when encountering M. coronaria are discussed.

Proteomic analysis of 'Zaosu' pear (Pyrus bretschneideri Rehd.) and its red skin bud mutation.

BACKGROUND: Breeding for strong red skin color is an important objective of the pear breeding program. There are few reports of proteome research in green skin pear and its red skin bud mutation. The manuscript at hand is one of the first studies dealing with 2D-PAGE-based analysis of pear fruits and leaves, establishing a suitable sample preparation and testing different 2D-PAGE protocols. Therefore, it may grant a basis for further studies on the pear proteome being the studies main goal. A proteomic analysis was conducted on leaves and fruits of 'Zaosu' pear (Pyrus bretschneideri Rehd.) and its red skin bud mutation in order to reveal their genetic differences in the protein level. RESULTS: In the present study, the optimized two-dimensional (2-D) gel electrophoresis system of pear leaf and fruit was set up, and applied to analyze the leaves and fruit protein. The interesting peptide fragments were determined using 4800 Plus MALDI TOF/TOFTM Analyzer mass spectrometer, and the sequence obtained was blasted in NCBInr to identify the differentially-expressed protein. In the 1.5-fold differently-expressed proteins between 'Zaosu' pear and its mutant, 10 out of 35 proteins in fruit and 12 out of 24 ones in leaves were identified successfully. Among the 22 identified proteins, 7 protein spots were related to photosynthesis and energy metabolism; 4 were associated with environmental stress; 4 with disease defense; 2 with amino acid metabolism; 2 with cytoskeleton; 1 with antioxidant function; 1 with calcium metabolism; and 1 with unknown function. Moreover, related physiological index, such as chlorophyll content, Rubisco content and polyphone oxidase activity, were different between 'Zaosu' pear and its mutant. CONCLUSION: A 2-D gel electrophoresis system of pear leaves and fruits was established, which was suitable for the analysis of proteome comparison. To the best of our knowledge, we have performed the first analysis of the proteomic changes in leaves and fruits of 'Zaosu' pear and its red skin bud mutation. Our study provides important information on the use of proteomic methods for studying protein regulation of 'Zaosu' pear and its red skin bud mutation.

[Biocompatibility of silk fibroin nanofibers scaffold with olfactory ensheathing cells].

OBJECTIVE: To investigate the biocompatibility of silk fibroin nanofibers scaffold with olfactory ensheathing cells (OECs) and to provide an ideal tissue engineered scaffold for the repair of spinal cord injury (SCI). METHODS: Silk fibroin nanofibers were prepared using electrospinning techniques and were observed by scanning electron microscope (SEM). Freshly isolated OECs from SD rats purified by the modified differential adherent velocity method were cultured. The cells at passage 1 (1 x 10(4) cells/cm2) were seeded on the poly-l-lysine (control group) and the silk fibroin nanofibers (experimental group) coated coverslips in Petri dish. At desired time points, the morphological features, growth, and adhesion of the cells were observed using phase contrast inverted microscopy. The OECs were identified by the nerve growth factor receptor p75 (NGFR p75) immunofluorescence staining. The viability of OECs was examined by live/dead assay. The proliferation of OECs was examined by MTT assay. The cytotoxicity of the nanofibers was evaluated. RESULTS: The SEM micrographs showed that the nanofibers had a smooth surface with solid voids among the fibers, interconnecting a porous network, constituted a fibriform three dimensional structure and the average diameter of the fibers was about (260 +/- 84) nm. The morphology of OECs on the experimental group was similar to the cell morphology on the control group, the cells distributed along the fibers, and the directions of the cell protrusions were in the same as that of the fibers. Fluorescence microscopy showed that the purity of OECs was 74.21% +/- 2.48% in the experimental group and 79.05% +/- 2.52% in the control group 5 days after culture. There was no significant difference on cell purity between two groups (P > 0.05). The OECs in the experimental group stained positive for NGFR p75 compared to the control group, indicating that the cells in the experimental group still maintained the OECs characteristic phenotype. Live/dead staining showed that high viability was observed in both groups 3 days after culture. There was no significant difference on cell viability between two groups. The proliferation activity at 1, 3, 5, 7, and 10 days was examined by MTT assay. The absorbency values of the control group and the experimental group had significant differences 3 and 5 days after culture (P < 0.05). The relative growth rates were 95.11%, 90.35%, 92.63%, 94.12%, and 94.81%. The cytotoxicity of the material was grade 1 and nonvenomous according to GB/T 16886 standard. CONCLUSION: Silk fibroin nanofibers scaffold has good compatibility with OECs and is a promising tissue engineered scaffold for the repair of SCI.