Tracing Oncogene Rearrangements in the Mutational History of Lung Adenocarcinoma.

Mutational processes giving rise to lung adenocarcinomas (LADCs) in non-smokers remain elusive. We analyzed 138 LADC whole genomes, including 83 cases with minimal contribution of smoking-associated mutational signature. Genomic rearrangements were not correlated with smoking-associated mutations and frequently served as driver events of smoking-signature-low LADCs. Complex genomic rearrangements, including chromothripsis and chromoplexy, generated 74% of known fusion oncogenes, including EML4-ALK, CD74-ROS1, and KIF5B-RET. Unlike other collateral rearrangements, these fusion-oncogene-associated rearrangements were frequently copy-number-balanced, representing a genomic signature of early oncogenesis. Analysis of mutation timing revealed that fusions and point mutations of canonical oncogenes were often acquired in the early decades of life. During a long latency, cancer-related genes were disrupted or amplified by complex rearrangements. The genomic landscape was different between subgroups-EGFR-mutant LADCs had frequent whole-genome duplications with p53 mutations, whereas fusion-oncogene-driven LADCs had frequent SETD2 mutations. Our study highlights LADC oncogenesis driven by endogenous mutational processes.

Long-term inhibition of chlortetracycline antibiotics on anaerobic digestion of swine manure.

This study aimed to identify whether chronic effects are present in the anaerobic digestion (AD) of swine manure (SM) containing chlortetracycline (CTC), which is one of the major broad-spectrum veterinary antibiotics, and to elucidate the long-term inhibitory effects and recovery from the inhibition based on AD performance and microbial community. Two continuous-stirred tank reactors treating SM with and without CTC spiking (3 mg/L) were operated for 900 days. Due to the degradation and transformation, the total concentration including CTC's epimer and isomer in the test reactor was 1.5 mg/L. The exposure level was determined according to probabilistically estimated concentrations with uncertainties in field conditions. Until the cessation of CTC exposure on day 585, the methane generation of test reactor continuously decreased to 55 ± 17 mL/g-VS/day, 53% that of control. The methane generation and organic removal were not recovered within 300 days after the CTC exposure was stopped. During the experiment, stability parameters such as pH, total ammonium nitrogen, the composition of methane and alkalinity were the same for both reactors. The concentration and composition of VFAs in the test reactor were different with those of control but not in inhibition level. Microbial profiles revealed that reduction in bacterial diversity and changed balance in microbial species resulted in the performance downgrade under the long-term antibiotic pressure. Since it is hard to recover from the inhibition and difficult to predict the inhibition using physicochemical indicators, continuous exposure to CTC needs to be avoided for the sustainable management of AD plants treating SM.

Mutalisk: a web-based somatic MUTation AnaLyIS toolKit for genomic, transcriptional and epigenomic signatures.

Somatic genome mutations occur due to combinations of various intrinsic/extrinsic mutational processes and DNA repair mechanisms. Different molecular processes frequently generate different signatures of somatic mutations in their own favored contexts. As a result, the regional somatic mutation rate is dependent on the local DNA sequence, the DNA replication/RNA transcription dynamics and epigenomic chromatin organization landscape in the genome. Here, we propose an online computational framework, termed Mutalisk, which correlates somatic mutations with various genomic, transcriptional and epigenomic features in order to understand mutational processes that contribute to the generation of the mutations. This user-friendly tool explores the presence of localized hypermutations (kataegis), dissects the spectrum of mutations into the maximum likelihood combination of known mutational signatures and associates the mutation density with numerous regulatory elements in the genome. As a result, global patterns of somatic mutations in any query sample can be efficiently screened, thus enabling a deeper understanding of various mutagenic factors. This tool will facilitate more effective downstream analyses of cancer genome sequences to elucidate the diversity of mutational processes underlying the development and clonal evolution of cancer cells. Mutalisk is freely available at http://mutalisk.org.

Hydrothermal carbonization of waste from leather processing and feasibility of produced hydrochar as an alternative solid fuel.

This study presents hydrothermal carbonization (HTC) of leather waste (LW) to produce hydrochar and feasibility of using produced hydrochar as solid fuel. The results showed that a relatively low HTC treatment temperature (180-200 °C) improved both the hydrochar product yield (>82.9% by dry weight) and its potential use as a solid fuel with in terms of its physicochemical properties and heating value. Furthermore, the hydrochar showed a higher heating value (5807-6508 kcal kg-1) compared to that of low-ranked coals (i.e., sub-bituminous and lignite), and stable combustion characteristics at a higher temperature. This allows the hydrochar to be considered as a suitable alternative to conventional fossil fuel. In addition, the decrease of nitrogen content in the hydrochar during the HTC treatment, and the inherent low sulfur content of LW could make hydrochar a more appealing clean energy source. The findings of this study suggest that the conversion of LW through HTC can be a useful method for waste management and energy recovery from abandoned biomass.

Alanine aminotransferase and gamma-glutamyl transferase have different dose-response relationships with risk of mortality by age.

BACKGROUND & AIMS: It remains unclear whether the respective dose-response relationships between serum alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) levels and risk of mortality are consistent by age. METHODS: We used sampled cohort data from the National Health Insurance Corporation to conduct a retrospective cohort study. A total of 313 252 participants who received medical health check-ups from 2002 to 2008 were assessed for risk of death according to serum ALT and GGT levels over an average of 6 years. The hazard ratios (HRs) for mortality were analysed with Cox proportional hazard model. RESULTS: The crude mortality rate increased linearly with increasing serum ALT and GGT levels in adults aged <60 years. However, the all-cause mortality rate showed a J-shaped relationship with increasing serum ALT levels whereas all-cause mortality rate showed a linear relationship with increasing serum GGT levels in adults aged ≥60 years. The HR of death showed U-shaped relationships with increasing serum ALT levels in adults aged ≥60 years. On the contrary, the HR of death from any cause had a linear association with increasing serum GGT levels among all age groups. CONCLUSIONS: In this study, U-shaped relationship patterns were demonstrated between serum ALT levels and risk for all-cause mortality in adults aged ≥60 years while serum GGT levels showed a linear relationship with risk for all-cause death. Very low levels of serum ALT in elderly patients suggest that they are at high risk of mortality.

Blood cadmium levels are associated with a decline in lung function in males.

BACKGROUND: Cadmium exposure was found to cause a decline in lung function among the general population, but these findings were limited to smokers and gender differences were not explored. OBJECTIVES: To examine the relationship between cadmium and chronic obstructive pulmonary disease (COPD) according to gender and smoking status in Korea. METHODS: Cross-sectional data from the Korean National Health and Nutrition Examination Survey from 2008 to 2011 were analyzed. COPD was defined by a pre-bronchodilator forced expiratory volume in 1s divided by forced vital capacity of <0.70. A logistic regression model was used to elucidate the association between blood cadmium levels and COPD according to gender and smoking status. RESULTS: Among 3861 eligible participants, 3622 were included in the analysis. The prevalence of COPD demonstrated an increasing trend in males (P for trend<0.001), but not in females (P for trend=0.67). After adjusting for covariates, a higher blood cadmium level, but within the normal range, was associated with COPD in males, including those who had never-smoked (P for trend <0.001 and P for trend=0.008). However, a higher blood cadmium level was not significantly associated with COPD in females, including those who had never smoked (P for trend=0.39 and P for trend=0.43). CONCLUSIONS: A higher blood cadmium level, within the normal range, was associated with COPD in males, including those who had never smoked. However, there was no significant association between blood cadmium levels and COPD in females.

Clinical significance of non-alcoholic fatty liver disease as a risk factor for prehypertension.

Previous epidemiologic studies have shown the clinical association between non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD). However, there is only limited information about the effect of NAFLD on the development of hypertension. Accordingly, we investigated the clinical association between NAFLD and prehypertension. A prospective cohort study was conducted on the 11,350 Korean men without prehypertension for 5 yr. The incidences of prehypertension were evaluated, and Cox proportional hazard model was used to measure the hazard ratios (HRs) for the development of prehypertension according to the degree of NAFLD (normal, mild, moderate to severe). The incidence of prehypertension increased according to NAFLD states (normal: 55.5%, mild: 63.7%, moderate to severe: 70.3%, P<0.001). Even after adjusting for multiple covariates, the HRs (95% confidence interval) for prehypertension were higher in the mild group (1.18; 1.07-1.31) and moderate to severe group (1.62; 1.21-2.17), compared to normal group, respectively (P for trend <0.001). The development of prehypertension is more potentially associated with the more progressive NAFLD than normal and milder state. These findings suggest the clinical significance of NAFLD as one of risk factors for prehypertension.

Fabrication and Characterization of Al2O3-Siloxane Composite Thermal Pads for Thermal Interface Materials.

In this study, Al2O3-siloxane composite thermal pads were fabricated using a tape-casting technique, and the thermal conductivity effect of the Al2O3 nanoparticle powder synthesized using a flame fusion process on siloxane composite thermal pads was investigated. Furthermore, various case studies were implemented, wherein the synthesized Al2O3 nanoparticle powder was subjected to different surface treatments, including dehydration, decarbonization, and silylation, to obtain Al2O3-siloxane composite thermal pads with high thermal conductivity. The experimental results confirmed that the thermal conductivity of the Al2O3-siloxane composite pads improved when fabricated using surface-treated Al2O3 nanoparticle powder synthesized with an optimally spheroidized crystal structure compared to that produced using non-treated Al2O3 nanoparticle powder. Therefore, this study provides guidelines for fabricating Al2O3-siloxane composite thermal pads with high thermal conductivity in the field of thermal interface materials.

A computational method for detecting copy number variations using scale-space filtering.

BACKGROUND: As next-generation sequencing technology made rapid and cost-effective sequencing available, the importance of computational approaches in finding and analyzing copy number variations (CNVs) has been amplified. Furthermore, most genome projects need to accurately analyze sequences with fairly low-coverage read data. It is urgently needed to develop a method to detect the exact types and locations of CNVs from low coverage read data. RESULTS: Here, we propose a new CNV detection method, CNV_SS, which uses scale-space filtering. The scale-space filtering is evaluated by applying to the read coverage data the Gaussian convolution for various scales according to a given scaling parameter. Next, by differentiating twice and finding zero-crossing points, inflection points of scale-space filtered read coverage data are calculated per scale. Then, the types and the exact locations of CNVs are obtained by analyzing the finger print map, the contours of zero-crossing points for various scales. CONCLUSIONS: The performance of CNV_SS showed that FNR and FPR stay in the range of 1.27% to 2.43% and 1.14% to 2.44%, respectively, even at a relatively low coverage (0.5x ≤C ≤2x). CNV_SS gave also much more effective results than the conventional methods in the evaluation of FNR, at 3.82% at least and 76.97% at most even when the coverage level of read data is low. CNV_SS source code is freely available from http://dblab.hallym.ac.kr/CNV SS/.

FX: an RNA-Seq analysis tool on the cloud.

UNLABELLED: FX is an RNA-Seq analysis tool, which runs in parallel on cloud computing infrastructure, for the estimation of gene expression levels and genomic variant calling. In the mapping of short RNA-Seq reads, FX uses a transcriptome-based reference primarily, generated from ~160 000 mRNA sequences from RefSeq, UCSC and Ensembl databases. This approach reduces the misalignment of reads originating from splicing junctions. Unmapped reads not aligned on known transcripts are then mapped on the human genome reference. FX allows analysis of RNA-Seq data on cloud computing infrastructures, supporting access through a user-friendly web interface. AVAILABILITY: FX is freely available on the web at (http://fx.gmi.ac.kr), and can be installed on local Hadoop clusters. Guidance for the installation and operation of FX can be found under the 'Documentation' menu on the website. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Size dependent impacts of a model microplastic on nitrification induced by interaction with nitrifying bacteria.

Two sizes of polystyrene (PS) were compared to investigate their impact on nitrification. The smaller PS (50 nm) had a higher impact than the larger PS (500 nm). Lower NO2- and NO3- accumulation was observed in the 50 nm PS treatment. There was no significant difference in DIN concentration between the control and 500 nm PS treatments. PS treatment did not have a significant influence on the specific ammonia oxidation rate, but the specific nitrite utilization rate was the lowest in the 50 nm PS treatment. The changes in transcript levels of amoA gene did not correspond well with the observed changes in DIN concentrations, suggesting that the effects of 50 nm PS treatment might be unrelated to biological phenomena, for which an actual uptake of PS is needed. The fluorescent images revealed that the smaller PS can easily access bacterial cells, which corroborated the results of inhibition of nitrification by the smaller PS. Notably, most of the PS particles did not penetrate bacterial cells, suggesting that the observed effects of 50 nm PS on nitrification might be due to disruption of the membrane potential of the cells.

Conversion of heavy metal-containing biowaste from phytoremediation site to value-added solid fuel through hydrothermal carbonization.

In this study, heavy metal-containing sunflower residues obtained from a phytoremediation site were hydrothermally carbonized at 160-260 °C. The properties of hydrochar thus produced were evaluated with respect to its potential as solid fuel. The results confirmed that hydrothermal carbonization (HTC) reduced the concentration of heavy metals in hydrochars, with the concentration lower than the maximum permissible level of domestic standards for bio-solid refuse fuel. Higher HTC temperatures resulted in improved energy-related properties of the hydrochar (i.e., coalification degree, fuel ratio, and higher heating value); however, HTC temperatures between 200 and 220 °C were deemed suitable for energy retention efficiency. Furthermore, as hydrochar contains low nitrogen and ash content, it can be considered as a clean energy source. The results of this study suggest a sustainable approach to the disposal and effective utilization of contaminant-containing biowastes. Moreover, this study suggests linking biomass cultivation for phytoremediation and converting the phytoremediated biomass into value-added solid fuel.

Evaluation of silver nanoparticles (AgNPs) penetration through a clay liner in landfills.

Most products containing engineered nanomaterials are disposed at landfills in the final stage of their lifecycle. This study aims to assess landfill liners as a final barrier of disposed silver nanoparticles (AgNPs). Sorption and transport of AgNPs were investigated in the laboratory-scale simulation of landfill liner conditions. Field soil (silt loam) and bentonite were tested in batch sorption experiments respectively. To test transportation, 3 cm thick mixture of the field soil and the bentonite constituted the porous media to meet the criteria for compacted clay liner of landfill. Mathematical modeling in the experimental and actual landfill conditions was also conducted. The results demonstrated considerable extent of sorption by both types of sorbents. The breakthrough of AgNPs was not observed for 200 days (over 20 pore volume). In general, the experimental results indicated that AgNPs cannot easily pass through the landfill clay liner under present standards. Modeling results also showed that AgNPs could be blocked effectively. Although long-term tests are still required, these results clearly show resistance to current sanitary landfill liners against AgNP penetration. As the trial to assess the safety of landfills against AgNP migration, this work provides insights into the fate and transport of nanomaterials in the landfill environment.

Protein-gene Expression Nexus: Comprehensive characterization of human cancer cell lines with proteogenomic analysis.

Researchers have gained new therapeutic insights using multi-omics platform approaches to study DNA, RNA, and proteins of comprehensively characterized human cancer cell lines. To improve our understanding of the molecular features associated with oncogenic modulation in cancer, we proposed a proteogenomic database for human cancer cell lines, called Protein-gene Expression Nexus (PEN). We have expanded the characterization of cancer cell lines to include genetic, mRNA, and protein data of 145 cancer cell lines from various public studies. PEN contains proteomic and phosphoproteomic data on 4,129,728 peptides, 13,862 proteins, 7,138 phosphorylation site-associated genomic variations, 117 studies, and 12 cancer. We analyzed functional characterizations along with the integrated datasets, such as cis/trans association for copy number alteration (CNA), single amino acid variation for coding genes, post-translation modification site variation for Single Amino Acid Variation, and novel peptide expression for noncoding regions and fusion genes. PEN provides a user-friendly interface for searching, browsing, and downloading data and also supports the visualization of genome-wide association between CNA and expression, novel peptide landscape, mRNA-protein abundance, and functional annotation. Together, this dataset and PEN data portal provide a resource to accelerate cancer research using model cancer cell lines. PEN is freely accessible at http://combio.snu.ac.kr/pen.

Impact of hydrothermal pretreatment on anaerobic digestion efficiency for lignocellulosic biomass: Influence of pretreatment temperature on the formation of biomass-degrading byproducts.

Anaerobic digestion (AD) of lignocellulosic biomass is appealing because of the abundance and ease of obtaining the biomass locally. However, the recalcitrance of lignocellulosic biomass presents an obstacle in the hydrolysis step of AD and lowers the process efficiency. In this study, sunflower, which is a model lignocellulosic biomass, was pretreated by thermal (hydrothermal pretreatment, HTP) and non-thermal (milling) methods; the methane yield and biodegradability of the pretreated biomass were determined using a series of batch tests. The thermal pretreatment method showed a significantly higher methane yield (213.87-289.47 mL g-1 VS) and biodegradability (43-63%) than those of the non-thermally pretreated biomass, and the optimum pretreatment effect was observed at an HTP temperature of 180 °C. However, at an HTP temperature exceeding 200 °C, the induced formation of 5-hydroxymethylfurfural and furfural significantly lowered the methane yield and biodegradability. This study revealed that the HTP temperature is closely related to the formation of lignocellulosic biomass-degrading byproducts, which potentially hinder the methanogenesis step in AD; severe HTP conditions may have the opposite effect on the AD performance of lignocellulosic biomass.

Interactions between substrate characteristics and microbial communities on biogas production yield and rate.

In this study, leather fleshing waste (LFW) and a complementary substrate (food waste leachate; FWL) were co-digested. The main focus of research was to study effects on biogas production caused by interactions between co-substrates when combined in different mixing ratios and changes on microbial community structures. Due to a positive effect of co-digestion (i.e., establishing nutrient equilibrium), the adjusted substrates for optimum C/N ratio by blending LFW and FWL resulted in significantly higher biodegradability and biomethane production (375.5-520.8 mL CH4 g-1 VS) than the mono-digestion of each substrate. According to co-digestion of LFW and FWL, microbial communities became more diverse and the changes of microbial structure influenced the biomethane production performance. Among the co-digesting conditions, the biomethane production yield and rate of the samples were in reverse order and the results were firmly associated with the relative richness of lipids (yield-related) and proteins (rate-related) in the co-substrates.

Epithelial Splicing Regulatory Protein (ESPR1) Expression in an Unfavorable Prognostic Factor in Prostate Cancer Patients.

BACKGROUND: To evaluate the role of epithelial splicing regulatory protein 1 (ESRP1) expression in survival prognoses and disease progression for prostate cancer (PC) using The Cancer Genome Atlas (TCGA) dataset and to validate it using patients' prostatectomy specimens. METHODS: A preliminary investigation into the clinical significance of ESRP1 in PC was conducted using TCGA PC PRAD dataset and then using immunohistochemistry in 514 PC patients' tissue microarrays of radical prostatectomy specimens. The interpretation of immunohistochemistry was done using its intensity (high vs. low) or the semi-quantitative expression value (H-score, 0-300). The prognostic significance of ESRP1 expression was analyzed for biochemical recurrence (BCR), recurrence-free survival (RFS), overall survival (OS) and cancer-specific survival (CSS) using the Cox proportional-hazards model (p < 0.05). RESULTS: In the publicly available prostate adenocarcinoma dataset, ESRP1 expression was significantly higher in the tumor samples compared to the normal samples (p < 0.001). Survival analysis showed that the tumor samples in the ESRP1-high group had significantly worse BCR-free survival and RFS compared to the ESRP1-low group (p < 0.05), whereas OS was not (p=0.08). These results were largely consistent with the 514 patients' clinical data during a median 91.2 months of follow-up. After adjusting for significant prognostic clinicopathological factors, the multivariable models showed that the ESRP1 was a significantly risk factor for CSS (Hazard ratio 3.37, p = 0.034) and for BCR (HR 1.34, p=0.049) without any significance for OS (p=0.464). CONCLUSIONS: The higher ESRP1 expression appeared increased risk of disease progression and cancer-specific death in PC.

Solid fuel production through hydrothermal carbonization of sewage sludge and microalgae Chlorella sp. from wastewater treatment plant.

This study presents co-hydrothermal treatment of primary sludge (PS) from wastewater treatment plant (WWTP) and Chlorella sp., cultivated using WWTP effluent, and feasibility of using produced hydrochar as solid fuel. The results showed that properties of PS were improved through blending with Chlorella sp., in terms of mixture hydrochar properties (physicochemical composition, calorific value, fuel ratio, product yield, and energy recovery potential). The coalification degree (1.63 of H/C and 0.41 of O/C) and calorific value (5810 kcal kg-1) of hydrochar at 210 °C, defined as suitable hydrothermal carbonization temperature for mixture hydrochar production, were comparable to those of low-ranked coals (i.e., sub-bituminous and lignite). The low ash (<16.01% by dry weight until treatment temperature of 210 °C) and sulfur (0.64-0.78% by dry weight for all treatment temperature) contents of mixture hydrochar make it more attractive solid fuel as clean energy source. The findings suggest that the co-hydrothermal treatment of biomass (generated sludge and cultivated microalgae from WWTP) helps energy self-sufficiency in municipal WWTP.

Oxidation resistance of nanoscale zero-valent iron supported on exhausted coffee grounds.

In this study, nanoscale zero-valent iron (NZVI) was supported by exhausted coffee grounds. Exhausted coffee grounds are a crucial waste generated in enormous amounts. Since supported nanoscale particles have a lower free energy than bare particles, oxidation resistance of supported NZVI on coffee grounds (NZVI-Coffee ground) is postulated. The main aim of this study was to ascertain the enhanced oxidation resistance of NZVI-Coffee ground. Synthesized materials were dried and stored in the air at temperatures of 4, 20, and 35 °C. Changes in the surface characteristics and cadmium removal efficiency of the supported NZVI were investigated. Fourier transformation infrared spectroscopy and X-ray photoelectron spectroscopy showed that supported NZVI underwent less oxidation compared to bare NZVI. Cadmium removal efficiencies of supported NZVI did not deteriorate with age, while those of bare NZVI decreased by 9.5 ±â€¯0.1, 13.0 ±â€¯0.1, and 18.3 ±â€¯0.2% compared to their initial removal efficiencies when stored 8 weeks at 4, 20, and 35 °C, respectively. This is because the surface free energy of the NZVI decreased via strong interaction with the functional groups of the coffee grounds. According to the results, exhausted coffee grounds are an effective supporting material for NZVI to enhance its storage stability.

FIREVAT: finding reliable variants without artifacts in human cancer samples using etiologically relevant mutational signatures.

BACKGROUND: Accurate identification of real somatic variants is a primary part of cancer genome studies and precision oncology. However, artifacts introduced in various steps of sequencing obfuscate confidence in variant calling. Current computational approaches to variant filtering involve intensive interrogation of Binary Alignment Map (BAM) files and require massive computing power, data storage, and manual labor. Recently, mutational signatures associated with sequencing artifacts have been extracted by the Pan-cancer Analysis of Whole Genomes (PCAWG) study. These spectrums can be used to evaluate refinement quality of a given set of somatic mutations. RESULTS: Here we introduce a novel variant refinement software, FIREVAT (FInding REliable Variants without ArTifacts), which uses known spectrums of sequencing artifacts extracted from one of the largest publicly available catalogs of human tumor samples. FIREVAT performs a quick and efficient variant refinement that accurately removes artifacts and greatly improves the precision and specificity of somatic calls. We validated FIREVAT refinement performance using orthogonal sequencing datasets totaling 384 tumor samples with respect to ground truth. Our novel method achieved the highest level of performance compared to existing filtering approaches. Application of FIREVAT on additional 308 The Cancer Genome Atlas (TCGA) samples demonstrated that FIREVAT refinement leads to identification of more biologically and clinically relevant mutational signatures as well as enrichment of sequence contexts associated with experimental errors. FIREVAT only requires a Variant Call Format file (VCF) and generates a comprehensive report of the variant refinement processes and outcomes for the user. CONCLUSIONS: In summary, FIREVAT facilitates a novel refinement strategy using mutational signatures to distinguish artifactual point mutations called in human cancer samples. We anticipate that FIREVAT results will further contribute to precision oncology efforts that rely on accurate identification of variants, especially in the context of analyzing mutational signatures that bear prognostic and therapeutic significance. FIREVAT is freely available at https://github.com/cgab-ncc/FIREVAT.