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Systems Biology
Modeling genome-wide enzyme evolution predicts strong epistasis underlying catalytic turnover rates.
Dec 12, 2018   Nature Communications
Heckmann D, Zielinski DC, Palsson BO
Modeling genome-wide enzyme evolution predicts strong epistasis underlying catalytic turnover rates.
Dec 12, 2018
Nature Communications
Systems biology describes cellular phenotypes as properties that emerge from the complex interactions of individual system components. Little is known about how these interactions have affected the evolution of metabolic enzymes. Here, we combine genome-scale metabolic modeling with population genetics models to simulate the evolution of enzyme turnover numbers (kcats) from a theoretical ancestor with inefficient enzymes. This systems view of biochemical evolution reveals strong epistatic interactions between metabolic genes that shape evolutionary trajectories and influence the magnitude of evolved kcats. Diminishing returns epistasis prevents enzymes from developing higher kcats in all reactions and keeps the organism far from the potential fitness optimum. Multifunctional enzymes cause synergistic epistasis that slows down adaptation. The resulting fitness landscape allows kcat evolution to be convergent. Predicted kcat parameters show a significant correlation with experimental data, validating our modeling approach. Our analysis reveals how evolutionary forces shape modern kcats and the whole of metabolism.
Actin polymerization and cell motility are affected by NAA80-mediated posttranslational N-terminal acetylation of actin.
Dec 11, 2018   Communicative & Integrative Biology
Aksnes H, Marie M, Arnesen T, Drazic A
Actin polymerization and cell motility are affected by NAA80-mediated posttranslational N-terminal acetylation of actin.
Dec 11, 2018
Communicative & Integrative Biology
Actin is the most abundant protein in our cells, and also one of the most studied. Nevertheless, an important modifier of actin, the N-terminal acetyltransferase (NAT) for actin, remained unknown until now. The recent identification of the enzyme that catalyzes actin acetylation, has opened up for functional studies of unacetylated actin using knockout cells. This enzyme, called NAA80 (Nα-acetyltransferase 80) or NatH, belongs to the NAT family of enzymes, which together provides N-terminal acetylation for around 80 % of the human proteome. In many cases, N-terminal acetylation is essential. In the case of actin, the acetyl group that NAA80 attaches to actin plays an important role in actin's polymerization properties as well as in actin's function in cell migration.
Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories.
Dec 11, 2018   Cancer Cell
Gerhauser C, Favero F, Risch T, Simon R, Feuerbach L,   . . . . . .   , Plass C, Yaspo ML, Korbel JO, Schlomm T, Weischenfeldt J
Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories.
Dec 11, 2018
Cancer Cell
Identifying the earliest somatic changes in prostate cancer can give important insights into tumor evolution and aids in stratifying high- from low-risk disease. We integrated whole genome, transcriptome and methylome analysis of early-onset prostate cancers (diagnosis ≤55 years). Characterization across 292 prostate cancer genomes revealed age-related genomic alterations and a clock-like enzymatic-driven mutational process contributing to the earliest mutations in prostate cancer patients. Our integrative analysis identified four molecular subgroups, including a particularly aggressive subgroup with recurrent duplications associated with increased expression of ESRP1, which we validate in 12,000 tissue microarray tumors. Finally, we combined the patterns of molecular co-occurrence and risk-based subgroup information to deconvolve the molecular and clinical trajectories of prostate cancer from single patient samples.
Glucocorticoid Resistance in Acute Lymphoblastic Leukemia: BIM Finally.
Dec 11, 2018   Cancer Cell
Brown JA, Ferrando A
Glucocorticoid Resistance in Acute Lymphoblastic Leukemia: BIM Finally.
Dec 11, 2018
Cancer Cell
Glucocorticoid resistance represents a major challenge in treating acute lymphoblastic leukemia. In this issue of Cancer Cell, Jing and colleagues show epigenetic deregulation of glucocorticoid-induced BIM activation in glucocorticoid-resistant leukemia cells, and restore glucocorticoid-receptor-induced BIM upregulation with DNA demethylating agents to effectively enhance glucocorticoid response.
Towards the molecular deciphering of Pomacea canaliculata immunity: first proteomic analysis of circulating hemocytes.
Dec 11, 2018   Proteomics
Boraldi F, Lofaro FD, Accorsi A, Ross E, Malagoli D, Boraldi F, Lofaro FD
Towards the molecular deciphering of Pomacea canaliculata immunity: first proteomic analysis of circulating hemocytes.
Dec 11, 2018
Proteomics
Pomacea canaliculata is a freshwater snail with interesting biological features that include invasiveness, human parasite hosting and adult regeneration. Its immune system may represent the target for strategies aimed at controlling the spread of the snail population and its hosting of the human parasite Angiostrongylus cantonensis. Moreover, immune functions likely have a role in the snail's ability to wound heal and regenerate. Despite its importance in multiple processes, very little is known about the molecular basis of P. canaliculata immunity. Aiming to contribute to filling this gap, we have studied the ultrastructure and performed the first proteomic analysis of circulating hemocytes in healthy snails, evidencing 83 unique proteins, 96% of which have identifiable homologs in other species. Fifteen proteins were retrieved as potentially involved in immune-related signaling pathways, including hemocyanin, C1q-like protein and HSP90 together with cytoskeleton and cytoskeleton-related proteins involved in cell motility and membrane dynamism. This first proteome study on non-stimulated hemocytes, provides a valid reference for future investigations on the molecular changes under stressful circumstances, like pathogen exposure, wounding or environmental changes. This article is protected by copyright. All rights reserved.
An Updated Gene Atlas for Maize Reveals Organ-Specific and Stress-Induced Genes.
Dec 11, 2018   The Plant Journal : For Cell And Molecular Biology
Hoopes GM, Hamilton JP, Wood JC, Esteban E, Pasha A, Vaillancourt B, Provart NJ, Buell CR
An Updated Gene Atlas for Maize Reveals Organ-Specific and Stress-Induced Genes.
Dec 11, 2018
The Plant Journal : For Cell And Molecular Biology
Maize(Zea mays L.), a model species for genetic studies, is one of the two most important crop species worldwide.The genome sequence of the reference genotype, B73, representative of the stiff stalk heterotic group was recently updated (AGPv4) using long-read sequencing and optical mapping technology. To facilitate the use of AGPv4 and to enable functional genomic studies and association of genotype with phenotype, we determined expression abundances for replicated mRNA-sequencing datasets from 79 tissues and five abiotic/biotic stress treatments revealing 36,207 expressed genes. Characterization of the B73 transcriptome across six organs revealed 4,154 organ-specific and 7,704 differentially expressed genes following stress treatment. Gene co-expression network analyses revealed 12 modules associated with distinct biological processes containing 13,590 genes providing a resource for further association of gene function based on co-expression patterns. Presence/absence variants (PAVs) previously identified using whole genome resequencing data from 61 additional inbred lines were enriched in organ-specific and stress-induced differentially expressed genes, suggesting PAVs may function in phenological variation and adaptation to environment. Relative to core genes conserved across the 62 profiled inbreds, PAVs have lower expression abundances which are correlated with their frequency of dispersion across inbreds and on average, have significantly fewer co-expression network connections suggesting that a subset of PAVs may be on an evolutionary path to pseudogenization. To facilitate use by the community, we developed the Maize Genomics Resource website(maize.plantbiology.msu.edu) for viewing and data-mining these resources and deployed two new views on the Maize electronic Fluorescent Pictograph Browser (bar.utoronto. ca/efp_maize) This article is protected by copyright. All rights reserved.
Mitochondrial Function Modulates Touch Signalling in Arabidopsis thaliana.
Dec 11, 2018   The Plant Journal : For Cell And Molecular Biology
Xu Y, Berkowitz O, Narsai R, De Clercq I, Hooi M, Vincent B, Van Breusegem F, Whelan J, Wang Y
Mitochondrial Function Modulates Touch Signalling in Arabidopsis thaliana.
Dec 11, 2018
The Plant Journal : For Cell And Molecular Biology
Plants respond to short- and long-term mechanical stimuli, via altered transcript abundance and growth respectively. Jasmonate, gibberellic acid and calcium have been implicated in mediating responses to mechanical stimuli. Previously it was shown that the transcript abundance for the outer mitochondrial membrane protein of 66 kDa (OM66), is induced several-fold after 30 min in response to touch. Thus, the impact of mitochondrial function on the response to mechanical stimulation by touch at 30 min was investigated. Twenty-five mutants targeting mitochondrial function or regulators revealed that all affected the touch transcriptome. Double and triple mutants revealed synergistic or antagonistic effects following the observed responses in the single mutants. Changes in the touch-responsive transcriptome were localised, recurring with repeated rounds of stimulus. The gene expression kinetics after repeated touch were complex displaying five distinct patterns. These transcriptomic responses were altered by some regulators of mitochondrial retrograde signalling, such as Cyclic Dependent Protein Kinase E1, a kinase protein in the mediator complex, and KIN10 (SnRK1 - Sucrose non-fermenting Related protein Kinase 1), revealing overlap between the touch response and mitochondrial stress signalling and alternative mitochondrial metabolic pathways. Regulatory network analyses revealed that touch induced stress responses and suppressed growth and biosynthetic processes. Interaction with phytohormone signalling pathways indicated that ethylene and gibberellic acid had the greatest effect. Hormone measurements revealed that mutations of genes encoding mitochondrial proteins altered hormone concentrations. Mitochondrial function modulates touch-induced changes in gene expression directly through altered regulatory networks, and indirectly via altering hormonal levels. This article is protected by copyright. All rights reserved.
Modeling and multi-scale characterization of the quantitative imaging based fibrosis index reveals pathophysiological, transcriptome and proteomic correlates of lung fibrosis induced by fractionated irradiation.
Dec 11, 2018   International Journal Of Cancer
Zhou C, Moustafa MR, Cao L, Kriegsmann M, Winter M, Schwager C, Jones B, Wang S, Bäuerle T, Zhou PK, Schnölzer M, Weichert W, Debus J, Abdollahi A
Modeling and multi-scale characterization of the quantitative imaging based fibrosis index reveals pathophysiological, transcriptome and proteomic correlates of lung fibrosis induced by fractionated irradiation.
Dec 11, 2018
International Journal Of Cancer
Pulmonary fibrosis represents a leading cause of morbidity and mortality worldwide. Therapy induced lung fibrosis constitutes a pivotal dose-limiting side effect of radiotherapy and other anticancer agents. We aimed to develop objective criteria for assessment of fibrosis and discover pathophysiological and molecular correlates of lung fibrosis as a function of fractionated whole thoracic irradiation. Dose-response series of fractionated irradiation was utilized to develop a non-invasive and quantitative measure for the degree of fibrosis - the fibrosis index (FI). The correlation of FI with histopathology, blood-gas, transcriptome and proteome responses of the lung tissue was analyzed. Macrophages infiltration and polarization was assessed by immunohistochemistry. Fibrosis development followed a slow kinetic with maximum lung fibrosis levels detected at 24-week post radiation insult. FI favorably correlated with radiation dose and surrogates of lung fibrosis i.e., enhanced pro-inflammatory response, tissue remodeling and extracellular matrix deposition. The loss of lung architecture correlated with decreased epithelial marker, loss of microvascular integrity with decreased endothelial and elevated mesenchymal markers. Lung fibrosis was further attributed to a switch of the inflammatory state towards a macrophage/T-helper cell type 2-like (M2/Th2) polarized phenotype. Together, the multi-scale characterization of FI in radiation-induced lung fibrosis (RILF) model identified pathophysiological, transcriptional and proteomic correlates of fibrosis. Pathological immune response and endothelial/epithelial to mesenchymal transition were discovered as critical events governing lung tissue remodeling. FI will be instrumental for deciphering the molecular mechanisms governing lung fibrosis and discovery of novel targets for treatment of this devastating disease with an unmet medical need. This article is protected by copyright. All rights reserved.
Hypermutagenesis in untreated adult gliomas due to inherited mismatch mutations.
Dec 11, 2018   International Journal Of Cancer
Sa JK, Choi SW, Zhao J, Lee Y, Zhang J, Kong DS, Choi JW, Seol HJ, Lee JI, Iavarone A, Rabadan R, Nam DH
Hypermutagenesis in untreated adult gliomas due to inherited mismatch mutations.
Dec 11, 2018
International Journal Of Cancer
Hypermutagenesis refers to marked increase in the number of mutations due to continuous mutagenic process. Hypermutated tumors, have being found in several tumor types, are associated with inherited or acquired alterations in DNA repair pathways. Hypermutation has been observed in a subset of adult glioma patients as a direct result of temozolomide(TMZ)-induced mutagenesis. In present study, we have identified a rare subset of treatment-naïve adult gliomas with de novo hypermutator phenotype and explored the evolution of spontaneous and treatment-induced hypermutagenesis. We conducted Whole-Exome Sequencing (WES), Whole-Transcriptome Sequencing (WTS), and Single-Cell Sequencing (SCS) of TMZ-naïve and post-TMZ treated hypermutated tumors to identify distinct clinical or genomic manifestations that contribute to the development of hypermutation in untreated adult gliomas. TMZ-naïve hypermutated tumors were marked by absence of IDH1 somatic mutation and MGMT promoter (pMGMT) methylation, two genomic traits that were significantly associated with TMZ-induced hypermutagenic event in glioblastoma, and harbored inherited alterations in the mismatch repair (MMR) machinery. The immediate family members of the TMZ-naive hypermutated glioma patients were also previous diagnosed with cancer development history, suggesting that germline dysfunction of the MMR pathway could potentially pose hereditary risk to genetic predisposition of carcinogenesis in gliomas. Lastly, both TMZ-naïve and post-TMZ treated hypermutated tumors exhibited a significant increase in neoantigen load suggesting immunotherapeutic alternatives. Our results present new and unique understanding of hypermutagenic process in adult gliomas and an important step towards clinical implication of immunotherapy in glioma treatment. This article is protected by copyright. All rights reserved.
A Complete Proteomic Workflow to Study Brain-Related Disorders via Postmortem Tissue.
Dec 11, 2018   Methods In Molecular Biology (Clifton, N.J.)
Reis-de-Oliveira G, Fioramonte M, Martins-de-Souza D
A Complete Proteomic Workflow to Study Brain-Related Disorders via Postmortem Tissue.
Dec 11, 2018
Methods In Molecular Biology (Clifton, N.J.)
Here we describe a mass spectrometry-based proteomics workflow to discovery proteins differentially regulated in brains collected postmortem from mental, neurological, or substance abuse disorders (MNS) patients. One way to maximize protein detection is to carry out enrichment of cellular compartments such as the nucleus, mitochondria and cytosol. Subcellular fractionation improves proteome coverage and may shed light on the role of these organelles in the pathophysiology of MNS.
Prot-SpaM: Fast alignment-free phylogeny reconstruction based on whole-proteome sequences.
Dec 11, 2018   GigaScience
Leimeister CA, Schellhorn J, Dörrer S, Gerth M, Bleidorn C, Morgenstern B
Prot-SpaM: Fast alignment-free phylogeny reconstruction based on whole-proteome sequences.
Dec 11, 2018
GigaScience
Word-based or 'alignment-free' sequence comparison has become an active research area in bioinformatics. While previous word-frequency approaches calculated rough measures of sequence similarity or dissimilarity, some new alignment-free methods are able to accurately estimate phylogenetic distances between genomic sequences. One of these approaches is Filtered Spaced Word Matches. Herein, we extend this approach to estimate evolutionary distances between complete or incomplete proteomes; our implementation of this approach is called Prot-SpaM. We compare the performance of Prot-SpaM to other alignment-free methods on simulated sequences and on various groups of eukaryotic and prokaryotic taxa. Prot-SpaM can be used to calculate high-quality phylogenetic trees for dozens of whole-proteome sequences in a matter of seconds or minutes and often outperforms other alignment-free approaches. The source code of our software is available through Github: https://github.com/jschellh/ProtSpaM.
AStrap: identification of alternative splicing from transcript sequences without a reference genome.
Dec 11, 2018   Bioinformatics (Oxford, England)
Ji G, Ye W, Su Y, Chen M, Huang G, Wu X
AStrap: identification of alternative splicing from transcript sequences without a reference genome.
Dec 11, 2018
Bioinformatics (Oxford, England)
Summary: Alternative splicing (AS) is a well-established mechanism for increasing transcriptome and proteome diversity, however, detecting AS events and distinguishing among AS types in organisms without available reference genomes remains challenging. We developed a de novo approach called AStrap for AS analysis without using a reference genome. AStrap identifies AS events by extensive pair-wise alignments of transcript sequences and predicts AS types by a machine-learning model integrating more than 500 assembled features. We evaluated AStrap using collected AS events from reference genomes of rice and human as well as single-molecule real-time sequencing data from Amborella trichopoda. Results show that AStrap can identify much more AS events with comparable or higher accuracy than the competing method. AStrap also possesses a unique feature of predicting AS types, which achieves an overall accuracy of ∼0.87 for different species. Extensive evaluation of AStrap using different parameters, sample sizes and machine-learning models on different species also demonstrates the robustness and flexibility of AStrap. AStrap could be a valuable addition to the community for the study of AS in nonmodel organisms with limited genetic resources. Availability: AStrap is available for download at https://github.com/BMILAB/AStrap. Supp. information: Supplementary data are available at Bioinformatics online.
Neuro-Immune Hemostasis: Homeostasis and Diseases in the Central Nervous System.
Dec 11, 2018   Frontiers In Cellular Neuroscience
De Luca C, Colangelo AM, Alberghina L, Papa M
Neuro-Immune Hemostasis: Homeostasis and Diseases in the Central Nervous System.
Dec 11, 2018
Frontiers In Cellular Neuroscience
Coagulation and the immune system interact in several physiological and pathological conditions, including tissue repair, host defense, and homeostatic maintenance. This network plays a key role in diseases of the central nervous system (CNS) by involving several cells (CNS resident cells, platelets, endothelium, and leukocytes) and molecular pathways (protease activity, complement factors, platelet granule content). Endothelial damage prompts platelet activation and the coagulation cascade as the first physiological step to support the rescue of damaged tissues, a flawed rescuing system ultimately producing neuroinflammation. Leukocytes, platelets, and endothelial cells are sensitive to the damage and indeed can release or respond to chemokines and cytokines (platelet factor 4, CXCL4, TNF, interleukins), and growth factors (including platelet-derived growth factor, vascular endothelial growth factor, and brain-derived neurotrophic factor) with platelet activation, change in capillary permeability, migration or differentiation of leukocytes. Thrombin, plasmin, activated complement factors and matrix metalloproteinase-1 (MMP-1), furthermore, activate intracellular transduction through complement or protease-activated receptors. Impairment of the neuro-immune hemostasis network induces acute or chronic CNS pathologies related to the neurovascular unit, either directly or by the systemic activation of its main steps. Neurons, glial cells (astrocytes and microglia) and the extracellular matrix play a crucial function in a "tetrapartite" synaptic model. Taking into account the neurovascular unit, in this review we thoroughly analyzed the influence of neuro-immune hemostasis on these five elements acting as a functional unit ("pentapartite" synapse) in the adaptive and maladaptive plasticity and discuss the relevance of these events in inflammatory, cerebrovascular, Alzheimer, neoplastic and psychiatric diseases. Finally, based on the solid reviewed data, we hypothesize a model of neuro-immune hemostatic network based on protein-protein interactions. In addition, we propose that, to better understand and favor the maintenance of adaptive plasticity, it would be useful to construct predictive molecular models, able to enlighten the regulating logic of the complex molecular network, which belongs to different cellular domains. A modeling approach would help to define how nodes of the network interact with basic cellular functions, such as mitochondrial metabolism, autophagy or apoptosis. It is expected that dynamic systems biology models might help to elucidate the fine structure of molecular events generated by blood coagulation and neuro-immune responses in several CNS diseases, thereby opening the way to more effective treatments.
Transcriptome and protein interaction profiling in cancer cells with mutations in histone H3.3.
Dec 11, 2018   Scientific Data
Lim J, Park JH, Baude A, Fellenberg J, Zustin J, Haller F, Krücken I, Kang HG, Park YJ, Plass C, Lindroth AM
Transcriptome and protein interaction profiling in cancer cells with mutations in histone H3.3.
Dec 11, 2018
Scientific Data
Mutations of histone variant H3.3 are highly recurrent in childhood glioblastoma and in young adults with Giant Cell Tumor of the Bone (GCTB). The heterozygotic representation of the mutations in the tumors, and with potential histone H3 and H3.3 redundancy, suggest that the mutations are gain-of-function by nature. To address common H3.3 point mutations, we have generated data from GCTB patient samples with H3.3 G34W substitutions and engineered human GFP-tagged H3.3-mutated isogenic cell lines for high throughput data comparisons. First, a total of thirty-six patient samples and cell lines were used to acquire gene expression transcriptome data using microarray and RNA-sequencing. The expression data were validated with the orthogonal nCounter assay. Second, to uncover the H3.3-GFP interaction proteomes from the isogenic cell lines, immunoprecipitation of unmutated wild type, K27M, G34R, and G34W substitutions were performed. The RNA-sequencing data and the H3.3 interaction proteome enable potentially important functional insight into the tumorigenic process and should spur further detailed analysis.
Draft Genome Assembly of the Poultry Red Mite, Dermanyssus gallinae.
Dec 11, 2018   Microbiology Resource Announcements
Burgess STG, Bartley K, Nunn F, Wright HW, Hughes M,   . . . . . .   , Strube C, Øines Ø, Van Leeuwen T, Van de Peer Y, Nisbet AJ
Draft Genome Assembly of the Poultry Red Mite, Dermanyssus gallinae.
Dec 11, 2018
Microbiology Resource Announcements
The poultry red mite, Dermanyssus gallinae, is a major worldwide concern in the egg-laying industry. Here, we report the first draft genome assembly and gene prediction of Dermanyssus gallinae, based on combined PacBio and MinION long-read de novo sequencing. The ∼959-Mb genome is predicted to encode 14,608 protein-coding genes.
High-Quality Draft Genome Sequence of Xanthomonas arboricola pv. juglandis CPBF 1521, Isolated from Leaves of a Symptomatic Walnut Tree in Portugal without a Past of Phytosanitary Treatment.
Dec 11, 2018   Microbiology Resource Announcements
Fernandes C, Blom J, Pothier JF, Tavares F
High-Quality Draft Genome Sequence of Xanthomonas arboricola pv. juglandis CPBF 1521, Isolated from Leaves of a Symptomatic Walnut Tree in Portugal without a Past of Phytosanitary Treatment.
Dec 11, 2018
Microbiology Resource Announcements
Here, we report the draft genome sequence of Xanthomonas arboricola pv. juglandis CPBF 1521, isolated from symptomatic leaves of an ornamental walnut in a public site in Portugal without any record of phytosanitary treatment. This isolate may constitute a genomic reference of a wild-type strain in comparative genomics studies.
High-Quality Draft Genome Sequence of Pseudomonas wadenswilerensis CCOS 864T.
Dec 11, 2018   Microbiology Resource Announcements
Rutz D, Frasson D, Sievers M, Blom J, Rezzonico F, Pothier JF, Smits THM
High-Quality Draft Genome Sequence of Pseudomonas wadenswilerensis CCOS 864T.
Dec 11, 2018
Microbiology Resource Announcements
Pseudomonas wadenswilerensis CCOS 864T was isolated in 2014 from forest soil. The organism belongs taxonomically to the Pseudomonas putida group, members of which have been well studied for their potential in biotechnological applications. We present here the draft genome sequence of P. wadenswilerensis CCOS 864T.
High-Quality Draft Genome Sequence of Xanthomonas sp. Strain CPBF 424, a Walnut-Pathogenic Strain with Atypical Features.
Dec 11, 2018   Microbiology Resource Announcements
Fernandes C, Blom J, Pothier JF, Tavares F
High-Quality Draft Genome Sequence of Xanthomonas sp. Strain CPBF 424, a Walnut-Pathogenic Strain with Atypical Features.
Dec 11, 2018
Microbiology Resource Announcements
We report here the draft genome sequence of Xanthomonas sp. strain CPBF 424, isolated from a diseased walnut tree. Multilocus sequence analysis showed that this walnut-pathogenic isolate is located between the nonpathogenic X. arboricola and X. prunicola clusters. These features make this strain a promising reference to disclose new genetic determinants of pathogenesis.
Zebrafish model of KRAS-initiated pancreatic cancer.
Dec 11, 2018   Animal Cells And Systems
Park JT, Leach SD
Zebrafish model of KRAS-initiated pancreatic cancer.
Dec 11, 2018
Animal Cells And Systems
Pancreatic cancer constitutes a genetic disease in which somatic mutations in the KRAS proto-oncogene are detected in a majority of tumors. KRAS mutations represent an early event during pancreatic tumorigenesis that crucial for cancer initiation and progression. Here, we established a zebrafish pancreatic cancer model that highly recapitulates human pancreatic intraepithelial neoplasia (PanIN) development. We established a novel system combining CRE/Lox technology with the GAL4/UAS system to express oncogenic KRAS in the ptf1a domain temporarily. In this system, zebrafish developed PanIN at an 11.1% rate by 24 and 36 weeks after KRASG12V induction. The histological and immunohistochemical profiles of these experimental tumors bore striking resemblance to human PanIN. Within the whole abnormal area, the entire spectrum of differentiation ranging from PanIN-1 to PanIN-3 was noted. Immunohistochemical analysis including Alcian blue, CK-18, cadhedrin-1, and DCLK1 staining confirmed the PanIN region as a characteristic pancreatic cancer precursor lesion. Taken together, these findings demonstrate that this zebrafish model may offer the possibility of an experimental and preclinical system to evaluate different strategies for targeting pancreatic tumors and finally improve the outcome for the patients with pancreatic tumors.
Predicting protein targets for drug-like compounds using transcriptomics.
Dec 11, 2018   PLoS Computational Biology
Pabon NA, Xia Y, Estabrooks SK, Ye Z, Herbrand AK, Süß E, Biondi RM, Assimon VA, Gestwicki JE, Brodsky JL, Camacho CJ, Bar-Joseph Z
Predicting protein targets for drug-like compounds using transcriptomics.
Dec 11, 2018
PLoS Computational Biology
An expanded chemical space is essential for improved identification of small molecules for emerging therapeutic targets. However, the identification of targets for novel compounds is biased towards the synthesis of known scaffolds that bind familiar protein families, limiting the exploration of chemical space. To change this paradigm, we validated a new pipeline that identifies small molecule-protein interactions and works even for compounds lacking similarity to known drugs. Based on differential mRNA profiles in multiple cell types exposed to drugs and in which gene knockdowns (KD) were conducted, we showed that drugs induce gene regulatory networks that correlate with those produced after silencing protein-coding genes. Next, we applied supervised machine learning to exploit drug-KD signature correlations and enriched our predictions using an orthogonal structure-based screen. As a proof-of-principle for this regimen, top-10/top-100 target prediction accuracies of 26% and 41%, respectively, were achieved on a validation set 152 FDA-approved drugs and 3104 potential targets. We then predicted targets for 1680 compounds and validated chemical interactors with four targets that have proven difficult to chemically modulate, including non-covalent inhibitors of HRAS and KRAS. Importantly, drug-target interactions manifest as gene expression correlations between drug treatment and both target gene KD and KD of genes that act up- or down-stream of the target, even for relatively weak binders. These correlations provide new insights on the cellular response of disrupting protein interactions and highlight the complex genetic phenotypes of drug treatment. With further refinement, our pipeline may accelerate the identification and development of novel chemical classes by screening compound-target interactions.
De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders.
Dec 11, 2018   PLoS Genetics
Qi H, Yu L, Zhou X, Wynn J, Zhao H,   . . . . . .   , High FA, Longoni M, Donahoe PK, Chung WK, Shen Y
De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders.
Dec 11, 2018
PLoS Genetics
Congenital diaphragmatic hernia (CDH) is a severe birth defect that is often accompanied by other congenital anomalies. Previous exome sequencing studies for CDH have supported a role of de novo damaging variants but did not identify any recurrently mutated genes. To investigate further the genetics of CDH, we analyzed de novo coding variants in 362 proband-parent trios including 271 new trios reported in this study. We identified four unrelated individuals with damaging de novo variants in MYRF (P = 5.3x10-8), including one likely gene-disrupting (LGD) and three deleterious missense (D-mis) variants. Eight additional individuals with de novo LGD or missense variants were identified from our other genetic studies or from the literature. Common phenotypes of MYRF de novo variant carriers include CDH, congenital heart disease and genitourinary abnormalities, suggesting that it represents a novel syndrome. MYRF is a membrane associated transcriptional factor highly expressed in developing diaphragm and is depleted of LGD variants in the general population. All de novo missense variants aggregated in two functional protein domains. Analyzing the transcriptome of patient-derived diaphragm fibroblast cells suggest that disease associated variants abolish the transcription factor activity. Furthermore, we showed that the remaining genes with damaging variants in CDH significantly overlap with genes implicated in other developmental disorders. Gene expression patterns and patient phenotypes support pleiotropic effects of damaging variants in these genes on CDH and other developmental disorders. Finally, functional enrichment analysis implicates the disruption of regulation of gene expression, kinase activities, intra-cellular signaling, and cytoskeleton organization as pathogenic mechanisms in CDH.
A genome-wide association analysis reveals a potential role for recombination in the evolution of antimicrobial resistance in Burkholderia multivorans.
Dec 11, 2018   PLoS Pathogens
Diaz Caballero J, Clark ST, Wang PW, Donaldson SL, Coburn B, Tullis DE, Yau YCW, Waters VJ, Hwang DM, Guttman DS
A genome-wide association analysis reveals a potential role for recombination in the evolution of antimicrobial resistance in Burkholderia multivorans.
Dec 11, 2018
PLoS Pathogens
Cystic fibrosis (CF) lung infections caused by members of the Burkholderia cepacia complex, such as Burkholderia multivorans, are associated with high rates of mortality and morbidity. We performed a population genomics study of 111 B. multivorans sputum isolates from one CF patient through three stages of infection including an early incident isolate, deep sampling of a one-year period of chronic infection occurring weeks before a lung transplant, and deep sampling of a post-transplant infection. We reconstructed the evolutionary history of the population and used a lineage-controlled genome-wide association study (GWAS) approach to identify genetic variants associated with antibiotic resistance. We found the incident isolate was basally related to the rest of the strains and more susceptible to antibiotics from three classes (β-lactams, aminoglycosides, quinolones). The chronic infection isolates diversified into multiple, distinct genetic lineages and showed reduced antimicrobial susceptibility to the same antibiotics. The post-transplant reinfection isolates derived from the same source as the incident isolate and were genetically distinct from the chronic isolates. They also had a level of susceptibility in between that of the incident and chronic isolates. We identified numerous examples of potential parallel pathoadaptation, in which multiple mutations were found in the same locus or even codon. The set of parallel pathoadaptive loci was enriched for functions associated with virulence and resistance. Our GWAS analysis identified statistical associations between a polymorphism in the ampD locus with resistance to β-lactams, and polymorphisms in an araC transcriptional regulator and an outer membrane porin with resistance to both aminoglycosides and quinolones. Additionally, these three loci were independently mutated four, three and two times, respectively, providing further support for parallel pathoadaptation. Finally, we identified a minimum of 14 recombination events, and observed that loci carrying putative parallel pathoadaptations and polymorphisms statistically associated with β-lactam resistance were over-represented in these recombinogenic regions.
Automated phosphopeptide enrichment from minute quantities of frozen malignant melanoma tissue.
Dec 11, 2018   PloS One
Murillo JR, Kuras M, Rezeli M, Milliotis T, Betancourt L, Marko-Varga G
Automated phosphopeptide enrichment from minute quantities of frozen malignant melanoma tissue.
Dec 11, 2018
PloS One
To acquire a deeper understanding of malignant melanoma (MM), it is essential to study the proteome of patient tissues. In particular, phosphoproteomics of MM has become of significant importance because of the central role that phosphorylation plays in the development of MM. Investigating clinical samples, however, is an extremely challenging task as there is usually only very limited quantities of material available to perform targeted enrichment approaches. Here, an automated phosphopeptide enrichment protocol using the AssayMap Bravo platform was applied to MM tissues and assessed for performance. The strategy proved to be highly-sensitive, less prone to variability, less laborious than existing techniques and adequate for starting quantities at the microgram level. An Fe(III)-NTA-IMAC-based enrichment workflow was applied to a dilution series of MM tissue lysates. The workflow was efficient in terms of sensitivity, reproducibility and phosphosite localization; and from only 12.5 μg of sample, more than 1,000 phosphopeptides were identified. In addition, from 60 μg of protein material the number of identified phosphoproteins from individual MM samples was comparable to previous reports that used extensive fractionation methods. Our data set included key pathways that are involved in MM progression; such as MAPK, melanocyte development and integrin signaling. Moreover, tissue-specific immunological proteins were identified, that have not been previously observed in the proteome of MM-derived cell lines. In conclusion, this workflow is suitable to study large cohorts of clinical samples that demand automatic and careful handling.
Author Correction: Genomic analysis of a large set of currently-and historically-important human adenovirus pathogens.
Dec 11, 2018   Emerging Microbes & Infections
Ismail AM, Cui T, Dommaraju K, Singh G, Dehghan S,   . . . . . .   , Jones MS, Rajaiya J, Dyer DW, Chodosh J, Seto D
Comparative physiological and proteomic analyses of the chloroplasts in halophyte Sesuvium portulacastrum under differential salt conditions.
Dec 13, 2018   Journal Of Plant Physiology
Peng C, Chang L, Yang Q, Tong Z, Wang D, Tan Y, Sun Y, Yi X, Ding G, Xiao J, Zhang Y, Wang X
Comparative physiological and proteomic analyses of the chloroplasts in halophyte Sesuvium portulacastrum under differential salt conditions.
Dec 13, 2018
Journal Of Plant Physiology
Sesuvium portulacastrum, an important mangrove-associated true halophyte belongs to the family Aizoaceae, has excellent salt tolerance. Chloroplasts are the most sensitive organelles involved in the response to salinity. However, the regulation mechanism of chloroplasts of S. portulacastrum under salinity stress has not been reported. In this study, morphological and physiological analyses of leaves and comparative proteomics of chloroplasts isolated from the leaves of S. portulacastrum under different NaCl treatments were performed. Our results showed that the thickness of the palisade tissue, the leaf area, the maximum photochemical efficiency of photosystem II, and the electron transport rate increased remarkably after the plants were subjected to differential saline environments, indicating that salinity can increase photosynthetic efficiency and improve the growth of S. portulacastrum. Subsequently, 55 differentially expressed protein species (DEPs) from the chloroplasts of S. portulacastrum under differential salt conditions were positively identified by mass spectrometry. These DEPs were involved in multiple metabolic pathways, such as photosynthesis, carbon metabolism, ATP synthesis and the cell structure. Among these DEPs, the abundance of most proteins was induced by salt stress. Based on a combination of the morphological and physiological data, as well as the chloroplast proteome results, we speculated that S. portulacastrum can maintain photosynthetic efficiency and growth by maintaining the stability of the photosystem II complex, promoting the photochemical reaction rate, enhancing carbon fixation, developing plastoglobules, and preserving the biomembrane system of chloroplasts under salt stress.

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