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Quality metrics for the targeted sequencing of the 46 plasma samples.

Relation between number of ctDNA mutations and total number of somatic mutations.

Performance summary of somatic mutation calling using Mutect, Mutect+cmDetect, Varscan2, Varscan2+cmDetect with different filters on maximum variant allele read count and frequency in the blood

List of mutations inserted in the simulated data set

ctDNA mutations identified by cmDetect for the breast cancer metastatic cases.

DNA extracted from cancer patients' whole blood may contain somatic mutations from circulating tumor DNA (ctDNA) fragments. In this study, we introduce cmDetect, a computational method for the systematic identification of ctDNA mutations using whole-exome sequencing of a cohort of tumor and corresponding peripheral whole-blood samples. Through the analysis of simulated data, we demonstrated an increase in sensitivity in calling somatic mutations by combining cmDetect to two widely used mutation callers. In a cohort of 93 breast cancer metastatic patients, cmDetect identified ctDNA mutations in 54% of the patients and recovered somatic mutations in cancer genes EGFR, PIK3CA, and TP53. We further showed that cmDetect detected ctDNA in 89% of patients with confirmed mutated cell–free tumor DNA by plasma analyses (n = 9) within 46 pan-cancer patients. Our results prompt immediate consideration of the use of this method as an additional step in somatic mutation calling using whole-exome sequencing data with blood samples as controls. Cancer Res; 76(20); 5954–61. ©2016 AACR.

ctDNA mutations identified by somatic mutation callers and cmDetect in the simulated data set. Scatter plot of the allele frequency in blood (x-axis) and in tumor (y-axis) of the simulated ctDNA mutations. ctDNA mutations identified by Mutect (Varscan2) or cmDetect are shown in green; ctDNA mutations identified only by cmDetect are shown in blue; ctDNA mutations not identified are shown in gray.

Clinical information for the 93 breast cancer and 60 pan cancer metastatic patients.

Number of ctDNA mutations according to previous chemotherapy treatment.

List of somatic mutations identified in the 93 breast cancer metastases

ctDNA mutations identified in the simulated data set by cmDetect

Details of the 1000 Genomes samples used in data simulation

NF-κB mediates acquired resistance in acute myeloid leukemia (AML) cells treated with DNA-damaging agents. Because DNA repair is the major molecular shift that alters sensitivity to DNA-damaging agents, we explored whether activation of the NF-κB pathway promotes AML cell survival by regulating DNA repair after chemotherapy. Our results showed that RELA, an important subunit of NF-κB, regulated DNA repair by binding to the promoter region of the PARP1 gene and affecting PARP1 gene transcription. Conversely, PARP1 knockdown reduced NF-κB activity, indicating that NF-κB and PARP1 create a positive feedback loop in DNA repair. Simultaneous treatment with the NF-κB inhibitor BMS-345541 and the PARP1 inhibitor olaparib resulted in robust killing of AML cells. This dual inhibition significantly suppressed tumor growth and extended survival times in xenograft tumor models. Implications: RELA and PARP1 form a positive feedback loop to regulate DNA damage repair, simultaneous inhibition of NF-κB and PARP1 increases the antileukemic efficacy of daunorubicin in vitro and in vivo, broadening the use of PARP1 inhibitors.

Background Infestation by tea green leafhoppers (Empoasca (Matsumurasca) onukii) can cause a series of biochemical changes in tea leaves. As a typical cell-rupture feeder, E. onukii secretes proteases while using its stylet to probe the tender shoots of tea plants (Camellia sinensis). This study identified and analyzed proteases expressed specifically in the salivary gland (SG) and gut of E. onukii through enzymatic activity assays complemented with an integrated analysis of transcriptomic and proteomic data. Results In total, 129 contigs representing seven types of putative proteases were identified. Transcript abundance of digestive proteases and enzymatic activity assays showed that cathepsin B-like protease, cathepsin L-like protease, and serine proteases (trypsin- and chymotrypsin-like protease) were highly abundant in the gut but moderately abundant in the SG. The abundance pattern of digestive proteases in the SG and gut of E. onukii differed from that of other hemipterans, including Nilaparvata lugens, Laodelphax striatellus, Acyrthosiphum pisum, Halyomorpha halys and Nephotettix cincticeps. Phylogenetic analysis showed that aminopeptidase N-like proteins and serine proteases abundant in the SG or gut of hemipterans formed two distinct clusters. Conclusions Altogether, this study provides insightful information on the digestive system of E. onukii. Compared to five other hemipteran species, we observed different patterns of proteases abundant in the SG and gut of E. onukii. These results will be beneficial in understanding the interaction between tea plants and E. onukii.

Additional file 2. Additional figures. This file contains 4 additional figures

Additional file 1. Additional tables. This file contains 2 additional tables

Background: Infestation by tea green leafhoppers, Empoasca (Matsumurasca) onukii , could cause a series of biochemical changes in tea leaves. As a typical cell-rupture feeder, E. onukii secretes proteases while probing with its stylet into the tender shoots of tea plants ( Camellia sinensis ). This study identified and analyzed proteases specifically expressed in the salivary gland (SG) and gut of E. onukii through enzymatic activity assays, complemented with an integrated analysis of transcriptome and proteome data.Results: In total, 129 contigs representing seven types of putative proteases were identified. Transcript abundance of digestive proteases and enzymatic activity assays showed that cathepsin B-like protease, cathepsin L-like protease, and serine proteases (trypsin- and chymotrypsin-like protease) were highly abundant in the gut while moderately abundant in the SG. The abundance pattern of digestive proteases in the SG and gut of E. onukii differed from that of other hemipterans including Nilaparvata lugens , Laodelphax striatellus , Acyrthosiphum pisum , Halyomorpha halys and Nephotettix cincticeps . Phylogenetic analysis showed that aminopeptidase N-like proteins and serine proteases abundant in the SG or gut of hemipterans were distributed to two distinct clusters.Conclusions: Altogether, this study provide insightful information on the digestive system of E. onukii and observed different patterns of proteases abundant in the SG and gut of E. onukii , in comparison with other five hemipteran species. These results will be beneficial in understanding the interaction between tea plants and E. onukii .

Humans homozygous or hemizygous for variants predicted to cause a loss of function of the corresponding protein do not necessarily present with overt clinical phenotypes. However, the set of effectively dispensable genes in the human genome has not yet been fully characterized. We report here 190 autosomal genes with 207 predicted loss-of-function variants, for which the frequency of homozygous individuals exceeds 1% in at least one human population from five major ancestry groups. No such genes were identified on the X and Y chromosomes. Manual curation revealed that 28 variants (15%) had been misannotated as loss-of-function, mainly due to linkage disequilibrium with different compensatory variants. Of the 179 remaining variants in 166 genes (0.82% of 20,232 genes), only 11 alleles in 11 genes had previously been confirmed experimentally to be loss-of-function. The set of 166 dispensable genes was enriched in olfactory receptor genes (41 genes), but depleted of genes expressed in a wide range of organs and in leukocytes. The 125 dispensable non-olfactory receptor genes displayed a relaxation of selective constraints both between species and within humans, consistent with greater redundancy. In total, 62 of these 125 genes were found to be dispensable in at least three human populations, suggesting possible evolution toward pseudogenes. Out of the 179 common loss-of-function variants, 72 could be tested for two neutrality selection statistics, and eight displayed robust signals of positive selection. These variants included the knownFUT2mutant allele conferring resistance to intestinal viruses and anAPOL3variant involved in resistance to parasitic infections. Finally, the 41 dispensable olfactory receptor genes also displayed a strong relaxation of selective constraints similar to that observed for the 341 non-dispensable olfactory receptor genes. Overall, the identification of 166 genes for which a sizeable proportion of humans are homozygous for predicted loss-of-function alleles reveals both redundancies and advantages of such deficiencies for human survival.Significance statementHuman genes homozygous for seemingly loss of function (LoF) variants are increasingly reported in a sizeable proportion of individuals without overt clinical phenotypes. Here, we found 166 genes with 179 predicted LoF variants for which the frequency of homozygous individuals exceeds 1% in at least one of the populations present in databases ExAC and gnomAD. This set of putatively dispensable genes showed relaxation of selective constraints suggesting that a large number of these genes are undergoing pseudogenization. Eight of the common LoF variants displayed robust signals of positive selection including two variants located in genes involved in resistance to infectious diseases. The identification of dispensable genes will allow identifying functions that are, at least nowadays, redundant, or possibly advantageous, for human survival.

Background: Infestation by tea green leafhoppers, Empoasca (Matsumurasca) onukii, could cause a series of biochemical changes in tea leaves. As a typical cell-rupture feeder, E. onukii secretes proteases while probing with its stylet into the tender shoots of tea plants (Camellia sinensis). This study identified and analyzed proteases specifically expressed in the salivary gland (SG) and gut of E. onukii through enzymatic activity assays, complemented with an integrated analysis of transcriptome and proteome data.Results: In total, 129 contigs representing seven types of putative proteases were identified. Transcript abundance of digestive proteases and enzymatic activity assays showed that cathepsin B, cathepsin L, and serine proteases (trypsin and chymotrypsin) were highly abundant in the gut while moderately abundant in the SG. The abundance pattern of digestive proteases in the SG and gut of E. onukii differed from that of other hemipterans including Nilaparvata lugens, Laodelphax striatellus, Nephotettix cincticeps and Acyrthosiphum pisum. Phylogenetic analysis showed that aminopeptidase N-like proteins and serine proteases abundant in the SG or gut of hemipterans were distributed to two distinct clusters. Conclusions: Altogether, this study provide insightful information on the digestive system of E. onukii and observed different patterns of proteases abundant in the SG and gut of E. onukii, in comparison with other five hemipteran species. These results will be beneficial in understanding the interaction between tea plants and E. onukii.

In this paper, we present the unified closed-form expressions of average symbol error probability (ASEP) for both types of system (i.e. coherent and incoherent system) in the presence of pointing error over Malaga ( M ) turbulence channel. With the help of the approximation of exponential-type presentation of Q-function, the unified closed-form expressions are presented, which are generic enough to encompass almost all the modulation techniques of which ASEP involves the integral power of Q-function. Then, we capitalize on the results to provide the asymptotic expressions at high signal-to-noise ratio (SNR). Additionally, the diversity order and coding gain are presented, which reveal that the diversity order is depended on the channel condition and detection scheme, while the coding gain is relevant to the modulation techniques. Moreover, some special cases are presented, such as the results under Gamma–Gamma distribution and K-distribution. Numerical results corroborate the accuracy of the closed-form expressions for different modulation techniques under different turbulence conditions.

Objective: Understanding the heterogeneity and pathophysiology of osteoarthritis (OA) is critical to support the development of tailored disease-modifying treatments. To this aim, transcriptomics tools are highly relevant to delineate dysregulated molecular pathways and identify new therapeutic targets. Methods: We review the methodology and outcomes of transcriptomics studies conducted in OA, based on a comprehensive literature search of the PubMed and Google Scholar databases using the terms “osteoarthritis”, “OA”, “knee OA”, “hip OA”, “genes”, “RNA-seq”, “microarray”, “transcriptomic” and “PCR” as key words. Beyond target-focused RT-qPCR, more comprehensive techniques include microarrays, RNA sequencing (RNA-seq) and single cell RNA-seq analyses. Results: The standardization of those methods to ensure the quality of both RNA extraction and sequencing is critical to get meaningful insights. Transcriptomics studies have been conducted in various tissues involved in the pathogenesis of OA, including articular cartilage, subchondral bone and synovium, as well as in the blood of patients. Molecular pathways dysregulated in OA relate to cartilage degradation, matrix and bone remodeling, neurogenic pain, inflammation, apoptosis and angiogenesis. This knowledge has direct application to patient stratification and further, to the identification of candidate therapeutic targets and biomarkers intended to monitor OA progression. Conclusion: In light of its high-throughput capabilities and ability to provide comprehensive information on major biological processes, transcriptomics represents a powerful method to support the development of new disease-modifying drugs in OA.

As a core equipment in power system, power transformer plays a vital role in the stability of the power grid. It is necessary to quickly and accurately monitor the fault of the transformer. Frequency response method is an important method for fault diagnosis of transformers. It has many advantages, such as simple and light test equipment, easy measurement and high test sensitivity, intuitive analysis of experimental maps, and comparability of data magnitude analysis. It is considered to be a detection method with good application prospects. In this paper, the monitoring principle of frequency response method and the influencing factors in practical application are analyzed, and the shortcomings of the method and the research direction of the next step are prospected.

The study of rare Mendelian diseases through exome sequencing typically yields incomplete diagnostic rates, ~8-70% depending on the disease type. Whole genome sequencing of the unresolved cases allows addressing the hypothesis that causal variants could lay in non-coding regions with damaging regulatory consequences. The large amount of rare and singleton variants found in each individual genome requires computational filtering and scoring strategies to gain power in downstream statistical genetics tests. However, state-of-the-art methods estimating the functional relevance of non-coding genomic regions have been mostly characterized on sets of variants largely composed of trait-associated polymorphisms and associated to common diseases, yet with modest accuracy and strong positional biases. In this work we first curated a collection of n=737 high-confidence pathogenic non-coding single-nucleotide variants in proximalcis-regulatory genomic regions associated to monogenic Mendelian diseases. We then systematically evaluated the ability to predict causal variants of a comprehensive set of natural selection features extracted at three genomic levels: the affected position, the flanking region and the associated gene. In addition to inter-species conservation, a comprehensive set of recent and ongoing purifying selection signals in human was explored, allowing to capture potential constraints associated to recently acquired regulatory elements in the human lineage. A supervised learning approach using gradient tree boosting on such features reached a high predictive performance characterized by an area under the ROC curve = 0.84 and an area under the Precision-Recall curve = 0.47. The figures represent a relative improvement of >10% and >34% respectively upon the performance of current state-of-the-art methods for prioritizing non-coding variants. Performance was consistent under multiple configurations of the sets of variants used for learning and for independent testing. The supervised learning design allowed the assessment of newly seen non-coding variants overcoming gene and positional bias. The scores produced by the approach allow a more consistent weighting and aggregation of candidate pathogenic variants from diverse non-coding regions within and across genes in the context of statistical tests for rare variant association analysis.

Optical mobile ad-hoc networks suffer from the atmospheric turbulence. A new kind of routing algorithm based on disruption-tolerant network protocols is proposed. The proposed scheme improves the delivery ratio by 40% in severe network environment.

DNA extracted from cancer patients' whole blood may contain somatic mutations from circulating tumor DNA (ctDNA) fragments. In this study, we introduce cmDetect, a computational method for the systematic identification of ctDNA mutations using whole-exome sequencing of a cohort of tumor and corresponding peripheral whole-blood samples. Through the analysis of simulated data, we demonstrated an increase in sensitivity in calling somatic mutations by combining cmDetect to two widely used mutation callers. In a cohort of 93 breast cancer metastatic patients, cmDetect identified ctDNA mutations in 54% of the patients and recovered somatic mutations in cancer genes EGFR, PIK3CA, and TP53. We further showed that cmDetect detected ctDNA in 89% of patients with confirmed mutated cell–free tumor DNA by plasma analyses (n = 9) within 46 pan-cancer patients. Our results prompt immediate consideration of the use of this method as an additional step in somatic mutation calling using whole-exome sequencing data with blood samples as controls. Cancer Res; 76(20); 5954–61. ©2016 AACR.

Leflunomide is an effective drug used in the treatment of rheumatoid arthritis. Here we report the findings of an open-label pilot study, which found that leflunomide is also an effective treatment for myasthenia gravis (MG). This study recruited 15 corticosteroid-dependent MG patients. For 6 months, leflunomide 20 mg was given to these patients daily along with prednisone. The quantitative myasthenia gravis (QMG) scores and MG activities of daily living (MG-ADL) profiles were measured in these MG patients. After 6 months of treatment, 9 of the 15 patients enrolled in this study showed improvements in both QMG and MG-ADL. The mean QMG scores (13.4 to 8.5) and MG-ADL profiles (5.8 to 2.8) were significantly decreased (P = 0.01, 0.006 respectively). Furthermore, we found that the mean corticosteroid doses were reduced after treatment with leflunomide (24.3 to 12.3 mg per day). Leflunomide is a well-tolerated and efficacious treatment for corticosteroid-dependent MG, which may also enable lower doses of corticosteroids to be administered.

Ag-dendrimer nanoclusters were prepared with Ag+ and carboxyl shell (G4.5) poly(amino amine) dendrimers. Self-assembly photosensitive ultrathin films were then fabricated with these Ag-dendrimer nanoclusters as polyanions and diazoresin (DR) as polycation. With UV irradiating the films became stable because of the formation of covalent linkages between the layers. Compared to similar films containing no Ag nanoclusters, the obtained films showed greatly enhanced electric conductivity. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 1515–1519, 2003