Showing papers by "Institute for Systems Biology published in 2015"
TL;DR: A browser for the first new human genome reference assembly in 4 years in December 2013, a watershed comparative genomics annotation (100-species multiple alignment and conservation), and a novel distribution mechanism for the browser are among the highlights of the past year.
Abstract: Launched in 2001 to showcase the draft human genome assembly, the UCSC Genome Browser database (http://genome.ucsc.edu) and associated tools continue to grow, providing a comprehensive resource of genome assemblies and annotations to scientists and students worldwide. Highlights of the past year include the release of a browser for the first new human genome reference assembly in 4 years in December 2013 (GRCh38, UCSC hg38), a watershed comparative genomics annotation (100-species multiple alignment and conservation) and a novel distribution mechanism for the browser (GBiB: Genome Browser in a Box). We created browsers for new species (Chinese hamster, elephant shark, minke whale), 'mined the web' for DNA sequences and expanded the browser display with stacked color graphs and region highlighting. As our user community increasingly adopts the UCSC track hub and assembly hub representations for sharing large-scale genomic annotation data sets and genome sequencing projects, our menu of public data hubs has tripled.
984 citations
University of Nottingham1, University of Manchester2, National Institutes of Health3, St Mary's Hospital4, University of Southampton5, AstraZeneca6, Imperial College London7, St John's Innovation Centre8, University of Amsterdam9, Institute for Systems Biology10, University of Copenhagen11, University of Catania12, Aix-Marseille University13, Karolinska University Hospital14, Karolinska Institutet15, University of Stirling16, Boston Children's Hospital17, Semmelweis University18, Fraunhofer Society19, Novartis20, Genentech21, Catholic University of the Sacred Heart22, Jagiellonian University Medical College23, GlaxoSmithKline24, Umeå University25, Boehringer Ingelheim26, University Hospital of South Manchester NHS Foundation Trust27, Janssen Pharmaceutica28
TL;DR: U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment, and is well suited to identify asthma phenotypes using the array of "omic" datasets that are at the core of this systems medicine approach.
Abstract: U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach.This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements.Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids.Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of "omic" datasets that are at the core of this systems medicine approach.
407 citations
TL;DR: It is demonstrated that ADAR1 is a specific and essential negative regulator of the MDA5-MAVS RNA sensing pathway and that both of these functions were required throughout life.
342 citations
TL;DR: The data support a novel model that links a mixed EM signature with stemness in individual cells, luminal and basal cell lines, in vivo xenograft mouse models, and in all breast cancer subtypes and suggest that targeting E/M heterogeneity by eliminating hybrid E-M cells and cooperation between E and M cell-types could improve breast cancer patient survival independent of breast cancer-subtype.
Abstract: Breast cancer stem cells (CSCs) are thought to drive recurrence and metastasis. Their identity has been linked to the epithelial to mesenchymal transition (EMT) but remains highly controversial since--depending on the cell-line studied--either epithelial (E) or mesenchymal (M) markers, alone or together have been associated with stemness. Using distinct transcript expression signatures characterizing the three different E, M and hybrid E/M cell-types, our data support a novel model that links a mixed EM signature with stemness in 1) individual cells, 2) luminal and basal cell lines, 3) in vivo xenograft mouse models, and 4) in all breast cancer subtypes. In particular, we found that co-expression of E and M signatures was associated with poorest outcome in luminal and basal breast cancer patients as well as with enrichment for stem-like cells in both E and M breast cell-lines. This link between a mixed EM expression signature and stemness was explained by two findings: first, mixed cultures of E and M cells showed increased cooperation in mammosphere formation (indicative of stemness) compared to the more differentiated E and M cell-types. Second, single-cell qPCR analysis revealed that E and M genes could be co-expressed in the same cell. These hybrid E/M cells were generated by both E or M cells and had a combination of several stem-like traits since they displayed increased plasticity, self-renewal, mammosphere formation, and produced ALDH1+ progenies, while more differentiated M cells showed less plasticity and E cells showed less self-renewal. Thus, the hybrid E/M state reflecting stemness and its promotion by E-M cooperation offers a dual biological rationale for the robust association of the mixed EM signature with poor prognosis, independent of cellular origin. Together, our model explains previous paradoxical findings that breast CSCs appear to be M in luminal cell-lines but E in basal breast cancer cell-lines. Our results suggest that targeting E/M heterogeneity by eliminating hybrid E/M cells and cooperation between E and M cell-types could improve breast cancer patient survival independent of breast cancer-subtype.
327 citations
TL;DR: The observations that IL-10 has an unexpected negative effect on Aβ proteostasis and cognition in APP mouse models demonstrate the complex interplay between innate immunity and protestasis in neurodegenerative diseases, an interaction the authors call immunoproteostasis.
314 citations
TL;DR: A review of the overall proteomics workflow supported by the TPP, its major tools, and how it can be used in its various modes from desktop to cloud computing is provided.
Abstract: Democratization of genomics technologies has enabled the rapid determination of genotypes. More recently the democratization of comprehensive proteomics technologies is enabling the determination of the cellular phenotype and the molecular events that define its dynamic state. Core proteomic technologies include MS to define protein sequence, protein:protein interactions, and protein PTMs. Key enabling technologies for proteomics are bioinformatic pipelines to identify, quantitate, and summarize these events. The Trans-Proteomics Pipeline (TPP) is a robust open-source standardized data processing pipeline for large-scale reproducible quantitative MS proteomics. It supports all major operating systems and instrument vendors via open data formats. Here, we provide a review of the overall proteomics workflow supported by the TPP, its major tools, and how it can be used in its various modes from desktop to cloud computing. We describe new features for the TPP, including data visualization functionality. We conclude by describing some common perils that affect the analysis of MS/MS datasets, as well as some major upcoming features.
311 citations
TL;DR: Considering non-genetic cell state dynamics and the relative ease with which surviving but stressed cells can be tipped into latent attractors provides a foundation for exploring new therapeutic approaches that seek not only to kill cancer cells but also to avoid promoting resistance and relapse that are inherently linked to the attempts to kill them.
Abstract: Therapy resistance and tumour relapse after drug therapy are commonly explained by Darwinian selection of pre-existing drug-resistant, often stem-like cancer cells resulting from random mutations. However, the ubiquitous non-genetic heterogeneity and plasticity of tumour cell phenotype raises the question: are mutations really necessary and sufficient to promote cell phenotype changes during tumour progression? Cancer therapy inevitably spares some cancer cells, even in the absence of resistant mutants. Accumulating observations suggest that the non-killed, residual tumour cells actively acquire a new phenotype simply by exploiting their developmental potential. These surviving cells are stressed by the cytotoxic treatment, and owing to phenotype plasticity, exhibit a variety of responses. Some are pushed into nearby, latent attractor states of the gene regulatory network which resemble evolutionary ancient or early developmental gene expression programs that confer stemness and resilience. By entering such stem-like, stress-response states, the surviving cells strengthen their capacity to cope with future noxious agents. Considering non-genetic cell state dynamics and the relative ease with which surviving but stressed cells can be tipped into latent attractors provides a foundation for exploring new therapeutic approaches that seek not only to kill cancer cells but also to avoid promoting resistance and relapse that are inherently linked to the attempts to kill them.
264 citations
TL;DR: The genome-wide distribution of 5 hmC in CD4(+) T cells is characterized and it is found that 5hmC marks putative regulatory elements in signature genes associated with effector cell differentiation, suggesting that Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells.
245 citations
TL;DR: Results suggest that it may be possible to use miRNAs to detect cancers in general, and better understanding of intra- and intercellular miRNA trafficking and the fundamental biology of cancer cell-derived lipid vesicles may facilitate the development of circulating miRNA-based biomarkers for cancer detection and classification.
Abstract: BACKGROUND: Numerous studies have demonstrated the existence of stable regulatory RNAs, microRNAs (miRNAs), in the circulation and have shown that the spectrum of these extracellular miRNAs is affected by various pathologic conditions including cancers. CONTENT: Circulating miRNAs have been the focus of numerous cancer biomarker discovery efforts over the past few years; however, a considerable number of these studies have yielded inconsistent and irreproducible findings. Here, we have summarized and compared the results of studies covering 8 different cancer types to address key questions, including the possibility of using circulating miRNA to detect cancers and what factors may affect miRNA signatures. Although identifying circulating miRNA signatures to detect specific types of early stage cancers can be challenging, study results suggest that it may be possible to use miRNAs to detect cancers in general. SUMMARY: Circulating miRNA is a rich source for potential disease biomarkers; however, factors, both intrinsic and extrinsic, that may affect measurement of circulating miRNA have not been fully characterized. Better understanding of intra- and intercellular miRNA trafficking and the fundamental biology of cancer cell–derived lipid vesicles may facilitate the development of circulating miRNA-based biomarkers for cancer detection and classification.
199 citations
TL;DR: In this article, the DNA binding and transcriptional profile of 80% of all predicted M. tuberculosis transcription factors were reported, and wide-spread dormant DNA binding was found across all predicted transcription factors.
Abstract: Adaptation of Mycobacterium tuberculosis to the host environment is principally mediated through its transcription factors. Here, the authors report the DNA binding and transcriptional profile of ~80% of all predicted M. tuberculosis transcription factors, and find wide-spread dormant DNA binding.
191 citations
TL;DR: The Comet database search software was initially released as an open source project in late 2012 and it can be accessed as a component of a number of larger software projects into which it has been incorporated.
TL;DR: High TRAIL-R2 expression correlates with invasion of human PDAC into lymph vessels and with shortened metastasis-free survival of KRAS-mutated colorectal cancer patients, and reduces tumor growth, blunts metastasis, and prolongs survival by inhibiting cancer cell-autonomous migration, proliferation, and invasion.
TL;DR: It is concluded that rare variants in neuronal excitability genes contribute to risk for bipolar disorder, both in pedigrees and in the case-control cohort.
Abstract: We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genome-wide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABAA receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, CACNG2, CAMK2A, and NGF. Variants in promoters and 5' and 3' UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD.
TL;DR: The Kojak cross-link software application is a new, efficient approach to identify cross-linked peptides, enabling large-scale analysis of protein-protein interactions by chemical cross-linking techniques.
Abstract: Protein chemical cross-linking and mass spectrometry enable the analysis of protein–protein interactions and protein topologies; however, complicated cross-linked peptide spectra require specialized algorithms to identify interacting sites. The Kojak cross-linking software application is a new, efficient approach to identify cross-linked peptides, enabling large-scale analysis of protein–protein interactions by chemical cross-linking techniques. The algorithm integrates spectral processing and scoring schemes adopted from traditional database search algorithms and can identify cross-linked peptides using many different chemical cross-linkers with or without heavy isotope labels. Kojak was used to analyze both novel and existing data sets and was compared to existing cross-linking algorithms. The algorithm provided increased cross-link identifications over existing algorithms and, equally importantly, the results in a fraction of computational time. The Kojak algorithm is open-source, cross-platform, and f...
21 Jan 2015
TL;DR: This study provides the first detailed characterization of the extracellular RNA complement of the enteric model bacterium E. coli and suggests the selective export of specific RNA biotypes by E. Escherichia coli, which indicates a potential role forextracellular bacterial RNAs in intercellular communication.
Abstract: The secretion of biomolecules into the extracellular milieu is a common and well-conserved phenomenon in biology. In bacteria, secreted biomolecules are not only involved in intra-species communication but they also play roles in inter-kingdom exchanges and pathogenicity. To date, released products, such as small molecules, DNA, peptides, and proteins, have been well studied in bacteria. However, the bacterial extracellular RNA complement has so far not been comprehensively characterized. Here, we have analyzed, using a combination of physical characterization and high-throughput sequencing, the extracellular RNA complement of both outer membrane vesicle (OMV)-associated and OMV-free RNA of the enteric Gram-negative model bacterium Escherichia coli K-12 substrain MG1655 and have compared it to its intracellular RNA complement. Our results demonstrate that a large part of the extracellular RNA complement is in the size range between 15 and 40 nucleotides and is derived from specific intracellular RNAs. Furthermore, RNA is associated with OMVs and the relative abundances of RNA biotypes in the intracellular, OMV and OMV-free fractions are distinct. Apart from rRNA fragments, a significant portion of the extracellular RNA complement is composed of specific cleavage products of functionally important structural noncoding RNAs, including tRNAs, 4.5S RNA, 6S RNA, and tmRNA. In addition, the extracellular RNA pool includes RNA biotypes from cryptic prophages, intergenic, and coding regions, of which some are so far uncharacterised, for example, transcripts mapping to the fimA-fimL and ves-spy intergenic regions. Our study provides the first detailed characterization of the extracellular RNA complement of the enteric model bacterium E. coli. Analogous to findings in eukaryotes, our results suggest the selective export of specific RNA biotypes by E. coli, which in turn indicates a potential role for extracellular bacterial RNAs in intercellular communication.
Fred Hutchinson Cancer Research Center1, University of Washington2, Icahn School of Medicine at Mount Sinai3, Canadian Institute for Advanced Research4, Cincinnati Children's Hospital Medical Center5, Institute for Systems Biology6, University of Toronto7, Baylor College of Medicine8, Sungkyunkwan University9, Cleveland Clinic Lerner Research Institute10, University of Edinburgh11
TL;DR: In vitro and in vivo validation of GSC-specific targets revealed several strong hits, including the wee1-like kinase, PKMYT1/Myt1, which acts redundantly with WEE1 to inhibit cyclin B-CDK1 activity via CDK1-Y15 phosphorylation and to promote timely completion of mitosis in NSCs.
TL;DR: The results point to an important role for RAD51-mediated homologous recombination in neurodevelopment, in addition to DNA repair and cancer susceptibility, as well as a dominant-negative mutation in an FA-like patient.
Abstract: Fanconi anaemia (FA) is a hereditary disease featuring hypersensitivity to DNA cross-linker-induced chromosomal instability in association with developmental abnormalities, bone marrow failure and a strong predisposition to cancer. A total of 17 FA disease genes have been reported, all of which act in a recessive mode of inheritance. Here we report on a de novo g.41022153G>A; p.Ala293Thr (NM_002875) missense mutation in one allele of the homologous recombination DNA repair gene RAD51 in an FA-like patient. This heterozygous mutation causes a novel FA subtype, ‘FA-R’, which appears to be the first subtype of FA caused by a dominant-negative mutation. The patient, who features microcephaly and mental retardation, has reached adulthood without the typical bone marrow failure and paediatric cancers. Together with the recent reports on RAD51-associated congenital mirror movement disorders, our results point to an important role for RAD51-mediated homologous recombination in neurodevelopment, in addition to DNA repair and cancer susceptibility. Fanconi anaemia is an inherited disorder characterised by developmental abnormalities, bone marrow failure and predisposition to cancer. Here the authors report a de novo mutation in the DNA repair gene Rad51in an atypical subtype of Fanconi anaemia.
TL;DR: This study represents the first community-based effort to develop a robust platform for the reproducible and quantitative measurement of the entire repertoire of peptides presented by HLA molecules, an essential step towards the design of efficient immunotherapies.
Abstract: We present a novel mass spectrometry-based high-throughput workflow and an open-source computational and data resource to reproducibly identify and quantify HLA-associated peptides. Collectively, the resources support the generation of HLA allele-specific peptide assay libraries consisting of consensus fragment ion spectra, and the analysis of quantitative digital maps of HLA peptidomes generated from a range of biological sources by SWATH mass spectrometry (MS). This study represents the first community-based effort to develop a robust platform for the reproducible and quantitative measurement of the entire repertoire of peptides presented by HLA molecules, an essential step towards the design of efficient immunotherapies.
TL;DR: MiR-506 is a robust clinical marker for chemotherapy response and survival in serous ovarian cancers and has important therapeutic value in sensitizing cancer cells to chemotherapy.
Abstract: Epithelial ovarian cancer remains the most lethal gynecological malignancy (1). The current standard of care consists of radical surgery and platinum-based chemotherapy. The five-year survival rate for patients with advanced ovarian cancer is only 30% to 40%, and acquired resistance to platinum is considered a major factor in disease relapse. Platinum-based drugs form intra- and interstrand adducts with DNA, which causes DNA double-strand breaks and triggers DNA damage and repair pathways. Homologous recombination is a critical pathway for DNA double-strand break repair (2) and is responsible for the resistance of high-grade serous ovarian cancer to frontline platinum-based chemotherapy (3). Cells with compromised homologous recombination machinery are highly sensitive to apoptosis triggered by platinum-induced DNA damage through a mechanism termed synthetic lethality (4). Thus, the ability to block homologous recombination-mediated repair is a focus of intense investigation as an approach to improve treatment outcomes in high-grade serous ovarian cancers.
Recent studies demonstrated that BRCA2 mutations, and to a lesser extent BRCA1 mutations/methylation, are associated with improved survival and response to therapy in serous ovarian cancer (5,6). Whereas BRCA1 plays diverse roles in DNA damage pathways, the primary role of BRCA2 is to mediate homologous recombination by directly loading the RAD51 protein onto damage sites or stalled replication forks (7,8). RAD51 is a critical component of the homologous recombination-mediated double-strand DNA break repair machinery and assembles onto single-stranded DNA as a nucleoprotein filament and catalyzes the exchange of homologous DNA sequences (9). RAD51 suppression can sensitize cancer cells to DNA-damaging drugs (10–14), and RAD51 overexpression contributes to chemotherapy resistance in human soft tissue sarcoma cells (15).
MicroRNAs (miRNAs) are a class of small noncoding RNAs (~22 nt) that regulate gene expression. MiRNAs bind to the 3′-untranslated region (3′-UTR) of target genes, which either leads to mRNA degradation or inhibits protein translation (16). Nearly 2578 miRNAs have been identified in the human genome and are thought to regulate 30% of the transcriptome (17). Increasing evidence has demonstrated that miRNA are highly deregulated in cancer, suggesting they may function as therapeutic tools (17–20).
In a recent high-throughput miRNA signature screen, decreased expression of the chrXq27.3-miRNA cluster that included miR-506 was associated with early relapse in patients with advanced-stage epithelial ovarian cancer (21). Our studies established that miR-506 is a potent inhibitor of the epithelial-to-mesenchymal transition (EMT) (22,23), which is also associated with chemoresistance. In addition, we found that miR-506 could suppress proliferation and induce senescence by directly targeting the CDK4/6-FOXM1 axis in ovarian cancer (24). However, it is unknown whether miR-506 is involved in the chemotherapy response.
TL;DR: A small-molecule Bcl2-BH4 domain antagonist, BDA-366, that binds BH4 with high affinity and selectivity is identified that exhibits strong synergy against lung cancer in vivo.
TL;DR: The origins of life likely required the cooperation among a set of molecular species interacting in a network, and six parameters emerge as the most influential when one considers the molecular characteristics of the best candidates for the emergence of biological information: polypeptides, RNA-like polymers, and lipids.
Abstract: The origins of life likely required the cooperation among a set of molecular species interacting in a network. If so, then the earliest modes of evolutionary change would have been governed by the manners and mechanisms by which networks change their compositions over time. For molecular events, especially those in a pre-biological setting, these mechanisms have rarely been considered. We are only recently learning to apply the results of mathematical analyses of network dynamics to prebiotic events. Here, we attempt to forge connections between such analyses and the current state of knowledge in prebiotic chemistry. Of the many possible influences that could direct primordial network, six parameters emerge as the most influential when one considers the molecular characteristics of the best candidates for the emergence of biological information: polypeptides, RNA-like polymers, and lipids. These parameters are viable cores, connectivity kinetics, information control, scalability, resource availability, and compartmentalization. These parameters, both individually and jointly, guide the aggregate evolution of collectively autocatalytic sets. We are now in a position to translate these conclusions into a laboratory setting and test empirically the dynamics of prebiotic network evolution.
TL;DR: Akt3 is identified as the dominant Akt isoform that robustly stimulates glioma progression and key roles for Akt3 in activating DNA repair pathways are discovered, which led to enhanced survival of human glioblastoma cells following radiation or temozolomide treatment.
Abstract: Akt is a robust oncogene that plays key roles in the development and progression of many cancers, including glioma. We evaluated the differential propensities of the Akt isoforms toward progression in the well-characterized RCAS/Ntv-a mouse model of PDGFB-driven low grade glioma. A constitutively active myristoylated form of Akt1 did not induce high-grade glioma (HGG). In stark contrast, Akt2 and Akt3 showed strong progression potential with 78% and 97% of tumors diagnosed as HGG, respectively. We further revealed that significant variations in polarity and hydropathy values among the Akt isoforms in both the pleckstrin homology domain (P domain) and regulatory domain (R domain) were critical in mediating glioma progression. Gene expression profiles from representative Akt-derived tumors indicated dominant and distinct roles for Akt3, consisting primarily of DNA repair pathways. TCGA data from human GBM closely reflected the DNA repair function, as Akt3 was significantly correlated with a 76-gene signature DNA repair panel. Consistently, compared with Akt1 and Akt2 overexpression models, Akt3-expressing human GBM cells had enhanced activation of DNA repair proteins, leading to increased DNA repair and subsequent resistance to radiation and temozolomide. Given the wide range of Akt3-amplified cancers, Akt3 may represent a key resistance factor.
TL;DR: The molecular architecture of human and yeast TFIIH is determined by an integrative approach using chemical crosslinking/mass spectrometry data, biochemical analyses, and previously published electron microscopy maps, and it is shown that one of these conserved regions, the p62/Tfb1 Anchor region, directly interacts with the DNA helicase subunit XPD/Rad3 in nativeTFIIH and is required for the integrity and function of TFIIh.
TL;DR: The importance of assessing the quality of evidence, confirming automated findings and considering alternative protein matches for spectra and peptides is discussed and guidelines for proteomics investigators to apply in reporting newly identified proteins are provided.
Abstract: Remarkable progress continues on the annotation of the proteins identified in the Human Proteome and on finding credible proteomic evidence for the expression of “missing proteins”. Missing proteins are those with no previous protein-level evidence or insufficient evidence to make a confident identification upon reanalysis in PeptideAtlas and curation in neXtProt. Enhanced with several major new data sets published in 2014, the human proteome presented as neXtProt, version 2014-09-19, has 16 491 unique confident proteins (PE level 1), up from 13 664 at 2012-12 and 15 646 at 2013-09. That leaves 2948 missing proteins from genes classified having protein existence level PE 2, 3, or 4, as well as 616 dubious proteins at PE 5. Here, we document the progress of the HPP and discuss the importance of assessing the quality of evidence, confirming automated findings and considering alternative protein matches for spectra and peptides. We provide guidelines for proteomics investigators to apply in reporting newly i...
Karolinska Institutet1, Boston Children's Hospital2, Charité3, University of Würzburg4, Medical University of Vienna5, University of Helsinki6, University of Oslo7, Oslo University Hospital8, Swiss Institute of Allergy and Asthma Research9, Ghent University Hospital10, Institute for Systems Biology11, Pierre-and-Marie-Curie University12, French Institute of Health and Medical Research13, Odense University Hospital14, University of Toulouse15, University of Crete16, Utrecht University17, University Medical Center Groningen18, Medical University of Łódź19, Ghent University20, Paris Descartes University21, Bradford Royal Infirmary22, Versailles Saint-Quentin-en-Yvelines University23, Maastricht University24, National Institutes of Health25, University of Montpellier26, University of Bologna27, University of Paris28
TL;DR: A new classification of IgE‐mediated allergic diseases is proposed that allows the definition of novel phenotypes to better understand genetic and epigenetic mechanisms, better stratify allergic preschool children for prognosis and propose novel strategies of treatment and prevention.
Abstract: Allergic diseases [asthma, rhinitis and atopic dermatitis (AD)] are complex. They are associated with allergen-specific IgE and nonallergic mechanisms that may coexist in the same patient. In addition, these diseases tend to cluster and patients present concomitant or consecutive diseases (multimorbidity). IgE sensitization should be considered as a quantitative trait. Important clinical and immunological differences exist between mono- and polysensitized subjects. Multimorbidities of allergic diseases share common causal mechanisms that are only partly IgE-mediated. Persistence of allergic diseases over time is associated with multimorbidity and/or IgE polysensitization. The importance of the family history of allergy may decrease with age. This review puts forward the hypothesis that allergic multimorbidities and IgE polysensitization are associated and related to the persistence or re-occurrence of foetal type 2 signalling. Asthma, rhinitis and AD are manifestations of a common systemic immune imbalance (mesodermal origin) with specific patterns of remodelling (ectodermal or endodermal origin). This study proposes a new classification of IgE-mediated allergic diseases that allows the definition of novel phenotypes to (i) better understand genetic and epigenetic mechanisms, (ii) better stratify allergic preschool children for prognosis and (iii) propose novel strategies of treatment and prevention.
TL;DR: The importance of integrating metabolic networks with regulatory information is emphasized—an area which is expected to become increasingly important for metabolic engineering—and recent developments in the field of metabolic and regulatory integration are presented.
Abstract: We focus on the application of constraint-based methodologies and, more specifically, flux balance analysis in the field of metabolic engineering, and enumerate recent developments and successes of the field. We also review computational frameworks that have been developed with the express purpose of automatically selecting optimal gene deletions for achieving improved production of a chemical of interest. The application of flux balance analysis methods in rational metabolic engineering requires a metabolic network reconstruction and a corresponding in silico metabolic model for the microorganism in question. For this reason, we additionally present a brief overview of automated reconstruction techniques. Finally, we emphasize the importance of integrating metabolic networks with regulatory information—an area which we expect will become increasingly important for metabolic engineering—and present recent developments in the field of metabolic and regulatory integration.
17 Jun 2015
TL;DR: The linking of key functionalities to community members through integrated omics opens up exciting possibilities for devising prediction and control strategies for microbial communities in the future.
Abstract: Mixed microbial communities underpin important biotechnological processes such as biological wastewater treatment (BWWT). A detailed knowledge of community structure and function relationships is essential for ultimately driving these systems towards desired outcomes, e.g., the enrichment in organisms capable of accumulating valuable resources during BWWT. A comparative integrated omic analysis including metagenomics, metatranscriptomics and metaproteomics was carried out to elucidate functional differences between seasonally distinct oleaginous mixed microbial communities (OMMCs) sampled from an anoxic BWWT tank. A computational framework for the reconstruction of community-wide metabolic networks from multi-omic data was developed. These provide an overview of the functional capabilities by incorporating gene copy, transcript and protein abundances. To identify functional genes, which have a disproportionately important role in community function, we define a high relative gene expression and a high betweenness centrality relative to node degree as gene-centric and network topological features, respectively. Genes exhibiting high expression relative to gene copy abundance include genes involved in glycerolipid metabolism, particularly triacylglycerol lipase, encoded by known lipid accumulating populations, e.g., Candidatus Microthrix parvicella. Genes with a high relative gene expression and topologically important positions in the network include genes involved in nitrogen metabolism and fatty acid biosynthesis, encoded by Nitrosomonas spp. and Rhodococcus spp. Such genes may be regarded as ‘keystone genes’ as they are likely to be encoded by keystone species. The linking of key functionalities to community members through integrated omics opens up exciting possibilities for devising prediction and control strategies for microbial communities in the future. Charting metabolic activity in diverse microbial communities could help scientists control the behavior of these communities, new research shows. Paul Wilmes and colleagues at the University of Luxembourg, alongside scientists from the United States, set out to characterize the biological function of bacterial communities—normally a daunting task due to the sheer number of species involved. To accomplish this, Wilmes and colleagues took a community-wide approach, collecting genomic, transcriptomic and proteomic data from lipid-accumulating microbial consortia in a wastewater treatment tank and assembling functional maps reflecting overall biochemical processes. The scientists were then able to identify ‘keystone’ genes that play a critical role in the community—for example, genes involved in fatty acid biosynthesis were particularly prominent. Such findings could guide strategies for manipulating microbial communities for optimized disease control or biofuel production in future.
TL;DR: Small-RNA sequencing of samples from GBM patients demonstrated that both mature products of MIR-491 (miR-491-5p and -3p) are downregulated in tumors compared with the normal brain, and these products are a tumor suppressor gene that coordinately controls the key cancer hallmarks: proliferation, invasion and stem cell propagation.
Abstract: MIR-491 is commonly co-deleted with its adjacent CDKN2A on chromosome 9p21.3 in glioblastoma multiforme (GBM). However, it is not known whether deletion of MIR-491 is only a passenger event or has an important role. Small-RNA sequencing of samples from GBM patients demonstrated that both mature products of MIR-491 (miR-491-5p and -3p) are downregulated in tumors compared with the normal brain. The integration of GBM data from The Cancer Genome Atlas (TCGA), miRNA target prediction and reporter assays showed that miR-491-5p directly targets EGFR, CDK6 and Bcl-xL, whereas miR-491-3p targets IGFBP2 and CDK6. Functionally, miR-491-3p inhibited glioma cell invasion; overexpression of both miR-491-5p and -3p inhibited proliferation of glioma cell lines and impaired the propagation of glioma stem cells (GSCs), thereby prolonging survival of xenograft mice. Moreover, knockdown of miR-491-5p in primary Ink4a-Arf-null mouse glial progenitor cells exacerbated cell proliferation and invasion. Therefore, MIR-491 is a tumor suppressor gene that, by utilizing both mature forms, coordinately controls the key cancer hallmarks: proliferation, invasion and stem cell propagation.
TL;DR: In this paper, the authors delineate the molecular cause in a large family with primary macronodular adrenal hyperplasia (PMAH) and other neoplasias.
Abstract: Context: Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing's syndrome, which may present in the context of different familial multitumor syndromes. Heterozygous inactivating germline mutations of armadillo repeat containing 5 (ARMC5) have very recently been described as cause for sporadic PMAH. Whether this genetic condition also causes familial PMAH in association with other neoplasias is unclear. Objective: The aim of the present study was to delineate the molecular cause in a large family with PMAH and other neoplasias. Patients and Methods: Whole-genome sequencing and comprehensive clinical and biochemical phenotyping was performed in members of a PMAH affected family. Nodules derived from adrenal surgery and pancreatic and meningeal tumor tissue were analyzed for accompanying somatic mutations in the identified target genes. Results: PMAH presenting either as overt or subclinical Cushing's syndrome was accompanied by a heterozygous germline mutation in ARMC5 (p.A110fs*9) loca...
University of Antwerp1, Utrecht University2, University of Paris3, University of Luxembourg4, Institute for Systems Biology5, University of Tübingen6, University of Zagreb7, Carol Davila University of Medicine and Pharmacy8, University of Cologne9, University of Kiel10, Children's Hospital of Philadelphia11
TL;DR: It is demonstrated that cells expressing mutant sodium-dependent citrate transporter have a complete loss of citrate uptake due to various cellular loss-of-function mechanisms.
Abstract: The epileptic encephalopathies are a clinically and aetiologically heterogeneous subgroup of epilepsy syndromes. Most epileptic encephalopathies have a genetic cause and patients are often found to carry a heterozygous de novo mutation in one of the genes associated with the disease entity. Occasionally recessive mutations are identified: a recent publication described a distinct neonatal epileptic encephalopathy (MIM 615905) caused by autosomal recessive mutations in the SLC13A5 gene. Here, we report eight additional patients belonging to four different families with autosomal recessive mutations in SLC13A5. SLC13A5 encodes a high affinity sodium-dependent citrate transporter, which is expressed in the brain. Neurons are considered incapable of de novo synthesis of tricarboxylic acid cycle intermediates; therefore they rely on the uptake of intermediates, such as citrate, to maintain their energy status and neurotransmitter production. The effect of all seven identified mutations (two premature stops and five amino acid substitutions) was studied in vitro, using immunocytochemistry, selective western blot and mass spectrometry. We hereby demonstrate that cells expressing mutant sodium-dependent citrate transporter have a complete loss of citrate uptake due to various cellular loss-of-function mechanisms. In addition, we provide independent proof of the involvement of autosomal recessive SLC13A5 mutations in the development of neonatal epileptic encephalopathies, and highlight teeth hypoplasia as a possible indicator for SLC13A5 screening. All three patients who tried the ketogenic diet responded well to this treatment, and future studies will allow us to ascertain whether this is a recurrent feature in this severe disorder.