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Sample records for early genomic response

  1. Enabling responsible public genomics.

    PubMed

    Conley, John M; Doerr, Adam K; Vorhaus, Daniel B

    2010-01-01

    As scientific understandings of genetics advance, researchers require increasingly rich datasets that combine genomic data from large numbers of individuals with medical and other personal information. Linking individuals' genetic data and personal information precludes anonymity and produces medically significant information--a result not contemplated by the established legal and ethical conventions governing human genomic research. To pursue the next generation of human genomic research and commerce in a responsible fashion, scientists, lawyers, and regulators must address substantial new issues, including researchers' duties with respect to clinically significant data, the challenges to privacy presented by genomic data, the boundary between genomic research and commerce, and the practice of medicine. This Article presents a new model for understanding and addressing these new challenges--a "public genomics" premised on the idea that ethically, legally, and socially responsible genomics research requires openness, not privacy, as its organizing principle. Responsible public genomics combines the data contributed by informed and fully consenting information altruists and the research potential of rich datasets in a genomic commons that is freely and globally available. This Article examines the risks and benefits of this public genomics model in the context of an ambitious genetic research project currently under way--the Personal Genome Project. This Article also (i) demonstrates that large-scale genomic projects are desirable, (ii) evaluates the risks and challenges presented by public genomics research, and (iii) determines that the current legal and regulatory regimes restrict beneficial and responsible scientific inquiry while failing to adequately protect participants. The Article concludes by proposing a modified normative and legal framework that embraces and enables a future of responsible public genomics.

  2. The genome-wide early temporal response of Saccharomyces cerevisiae to oxidative stress induced by cumene hydroperoxide.

    PubMed

    Sha, Wei; Martins, Ana M; Laubenbacher, Reinhard; Mendes, Pedro; Shulaev, Vladimir

    2013-01-01

    Oxidative stress is a well-known biological process that occurs in all respiring cells and is involved in pathophysiological processes such as aging and apoptosis. Oxidative stress agents include peroxides such as hydrogen peroxide, cumene hydroperoxide, and linoleic acid hydroperoxide, the thiol oxidant diamide, and menadione, a generator of superoxide, amongst others. The present study analyzed the early temporal genome-wide transcriptional response of Saccharomyces cerevisiae to oxidative stress induced by the aromatic peroxide cumene hydroperoxide. The accurate dataset obtained, supported by the use of temporal controls, biological replicates and well controlled growth conditions, provided a detailed picture of the early dynamics of the process. We identified a set of genes previously not implicated in the oxidative stress response, including several transcriptional regulators showing a fast transient response, suggesting a coordinated process in the transcriptional reprogramming. We discuss the role of the glutathione, thioredoxin and reactive oxygen species-removing systems, the proteasome and the pentose phosphate pathway. A data-driven clustering of the expression patterns identified one specific cluster that mostly consisted of genes known to be regulated by the Yap1p and Skn7p transcription factors, emphasizing their mediator role in the transcriptional response to oxidants. Comparison of our results with data reported for hydrogen peroxide identified 664 genes that specifically respond to cumene hydroperoxide, suggesting distinct transcriptional responses to these two peroxides. Genes up-regulated only by cumene hydroperoxide are mainly related to the cell membrane and cell wall, and proteolysis process, while those down-regulated only by this aromatic peroxide are involved in mitochondrial function.

  3. Wolbachia Blocks Viral Genome Replication Early in Infection without a Transcriptional Response by the Endosymbiont or Host Small RNA Pathways.

    PubMed

    Rainey, Stephanie M; Martinez, Julien; McFarlane, Melanie; Juneja, Punita; Sarkies, Peter; Lulla, Aleksei; Schnettler, Esther; Varjak, Margus; Merits, Andres; Miska, Eric A; Jiggins, Francis M; Kohl, Alain

    2016-04-01

    The intracellular endosymbiotic bacterium Wolbachia can protect insects against viral infection, and is being introduced into mosquito populations in the wild to block the transmission of arboviruses that infect humans and are a major public health concern. To investigate the mechanisms underlying this antiviral protection, we have developed a new model system combining Wolbachia-infected Drosophila melanogaster cell culture with the model mosquito-borne Semliki Forest virus (SFV; Togaviridae, Alphavirus). Wolbachia provides strong antiviral protection rapidly after infection, suggesting that an early stage post-infection is being blocked. Wolbachia does appear to have major effects on events distinct from entry, assembly or exit as it inhibits the replication of an SFV replicon transfected into the cells. Furthermore, it causes a far greater reduction in the expression of proteins from the 3' open reading frame than the 5' non-structural protein open reading frame, indicating that it is blocking the replication of viral RNA. Further to this separation of the replicase proteins and viral RNA in transreplication assays shows that uncoupling of viral RNA and replicase proteins does not overcome Wolbachia's antiviral activity. This further suggests that replicative processes are disrupted, such as translation or replication, by Wolbachia infection. This may occur by Wolbachia mounting an active antiviral response, but the virus did not cause any transcriptional response by the bacterium, suggesting that this is not the case. Host microRNAs (miRNAs) have been implicated in protection, but again we found that host cell miRNA expression was unaffected by the bacterium and neither do our findings suggest any involvement of the antiviral siRNA pathway. We conclude that Wolbachia may directly interfere with early events in virus replication such as translation of incoming viral RNA or RNA transcription, and this likely involves an intrinsic (as opposed to an induced

  4. Wolbachia Blocks Viral Genome Replication Early in Infection without a Transcriptional Response by the Endosymbiont or Host Small RNA Pathways

    PubMed Central

    McFarlane, Melanie; Juneja, Punita; Sarkies, Peter; Lulla, Aleksei; Schnettler, Esther; Varjak, Margus; Merits, Andres; Miska, Eric A.; Jiggins, Francis M.; Kohl, Alain

    2016-01-01

    The intracellular endosymbiotic bacterium Wolbachia can protect insects against viral infection, and is being introduced into mosquito populations in the wild to block the transmission of arboviruses that infect humans and are a major public health concern. To investigate the mechanisms underlying this antiviral protection, we have developed a new model system combining Wolbachia-infected Drosophila melanogaster cell culture with the model mosquito-borne Semliki Forest virus (SFV; Togaviridae, Alphavirus). Wolbachia provides strong antiviral protection rapidly after infection, suggesting that an early stage post-infection is being blocked. Wolbachia does appear to have major effects on events distinct from entry, assembly or exit as it inhibits the replication of an SFV replicon transfected into the cells. Furthermore, it causes a far greater reduction in the expression of proteins from the 3´ open reading frame than the 5´ non-structural protein open reading frame, indicating that it is blocking the replication of viral RNA. Further to this separation of the replicase proteins and viral RNA in transreplication assays shows that uncoupling of viral RNA and replicase proteins does not overcome Wolbachia’s antiviral activity. This further suggests that replicative processes are disrupted, such as translation or replication, by Wolbachia infection. This may occur by Wolbachia mounting an active antiviral response, but the virus did not cause any transcriptional response by the bacterium, suggesting that this is not the case. Host microRNAs (miRNAs) have been implicated in protection, but again we found that host cell miRNA expression was unaffected by the bacterium and neither do our findings suggest any involvement of the antiviral siRNA pathway. We conclude that Wolbachia may directly interfere with early events in virus replication such as translation of incoming viral RNA or RNA transcription, and this likely involves an intrinsic (as opposed to an induced

  5. Chloroplast genome evolution in early diverged leptosporangiate ferns.

    PubMed

    Kim, Hyoung Tae; Chung, Myong Gi; Kim, Ki-Joong

    2014-05-01

    In this study, the chloroplast (cp) genome sequences from three early diverged leptosporangiate ferns were completed and analyzed in order to understand the evolution of the genome of the fern lineages. The complete cp genome sequence of Osmunda cinnamomea (Osmundales) was 142,812 base pairs (bp). The cp genome structure was similar to that of eusporangiate ferns. The gene/intron losses that frequently occurred in the cp genome of leptosporangiate ferns were not found in the cp genome of O. cinnamomea. In addition, putative RNA editing sites in the cp genome were rare in O. cinnamomea, even though the sites were frequently predicted to be present in leptosporangiate ferns. The complete cp genome sequence of Diplopterygium glaucum (Gleicheniales) was 151,007 bp and has a 9.7 kb inversion between the trnL-CAA and trnVGCA genes when compared to O. cinnamomea. Several repeated sequences were detected around the inversion break points. The complete cp genome sequence of Lygodium japonicum (Schizaeales) was 157,142 bp and a deletion of the rpoC1 intron was detected. This intron loss was shared by all of the studied species of the genus Lygodium. The GC contents and the effective numbers of codons (ENCs) in ferns varied significantly when compared to seed plants. The ENC values of the early diverged leptosporangiate ferns showed intermediate levels between eusporangiate and core leptosporangiate ferns. However, our phylogenetic tree based on all of the cp gene sequences clearly indicated that the cp genome similarity between O. cinnamomea (Osmundales) and eusporangiate ferns are symplesiomorphies, rather than synapomorphies. Therefore, our data is in agreement with the view that Osmundales is a distinct early diverged lineage in the leptosporangiate ferns.

  6. Early detection and rapid response

    USGS Publications Warehouse

    Westbrooks, Randy G.; Eplee, Robert E.; Simberloff, Daniel; Rejmánek, Marcel

    2011-01-01

    Prevention is the first line of defense against introduced invasive species - it is always preferable to prevent the introduction of new invaders into a region or country. However, it is not always possible to detect all alien hitchhikers imported in cargo, or to predict with any degree of certainty which introduced species will become invasive over time. Fortunately, the majority of introduced plants and animals don't become invasive. But, according to scientists at Cornell University, costs and losses due to species that do become invasive are now estimated to be over $137 billion/year in the United States. Early detection and rapid response (EDRR) is the second line of defense against introduced invasive species - EDRR is the preferred management strategy for preventing the establishment and spread of invasive species. Over the past 50 years, there has been a gradual shift away from large and medium scale federal/state single-agency-led weed eradication programs in the United States, to smaller interagency-led projects involving impacted and potential stakeholders. The importance of volunteer weed spotters in detecting and reporting suspected new invasive species has also been recognized in recent years.

  7. Early and Late Responses to Ion Irradiation

    NASA Astrophysics Data System (ADS)

    Schulte, Reinhard; Ling, Ted

    Early and late responses to ion beam therapy (IBT) are the result of complex interactions between host, dose volume, and radiobiological factors. Our understanding of these early and late tissue responses has improved greatly with the accumulation of laboratory and clinical experience with proton and heavy ion irradiation. With photon therapy becoming increasingly conformal, many concepts developed for 3D conformal radiotherapy and intensity modulated radiation therapy with photons are also applicable to IBT. This chapter reviews basic concepts and experimental data of early and late tissue responses to protons and ions.

  8. Genomic Characterization of Metformin Hepatic Response

    PubMed Central

    Jones, Stacy L.; Smith, Robin P.; Lin, Lawrence; Gallins, Paul J.; Etheridge, Amy S.; Wright, Fred; Zhou, Yihui; Innocenti, Federico; Yee, Sook Wah; Giacomini, Kathleen M.; Ahituv, Nadav

    2016-01-01

    Metformin is used as a first-line therapy for type 2 diabetes (T2D) and prescribed for numerous other diseases. However, its mechanism of action in the liver has yet to be characterized in a systematic manner. To comprehensively identify genes and regulatory elements associated with metformin treatment, we carried out RNA-seq and ChIP-seq (H3K27ac, H3K27me3) on primary human hepatocytes from the same donor treated with vehicle control, metformin or metformin and compound C, an AMP-activated protein kinase (AMPK) inhibitor (allowing to identify AMPK-independent pathways). We identified thousands of metformin responsive AMPK-dependent and AMPK-independent differentially expressed genes and regulatory elements. We functionally validated several elements for metformin-induced promoter and enhancer activity. These include an enhancer in an ataxia telangiectasia mutated (ATM) intron that has SNPs in linkage disequilibrium with a metformin treatment response GWAS lead SNP (rs11212617) that showed increased enhancer activity for the associated haplotype. Expression quantitative trait locus (eQTL) liver analysis and CRISPR activation suggest that this enhancer could be regulating ATM, which has a known role in AMPK activation, and potentially also EXPH5 and DDX10, its neighboring genes. Using ChIP-seq and siRNA knockdown, we further show that activating transcription factor 3 (ATF3), our top metformin upregulated AMPK-dependent gene, could have an important role in gluconeogenesis repression. Our findings provide a genome-wide representation of metformin hepatic response, highlight important sequences that could be associated with interindividual variability in glycemic response to metformin and identify novel T2D treatment candidates. PMID:27902686

  9. Early Neolithic genomes from the eastern Fertile Crescent

    PubMed Central

    Broushaki, Farnaz; Thomas, Mark G; Link, Vivian; López, Saioa; van Dorp, Lucy; Kirsanow, Karola; Hofmanová, Zuzana; Diekmann, Yoan; Cassidy, Lara M.; Díez-del-Molino, David; Kousathanas, Athanasios; Sell, Christian; Robson, Harry K.; Martiniano, Rui; Blöcher, Jens; Scheu, Amelie; Kreutzer, Susanne; Bollongino, Ruth; Bobo, Dean; Davudi, Hossein; Munoz, Olivia; Currat, Mathias; Abdi, Kamyar; Biglari, Fereidoun; Craig, Oliver E.; Bradley, Daniel G; Shennan, Stephen; Veeramah, Krishna; Mashkour, Marjan

    2016-01-01

    We sequenced Early Neolithic genomes from the Zagros region of Iran (eastern Fertile Crescent), where some of the earliest evidence for farming is found, and identify a previously uncharacterized population that is neither ancestral to the first European farmers nor has contributed significantly to the ancestry of modern Europeans. These people are estimated to have separated from Early Neolithic farmers in Anatolia some 46-77,000 years ago and show affinities to modern day Pakistani and Afghan populations, but particularly to Iranian Zoroastrians. We conclude that multiple, genetically differentiated hunter-gatherer populations adopted farming in SW-Asia, that components of pre-Neolithic population structure were preserved as farming spread into neighboring regions, and that the Zagros region was the cradle of eastward expansion. PMID:27417496

  10. Early Neolithic genomes from the eastern Fertile Crescent.

    PubMed

    Broushaki, Farnaz; Thomas, Mark G; Link, Vivian; López, Saioa; van Dorp, Lucy; Kirsanow, Karola; Hofmanová, Zuzana; Diekmann, Yoan; Cassidy, Lara M; Díez-del-Molino, David; Kousathanas, Athanasios; Sell, Christian; Robson, Harry K; Martiniano, Rui; Blöcher, Jens; Scheu, Amelie; Kreutzer, Susanne; Bollongino, Ruth; Bobo, Dean; Davoudi, Hossein; Munoz, Olivia; Currat, Mathias; Abdi, Kamyar; Biglari, Fereidoun; Craig, Oliver E; Bradley, Daniel G; Shennan, Stephen; Veeramah, Krishna R; Mashkour, Marjan; Wegmann, Daniel; Hellenthal, Garrett; Burger, Joachim

    2016-07-29

    We sequenced Early Neolithic genomes from the Zagros region of Iran (eastern Fertile Crescent), where some of the earliest evidence for farming is found, and identify a previously uncharacterized population that is neither ancestral to the first European farmers nor has contributed substantially to the ancestry of modern Europeans. These people are estimated to have separated from Early Neolithic farmers in Anatolia some 46,000 to 77,000 years ago and show affinities to modern-day Pakistani and Afghan populations, but particularly to Iranian Zoroastrians. We conclude that multiple, genetically differentiated hunter-gatherer populations adopted farming in southwestern Asia, that components of pre-Neolithic population structure were preserved as farming spread into neighboring regions, and that the Zagros region was the cradle of eastward expansion.

  11. Early identification of cardiovascular risk using genomics and proteomics

    PubMed Central

    Kullo, Iftikhar J.; Cooper, Leslie T.

    2010-01-01

    Coronary heart disease (CHD) will soon become the leading cause of death and morbidity in the world. Early detection and treatment of CHD is thus imperative to improve global health. Atherosclerosis of the coronary arteries is a complex multifactorial disease process involving multiple pathways that can be influenced by both genetic and environmental factors. With the recent advances in genomics and proteomics, many new risk factors with small-to-moderate effects are likely to be identified. Additionally, individualized risk stratification and targeted therapy may become feasible; each individual could potentially be assessed with a panel of tests for genomic and proteomic markers and, on the basis of the individual’s composite risk profile, preventive and therapeutic steps could then be undertaken. With a multimarker approach, it may also be possible to identify alterations in pathways involved in atherogenesis, rather than focus on individual risk factors. In this article, we use the specific example of atherosclerosis to discuss the role of genomics and proteomics in cardiovascular risk assessment. PMID:20440292

  12. Radiation-induced genomic instability: radiation quality and dose response

    NASA Technical Reports Server (NTRS)

    Smith, Leslie E.; Nagar, Shruti; Kim, Grace J.; Morgan, William F.

    2003-01-01

    Genomic instability is a term used to describe a phenomenon that results in the accumulation of multiple changes required to convert a stable genome of a normal cell to an unstable genome characteristic of a tumor. There has been considerable recent debate concerning the importance of genomic instability in human cancer and its temporal occurrence in the carcinogenic process. Radiation is capable of inducing genomic instability in mammalian cells and instability is thought to be the driving force responsible for radiation carcinogenesis. Genomic instability is characterized by a large collection of diverse endpoints that include large-scale chromosomal rearrangements and aberrations, amplification of genetic material, aneuploidy, micronucleus formation, microsatellite instability, and gene mutation. The capacity of radiation to induce genomic instability depends to a large extent on radiation quality or linear energy transfer (LET) and dose. There appears to be a low dose threshold effect with low LET, beyond which no additional genomic instability is induced. Low doses of both high and low LET radiation are capable of inducing this phenomenon. This report reviews data concerning dose rate effects of high and low LET radiation and their capacity to induce genomic instability assayed by chromosomal aberrations, delayed lethal mutations, micronuclei and apoptosis.

  13. Early cytokine responses during intestinal parasitic infections.

    PubMed Central

    Ishikawa, N; Goyal, P K; Mahida, Y R; Li, K F; Wakelin, D

    1998-01-01

    Infections with gastro-intestinal nematodes elicit immune and inflammatory responses mediated by cytokines released from T-helper type-2 (Th2) cells. In vitro assays of cells from the mesenteric lymph nodes (MLN) of experimentally infected rodents confirm that, after about 1 week, the dominant cytokine responses to mitogens and antigens are those associated with this Th-cell subset. Polarization of the Th response in this way implies an initial local cytokine environment that favours Th2 development. However, experimental infections with Trichinella spiralis and Nippostrongylus brasiliensis show that, within 2 days of worms reaching the intestine, MLN cells (MLNC) respond with a Th1 rather than a Th2 response [i.e. there is an increase in mRNA for the type 1 cytokine interferon-gamma (IFN-gamma), and mitogen-stimulated MLNC release IFN-gamma rather than interleukin-5 (IL-5)]. Antigen stimulation at this time does not elicit IFN-gamma release and the MLNC cannot adoptively transfer immunity. Within a few days the MLNC phenotype changes. There is a Th2 response (IL-5 release) to both mitogen and antigen stimulation and MLNC can adoptively transfer immunity. Early release of IFN-gamma is T-cell dependent, with CD4+ T cells playing the major role. The data are discussed in relation to factors regulating the mucosal response to invasion by parasites. PMID:9616376

  14. Early penguin fossils, plus mitochondrial genomes, calibrate avian evolution.

    PubMed

    Slack, Kerryn E; Jones, Craig M; Ando, Tatsuro; Harrison, G L Abby; Fordyce, R Ewan; Arnason, Ulfur; Penny, David

    2006-06-01

    Testing models of macroevolution, and especially the sufficiency of microevolutionary processes, requires good collaboration between molecular biologists and paleontologists. We report such a test for events around the Late Cretaceous by describing the earliest penguin fossils, analyzing complete mitochondrial genomes from an albatross, a petrel, and a loon, and describe the gradual decline of pterosaurs at the same time modern birds radiate. The penguin fossils comprise four naturally associated skeletons from the New Zealand Waipara Greensand, a Paleocene (early Tertiary) formation just above a well-known Cretaceous/Tertiary boundary site. The fossils, in a new genus (Waimanu), provide a lower estimate of 61-62 Ma for the divergence between penguins and other birds and thus establish a reliable calibration point for avian evolution. Combining fossil calibration points, DNA sequences, maximum likelihood, and Bayesian analysis, the penguin calibrations imply a radiation of modern (crown group) birds in the Late Cretaceous. This includes a conservative estimate that modern sea and shorebird lineages diverged at least by the Late Cretaceous about 74 +/- 3 Ma (Campanian). It is clear that modern birds from at least the latest Cretaceous lived at the same time as archaic birds including Hesperornis, Ichthyornis, and the diverse Enantiornithiformes. Pterosaurs, which also coexisted with early crown birds, show notable changes through the Late Cretaceous. There was a decrease in taxonomic diversity, and small- to medium-sized species disappeared well before the end of the Cretaceous. A simple reading of the fossil record might suggest competitive interactions with birds, but much more needs to be understood about pterosaur life histories. Additional fossils and molecular data are still required to help understand the role of biotic interactions in the evolution of Late Cretaceous birds and thus to test that the mechanisms of microevolution are sufficient to explain

  15. Integrated proteo-genomic approach for early diagnosis and prognosis of cancer.

    PubMed

    Shukla, Hem D; Mahmood, Javed; Vujaskovic, Zeljko

    2015-12-01

    Cancer is the leading cause of mortality among men and women worldwide. Despite the availability of numerous diagnostic techniques for various cancers, the overall survival rate remains low and the majority of patients die due to late diagnosis and advanced stage of the disease. Diagnosing and treating cancer at its early stages ideally during the precancerous phase could significantly increase survival rate with the possibility of cure and prolong survival. Cancer is a genetic disease and it is illicitly activated by the acquisition of somatic DNA lesions and aberrations in genome structure and defects in maintenance and repair. These somatic DNA mutations known as driver mutations seem to be the prime cause in initiating tumorigenesis. The advances in genomic technologies have immensely facilitated the understanding of cancer progression and metastasis, and the discovery of novel biomarkers. However, changes in somatic mutational landscape of the oncogenome are translated into aberrantly regulated oncoproteome which drives the cancer initiation. Thus, combination of proteomic and genomic technologies is urgently required to discover biomarkers for early diagnosis. The recent advances in human genome based detection of cancer using advanced genomic technologies like NextGen Sequencing, digital PCR, cfDNA technology have shown promise; for example oncogenic somatic mutation variants, transcriptomic analysis, copy number variant, and methylation data from the Cancer Genome Atlas. Similarly, oncoproteomics has the potential to revolutionize clinical management of the disease, including cancer diagnosis and screening based on new proteomic database which embodies somatic variants and post translational modifications, thus devising proteomic technologies as a complement to histopathology. Further, the use of multiple proteomic and genomic biomarkers rather than a single gene or protein could greatly improve diagnostic accuracy and enhance the predictive power for

  16. Multigenerational genomic responses to dietary phosphorus and temperature in Daphnia.

    PubMed

    Jalal, Marwa; Shala, Nita K; Wojewodzic, Marcin W; Andersen, Tom; Hessen, Dag O

    2014-08-01

    Temperature and nutrient availability are both hypothesized to affect organisms at the cellular and genomic levels. In this multigenerational study, Daphnia magna (D. magna) and Daphnia pulex (D. pulex) were maintained at high (20 °C) and low (10 °C) temperatures and nourished with phosphorus (P)-sufficient (50 μmol/L) and P-deficient (2 μmol/L) algae for up to 35 generations to assess the multigenerational impacts on genome size and nucleus size. Analysis by flow cytometry revealed significant increases in nucleus size for both species as well as genome size for D. magna in response to a low temperature. The degree of endoreplication, measured as cycle value, was species specific and responded to temperature and dietary composition. Under dietary P deficiency, D. magna, but not D. pulex, showed an apparent reduction in haploid genome size (C-value). These genomic responses are unlikely to reflect differences in nucleotide numbers, but rather structural changes affecting fluorochrome binding. While the ultimate and proximate causes of these responses are unknown, they suggest an intriguing potential for genomic responses that merits further research.

  17. Genome-Wide Chromatin Landscape Transitions Identify Novel Pathways in Early Commitment to Osteoblast Differentiation

    PubMed Central

    Thompson, Bethtrice; Varticovski, Lyuba; Baek, Songjoon; Hager, Gordon L.

    2016-01-01

    Bone continuously undergoes remodeling by a tightly regulated process that involves osteoblast differentiation from Mesenchymal Stem Cells (MSC). However, commitment of MSC to osteoblastic lineage is a poorly understood process. Chromatin organization functions as a molecular gatekeeper of DNA functions. Detection of sites that are hypersensitive to Dnase I has been used for detailed examination of changes in response to hormones and differentiation cues. To investigate the early steps in commitment of MSC to osteoblasts, we used a model human temperature-sensitive cell line, hFOB. When shifted to non-permissive temperature, these cells undergo "spontaneous" differentiation that takes several weeks, a process that is greatly accelerated by osteogenic induction media. We performed Dnase I hypersensitivity assays combined with deep sequencing to identify genome-wide potential regulatory events in cells undergoing early steps of commitment to osteoblasts. Massive reorganization of chromatin occurred within hours of differentiation. Whereas ~30% of unique DHS sites were located in the promoters, the majority was outside of the promoters, designated as enhancers. Many of them were at novel genomic sites and need to be confirmed experimentally. We developed a novel method for identification of cellular networks based solely on DHS enhancers signature correlated to gene expression. The analysis of enhancers that were unique to differentiating cells led to identification of bone developmental program encompassing 147 genes that directly or indirectly participate in osteogenesis. Identification of these pathways provided an unprecedented view of genomic regulation during early steps of differentiation and changes related to WNT, AP-1 and other pathways may have therapeutic implications. PMID:26890492

  18. An invertebrate signal transducer and activator of transcription 5 (STAT5) ortholog from the disk abalone, Haliotis discus discus: Genomic structure, early developmental expression, and immune responses to bacterial and viral stresses.

    PubMed

    Bathige, S D N K; Umasuthan, Navaneethaiyer; Park, Hae-Chul; Lee, Jehee

    2016-03-01

    Signal transducer and activator of transcription (STAT) family members are key signaling molecules that transduce cellular responses from the cell membrane to the nucleus upon Janus kinase (JAK) activation. Although seven STAT members have been reported in mammals, very limited information on STAT genes in molluscans is available. In this study, we identified and characterized a STAT paralog that is homologous to STAT5 from the disk abalone, Haliotis discus discus, and designated as AbSTAT5. Comparison of the deduced amino acid sequence for AbSTAT5 (790 amino acids) with other counterparts revealed conserved residues important for functions and typical domain regions, including the N-terminal domain, coiled-coil domain, DNA-binding domain, linker domain, and Src homology 2 (SH2) domains as mammalian counterparts. Analysis of STAT phylogeny revealed that AbSTAT5 was clustered with the molluscan subgroup in STAT5 clade with distinct evolution. According to the genomic structure of AbSTAT5, the coding sequence was distributed into 20 exons with 19 introns. Immunologically essential transcription factor-binding sites, such as GATA-1, HNF, SP1, C/EBP, Oct-1, AP1, c-Jun, and Sox-2, were predicted at the 5'-proximal region of AbSTAT5. Expression of AbSTAT5 mRNA was detected in different stages of embryonic development and observed at considerably higher levels in the morula and late veliger stages. Tissue-specific expressional studies revealed that the highest level of AbSTAT5 transcripts was detected in hemocytes, followed by gill tissues. Temporal expressions of AbSTAT5 were analyzed upon live bacterial (Vibrio parahemolyticus and Listeria monocytogenes), viral (viral hemorrhagic septicemia virus), and pathogen-associated molecular pattern (lipopolysaccharides and Poly I:C) stimulations, and significant elevations indicated immune modulation. These results suggest that AbSTAT5 may be involved in maintaining innate immune responses from developmental to adult stages in

  19. Genome Sequencing Highlights the Dynamic Early History of Dogs

    PubMed Central

    Freedman, Adam H.; Gronau, Ilan; Schweizer, Rena M.; Ortega-Del Vecchyo, Diego; Han, Eunjung; Silva, Pedro M.; Galaverni, Marco; Fan, Zhenxin; Marx, Peter; Lorente-Galdos, Belen; Beale, Holly; Ramirez, Oscar; Hormozdiari, Farhad; Alkan, Can; Vilà, Carles; Squire, Kevin; Geffen, Eli; Kusak, Josip; Boyko, Adam R.; Parker, Heidi G.; Lee, Clarence; Tadigotla, Vasisht; Siepel, Adam; Bustamante, Carlos D.; Harkins, Timothy T.; Nelson, Stanley F.; Ostrander, Elaine A.; Marques-Bonet, Tomas; Wayne, Robert K.; Novembre, John

    2014-01-01

    To identify genetic changes underlying dog domestication and reconstruct their early evolutionary history, we generated high-quality genome sequences from three gray wolves, one from each of the three putative centers of dog domestication, two basal dog lineages (Basenji and Dingo) and a golden jackal as an outgroup. Analysis of these sequences supports a demographic model in which dogs and wolves diverged through a dynamic process involving population bottlenecks in both lineages and post-divergence gene flow. In dogs, the domestication bottleneck involved at least a 16-fold reduction in population size, a much more severe bottleneck than estimated previously. A sharp bottleneck in wolves occurred soon after their divergence from dogs, implying that the pool of diversity from which dogs arose was substantially larger than represented by modern wolf populations. We narrow the plausible range for the date of initial dog domestication to an interval spanning 11–16 thousand years ago, predating the rise of agriculture. In light of this finding, we expand upon previous work regarding the increase in copy number of the amylase gene (AMY2B) in dogs, which is believed to have aided digestion of starch in agricultural refuse. We find standing variation for amylase copy number variation in wolves and little or no copy number increase in the Dingo and Husky lineages. In conjunction with the estimated timing of dog origins, these results provide additional support to archaeological finds, suggesting the earliest dogs arose alongside hunter-gathers rather than agriculturists. Regarding the geographic origin of dogs, we find that, surprisingly, none of the extant wolf lineages from putative domestication centers is more closely related to dogs, and, instead, the sampled wolves form a sister monophyletic clade. This result, in combination with dog-wolf admixture during the process of domestication, suggests that a re-evaluation of past hypotheses regarding dog origins is

  20. Genome sequencing highlights the dynamic early history of dogs.

    PubMed

    Freedman, Adam H; Gronau, Ilan; Schweizer, Rena M; Ortega-Del Vecchyo, Diego; Han, Eunjung; Silva, Pedro M; Galaverni, Marco; Fan, Zhenxin; Marx, Peter; Lorente-Galdos, Belen; Beale, Holly; Ramirez, Oscar; Hormozdiari, Farhad; Alkan, Can; Vilà, Carles; Squire, Kevin; Geffen, Eli; Kusak, Josip; Boyko, Adam R; Parker, Heidi G; Lee, Clarence; Tadigotla, Vasisht; Wilton, Alan; Siepel, Adam; Bustamante, Carlos D; Harkins, Timothy T; Nelson, Stanley F; Ostrander, Elaine A; Marques-Bonet, Tomas; Wayne, Robert K; Novembre, John

    2014-01-01

    To identify genetic changes underlying dog domestication and reconstruct their early evolutionary history, we generated high-quality genome sequences from three gray wolves, one from each of the three putative centers of dog domestication, two basal dog lineages (Basenji and Dingo) and a golden jackal as an outgroup. Analysis of these sequences supports a demographic model in which dogs and wolves diverged through a dynamic process involving population bottlenecks in both lineages and post-divergence gene flow. In dogs, the domestication bottleneck involved at least a 16-fold reduction in population size, a much more severe bottleneck than estimated previously. A sharp bottleneck in wolves occurred soon after their divergence from dogs, implying that the pool of diversity from which dogs arose was substantially larger than represented by modern wolf populations. We narrow the plausible range for the date of initial dog domestication to an interval spanning 11-16 thousand years ago, predating the rise of agriculture. In light of this finding, we expand upon previous work regarding the increase in copy number of the amylase gene (AMY2B) in dogs, which is believed to have aided digestion of starch in agricultural refuse. We find standing variation for amylase copy number variation in wolves and little or no copy number increase in the Dingo and Husky lineages. In conjunction with the estimated timing of dog origins, these results provide additional support to archaeological finds, suggesting the earliest dogs arose alongside hunter-gathers rather than agriculturists. Regarding the geographic origin of dogs, we find that, surprisingly, none of the extant wolf lineages from putative domestication centers is more closely related to dogs, and, instead, the sampled wolves form a sister monophyletic clade. This result, in combination with dog-wolf admixture during the process of domestication, suggests that a re-evaluation of past hypotheses regarding dog origins is

  1. Pharmacogenomics: The Genomics of Drug Response

    PubMed Central

    2000-01-01

    Pharmacogenomics is defined as the study of the association between genetics and drug response. This is a rapidly expanding field with the hope that, within a few years, prospective genotyping will lead to patients being prescribed drugs which are both safer and more effective (‘the right drug for the right patient’, or personalized medicine). There are many existing examples in the literature of strong associations between genetic variation and drug response, and some of these even form the basis of accepted clinical tests. The molecular basis for some of these associations is described, and includes examples of variation in genes responsible for absorption and metabolism of the drug, and in target and disease genes. However, there are many issues surrounding the legal, regulatory and ethical framework to these studies that remain unanswered, and a huge amount of education both for the public and haelthcare professionals will be needed bafore the results of this new madicine can be widely accepted. PMID:10797598

  2. Whole Genome Deep Sequencing of HIV-1 Reveals the Impact of Early Minor Variants Upon Immune Recognition During Acute Infection

    PubMed Central

    Henn, Matthew R.; Lennon, Niall J.; Power, Karen A.; Macalalad, Alexander R.; Berlin, Aaron M.; Malboeuf, Christine M.; Ryan, Elizabeth M.; Gnerre, Sante; Zody, Michael C.; Erlich, Rachel L.; Green, Lisa M.; Berical, Andrew; Wang, Yaoyu; Casali, Monica; Streeck, Hendrik; Bloom, Allyson K.; Dudek, Tim; Tully, Damien; Newman, Ruchi; Axten, Karen L.; Gladden, Adrianne D.; Battis, Laura; Kemper, Michael; Zeng, Qiandong; Shea, Terrance P.; Gujja, Sharvari; Zedlack, Carmen; Gasser, Olivier; Brander, Christian; Hess, Christoph; Günthard, Huldrych F.; Brumme, Zabrina L.; Brumme, Chanson J.; Bazner, Suzane; Rychert, Jenna; Tinsley, Jake P.; Mayer, Ken H.; Rosenberg, Eric; Pereyra, Florencia; Levin, Joshua Z.; Young, Sarah K.; Jessen, Heiko; Altfeld, Marcus; Birren, Bruce W.; Walker, Bruce D.; Allen, Todd M.

    2012-01-01

    Deep sequencing technologies have the potential to transform the study of highly variable viral pathogens by providing a rapid and cost-effective approach to sensitively characterize rapidly evolving viral quasispecies. Here, we report on a high-throughput whole HIV-1 genome deep sequencing platform that combines 454 pyrosequencing with novel assembly and variant detection algorithms. In one subject we combined these genetic data with detailed immunological analyses to comprehensively evaluate viral evolution and immune escape during the acute phase of HIV-1 infection. The majority of early, low frequency mutations represented viral adaptation to host CD8+ T cell responses, evidence of strong immune selection pressure occurring during the early decline from peak viremia. CD8+ T cell responses capable of recognizing these low frequency escape variants coincided with the selection and evolution of more effective secondary HLA-anchor escape mutations. Frequent, and in some cases rapid, reversion of transmitted mutations was also observed across the viral genome. When located within restricted CD8 epitopes these low frequency reverting mutations were sufficient to prime de novo responses to these epitopes, again illustrating the capacity of the immune response to recognize and respond to low frequency variants. More importantly, rapid viral escape from the most immunodominant CD8+ T cell responses coincided with plateauing of the initial viral load decline in this subject, suggestive of a potential link between maintenance of effective, dominant CD8 responses and the degree of early viremia reduction. We conclude that the early control of HIV-1 replication by immunodominant CD8+ T cell responses may be substantially influenced by rapid, low frequency viral adaptations not detected by conventional sequencing approaches, which warrants further investigation. These data support the critical need for vaccine-induced CD8+ T cell responses to target more highly constrained

  3. Whole genome deep sequencing of HIV-1 reveals the impact of early minor variants upon immune recognition during acute infection.

    PubMed

    Henn, Matthew R; Boutwell, Christian L; Charlebois, Patrick; Lennon, Niall J; Power, Karen A; Macalalad, Alexander R; Berlin, Aaron M; Malboeuf, Christine M; Ryan, Elizabeth M; Gnerre, Sante; Zody, Michael C; Erlich, Rachel L; Green, Lisa M; Berical, Andrew; Wang, Yaoyu; Casali, Monica; Streeck, Hendrik; Bloom, Allyson K; Dudek, Tim; Tully, Damien; Newman, Ruchi; Axten, Karen L; Gladden, Adrianne D; Battis, Laura; Kemper, Michael; Zeng, Qiandong; Shea, Terrance P; Gujja, Sharvari; Zedlack, Carmen; Gasser, Olivier; Brander, Christian; Hess, Christoph; Günthard, Huldrych F; Brumme, Zabrina L; Brumme, Chanson J; Bazner, Suzane; Rychert, Jenna; Tinsley, Jake P; Mayer, Ken H; Rosenberg, Eric; Pereyra, Florencia; Levin, Joshua Z; Young, Sarah K; Jessen, Heiko; Altfeld, Marcus; Birren, Bruce W; Walker, Bruce D; Allen, Todd M

    2012-01-01

    Deep sequencing technologies have the potential to transform the study of highly variable viral pathogens by providing a rapid and cost-effective approach to sensitively characterize rapidly evolving viral quasispecies. Here, we report on a high-throughput whole HIV-1 genome deep sequencing platform that combines 454 pyrosequencing with novel assembly and variant detection algorithms. In one subject we combined these genetic data with detailed immunological analyses to comprehensively evaluate viral evolution and immune escape during the acute phase of HIV-1 infection. The majority of early, low frequency mutations represented viral adaptation to host CD8+ T cell responses, evidence of strong immune selection pressure occurring during the early decline from peak viremia. CD8+ T cell responses capable of recognizing these low frequency escape variants coincided with the selection and evolution of more effective secondary HLA-anchor escape mutations. Frequent, and in some cases rapid, reversion of transmitted mutations was also observed across the viral genome. When located within restricted CD8 epitopes these low frequency reverting mutations were sufficient to prime de novo responses to these epitopes, again illustrating the capacity of the immune response to recognize and respond to low frequency variants. More importantly, rapid viral escape from the most immunodominant CD8+ T cell responses coincided with plateauing of the initial viral load decline in this subject, suggestive of a potential link between maintenance of effective, dominant CD8 responses and the degree of early viremia reduction. We conclude that the early control of HIV-1 replication by immunodominant CD8+ T cell responses may be substantially influenced by rapid, low frequency viral adaptations not detected by conventional sequencing approaches, which warrants further investigation. These data support the critical need for vaccine-induced CD8+ T cell responses to target more highly constrained

  4. The chemical defensome: environmental sensing and response genes in the Strongylocentrotus purpuratus genome.

    PubMed

    Goldstone, J V; Hamdoun, A; Cole, B J; Howard-Ashby, M; Nebert, D W; Scally, M; Dean, M; Epel, D; Hahn, M E; Stegeman, J J

    2006-12-01

    Metazoan genomes contain large numbers of genes that participate in responses to environmental stressors. We surveyed the sea urchin Strongylocentrotus purpuratus genome for homologs of gene families thought to protect against chemical stressors; these genes collectively comprise the 'chemical defensome.' Chemical defense genes include cytochromes P450 and other oxidases, various conjugating enzymes, ATP-dependent efflux transporters, oxidative detoxification proteins, and transcription factors that regulate these genes. Together such genes account for more than 400 genes in the sea urchin genome. The transcription factors include homologs of the aryl hydrocarbon receptor, hypoxia-inducible factor, nuclear factor erythroid-derived 2, heat shock factor, and nuclear hormone receptors, which regulate stress-response genes in vertebrates. Some defense gene families, including the ABCC, the UGT, and the CYP families, have undergone expansion in the urchin relative to other deuterostome genomes, whereas the stress sensor gene families do not show such expansion. More than half of the defense genes are expressed during embryonic or larval life stages, indicating their importance during development. This genome-wide survey of chemical defense genes in the sea urchin reveals evolutionary conservation of this network combined with lineage-specific diversification that together suggest the importance of these chemical stress sensing and response mechanisms in early deuterostomes. These results should facilitate future studies on the evolution of chemical defense gene networks and the role of these networks in protecting embryos from chemical stress during development.

  5. Hierarchical regulation of the genome: global changes in nucleosome organization potentiate genome response.

    PubMed

    Sexton, Brittany S; Druliner, Brooke R; Vera, Daniel L; Avey, Denis; Zhu, Fanxiu; Dennis, Jonathan H

    2016-02-09

    Nucleosome occupancy is critically important in regulating access to the eukaryotic genome. Few studies in human cells have measured genome-wide nucleosome distributions at high temporal resolution during a response to a common stimulus. We measured nucleosome distributions at high temporal resolution following Kaposi's-sarcoma-associated herpesvirus (KSHV) reactivation using our newly developed mTSS-seq technology, which maps nucleosome distribution at the transcription start sites (TSS) of all human genes. Nucleosomes underwent widespread changes in organization 24 hours after KSHV reactivation and returned to their basal nucleosomal architecture 48 hours after KSHV reactivation. The widespread changes consisted of an indiscriminate remodeling event resulting in the loss of nucleosome rotational phasing signals. Additionally, one in six TSSs in the human genome possessed nucleosomes that are translationally remodeled. 72% of the loci with translationally remodeled nucleosomes have nucleosomes that moved to positions encoded by the underlying DNA sequence. Finally we demonstrated that these widespread alterations in nucleosomal architecture potentiated regulatory factor binding. These descriptions of nucleosomal architecture changes provide a new framework for understanding the role of chromatin in the genomic response, and have allowed us to propose a hierarchical model for chromatin-based regulation of genome response.

  6. Identification of a Genomic Signature Predicting for Recurrence in Early Stage Ovarian Cancer

    DTIC Science & Technology

    2014-10-01

    Award Number: W81XWH-12-1-0521 TITLE: Identification of a Genomic Signature Predicting for Recurrence in Early Stage Ovarian Cancer PRINCIPAL...SUBTITLE 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-12-1-0521 Identification of a Genomic Signature Predicting for Recurrence in Early-Stage...clinical annotation and accurate pathological review (228 recurrent and 364 non-recurrent), 2) established a specimen repository and clinical data

  7. The Genome of Naegleria gruberi Illuminates Early Eukaryotic Versatility

    SciTech Connect

    Fritz-Laylin, Lillian K.; Prochnik, Simon E.; Ginger, Michael L.; Dacks, Joel; Carpenter, Meredith L.; Field, Mark C.; Kuo, Alan; Paredez, Alex; Chapman, Jarrod; Pham, Jonathan; Shu, Shengqiang; Neupane, Rochak; Cipriano, Michael; Mancuso, Joel; Tu, Hank; Salamov, Asaf; Lindquist, Erika; Shapiro, Harris; Lucas, Susan; Grigoriev, Igor V.; Cande, W. Zacheus; Fulton, Chandler; Rokhsar, Daniel S.; Dawson, Scott C.

    2010-03-01

    Genome sequences of diverse free-living protists are essential for understanding eukaryotic evolution and molecular and cell biology. The free-living amoeboflagellate Naegleria gruberi belongs to a varied and ubiquitous protist clade (Heterolobosea) that diverged from other eukaryotic lineages over a billion years ago. Analysis of the 15,727 protein-coding genes encoded by Naegleria's 41 Mb nuclear genome indicates a capacity for both aerobic respiration and anaerobic metabolism with concomitant hydrogen production, with fundamental implications for the evolution of organelle metabolism. The Naegleria genome facilitates substantially broader phylogenomic comparisons of free-living eukaryotes than previously possible, allowing us to identify thousands of genes likely present in the pan-eukaryotic ancestor, with 40% likely eukaryotic inventions. Moreover, we construct a comprehensive catalog of amoeboid-motility genes. The Naegleria genome, analyzed in the context of other protists, reveals a remarkably complex ancestral eukaryote with a rich repertoire of cytoskeletal, sexual, signaling, and metabolic modules.

  8. Early genome duplications in conifers and other seed plants.

    PubMed

    Li, Zheng; Baniaga, Anthony E; Sessa, Emily B; Scascitelli, Moira; Graham, Sean W; Rieseberg, Loren H; Barker, Michael S

    2015-11-01

    Polyploidy is a common mode of speciation and evolution in angiosperms (flowering plants). In contrast, there is little evidence to date that whole genome duplication (WGD) has played a significant role in the evolution of their putative extant sister lineage, the gymnosperms. Recent analyses of the spruce genome, the first published conifer genome, failed to detect evidence of WGDs in gene age distributions and attributed many aspects of conifer biology to a lack of WGDs. We present evidence for three ancient genome duplications during the evolution of gymnosperms, based on phylogenomic analyses of transcriptomes from 24 gymnosperms and 3 outgroups. We use a new algorithm to place these WGD events in phylogenetic context: two in the ancestry of major conifer clades (Pinaceae and cupressophyte conifers) and one in Welwitschia (Gnetales). We also confirm that a WGD hypothesized to be restricted to seed plants is indeed not shared with ferns and relatives (monilophytes), a result that was unclear in earlier studies. Contrary to previous genomic research that reported an absence of polyploidy in the ancestry of contemporary gymnosperms, our analyses indicate that polyploidy has contributed to the evolution of conifers and other gymnosperms. As in the flowering plants, the evolution of the large genome sizes of gymnosperms involved both polyploidy and repetitive element activity.

  9. Early genome duplications in conifers and other seed plants

    PubMed Central

    Li, Zheng; Baniaga, Anthony E.; Sessa, Emily B.; Scascitelli, Moira; Graham, Sean W.; Rieseberg, Loren H.; Barker, Michael S.

    2015-01-01

    Polyploidy is a common mode of speciation and evolution in angiosperms (flowering plants). In contrast, there is little evidence to date that whole genome duplication (WGD) has played a significant role in the evolution of their putative extant sister lineage, the gymnosperms. Recent analyses of the spruce genome, the first published conifer genome, failed to detect evidence of WGDs in gene age distributions and attributed many aspects of conifer biology to a lack of WGDs. We present evidence for three ancient genome duplications during the evolution of gymnosperms, based on phylogenomic analyses of transcriptomes from 24 gymnosperms and 3 outgroups. We use a new algorithm to place these WGD events in phylogenetic context: two in the ancestry of major conifer clades (Pinaceae and cupressophyte conifers) and one in Welwitschia (Gnetales). We also confirm that a WGD hypothesized to be restricted to seed plants is indeed not shared with ferns and relatives (monilophytes), a result that was unclear in earlier studies. Contrary to previous genomic research that reported an absence of polyploidy in the ancestry of contemporary gymnosperms, our analyses indicate that polyploidy has contributed to the evolution of conifers and other gymnosperms. As in the flowering plants, the evolution of the large genome sizes of gymnosperms involved both polyploidy and repetitive element activity. PMID:26702445

  10. Ecological genomics in Daphnia: stress responses and environmental sex determination.

    PubMed

    Eads, B D; Andrews, J; Colbourne, J K

    2008-02-01

    Ecological genomics is the study of adaptation of natural populations to their environment, and therefore seeks to link organism and population level processes through an understanding of genome organization and function. The planktonic microcrustacean Daphnia, which has long been an important system for ecology, is now being used as a genomic model as well. Here we review recent progress in selected areas of Daphnia genomics research. Production of parthenogenetic male offspring occurs through environmental cues, which clearly involves endocrine regulation and has also been studied as a toxicological response to juvenoid hormone analog insecticides. Recent progress has uncovered a putative juvenoid cis-response element, which together with microarray analysis will stimulate further research into nuclear hormone receptors and their associated transcriptional regulatory networks. Ecotoxicological studies indicate that mRNA profiling is a sensitive and specific research tool with promising applications in environmental monitoring and for uncovering conserved cellular processes. Rapid progress is expected to continue in these and other areas, as genomic tools for Daphnia become widely available to investigators.

  11. Complete chloroplast genome of Macadamia integrifolia confirms the position of the Gondwanan early-diverging eudicot family Proteaceae

    PubMed Central

    2014-01-01

    Background Sequence data from the chloroplast genome have played a central role in elucidating the evolutionary history of flowering plants, Angiospermae. In the past decade, the number of complete chloroplast genomes has burgeoned, leading to well-supported angiosperm phylogenies. However, some relationships, particulary among early-diverging lineages, remain unresolved. The diverse Southern Hemisphere plant family Proteaceae arose on the ancient supercontinent Gondwana early in angiosperm history and is a model group for adaptive radiation in response to changing climatic conditions. Genomic resources for the family are limited, and until now it is one of the few early-diverging 'basal eudicot' lineages not represented in chloroplast phylogenomic analyses. Results The chloroplast genome of the Australian nut crop tree Macadamia integrifolia was assembled de novo from Illumina paired-end sequence reads. Three contigs, corresponding to a collapsed inverted repeat, a large and a small single copy region were identified, and used for genome reconstruction. The complete genome is 159,714bp in length and was assembled at deep coverage (3.29 million reads; ~2000 x). Phylogenetic analyses based on 83-gene and inverted repeat region alignments, the largest sequence-rich datasets to include the basal eudicot family Proteaceae, provide strong support for a Proteales clade that includes Macadamia, Platanus and Nelumbo. Genome structure and content followed the ancestral angiosperm pattern and were highly conserved in the Proteales, whilst size differences were largely explained by the relative contraction of the single copy regions and expansion of the inverted repeats in Macadamia. Conclusions The Macadamia chloroplast genome presented here is the first in the Proteaceae, and confirms the placement of this family with the morphologically divergent Plantanaceae (plane tree family) and Nelumbonaceae (sacred lotus family) in the basal eudicot order Proteales. It provides a

  12. Defining Clinical Response Criteria and Early Response Criteria for Precision Oncology: Current State-of-the-Art and Future Perspectives

    PubMed Central

    Subbiah, Vivek; Chuang, Hubert H.; Gambhire, Dhiraj; Kairemo, Kalevi

    2017-01-01

    In this era of precision oncology, there has been an exponential growth in the armamentarium of genomically targeted therapies and immunotherapies. Evaluating early responses to precision therapy is essential for “go” versus “no go” decisions for these molecularly targeted drugs and agents that arm the immune system. Many different response assessment criteria exist for use in solid tumors and lymphomas. We reviewed the literature using the Medline/PubMed database for keywords “response assessment” and various known response assessment criteria published up to 2016. In this article we review the commonly used response assessment criteria. We present a decision tree to facilitate selection of appropriate criteria. We also suggest methods for standardization of various response assessment criteria. The relevant response assessment criteria were further studied for rational of development, key features, proposed use and acceptance by various entities. We also discuss early response evaluation and provide specific case studies of early response to targeted therapy. With high-throughput, advanced computing programs and digital data-mining it is now possible to acquire vast amount of high quality imaging data opening up a new field of “omics in radiology”—radiomics that complements genomics for personalized medicine. Radiomics is rapidly evolving and is still in the research arena. This cutting-edge technology is poised to move soon to the mainstream clinical arena. Novel agents with new mechanisms of action require advanced molecular imaging as imaging biomarkers. There is an urgent need for development of standardized early response assessment criteria for evaluation of response to precision therapy. PMID:28212290

  13. Defining Clinical Response Criteria and Early Response Criteria for Precision Oncology: Current State-of-the-Art and Future Perspectives.

    PubMed

    Subbiah, Vivek; Chuang, Hubert H; Gambhire, Dhiraj; Kairemo, Kalevi

    2017-02-15

    In this era of precision oncology, there has been an exponential growth in the armamentarium of genomically targeted therapies and immunotherapies. Evaluating early responses to precision therapy is essential for "go" versus "no go" decisions for these molecularly targeted drugs and agents that arm the immune system. Many different response assessment criteria exist for use in solid tumors and lymphomas. We reviewed the literature using the Medline/PubMed database for keywords "response assessment" and various known response assessment criteria published up to 2016. In this article we review the commonly used response assessment criteria. We present a decision tree to facilitate selection of appropriate criteria. We also suggest methods for standardization of various response assessment criteria. The relevant response assessment criteria were further studied for rational of development, key features, proposed use and acceptance by various entities. We also discuss early response evaluation and provide specific case studies of early response to targeted therapy. With high-throughput, advanced computing programs and digital data-mining it is now possible to acquire vast amount of high quality imaging data opening up a new field of "omics in radiology"-radiomics that complements genomics for personalized medicine. Radiomics is rapidly evolving and is still in the research arena. This cutting-edge technology is poised to move soon to the mainstream clinical arena. Novel agents with new mechanisms of action require advanced molecular imaging as imaging biomarkers. There is an urgent need for development of standardized early response assessment criteria for evaluation of response to precision therapy.

  14. Early Biventricular Molecular Responses to an Acute Myocardial Infarction

    PubMed Central

    Erdal, Cenk; Karakülah, Gökhan; Fermancı, Emel; Kunter, İmge; Silistreli, Erdem; Canda, Tülay; Erdal, Esra; Hepaguslar, Hasan

    2012-01-01

    Background: Acute myocardial infarction (AMI) remains as one of the most common lethal diseases in the world and therefore it is necessary to understand its effect on molecular basis. Genome-wide microarray analysis provides us to predict potential biomarkers and signaling pathways for this purpose. Objectives: The aim of this study is to understand the molecular basis of the immediate right ventricular cellular response to left ventricular AMI. Material and Methods: A rat model of left anterior descending coronary artery ligation was used to assess the effect of left ventricular AMI on both the right ventricle as a remote zone and the left ventricle as an ischemic/infarct zone. Microarray technology was applied to detect the gene expression. Gene Ontology and KEGG pathways analysis were done to identify effected pathways and related genes. Results: We found that immune response, cell chemotaxis, inflammation, cytoskeleton organization are significantly deregulated in ischemic zone as early response within 30 min. Unexpectedly, there were several affected signaling pathways such as cell chemotaxis, regulation of endothelial cell proliferation, and regulation of caveolea regulation of anti-apoptosis, regulation of cytoskeleton organization and cell adhesion on the remote zone in the right ventricle. Conclusion: This data demonstrates that there is an immediate molecular response in both ventricles after an AMI. Although the ischemia did not histologically involve the right ventricle; there is a clear molecular response to the infarct in the left ventricle. This provides us new insights to understand molecular mechanisms behind AMI and to find more effective drug targets. PMID:22211093

  15. BYSTANDERS, ADAPTIVE RESPONSES AND GENOMIC INSTABILITY - POTENTIAL MODIFIERS OF LOW-DOSE CANCER RESPONSES.

    EPA Science Inventory

    Bystanders, Adaptive Responses and Genomic Instability -Potential Modifiers ofLow-Dose
    Cancer Responses
    .
    There has been a concerted effort in the field of radiation biology to better understand cellular
    responses that could have an impact on the estin1ation of cancer...

  16. Simulation Training in Early Emergency Response (STEER).

    PubMed

    Generoso, Jose Roberto; Latoures, Renee Elizabeth; Acar, Yahya; Miller, Dean Scott; Ciano, Mark; Sandrei, Renan; Vieira, Marlon; Luong, Sean; Hirsch, Jan; Fidler, Richard Lee

    2016-06-01

    HOW TO OBTAIN CONTACT HOURS BY READING THIS ISSUE Instructions: 1.3 contact hours will be awarded by Villanova University College of Nursing upon successful completion of this activity. A contact hour is a unit of measurement that denotes 60 minutes of an organized learning activity. This is a learner-based activity. Villanova University College of Nursing does not require submission of your answers to the quiz. A contact hour certificate will be awarded after you register, pay the registration fee, and complete the evaluation form online at http://goo.gl/gMfXaf. In order to obtain contact hours you must: 1. Read the article, "Simulation Training in Early Emergency Response (STEER)," found on pages 255-263, carefully noting any tables and other illustrative materials that are included to enhance your knowledge and understanding of the content. Be sure to keep track of the amount of time (number of minutes) you spend reading the article and completing the quiz. 2. Read and answer each question on the quiz. After completing all of the questions, compare your answers to those provided within this issue. If you have incorrect answers, return to the article for further study. 3. Go to the Villanova website to register for contact hour credit. You will be asked to provide your name, contact information, and a VISA, MasterCard, or Discover card number for payment of the $20.00 fee. Once you complete the online evaluation, a certificate will be automatically generated. This activity is valid for continuing education credit until May 31, 2019. CONTACT HOURS This activity is co-provided by Villanova University College of Nursing and SLACK Incorporated. Villanova University College of Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. OBJECTIVES Define the purpose of the Simulation Training in Early Emergency Response (STEER) study. Review the outcome of the STEER study. DISCLOSURE

  17. Cadmium-induced genomic instability in Arabidopsis: Molecular toxicological biomarkers for early diagnosis of cadmium stress.

    PubMed

    Wang, Hetong; He, Lei; Song, Jie; Cui, Weina; Zhang, Yanzhao; Jia, Chunyun; Francis, Dennis; Rogers, Hilary J; Sun, Lizong; Tai, Peidong; Hui, Xiujuan; Yang, Yuesuo; Liu, Wan

    2016-05-01

    Microsatellite instability (MSI) analysis, random-amplified polymorphic DNA (RAPD), and methylation-sensitive arbitrarily primed PCR (MSAP-PCR) are methods to evaluate the toxicity of environmental pollutants in stress-treated plants and human cancer cells. Here, we evaluate these techniques to screen for genetic and epigenetic alterations of Arabidopsis plantlets exposed to 0-5.0 mg L(-1) cadmium (Cd) for 15 d. There was a substantial increase in RAPD polymorphism of 24.5, and in genomic methylation polymorphism of 30.5-34.5 at CpG and of 14.5-20 at CHG sites under Cd stress of 5.0 mg L(-1) by RAPD and of 0.25-5.0 mg L(-1) by MSAP-PCR, respectively. However, only a tiny increase of 1.5 loci by RAPD occurred under Cd stress of 4.0 mg L(-1), and an additional high dose (8.0 mg L(-1)) resulted in one repeat by MSI analysis. MSAP-PCR detected the most significant epigenetic modifications in plantlets exposed to Cd stress, and the patterns of hypermethylation and polymorphisms were consistent with inverted U-shaped dose responses. The presence of genomic methylation polymorphism in Cd-treated seedlings, prior to the onset of RAPD polymorphism, MSI and obvious growth effects, suggests that these altered DNA methylation loci are the most sensitive biomarkers for early diagnosis and risk assessment of genotoxic effects of Cd pollution in ecotoxicology.

  18. Identification of Ohnolog Genes Originating from Whole Genome Duplication in Early Vertebrates, Based on Synteny Comparison across Multiple Genomes.

    PubMed

    Singh, Param Priya; Arora, Jatin; Isambert, Hervé

    2015-07-01

    Whole genome duplications (WGD) have now been firmly established in all major eukaryotic kingdoms. In particular, all vertebrates descend from two rounds of WGDs, that occurred in their jawless ancestor some 500 MY ago. Paralogs retained from WGD, also coined 'ohnologs' after Susumu Ohno, have been shown to be typically associated with development, signaling and gene regulation. Ohnologs, which amount to about 20 to 35% of genes in the human genome, have also been shown to be prone to dominant deleterious mutations and frequently implicated in cancer and genetic diseases. Hence, identifying ohnologs is central to better understand the evolution of vertebrates and their susceptibility to genetic diseases. Early computational analyses to identify vertebrate ohnologs relied on content-based synteny comparisons between the human genome and a single invertebrate outgroup genome or within the human genome itself. These approaches are thus limited by lineage specific rearrangements in individual genomes. We report, in this study, the identification of vertebrate ohnologs based on the quantitative assessment and integration of synteny conservation between six amniote vertebrates and six invertebrate outgroups. Such a synteny comparison across multiple genomes is shown to enhance the statistical power of ohnolog identification in vertebrates compared to earlier approaches, by overcoming lineage specific genome rearrangements. Ohnolog gene families can be browsed and downloaded for three statistical confidence levels or recompiled for specific, user-defined, significance criteria at http://ohnologs.curie.fr/. In the light of the importance of WGD on the genetic makeup of vertebrates, our analysis provides a useful resource for researchers interested in gaining further insights on vertebrate evolution and genetic diseases.

  19. Genome-wide analysis of DNA methylation dynamics during early human development.

    PubMed

    Okae, Hiroaki; Chiba, Hatsune; Hiura, Hitoshi; Hamada, Hirotaka; Sato, Akiko; Utsunomiya, Takafumi; Kikuchi, Hiroyuki; Yoshida, Hiroaki; Tanaka, Atsushi; Suyama, Mikita; Arima, Takahiro

    2014-12-01

    DNA methylation is globally reprogrammed during mammalian preimplantation development, which is critical for normal development. Recent reduced representation bisulfite sequencing (RRBS) studies suggest that the methylome dynamics are essentially conserved between human and mouse early embryos. RRBS is known to cover 5-10% of all genomic CpGs, favoring those contained within CpG-rich regions. To obtain an unbiased and more complete representation of the methylome during early human development, we performed whole genome bisulfite sequencing of human gametes and blastocysts that covered>70% of all genomic CpGs. We found that the maternal genome was demethylated to a much lesser extent in human blastocysts than in mouse blastocysts, which could contribute to an increased number of imprinted differentially methylated regions in the human genome. Global demethylation of the paternal genome was confirmed, but SINE-VNTR-Alu elements and some other tandem repeat-containing regions were found to be specifically protected from this global demethylation. Furthermore, centromeric satellite repeats were hypermethylated in human oocytes but not in mouse oocytes, which might be explained by differential expression of de novo DNA methyltransferases. These data highlight both conserved and species-specific regulation of DNA methylation during early mammalian development. Our work provides further information critical for understanding the epigenetic processes underlying differentiation and pluripotency during early human development.

  20. Genomic response of the nematode Caenorhabditis elgans to spaceflight

    NASA Astrophysics Data System (ADS)

    Selch, F.; Szewczyk, N.; Conley, C.

    On Earth it is common practice to employ laboratory animals such as the nematode Caenorhabditis elegans to help understand human health concerns Studies of model organisms in Earth orbit should similarly help understand and address the concerns associated with spaceflight The International Ceonorhabditis elegans Experiment FIRST ICE FIRST was carried out onboard the Dutch Taxiflight in April of 2004 by an international collaboration of laboratories in France Canada Japan and the United States Animals developed normally in flight and returned in good apparent health With the exception of a slight movement defect upon return to Earth no significant abnormalities were detected Work from Japan revealed that apoptosis proceeds normally and work from Canada revealed no significant increase in the rate of mutation in flight These results appear similar to what is observed for humans and suggest that C elegans can be used to study non-lethal responses to spaceflight and can possibly be developed as a biological sensor To further our understanding of C elegans response to spaceflight we examined the gene transcription response using a near full genome microarray analysis Here we will report the transcriptional response of C elegans to the 10 days in space This transcriptional response is consistent with the observed normal development apoptosis and DNA repair Additionally several genes that may be involved in the movement defect have been identified Our presentation will compare the genome response of three independent samples in which stress

  1. Early pathogenesis during infectious bursal disease in susceptible chickens is associated with changes in B cell genomic methylation and loss of genome integrity.

    PubMed

    Ciccone, Nick A; Smith, Lorraine P; Mwangi, William; Boyd, Amy; Broadbent, Andrew J; Smith, Adrian L; Nair, Venugopal

    2017-03-17

    We propose a model by which an increase in the genomic modification, 5-hydroxymethylcytosine (5hmC), contributes to B cell death within the chicken bursa of Fabricus (BF) infected with infectious bursal disease virus (IBDV). Our findings indicate that, following an IBDV infection, Rhode Island Red (RIR) chickens have fewer surviving B cells and higher levels of 5hmC in the BF than the more resistant 15l line of birds. Elevated genomic 5hmC levels within the RIR BF are associated with markers of immune responses: infiltrating T cells and increased expression of CD40L, FasL and iNOS. Such changes correlate with genomic fragmentation and the presence of IBDV capsid protein, VP2. To explore the effects of CD40L, the immature B-cell line, DT40, was exposed to recombinant chicken CD40L that resulted in changes in nuclear 5hmC distribution. Collectively, our observations suggest that T cell infiltration exacerbates early immunopathology within the BF during an IBDV infection contributing to B cell genomic instability and death to facilitate viral egress and immunosuppression.

  2. Genome-Wide Detection of SNP and SV Variations to Reveal Early Ripening-Related Genes in Grape.

    PubMed

    Xu, Yanshuai; Gao, Zhihong; Tao, Jianmin; Jiang, Weihua; Zhang, Shijie; Wang, Qiunan; Qu, Shenchun

    2016-01-01

    Early ripening in grape (Vitis vinifera L.) is a crucial agronomic trait. The fruits of the grape line 'Summer Black' (SBBM), which contains a bud mutation, can be harvested approximately one week earlier than the 'Summer Black' (SBC)control. To investigate the molecular mechanism of the bud mutation related to early ripening, we detected genome-wide genetic variations based on re-sequencing. In total, 3,692,777 single nucleotide polymorphisms (SNPs) and 81,223 structure variations (SVs) in the SBC genome and 3,823,464 SNPs and 85,801 SVs in the SBBM genome were detected compared with the reference grape sequence. Of these, 635 SBC-specific genes and 665 SBBM-specific genes were screened. Ripening and colour-associated unigenes with non-synonymous mutations (NS), SVs or frame-shift mutations (F) were analysed. The results showed that 90 unigenes in SBC, 76 unigenes in SBBM and 13 genes that mapped to large fragment indels were filtered. The expression patterns of eight genes were confirmed using quantitative reverse transcription-polymerase chain reaction (qRT-PCR).The re-sequencing data showed that 635 SBC-specific genes and 665 SBBM-specific genes associated with early ripening were screened. Among these, NCED6 expression appears to be related to NCED1 and is involved in ABA biosynthesis in grape, which might play a role in the onset of anthocyanin accumulation. The SEP and ERF genes probably play roles in ethylene response.

  3. Who ate whom? Adaptive Helicobacter genomic changes that accompanied a host jump from early humans to large felines.

    PubMed

    Eppinger, Mark; Baar, Claudia; Linz, Bodo; Raddatz, Günter; Lanz, Christa; Keller, Heike; Morelli, Giovanna; Gressmann, Helga; Achtman, Mark; Schuster, Stephan C

    2006-07-01

    Helicobacter pylori infection of humans is so old that its population genetic structure reflects that of ancient human migrations. A closely related species, Helicobacter acinonychis, is specific for large felines, including cheetahs, lions, and tigers, whereas hosts more closely related to humans harbor more distantly related Helicobacter species. This observation suggests a jump between host species. But who ate whom and when did it happen? In order to resolve this question, we determined the genomic sequence of H. acinonychis strain Sheeba and compared it to genomes from H. pylori. The conserved core genes between the genomes are so similar that the host jump probably occurred within the last 200,000 (range 50,000-400,000) years. However, the Sheeba genome also possesses unique features that indicate the direction of the host jump, namely from early humans to cats. Sheeba possesses an unusually large number of highly fragmented genes, many encoding outer membrane proteins, which may have been destroyed in order to bypass deleterious responses from the feline host immune system. In addition, the few Sheeba-specific genes that were found include a cluster of genes encoding sialylation of the bacterial cell surface carbohydrates, which were imported by horizontal genetic exchange and might also help to evade host immune defenses. These results provide a genomic basis for elucidating molecular events that allow bacteria to adapt to novel animal hosts.

  4. Multiple Lineages of Ancient CR1 Retroposons Shaped the Early Genome Evolution of Amniotes

    PubMed Central

    Suh, Alexander; Churakov, Gennady; Ramakodi, Meganathan P.; Platt, Roy N.; Jurka, Jerzy; Kojima, Kenji K.; Caballero, Juan; Smit, Arian F.; Vliet, Kent A.; Hoffmann, Federico G.; Brosius, Jürgen; Green, Richard E.; Braun, Edward L.; Ray, David A.; Schmitz, Jürgen

    2015-01-01

    Chicken repeat 1 (CR1) retroposons are long interspersed elements (LINEs) that are ubiquitous within amniote genomes and constitute the most abundant family of transposed elements in birds, crocodilians, turtles, and snakes. They are also present in mammalian genomes, where they reside as numerous relics of ancient retroposition events. Yet, despite their relevance for understanding amniote genome evolution, the diversity and evolution of CR1 elements has never been studied on an amniote-wide level. We reconstruct the temporal and quantitative activity of CR1 subfamilies via presence/absence analyses across crocodilian phylogeny and comparative analyses of 12 crocodilian genomes, revealing relative genomic stasis of retroposition during genome evolution of extant Crocodylia. Our large-scale phylogenetic analysis of amniote CR1 subfamilies suggests the presence of at least seven ancient CR1 lineages in the amniote ancestor; and amniote-wide analyses of CR1 successions and quantities reveal differential retention (presence of ancient relics or recent activity) of these CR1 lineages across amniote genome evolution. Interestingly, birds and lepidosaurs retained the fewest ancient CR1 lineages among amniotes and also exhibit smaller genome sizes. Our study is the first to analyze CR1 evolution in a genome-wide and amniote-wide context and the data strongly suggest that the ancestral amniote genome contained myriad CR1 elements from multiple ancient lineages, and remnants of these are still detectable in the relatively stable genomes of crocodilians and turtles. Early mammalian genome evolution was thus characterized by a drastic shift from CR1 prevalence to dominance and hyperactivity of L2 LINEs in monotremes and L1 LINEs in therians. PMID:25503085

  5. Complete Sequence of a Sea Lamprey (Petromyzon Marinus) Mitochondrial Genome: Early Establishment of the Vertebrate Genome Organization

    PubMed Central

    Lee, W. J.; Kocher, T. D.

    1995-01-01

    The complete nucleotide sequence of a sea lamprey (Petromyzon marinus) mitochondrial genome has been determined. The lamprey genome is 16,201 bp in length and contains genes for 13 proteins, two rRNAs, 22 tRNAs and two major noncoding regions. The order and transcriptional polarities of protein-coding genes are basically identical to those of other chordate mtDNAs, demonstrating that the common mitochondrial gene organization of vertebrates was established at an early stage of vertebrate evolution. The two major noncoding regions are separated by two tRNA genes. The first region probably functions as the control region because it contains distinctive conserved sequence blocks (CSB-II and III) common to other vertebrate control regions. The central conserved domain observed in other vertebrate control regions is not found in the lamprey, suggesting that it is a recently evolved functional domain in vertebrates. Noncoding segments are not found in the expected position of the origin of replication for the second strand, suggesting either that one of the tRNA genes has a dual function or that the second noncoding region may function as the second-strand origin. The base composition at the wobble positions of fourfold degenerate codon families is highly biased toward thymine (32.7%). Values of GC-and AT-skew are typical of vertebrate mitochondrial genomes.genomes. PMID:7713438

  6. Motivations and Perceptions of Early Adopters of Personalized Genomics: Perspectives from Research Participants

    PubMed Central

    Gollust, S.E.; Gordon, E.S.; Zayac, C.; Griffin, G.; Christman, M.F.; Pyeritz, R.E.; Wawak, L.; Bernhardt, B.A.

    2011-01-01

    Background/Aims: To predict the potential public health impact of personal genomics, empirical research on public perceptions of these services is needed. In this study, ‘early adopters’ of personal genomics were surveyed to assess their motivations, perceptions and intentions. Methods: Participants were recruited from everyone who registered to attend an enrollment event for the Coriell Personalized Medicine Collaborative, a United States-based (Camden, N.J.) research study of the utility of personalized medicine, between March 31, 2009 and April 1, 2010 (n = 369). Participants completed an Internet-based survey about their motivations, awareness of personalized medicine, perceptions of study risks and benefits, and intentions to share results with health care providers. Results: Respondents were motivated to participate for their own curiosity and to find out their disease risk to improve their health. Fewer than 10% expressed deterministic perspectives about genetic risk, but 32% had misperceptions about the research study or personal genomic testing. Most respondents perceived the study to have health-related benefits. Nearly all (92%) intended to share their results with physicians, primarily to request specific medical recommendations. Conclusion: Early adopters of personal genomics are prospectively enthusiastic about using genomic profiling information to improve their health, in close consultation with their physicians. This suggests that early users (i.e. through direct-to-consumer companies or research) may follow up with the health care system. Further research should address whether intentions to seek care match actual behaviors. PMID:21654153

  7. Mitochondrial and Nuclear Genomic Responses to Loss of LRPPRC Expression*

    PubMed Central

    Gohil, Vishal M.; Nilsson, Roland; Belcher-Timme, Casey A.; Luo, Biao; Root, David E.; Mootha, Vamsi K.

    2010-01-01

    Rapid advances in genotyping and sequencing technology have dramatically accelerated the discovery of genes underlying human disease. Elucidating the function of such genes and understanding their role in pathogenesis, however, remain challenging. Here, we introduce a genomic strategy to characterize such genes functionally, and we apply it to LRPPRC, a poorly studied gene that is mutated in Leigh syndrome, French-Canadian type (LSFC). We utilize RNA interference to engineer an allelic series of cellular models in which LRPPRC has been stably silenced to different levels of knockdown efficiency. We then combine genome-wide expression profiling with gene set enrichment analysis to identify cellular responses that correlate with the loss of LRPPRC. Using this strategy, we discovered a specific role for LRPPRC in the expression of all mitochondrial DNA-encoded mRNAs, but not the rRNAs, providing mechanistic insights into the enzymatic defects observed in the disease. Our analysis shows that nuclear genes encoding mitochondrial proteins are not collectively affected by the loss of LRPPRC. We do observe altered expression of genes related to hexose metabolism, prostaglandin synthesis, and glycosphingolipid biology that may either play an adaptive role in cell survival or contribute to pathogenesis. The combination of genetic perturbation, genomic profiling, and pathway analysis represents a generic strategy for understanding disease pathogenesis. PMID:20220140

  8. Draft Genome Sequence of Cercospora arachidicola, Causal Agent of Early Leaf Spot in Peanuts

    PubMed Central

    Cantonwine, Emily G.; Wang, Xinye Monica; Abouelleil, Amr; Bochicchio, James; Nusbaum, Chad; Culbreath, Albert K.; Abdo, Zaid

    2015-01-01

    Cercospora arachidicola, causal agent of early leaf spot, is an economically important peanut pathogen. Lack of genetic information about this fungus prevents understanding the role that potentially diverse genotypes may have in peanut breeding programs. Here, we report for the first time a draft genome sequence of C. arachidicola. PMID:26543116

  9. [Symbiogenesis as a Model for Reconstructing the Early Stages of Genome Evolution].

    PubMed

    Provorov, N A; Tikhonovich, I A; Vorobyov, N I

    2016-02-01

    Symbiogenic evolution, which involves transformations of bacteria into the cellular organelles, is represented as a model for reconstructing the early stages of genome evolution, including the origin of DNA genomes from RNA genomes and the emergence of template processes on the basis of self-replicating molecular complexes in the ancestral metabolic systems. The antiquity of RNA genomes is supported by an increased evolutionary stability of ribosomal protein synthesis (translation) with respect to the DNA-dependent template processes (replication, transcription, recombination, and reparation). This stability is demonstrated by analysis of the deeply reduced genomes of symbiotic bacteria and cellular organelles as well as the "minimal" genomes which are common to phylogenetically diverse organisms. Higher evolutionary conservation of template biosynthetic processes with respect to step processes determining the metabolism and development in cells does not support the hypothesis about emergence ofgenomes within the ancestral cellular metabolic systems which are thought to be of abiogenic origin, instead suggesting dualistic origin of life on Earth. We suppose that the genome-free organelles of some eukaryotes (mitosomes, many hydrogenosomes, and some plastids) represent the products of reversion of symbiotic bacteria into ancestral forms which implemented their basic cellular functions using the informational macromolecules of exogenic origin. In the framework of this hypothesis the eukaryotic cells functioning based on the massive transfer of gene products (RNAs, proteins) from cytosol to organelles may represent the analogs of ancestral biocenoses that possessed integral hereditary systems (metagenomes).

  10. Genetics and genomics of alcohol responses in Drosophila.

    PubMed

    Park, Annie; Ghezzi, Alfredo; Wijesekera, Thilini P; Atkinson, Nigel S

    2017-02-01

    Drosophila melanogaster has become a significant model organism for alcohol research. In flies, a rich variety of behaviors can be leveraged for identifying genes affecting alcohol responses and adaptations. Furthermore, almost all genes can be easily genetically manipulated. Despite the great evolutionary distance between flies and mammals, many of the same genes have been implicated in strikingly similar alcohol-induced behaviors. A major problem in medical research today is that it is difficult to extrapolate from any single model system to humans. Strong evolutionary conservation of a mechanistic response between distantly related organisms, such as flies and mammals, is a powerful predictor that conservation will continue all the way to humans. This review describes the state of the Drosophila alcohol research field. It describes common alcohol behavioral assays, the independent origins of resistance and tolerance, the results of classical genetic screens and candidate gene analysis, and the outcomes of recent genomics studies employing GWAS, transcriptome, miRNA, and genome-wide histone acetylation surveys.

  11. Professionally Responsible Disclosure of Genomic Sequencing Results in Pediatric Practice.

    PubMed

    McCullough, Laurence B; Brothers, Kyle B; Chung, Wendy K; Joffe, Steven; Koenig, Barbara A; Wilfond, Benjamin; Yu, Joon-Ho

    2015-10-01

    Genomic sequencing is being rapidly introduced into pediatric clinical practice. The results of sequencing are distinctive for their complexity and subsequent challenges of interpretation for generalist and specialist pediatricians, parents, and patients. Pediatricians therefore need to prepare for the professionally responsible disclosure of sequencing results to parents and patients and guidance of parents and patients in the interpretation and use of these results, including managing uncertain data. This article provides an ethical framework to guide and evaluate the professionally responsible disclosure of the results of genomic sequencing in pediatric practice. The ethical framework comprises 3 core concepts of pediatric ethics: the best interests of the child standard, parental surrogate decision-making, and pediatric assent. When recommending sequencing, pediatricians should explain the nature of the proposed test, its scope and complexity, the categories of results, and the concept of a secondary or incidental finding. Pediatricians should obtain the informed permission of parents and the assent of mature adolescents about the scope of sequencing to be performed and the return of results.

  12. Genomic Analysis of Stress Response against Arsenic in Caenorhabditis elegans

    PubMed Central

    Sahu, Surasri N.; Lewis, Jada; Patel, Isha; Bozdag, Serdar; Lee, Jeong H.; Sprando, Robert; Cinar, Hediye Nese

    2013-01-01

    Arsenic, a known human carcinogen, is widely distributed around the world and found in particularly high concentrations in certain regions including Southwestern US, Eastern Europe, India, China, Taiwan and Mexico. Chronic arsenic poisoning affects millions of people worldwide and is associated with increased risk of many diseases including arthrosclerosis, diabetes and cancer. In this study, we explored genome level global responses to high and low levels of arsenic exposure in Caenorhabditis elegans using Affymetrix expression microarrays. This experimental design allows us to do microarray analysis of dose-response relationships of global gene expression patterns. High dose (0.03%) exposure caused stronger global gene expression changes in comparison with low dose (0.003%) exposure, suggesting a positive dose-response correlation. Biological processes such as oxidative stress, and iron metabolism, which were previously reported to be involved in arsenic toxicity studies using cultured cells, experimental animals, and humans, were found to be affected in C. elegans. We performed genome-wide gene expression comparisons between our microarray data and publicly available C. elegans microarray datasets of cadmium, and sediment exposure samples of German rivers Rhine and Elbe. Bioinformatics analysis of arsenic-responsive regulatory networks were done using FastMEDUSA program. FastMEDUSA analysis identified cancer-related genes, particularly genes associated with leukemia, such as dnj-11, which encodes a protein orthologous to the mammalian ZRF1/MIDA1/MPP11/DNAJC2 family of ribosome-associated molecular chaperones. We analyzed the protective functions of several of the identified genes using RNAi. Our study indicates that C. elegans could be a substitute model to study the mechanism of metal toxicity using high-throughput expression data and bioinformatics tools such as FastMEDUSA. PMID:23894281

  13. Genomic landscape of transcriptional and epigenetic dysregulation in early onset polyglutamine disease.

    PubMed

    Valor, Luis M; Guiretti, Deisy; Lopez-Atalaya, Jose P; Barco, Angel

    2013-06-19

    Transcriptional dysregulation is an important early feature of polyglutamine diseases. One of its proposed causes is defective neuronal histone acetylation, but important aspects of this hypothesis, such as the precise genomic topography of acetylation deficits and the relationship between transcriptional and acetylation alterations at the whole-genome level, remain unknown. The new techniques for the mapping of histone post-translational modifications at genomic scale enable such global analyses and are challenging some assumptions about the role of specific histone modifications in gene expression. We examined here the genome-wide correlation of histone acetylation and gene expression defects in a mouse model of early onset Huntington's disease. Our analyses identified hundreds of loci that were hypoacetylated for H3K9,14 and H4K12 in the chromatin of these mice. Surprisingly, few genes with altered transcript levels in mutant mice showed significant changes in these acetylation marks and vice versa. Our screen, however, identified a subset of genes in which H3K9,14 deacetylation and transcriptional dysregulation concur. Genes in this group were consistently affected in different brain areas, mouse models, and tissue from patients, which suggests a role in the etiology of this pathology. Overall, the combination of histone acetylation and gene expression screenings demonstrates that histone deacetylation and transcriptional dysregulation are two early, largely independent, manifestations of polyglutamine disease and suggests that additional epigenetic marks or mechanisms are required for explaining the full range of transcriptional alterations associated with this disorder.

  14. Complete sequence of a sea lamprey (Petromyzon marinus) mitochondrial genome: Early establishment of the vertebrate genome organization

    SciTech Connect

    Lee, W.J.; Kocher, T.D.

    1995-02-01

    The complete nucleotide sequence of a sea lamprey (Petromyzon marinus) mitochondrial genome has been determined. The lamprey genome is 16,201 bp in length and contains genes for 13 proteins, two rRNAs, 22 tRNAs and two major noncoding regions. The order and transcriptional polarities of protein-coding genes are basically identical to those of other chordate mtDNAs, demonstrating that the common mitochondrial gene organization of vertebrates was established at early stage of vertebrate evolution. The two major noncoding regions are separated by two tRNA genes. The first region probably functions as the control region because it contains distinctive conserved sequence blocks (CSB-II and III) common to other vertebrate control regions. The central conserved domain observed in other vertebrate control regions is not found in the lamprey, suggesting that it is a recently evolved functional domain in vertebrates. Noncoding segments are not found in the expected position of the origin of replication for the second strand, suggesting either that one of the tRNA genes has a dual function or that the second noncoding region may function as the second-strand origin. The base composition at the wobble positions of fourfold degenerate codon families is highly biased toward thymine (32.7%). Values of GC- and AT-skew are typical of vertebrate mitochondrial genomes. 38 refs., 11 figs., 5 tabs.

  15. Genomic response of the nematode Caenorhabditis elegans to spaceflight

    NASA Astrophysics Data System (ADS)

    Selch, Florian; Higashibata, Akira; Imamizo-Sato, Mari; Higashitani, Atsushi; Ishioka, Noriaki; Szewczyk, Nathaniel J.; Conley, Catharine A.

    On Earth, it is common to employ laboratory animals such as the nematode Caenorhabditis elegans to help understand human health concerns. Similar studies in Earth orbit should help understand and address the concerns associated with spaceflight. The “International Caenorhabditis elegans Experiment FIRST” (ICE FIRST), was carried out onboard the Dutch Taxiflight in April of 2004 by an international collaboration of laboratories in France, Canada, Japan and the United States. With the exception of a slight movement defect upon return to Earth, the result of altered muscle development, no significant abnormalities were detected in spaceflown C. elegans. Work from Japan revealed apoptosis proceeds normally and work from Canada revealed no significant increase in the rate of mutation. These results suggest that C. elegans can be used to study non-lethal responses to spaceflight and can possibly be developed as a biological sensor. To further our understanding of C. elegans response to spaceflight, we examined the gene transcription response to the 10 days in space using a near full genome microarray analysis. The transcriptional response is consistent with the observed normal developmental timing, apoptosis, DNA repair, and altered muscle development. The genes identified as altered in response to spaceflight are enriched for genes known to be regulated, in C. elegans, in response to altered environmental conditions (Insulin and TGF-β regulated). These results demonstrate C. elegans can be used to study the effects of altered gravity and suggest that C. elegans responds to spaceflight by altering the expression of at least some of the same metabolic genes that are altered in response to differing terrestrial environments.

  16. 350 my of mitochondrial genome stasis in mosses, an early land plant lineage.

    PubMed

    Liu, Yang; Medina, Rafael; Goffinet, Bernard

    2014-10-01

    Among land plants, angiosperms have the structurally most labile mitochondrial (mt) genomes. In contrast, the so-called early land plants (e.g., mosses) seem to have completely static mt chromosomes. We assembled the complete mt genomes from 12 mosses spanning the moss tree of life, to assess 1) the phylogenetic depth of the conserved mt gene content and order and 2) the correlation between scattered sequence repeats and gene order lability in land plants. The mt genome of most mosses is approximately 100 kb in size, and thereby the smallest among land plants. Based on divergence time estimates, moss mt genome structure has remained virtually frozen for 350 My, with only two independent gene losses and a single gene relocation detected across the macroevolutionary tree. This is the longest period of mt genome stasis demonstrated to date in a plant lineage. The complete lack of intergenic repeat sequences, considered to be essential for intragenomic recombinations, likely accounts for the evolutionary stability of moss mt genomes.

  17. Exploring early public responses to geoengineering.

    PubMed

    Pidgeon, Nick; Corner, Adam; Parkhill, Karen; Spence, Alexa; Butler, Catherine; Poortinga, Wouter

    2012-09-13

    Proposals for geoengineering the Earth's climate are prime examples of emerging or 'upstream' technologies, because many aspects of their effectiveness, cost and risks are yet to be researched, and in many cases are highly uncertain. This paper contributes to the emerging debate about the social acceptability of geoengineering technologies by presenting preliminary evidence on public responses to geoengineering from two of the very first UK studies of public perceptions and responses. The discussion draws upon two datasets: qualitative data (from an interview study conducted in 42 households in 2009), and quantitative data (from a subsequent nationwide survey (n=1822) of British public opinion). Unsurprisingly, baseline awareness of geoengineering was extremely low in both cases. The data from the survey indicate that, when briefly explained to people, carbon dioxide removal approaches were preferred to solar radiation management, while significant positive correlations were also found between concern about climate change and support for different geoengineering approaches. We discuss some of the wider considerations that are likely to shape public perceptions of geoengineering as it enters the media and public sphere, and conclude that, aside from technical considerations, public perceptions are likely to prove a key element influencing the debate over questions of the acceptability of geoengineering proposals.

  18. Characterizing Participants in the ClinSeq Genome Sequencing Cohort as Early Adopters of a New Health Technology

    PubMed Central

    Lewis, Katie L.; Han, Paul K. J.; Hooker, Gillian W.; Klein, William M. P.; Biesecker, Leslie G.; Biesecker, Barbara B.

    2015-01-01

    Genome sequencing is a novel clinical tool that has the potential to identify genetic origins of disease. However, the complexities of this new technology are significant and little is known about its integration into clinical care, and its potential adoption by patients. Expectations of its promise for personalized medicine are high and it is important to properly match expectations to the realities of the test. The NIH ClinSeq cohort study pilots the integration of genome sequencing into clinical research and care to assess the technical, medical and socio-behavioral aspects of implementing this technology. Over 950 adults ages 45-65 have been enrolled and clinically phenotyped. As an initial study, we describe the personality traits of ClinSeq participants, and explore how these traits compare to those that characterize early adopters of other new technologies. Our analysis was conducted on responses from 630 members of the cohort who completed a baseline survey on health cognitions, affect, health-related behaviors and personality traits, prior to receipt of any genome sequencing results. The majority of participants were white (90.5%), had at least a college degree (86.5%), and had at least one biological child (74.6%). Members of this ClinSeq sample were found to be high in dispositional optimism and resilience. Their high SES paralleled that of other early adopters of new technology. These attributes may contribute to participants’ expectations for favorable outcomes and willingness to take higher risks when compared to the general population. These characteristics may distinguish those who are most likely to pursue genome sequencing and be indicative of their psychological resources to manage returned results. PMID:26186621

  19. Genome-Wide Detection of SNP and SV Variations to Reveal Early Ripening-Related Genes in Grape

    PubMed Central

    Tao, Jianmin; Jiang, Weihua; Zhang, Shijie; Wang, Qiunan; Qu, Shenchun

    2016-01-01

    Early ripening in grape (Vitis vinifera L.) is a crucial agronomic trait. The fruits of the grape line ‘Summer Black’ (SBBM), which contains a bud mutation, can be harvested approximately one week earlier than the ‘Summer Black’ (SBC)control. To investigate the molecular mechanism of the bud mutation related to early ripening, we detected genome-wide genetic variations based on re-sequencing. In total, 3,692,777 single nucleotide polymorphisms (SNPs) and 81,223 structure variations (SVs) in the SBC genome and 3,823,464 SNPs and 85,801 SVs in the SBBM genome were detected compared with the reference grape sequence. Of these, 635 SBC-specific genes and 665 SBBM-specific genes were screened. Ripening and colour-associated unigenes with non-synonymous mutations (NS), SVs or frame-shift mutations (F) were analysed. The results showed that 90 unigenes in SBC, 76 unigenes in SBBM and 13 genes that mapped to large fragment indels were filtered. The expression patterns of eight genes were confirmed using quantitative reverse transcription-polymerase chain reaction (qRT-PCR).The re-sequencing data showed that 635 SBC-specific genes and 665 SBBM-specific genes associated with early ripening were screened. Among these, NCED6 expression appears to be related to NCED1 and is involved in ABA biosynthesis in grape, which might play a role in the onset of anthocyanin accumulation. The SEP and ERF genes probably play roles in ethylene response. PMID:26840449

  20. Genomic Prediction of Single Crosses in the Early Stages of a Maize Hybrid Breeding Pipeline

    PubMed Central

    Kadam, Dnyaneshwar C.; Potts, Sarah M.; Bohn, Martin O.; Lipka, Alexander E.; Lorenz, Aaron J.

    2016-01-01

    Prediction of single-cross performance has been a major goal of plant breeders since the beginning of hybrid breeding. Recently, genomic prediction has shown to be a promising approach, but only limited studies have examined the accuracy of predicting single-cross performance. Moreover, no studies have examined the potential of predicting single crosses among random inbreds derived from a series of biparental families, which resembles the structure of germplasm comprising the initial stages of a hybrid maize breeding pipeline. The main objectives of this study were to evaluate the potential of genomic prediction for identifying superior single crosses early in the hybrid breeding pipeline and optimize its application. To accomplish these objectives, we designed and analyzed a novel population of single crosses representing the Iowa Stiff Stalk synthetic/non-Stiff Stalk heterotic pattern commonly used in the development of North American commercial maize hybrids. The performance of single crosses was predicted using parental combining ability and covariance among single crosses. Prediction accuracies were estimated using cross-validation and ranged from 0.28 to 0.77 for grain yield, 0.53 to 0.91 for plant height, and 0.49 to 0.94 for staygreen, depending on the number of tested parents of the single cross and genomic prediction method used. The genomic estimated general and specific combining abilities showed an advantage over genomic covariances among single crosses when one or both parents of the single cross were untested. Overall, our results suggest that genomic prediction of single crosses in the early stages of a hybrid breeding pipeline holds great potential to redesign hybrid breeding and increase its efficiency. PMID:27646704

  1. B cells enhance early innate immune responses during bacterial sepsis

    PubMed Central

    Kelly-Scumpia, Kindra M.; Scumpia, Philip O.; Weinstein, Jason S.; Delano, Matthew J.; Cuenca, Alex G.; Nacionales, Dina C.; Wynn, James L.; Lee, Pui Y.; Kumagai, Yutaro; Efron, Philip A.; Akira, Shizuo; Wasserfall, Clive; Atkinson, Mark A.

    2011-01-01

    Microbes activate pattern recognition receptors to initiate adaptive immunity. T cells affect early innate inflammatory responses to viral infection, but both activation and suppression have been demonstrated. We identify a novel role for B cells in the early innate immune response during bacterial sepsis. We demonstrate that Rag1−/− mice display deficient early inflammatory responses and reduced survival during sepsis. Interestingly, B cell–deficient or anti-CD20 B cell–depleted mice, but not α/β T cell–deficient mice, display decreased inflammatory cytokine and chemokine production and reduced survival after sepsis. Both treatment of B cell–deficient mice with serum from wild-type (WT) mice and repletion of Rag1−/− mice with B cells improves sepsis survival, suggesting antibody-independent and antibody-dependent roles for B cells in the outcome to sepsis. During sepsis, marginal zone and follicular B cells are activated through type I interferon (IFN-I) receptor (IFN-α/β receptor [IFNAR]), and repleting Rag1−/− mice with WT, but not IFNAR−/−, B cells improves IFN-I–dependent and –independent early cytokine responses. Repleting B cell–deficient mice with the IFN-I–dependent chemokine, CXCL10 was also sufficient to improve sepsis survival. This study identifies a novel role for IFN-I–activated B cells in protective early innate immune responses during bacterial sepsis. PMID:21746813

  2. The structure and early evolution of recently arisen gene duplicates in the Caenorhabditis elegans genome.

    PubMed Central

    Katju, Vaishali; Lynch, Michael

    2003-01-01

    The significance of gene duplication in provisioning raw materials for the evolution of genomic diversity is widely recognized, but the early evolutionary dynamics of duplicate genes remain obscure. To elucidate the structural characteristics of newly arisen gene duplicates at infancy and their subsequent evolutionary properties, we analyzed gene pairs with < or =10% divergence at synonymous sites within the genome of Caenorhabditis elegans. Structural heterogeneity between duplicate copies is present very early in their evolutionary history and is maintained over longer evolutionary timescales, suggesting that duplications across gene boundaries in conjunction with shuffling events have at least as much potential to contribute to long-term evolution as do fully redundant (complete) duplicates. The median duplication span of 1.4 kb falls short of the average gene length in C. elegans (2.5 kb), suggesting that partial gene duplications are frequent. Most gene duplicates reside close to the parent copy at inception, often as tandem inverted loci, and appear to disperse in the genome as they age, as a result of reduced survivorship of duplicates located in proximity to the ancestral copy. We propose that illegitimate recombination events leading to inverted duplications play a disproportionately large role in gene duplication within this genome in comparison with other mechanisms. PMID:14704166

  3. The structure and early evolution of recently arisen gene duplicates in the Caenorhabditis elegans genome.

    PubMed

    Katju, Vaishali; Lynch, Michael

    2003-12-01

    The significance of gene duplication in provisioning raw materials for the evolution of genomic diversity is widely recognized, but the early evolutionary dynamics of duplicate genes remain obscure. To elucidate the structural characteristics of newly arisen gene duplicates at infancy and their subsequent evolutionary properties, we analyzed gene pairs with < or =10% divergence at synonymous sites within the genome of Caenorhabditis elegans. Structural heterogeneity between duplicate copies is present very early in their evolutionary history and is maintained over longer evolutionary timescales, suggesting that duplications across gene boundaries in conjunction with shuffling events have at least as much potential to contribute to long-term evolution as do fully redundant (complete) duplicates. The median duplication span of 1.4 kb falls short of the average gene length in C. elegans (2.5 kb), suggesting that partial gene duplications are frequent. Most gene duplicates reside close to the parent copy at inception, often as tandem inverted loci, and appear to disperse in the genome as they age, as a result of reduced survivorship of duplicates located in proximity to the ancestral copy. We propose that illegitimate recombination events leading to inverted duplications play a disproportionately large role in gene duplication within this genome in comparison with other mechanisms.

  4. Genome-Wide Meta-Analysis of Longitudinal Alcohol Consumption Across Youth and Early Adulthood.

    PubMed

    Adkins, Daniel E; Clark, Shaunna L; Copeland, William E; Kennedy, Martin; Conway, Kevin; Angold, Adrian; Maes, Hermine; Liu, Youfang; Kumar, Gaurav; Erkanli, Alaattin; Patkar, Ashwin A; Silberg, Judy; Brown, Tyson H; Fergusson, David M; Horwood, L John; Eaves, Lindon; van den Oord, Edwin J C G; Sullivan, Patrick F; Costello, E J

    2015-08-01

    The public health burden of alcohol is unevenly distributed across the life course, with levels of use, abuse, and dependence increasing across adolescence and peaking in early adulthood. Here, we leverage this temporal patterning to search for common genetic variants predicting developmental trajectories of alcohol consumption. Comparable psychiatric evaluations measuring alcohol consumption were collected in three longitudinal community samples (N=2,126, obs=12,166). Consumption-repeated measurements spanning adolescence and early adulthood were analyzed using linear mixed models, estimating individual consumption trajectories, which were then tested for association with Illumina 660W-Quad genotype data (866,099 SNPs after imputation and QC). Association results were combined across samples using standard meta-analysis methods. Four meta-analysis associations satisfied our pre-determined genome-wide significance criterion (FDR<0.1) and six others met our 'suggestive' criterion (FDR<0.2). Genome-wide significant associations were highly biological plausible, including associations within GABA transporter 1, SLC6A1 (solute carrier family 6, member 1), and exonic hits in LOC100129340 (mitofusin-1-like). Pathway analyses elaborated single marker results, indicating significant enriched associations to intuitive biological mechanisms, including neurotransmission, xenobiotic pharmacodynamics, and nuclear hormone receptors (NHR). These findings underscore the value of combining longitudinal behavioral data and genome-wide genotype information in order to study developmental patterns and improve statistical power in genomic studies.

  5. Genome of Acanthamoeba castellanii highlights extensive lateral gene transfer and early evolution of tyrosine kinase signaling

    PubMed Central

    2013-01-01

    Background The Amoebozoa constitute one of the primary divisions of eukaryotes, encompassing taxa of both biomedical and evolutionary importance, yet its genomic diversity remains largely unsampled. Here we present an analysis of a whole genome assembly of Acanthamoeba castellanii (Ac) the first representative from a solitary free-living amoebozoan. Results Ac encodes 15,455 compact intron-rich genes, a significant number of which are predicted to have arisen through inter-kingdom lateral gene transfer (LGT). A majority of the LGT candidates have undergone a substantial degree of intronization and Ac appears to have incorporated them into established transcriptional programs. Ac manifests a complex signaling and cell communication repertoire, including a complete tyrosine kinase signaling toolkit and a comparable diversity of predicted extracellular receptors to that found in the facultatively multicellular dictyostelids. An important environmental host of a diverse range of bacteria and viruses, Ac utilizes a diverse repertoire of predicted pattern recognition receptors, many with predicted orthologous functions in the innate immune systems of higher organisms. Conclusions Our analysis highlights the important role of LGT in the biology of Ac and in the diversification of microbial eukaryotes. The early evolution of a key signaling facility implicated in the evolution of metazoan multicellularity strongly argues for its emergence early in the Unikont lineage. Overall, the availability of an Ac genome should aid in deciphering the biology of the Amoebozoa and facilitate functional genomic studies in this important model organism and environmental host. PMID:23375108

  6. Genome-wide transcription responses to synchrotron microbeam radiotherapy.

    PubMed

    Sprung, Carl N; Yang, Yuqing; Forrester, Helen B; Li, Jason; Zaitseva, Marina; Cann, Leonie; Restall, Tina; Anderson, Robin L; Crosbie, Jeffrey C; Rogers, Peter A W

    2012-10-01

    The majority of cancer patients achieve benefit from radiotherapy. A significant limitation of radiotherapy is its relatively low therapeutic index, defined as the maximum radiation dose that causes acceptable normal tissue damage to the minimum dose required to achieve tumor control. Recently, a new radiotherapy modality using synchrotron-generated X-ray microbeam radiotherapy has been demonstrated in animal models to ablate tumors with concurrent sparing of normal tissue. Very little work has been undertaken into the cellular and molecular mechanisms that differentiate microbeam radiotherapy from broad beam. The purpose of this study was to investigate and compare the whole genome transcriptional response of in vivo microbeam radiotherapy versus broad beam irradiated tumors. We hypothesized that gene expression changes after microbeam radiotherapy are different from those seen after broad beam. We found that in EMT6.5 tumors at 4-48 h postirradiation, microbeam radiotherapy differentially regulates a number of genes, including major histocompatibility complex (MHC) class II antigen gene family members, and other immunity-related genes including Ciita, Ifng, Cxcl1, Cxcl9, Indo and Ubd when compared to broad beam. Our findings demonstrate molecular differences in the tumor response to microbeam versus broad beam irradiation and these differences provide insight into the underlying mechanisms of microbeam radiotherapy and broad beam.

  7. Early intranuclear replication of African swine fever virus genome modifies the landscape of the host cell nucleus.

    PubMed

    Simões, Margarida; Martins, Carlos; Ferreira, Fernando

    2015-12-02

    Although African swine fever virus (ASFV) replicates in viral cytoplasmic factories, the presence of viral DNA within the host cell nucleus has been previously reported to be essential for productive infection. Herein, we described, for the first time, the intranuclear distribution patterns of viral DNA replication events, preceding those that occur in the cytoplasmic compartment. Using BrdU pulse-labelling experiments, newly synthesized ASFV genomes were exclusively detected inside the host cell nucleus at the early phase of infection, both in swine monocyte-derived macrophages (MDMs) and Vero cells. From 8hpi onwards, BrdU labelling was only observed in ASFV cytoplasmic factories. Our results also show that ASFV specifically activates the Ataxia Telangiectasia Mutated Rad-3 related (ATR) pathway in ASFV-infected swine MDMs from the early phase of infection, most probably because ASFV genome is recognized as foreign DNA. Morphological changes of promyelocytic leukaemia nuclear bodies (PML-NBs), nuclear speckles and Cajal bodies were also found in ASFV-infected swine MDMs, strongly suggesting the viral modulation of cellular antiviral responses and cellular transcription, respectively. As described for other viral infections, the nuclear reorganization that takes place during ASFV infection may also provide an environment that favours its intranuclear replication events. Altogether, our results contribute for a better understanding of ASFV replication strategies, starting with an essential intranuclear DNA replication phase which induces host nucleus changes towards a successful viral infection.

  8. Outsmarting cancer: the power of hybrid genomic/proteomic biomarkers to predict drug response.

    PubMed

    Rexer, Brent N; Arteaga, Carlos L

    2014-01-01

    A recent study by Niepel and colleagues describes a novel approach to predicting response to targeted anti-cancer therapies. The authors used biochemical profiling of signaling activity in basal and ligand-stimulated states for a panel of receptor and intracellular kinases to develop predictive models of drug sensitivity. In some cases, the response to ligand stimulation predicted drug response better than did target abundance or genomic alterations in the targeted pathway. Furthermore, combining biochemical profiles with genomic information was better at predicting drug response. This work suggests that incorporating biochemical signaling profiles with genomic alterations should provide powerful predictors of response to molecularly targeted therapies.

  9. Genome Wide assessment of Early Osseointegration in Implant-Adherent Cells

    NASA Astrophysics Data System (ADS)

    Thalji, Ghadeer N.

    Objectives: To determine the molecular processes involved in osseointegration. Materials and methods: A structured literature review concerning in vitro and in vivo molecular assessment of osseointegration was performed. A rat and a human model were then used to identify the early molecular processes involved in osseointegration associated with a micro roughened and nanosurface superimposed featured implants. In the rat model, 32 titanium implants with surface topographies exhibiting a micro roughened (AT-II) and nanosurface superimposed featured implants (AT-I) were placed in the tibiae of 8 rats and subsequently harvested at 2 and 4 days after placement. Whereas in the human model, four titanium mini-implants with either a moderately roughened surface (TiOblast) or super-imposed nanoscale topography (Osseospeed) were placed in edentulous sites of eleven systemically healthy subjects and subsequently removed after 3 and 7 days. Total RNA was isolated from cells adherent to retrieved implants. A whole genome microarray using the Affymetrix 1.1 ST Array platform was used to describe the gene expression profiles that were differentially regulated by the implant surfaces. Results: The literature review provided evidence that particular topographic cues can be specifically integrated among the many extracellular signals received by the cell in its signal transduction network. In the rat model, functionally relevant categories related to ossification, skeletal system development, osteoblast differentiation, bone development and biomineral tissue development were upregulated and more prominent at AT-I compared to AT-II. In the human model, there were no significant differences when comparing the two-implant surfaces at each time point. However, the microarray identified several genes that were differentially regulated at day 7 vs. day 3 for both implant surfaces. Functionally relevant categories related to the extracellular matrix, collagen fibril organization and

  10. Functional genomics of HMGN3a and SMARCAL1 in early mammalian embryogenesis

    PubMed Central

    Uzun, Alper; Rodriguez-Osorio, Nelida; Kaya, Abdullah; Wang, Hongfeng; Parrish, John J; Ilyin, Valentin A; Memili, Erdogan

    2009-01-01

    Background Embryonic genome activation (EGA) is a critical event for the preimplantation embryo, which is manifested by changes in chromatin structure, transcriptional machinery, expression of embryonic genes, and degradation of maternal transcripts. The objectives of this study were to determine transcript abundance of HMGN3a and SMARCAL1 in mature bovine oocytes and early bovine embryos, to perform comparative functional genomics analysis of these genes across mammals. Results New annotations of both HMGN3a and SMARCAL1 were submitted to the Bovine Genome Annotation Submission Database at BovineGenome.org. Careful analysis of the bovine SMARCAL1 consensus gene set for this protein (GLEAN_20241) showed that the NCBI protein contains sequencing errors, and that the actual bovine protein has a high degree of homology to the human protein. Our results showed that there was a high degree of structural conservation of HMGN3a and SMARCAL1 in the mammalian species studied. HMGN3a transcripts were present at similar levels in bovine matured oocytes and 2–4-cell embryos but at higher levels in 8–16-cell embryos, morulae and blastocysts. On the other hand, transcript levels of SMARCAL1 decreased throughout preimplantation development. Conclusion The high levels of structural conservation of these proteins highlight the importance of chromatin remodeling in the regulation of gene expression, particularly during early mammalian embryonic development. The greater similarities of human and bovine HMGN3a and SMARCAL1 proteins may suggest the cow as a valuable model to study chromatin remodeling at the onset of mammalian development. Understanding the roles of chromatin remodeling proteins during embryonic development emphasizes the importance of epigenetics and could shed light on the underlying mechanisms of early mammalian development. PMID:19393058

  11. A Framework for Providing Culturally Responsive Early Intervention Services

    ERIC Educational Resources Information Center

    Bradshaw, Wendy

    2013-01-01

    The purpose of this article is to provide a framework that offers a way for early intervention (EI) service providers to better meet the needs of the culturally diverse children and families they serve. This framework was created to organize existing research and literature on cultural responsiveness in a way that fit the unique context of EI. The…

  12. Early Twentieth Century Responses to the Drug Problem.

    ERIC Educational Resources Information Center

    Pfennig, Dennis Joseph

    1991-01-01

    Describes early twentieth-century responses to the drug problem in the United States. Discusses pressure from the media and reformers to control the availability of drugs such as opium and cocaine that were widely available in over-the-counter medications. Focuses on New York State, which took the lead in enacting drug control legislation. (DK)

  13. A Comparison of Responsive Interventions on Kindergarteners' Early Reading Achievement

    ERIC Educational Resources Information Center

    Little, Mary E.; Rawlinson, D'Ann; Simmons, Deborah C.; Kim, Minjung; Kwok, Oi-man; Hagan-Burke, Shanna; Simmons, Leslie E.; Fogarty, Melissa; Oslund, Eric; Coyne, Michael D.

    2012-01-01

    This study compared the effects of Tier 2 reading interventions that operated in response-to-intervention contexts. Kindergarten children (N = 90) who were identified as at risk for reading difficulties were stratified by school and randomly assigned to receive (a) Early Reading Intervention (ERI; Pearson/Scott Foresman, 2004) modified in response…

  14. Determinants of early life immune responses to RSV infection.

    PubMed

    Ruckwardt, Tracy J; Morabito, Kaitlyn M; Graham, Barney S

    2016-02-01

    Respiratory syncytial virus causes significant morbidity and mortality in both developed and developing countries, and a vaccine that adequately protects from severe disease remains an important unmet need. RSV disease has an inordinate impact on the very young, and the physical and immunological immaturity of early life complicates vaccine design. Defining and targeting the functional capacities of early life immune responses and controlling responses during primary antigen exposure with selected vaccine delivery approaches will be important for protecting infants by active immunization. Alternatively, vaccination of older children and pregnant mothers may ameliorate disease burden indirectly until infants reach about six months of age, when they can generate more effective anti-RSV immune responses.

  15. Genome-wide data from two early Neolithic East Asian individuals dating to 7700 years ago.

    PubMed

    Siska, Veronika; Jones, Eppie Ruth; Jeon, Sungwon; Bhak, Youngjune; Kim, Hak-Min; Cho, Yun Sung; Kim, Hyunho; Lee, Kyusang; Veselovskaya, Elizaveta; Balueva, Tatiana; Gallego-Llorente, Marcos; Hofreiter, Michael; Bradley, Daniel G; Eriksson, Anders; Pinhasi, Ron; Bhak, Jong; Manica, Andrea

    2017-02-01

    Ancient genomes have revolutionized our understanding of Holocene prehistory and, particularly, the Neolithic transition in western Eurasia. In contrast, East Asia has so far received little attention, despite representing a core region at which the Neolithic transition took place independently ~3 millennia after its onset in the Near East. We report genome-wide data from two hunter-gatherers from Devil's Gate, an early Neolithic cave site (dated to ~7.7 thousand years ago) located in East Asia, on the border between Russia and Korea. Both of these individuals are genetically most similar to geographically close modern populations from the Amur Basin, all speaking Tungusic languages, and, in particular, to the Ulchi. The similarity to nearby modern populations and the low levels of additional genetic material in the Ulchi imply a high level of genetic continuity in this region during the Holocene, a pattern that markedly contrasts with that reported for Europe.

  16. Genome-wide data from two early Neolithic East Asian individuals dating to 7700 years ago

    PubMed Central

    Siska, Veronika; Jones, Eppie Ruth; Jeon, Sungwon; Bhak, Youngjune; Kim, Hak-Min; Cho, Yun Sung; Kim, Hyunho; Lee, Kyusang; Veselovskaya, Elizaveta; Balueva, Tatiana; Gallego-Llorente, Marcos; Hofreiter, Michael; Bradley, Daniel G.; Eriksson, Anders; Pinhasi, Ron; Bhak, Jong; Manica, Andrea

    2017-01-01

    Ancient genomes have revolutionized our understanding of Holocene prehistory and, particularly, the Neolithic transition in western Eurasia. In contrast, East Asia has so far received little attention, despite representing a core region at which the Neolithic transition took place independently ~3 millennia after its onset in the Near East. We report genome-wide data from two hunter-gatherers from Devil’s Gate, an early Neolithic cave site (dated to ~7.7 thousand years ago) located in East Asia, on the border between Russia and Korea. Both of these individuals are genetically most similar to geographically close modern populations from the Amur Basin, all speaking Tungusic languages, and, in particular, to the Ulchi. The similarity to nearby modern populations and the low levels of additional genetic material in the Ulchi imply a high level of genetic continuity in this region during the Holocene, a pattern that markedly contrasts with that reported for Europe. PMID:28164156

  17. Genomic evidence for rod monochromacy in sloths and armadillos suggests early subterranean history for Xenarthra

    PubMed Central

    Emerling, Christopher A.; Springer, Mark S.

    2015-01-01

    Rod monochromacy is a rare condition in vertebrates characterized by the absence of cone photoreceptor cells. The resulting phenotype is colourblindness and low acuity vision in dim-light and blindness in bright-light conditions. Early reports of xenarthrans (armadillos, sloths and anteaters) suggest that they are rod monochromats, but this has not been tested with genomic data. We searched the genomes of Dasypus novemcinctus (nine-banded armadillo), Choloepus hoffmanni (Hoffmann's two-toed sloth) and Mylodon darwinii (extinct ground sloth) for retinal photoreceptor genes and examined them for inactivating mutations. We performed PCR and Sanger sequencing on cone phototransduction genes of 10 additional xenarthrans to test for shared inactivating mutations and estimated the timing of inactivation for photoreceptor pseudogenes. We concluded that a stem xenarthran became an long-wavelength sensitive-cone monochromat following a missense mutation at a critical residue in SWS1, and a stem cingulate (armadillos, glyptodonts and pampatheres) and stem pilosan (sloths and anteaters) independently acquired rod monochromacy early in their evolutionary history following the inactivation of LWS and PDE6C, respectively. We hypothesize that rod monochromacy in armadillos and pilosans evolved as an adaptation to a subterranean habitat in the early history of Xenarthra. The presence of rod monochromacy has major implications for understanding xenarthran behavioural ecology and evolution. PMID:25540280

  18. Genomic evidence for rod monochromacy in sloths and armadillos suggests early subterranean history for Xenarthra.

    PubMed

    Emerling, Christopher A; Springer, Mark S

    2015-02-07

    Rod monochromacy is a rare condition in vertebrates characterized by the absence of cone photoreceptor cells. The resulting phenotype is colourblindness and low acuity vision in dim-light and blindness in bright-light conditions. Early reports of xenarthrans (armadillos, sloths and anteaters) suggest that they are rod monochromats, but this has not been tested with genomic data. We searched the genomes of Dasypus novemcinctus (nine-banded armadillo), Choloepus hoffmanni (Hoffmann's two-toed sloth) and Mylodon darwinii (extinct ground sloth) for retinal photoreceptor genes and examined them for inactivating mutations. We performed PCR and Sanger sequencing on cone phototransduction genes of 10 additional xenarthrans to test for shared inactivating mutations and estimated the timing of inactivation for photoreceptor pseudogenes. We concluded that a stem xenarthran became an long-wavelength sensitive-cone monochromat following a missense mutation at a critical residue in SWS1, and a stem cingulate (armadillos, glyptodonts and pampatheres) and stem pilosan (sloths and anteaters) independently acquired rod monochromacy early in their evolutionary history following the inactivation of LWS and PDE6C, respectively. We hypothesize that rod monochromacy in armadillos and pilosans evolved as an adaptation to a subterranean habitat in the early history of Xenarthra. The presence of rod monochromacy has major implications for understanding xenarthran behavioural ecology and evolution.

  19. Replicated evolution of integrated plastic responses during early adaptive divergence.

    PubMed

    Parsons, Kevin J; Robinson, Beren W

    2006-04-01

    Colonization of a novel environment is expected to result in adaptive divergence from the ancestral population when selection favors a new phenotypic optimum. Local adaptation in the new environment occurs through the accumulation and integration of character states that positively affect fitness. The role played by plastic traits in adaptation to a novel environment has generally been ignored, except for variable environments. We propose that if conditions in a relatively stable but novel environment induce phenotypically plastic responses in many traits, and if genetic variation exists in the form of those responses, then selection may initially favor the accumulation and integration of functionally useful plastic responses. Early divergence between ancestral and colonist forms will then occur with respect to their plastic responses across the gradient bounded by ancestral and novel environmental conditions. To test this, we compared the magnitude, integration, and pattern of plastic character responses in external body form induced by shallow versus open water conditions between two sunfish ecomorphs that coexist in four postglacial lakes. The novel sunfish ecomorph is present in the deeper open water habitat, whereas the ancestral ecomorph inhabits the shallow waters along the lake margin. Plastic responses by open water ecomorphs were more correlated than those of their local shallow water ecomorph in two of the populations, whereas equal levels of correlated plastic character responses occurred between ecomorphs in the other two populations. Small but persistent differences occurred between ecomorph pairs in the pattern of their character responses, suggesting a recent divergence. Open water ecomorphs shared some similarities in the covariance among plastic responses to rearing environment. Replication in the form of correlated plastic responses among populations of open water ecomorphs suggests that plastic character states may evolve under selection

  20. Recalibrating Equus evolution using the genome sequence of an early Middle Pleistocene horse.

    PubMed

    Orlando, Ludovic; Ginolhac, Aurélien; Zhang, Guojie; Froese, Duane; Albrechtsen, Anders; Stiller, Mathias; Schubert, Mikkel; Cappellini, Enrico; Petersen, Bent; Moltke, Ida; Johnson, Philip L F; Fumagalli, Matteo; Vilstrup, Julia T; Raghavan, Maanasa; Korneliussen, Thorfinn; Malaspinas, Anna-Sapfo; Vogt, Josef; Szklarczyk, Damian; Kelstrup, Christian D; Vinther, Jakob; Dolocan, Andrei; Stenderup, Jesper; Velazquez, Amhed M V; Cahill, James; Rasmussen, Morten; Wang, Xiaoli; Min, Jiumeng; Zazula, Grant D; Seguin-Orlando, Andaine; Mortensen, Cecilie; Magnussen, Kim; Thompson, John F; Weinstock, Jacobo; Gregersen, Kristian; Røed, Knut H; Eisenmann, Véra; Rubin, Carl J; Miller, Donald C; Antczak, Douglas F; Bertelsen, Mads F; Brunak, Søren; Al-Rasheid, Khaled A S; Ryder, Oliver; Andersson, Leif; Mundy, John; Krogh, Anders; Gilbert, M Thomas P; Kjær, Kurt; Sicheritz-Ponten, Thomas; Jensen, Lars Juhl; Olsen, Jesper V; Hofreiter, Michael; Nielsen, Rasmus; Shapiro, Beth; Wang, Jun; Willerslev, Eske

    2013-07-04

    The rich fossil record of equids has made them a model for evolutionary processes. Here we present a 1.12-times coverage draft genome from a horse bone recovered from permafrost dated to approximately 560-780 thousand years before present (kyr BP). Our data represent the oldest full genome sequence determined so far by almost an order of magnitude. For comparison, we sequenced the genome of a Late Pleistocene horse (43 kyr BP), and modern genomes of five domestic horse breeds (Equus ferus caballus), a Przewalski's horse (E. f. przewalskii) and a donkey (E. asinus). Our analyses suggest that the Equus lineage giving rise to all contemporary horses, zebras and donkeys originated 4.0-4.5 million years before present (Myr BP), twice the conventionally accepted time to the most recent common ancestor of the genus Equus. We also find that horse population size fluctuated multiple times over the past 2 Myr, particularly during periods of severe climatic changes. We estimate that the Przewalski's and domestic horse populations diverged 38-72 kyr BP, and find no evidence of recent admixture between the domestic horse breeds and the Przewalski's horse investigated. This supports the contention that Przewalski's horses represent the last surviving wild horse population. We find similar levels of genetic variation among Przewalski's and domestic populations, indicating that the former are genetically viable and worthy of conservation efforts. We also find evidence for continuous selection on the immune system and olfaction throughout horse evolution. Finally, we identify 29 genomic regions among horse breeds that deviate from neutrality and show low levels of genetic variation compared to the Przewalski's horse. Such regions could correspond to loci selected early during domestication.

  1. Cooperative Genome-Wide Analysis Shows Increased Homozygosity in Early Onset Parkinson's Disease

    PubMed Central

    Nalls, Michael A.; Martinez, Maria; Schulte, Claudia; Holmans, Peter; Gasser, Thomas; Hardy, John; Singleton, Andrew B.; Wood, Nicholas W.; Brice, Alexis; Heutink, Peter; Williams, Nigel; Morris, Huw R.

    2012-01-01

    Parkinson's disease (PD) occurs in both familial and sporadic forms, and both monogenic and complex genetic factors have been identified. Early onset PD (EOPD) is particularly associated with autosomal recessive (AR) mutations, and three genes, PARK2, PARK7 and PINK1, have been found to carry mutations leading to AR disease. Since mutations in these genes account for less than 10% of EOPD patients, we hypothesized that further recessive genetic factors are involved in this disorder, which may appear in extended runs of homozygosity. We carried out genome wide SNP genotyping to look for extended runs of homozygosity (ROHs) in 1,445 EOPD cases and 6,987 controls. Logistic regression analyses showed an increased level of genomic homozygosity in EOPD cases compared to controls. These differences are larger for ROH of 9 Mb and above, where there is a more than three-fold increase in the proportion of cases carrying a ROH. These differences are not explained by occult recessive mutations at existing loci. Controlling for genome wide homozygosity in logistic regression analyses increased the differences between cases and controls, indicating that in EOPD cases ROHs do not simply relate to genome wide measures of inbreeding. Homozygosity at a locus on chromosome19p13.3 was identified as being more common in EOPD cases as compared to controls. Sequencing analysis of genes and predicted transcripts within this locus failed to identify a novel mutation causing EOPD in our cohort. There is an increased rate of genome wide homozygosity in EOPD, as measured by an increase in ROHs. These ROHs are a signature of inbreeding and do not necessarily harbour disease-causing genetic variants. Although there might be other regions of interest apart from chromosome 19p13.3, we lack the power to detect them with this analysis. PMID:22427796

  2. Computational Identification Raises a Riddle for Distribution of Putative NACHT NTPases in the Genome of Early Green Plants

    PubMed Central

    Arya, Preeti; Acharya, Vishal

    2016-01-01

    NACHT NTPases and AP-ATPases belongs to STAND (signal transduction ATPases with numerous domain) P-loop NTPase class, which are known to be involved in defense signaling pathways and apoptosis regulation. The AP-ATPases (also known as NB-ARC) and NACHT NTPases are widely spread throughout all kingdoms of life except in plants, where only AP-ATPases have been extensively studied in the scenario of plant defense response against pathogen invasion and in hypersensitive response (HR). In the present study, we have employed a genome-wide survey (using stringent computational analysis) of 67 diverse organisms viz., archaebacteria, cyanobacteria, fungi, animalia and plantae to revisit the evolutionary history of these two STAND P-loop NTPases. This analysis divulged the presence of NACHT NTPases in the early green plants (green algae and the lycophyte) which had not been previously reported. These NACHT NTPases were known to be involved in diverse functional activities such as transcription regulation in addition to the defense signaling cascades depending on the domain association. In Chalmydomonas reinhardtii, a green algae, WD40 repeats found to be at the carboxyl-terminus of NACHT NTPases suggest probable role in apoptosis regulation. Moreover, the genome of Selaginella moellendorffii, an extant lycophyte, intriguingly shows the considerable number of both AP-ATPases and NACHT NTPases in contrast to a large repertoire of AP-ATPases in plants and emerge as an important node in the evolutionary tree of life. The large complement of AP-ATPases overtakes the function of NACHT NTPases and plausible reason behind the absence of the later in the plant lineages. The presence of NACHT NTPases in the early green plants and phyletic patterns results from this study raises a quandary for the distribution of this STAND P-loop NTPase with the apparent horizontal gene transfer from cyanobacteria. PMID:26930396

  3. Genome-wide association analysis to identify chromosomal regions determining components of earliness in wheat.

    PubMed

    Le Gouis, J; Bordes, J; Ravel, C; Heumez, E; Faure, S; Praud, S; Galic, N; Remoué, C; Balfourier, F; Allard, V; Rousset, M

    2012-02-01

    The modification of flowering date is considered an important way to escape the current or future climatic constraints that affect wheat crops. A better understanding of its genetic bases would enable a more efficient and rapid modification through breeding. The objective of this study was to identify chromosomal regions associated with earliness in wheat. A 227-wheat core collection chosen to be highly contrasted for earliness was characterized for heading date. Experiments were conducted in controlled conditions and in the field for 3 years to break down earliness in the component traits: photoperiod sensitivity, vernalization requirement and narrow-sense earliness. Whole-genome association mapping was carried out using 760 molecular markers and taking into account the five ancestral group structure. We identified 62 markers individually associated to earliness components corresponding to 33 chromosomal regions. In addition, we identified 15 other significant markers and seven more regions by testing marker pair interactions. Co-localizations were observed with the Ppd-1, Vrn-1 and Rht-1 candidate genes. Using an independent set of lines to validate the model built for heading date, we were able to explain 34% of the variation using the structure and the significant markers. Results were compared with already published data using bi-parental populations giving an insight into the genetic architecture of flowering time in wheat.

  4. Genome-wide transcriptomic analysis uncovers the molecular basis underlying early flowering and apetalous characteristic in Brassica napus L

    PubMed Central

    Yu, Kunjiang; Wang, Xiaodong; Chen, Feng; Chen, Song; Peng, Qi; Li, Hongge; Zhang, Wei; Hu, Maolong; Chu, Pu; Zhang, Jiefu; Guan, Rongzhan

    2016-01-01

    Floral transition and petal onset, as two main aspects of flower development, are crucial to rapeseed evolutionary success and yield formation. Currently, very little is known regarding the genetic architecture that regulates flowering time and petal morphogenesis in Brassica napus. In the present study, a genome-wide transcriptomic analysis was performed with an absolutely apetalous and early flowering line, APL01, and a normally petalled line, PL01, using high-throughput RNA sequencing. In total, 13,205 differential expressed genes were detected, of which 6111 genes were significantly down-regulated, while 7094 genes were significantly up-regulated in the young inflorescences of APL01 compared with PL01. The expression levels of a vast number of genes involved in protein biosynthesis were altered in response to the early flowering and apetalous character. Based on the putative rapeseed flowering genes, an early flowering network, mainly comprised of vernalization and photoperiod pathways, was built. Additionally, 36 putative upstream genes possibly governing the apetalous character of line APL01 were identified, and six genes potentially regulating petal origination were obtained by combining with three petal-related quantitative trait loci. These findings will facilitate understanding of the molecular mechanisms underlying floral transition and petal initiation in B. napus. PMID:27460760

  5. Living in an adaptive world: Genomic dissection of the genus Homo and its immune response.

    PubMed

    Quach, Hélène; Quintana-Murci, Lluis

    2017-04-03

    More than a decade after the sequencing of the human genome, a deluge of genome-wide population data are generating a portrait of human genetic diversity at an unprecedented level of resolution. Genomic studies have provided new insight into the demographic and adaptive history of our species, Homo sapiens, including its interbreeding with other hominins, such as Neanderthals, and the ways in which natural selection, in its various guises, has shaped genome diversity. These studies, combined with functional genomic approaches, such as the mapping of expression quantitative trait loci, have helped to identify genes, functions, and mechanisms of prime importance for host survival and involved in phenotypic variation and differences in disease risk. This review summarizes new findings in this rapidly developing field, focusing on the human immune response. We discuss the importance of defining the genetic and evolutionary determinants driving immune response variation, and highlight the added value of population genomic approaches in settings relevant to immunity and infection.

  6. Comparative Genomics of Oral Isolates of Streptococcus mutans by in silico Genome Subtraction Does Not Reveal Accessory DNA Associated with Severe Early Childhood Caries

    PubMed Central

    Argimón, Silvia; Konganti, Kranti; Chen, Hao; Alekseyenko, Alexander V.; Brown, Stuart; Caufield, Page W.

    2014-01-01

    Comparative genomics is a popular method for the identification of microbial virulence determinants, especially since the sequencing of a large number of whole bacterial genomes from pathogenic and non-pathogenic strains has become relatively inexpensive. The bioinformatics pipelines for comparative genomics usually include gene prediction and annotation and can require significant computer power. To circumvent this, we developed a rapid method for genome-scale in silico subtractive hybridization, based on blastn and independent of feature identification and annotation. Whole genome comparisons by in silico genome subtraction were performed to identify genetic loci specific to Streptococcus mutans strains associated with severe early childhood caries (S-ECC), compared to strains isolated from caries-free (CF) children. The genome similarity of the 20 S. mutans strains included in this study, calculated by Simrank k-mer sharing, ranged from 79.5 to 90.9%, confirming this is a genetically heterogeneous group of strains. We identified strain-specific genetic elements in 19 strains, with sizes ranging from 200 bp to 39 kb. These elements contained protein-coding regions with functions mostly associated with mobile DNA. We did not, however, identify any genetic loci consistently associated with dental caries, i.e., shared by all the S-ECC strains and absent in the CF strains. Conversely, we did not identify any genetic loci specific with the healthy group. Comparison of previously published genomes from pathogenic and carriage strains of Neisseria meningitidis with our in silico genome subtraction yielded the same set of genes specific to the pathogenic strains, thus validating our method. Our results suggest that S. mutans strains derived from caries active or caries free dentitions cannot be differentiated based on the presence or absence of specific genetic elements. Our in silico genome subtraction method is available as the Microbial Genome Comparison (MGC) tool

  7. Comparative genomics of oral isolates of Streptococcus mutans by in silico genome subtraction does not reveal accessory DNA associated with severe early childhood caries.

    PubMed

    Argimón, Silvia; Konganti, Kranti; Chen, Hao; Alekseyenko, Alexander V; Brown, Stuart; Caufield, Page W

    2014-01-01

    Comparative genomics is a popular method for the identification of microbial virulence determinants, especially since the sequencing of a large number of whole bacterial genomes from pathogenic and non-pathogenic strains has become relatively inexpensive. The bioinformatics pipelines for comparative genomics usually include gene prediction and annotation and can require significant computer power. To circumvent this, we developed a rapid method for genome-scale in silico subtractive hybridization, based on blastn and independent of feature identification and annotation. Whole genome comparisons by in silico genome subtraction were performed to identify genetic loci specific to Streptococcus mutans strains associated with severe early childhood caries (S-ECC), compared to strains isolated from caries-free (CF) children. The genome similarity of the 20 S. mutans strains included in this study, calculated by Simrank k-mer sharing, ranged from 79.5% to 90.9%, confirming this is a genetically heterogeneous group of strains. We identified strain-specific genetic elements in 19 strains, with sizes ranging from 200 to 39 kb. These elements contained protein-coding regions with functions mostly associated with mobile DNA. We did not, however, identify any genetic loci consistently associated with dental caries, i.e., shared by all the S-ECC strains and absent in the CF strains. Conversely, we did not identify any genetic loci specific with the healthy group. Comparison of previously published genomes from pathogenic and carriage strains of Neisseria meningitidis with our in silico genome subtraction yielded the same set of genes specific to the pathogenic strains, thus validating our method. Our results suggest that S. mutans strains derived from caries active or caries free dentitions cannot be differentiated based on the presence or absence of specific genetic elements. Our in silico genome subtraction method is available as the Microbial Genome Comparison (MGC) tool

  8. Identification of two novel functional p53 responsive elements in the herpes simplex virus-1 genome.

    PubMed

    Hsieh, Jui-Cheng; Kuta, Ryan; Armour, Courtney R; Boehmer, Paul E

    2014-07-01

    Analysis of the herpes simplex virus-1 (HSV-1) genome reveals two candidate p53 responsive elements (p53RE), located in proximity to the replication origins oriL and oriS, referred to as p53RE-L and p53RE-S, respectively. The sequences of p53RE-L and p53RE-S conform to the p53 consensus site and are present in HSV-1 strains KOS, 17, and F. p53 binds to both elements in vitro and in virus-infected cells. Both p53RE-L and p53RE-S are capable of conferring p53-dependent transcriptional activation onto a heterologous reporter gene. Importantly, expression of the essential immediate early viral transactivator ICP4 and the essential DNA replication protein ICP8, that are adjacent to p53RE-S and p53RE-L, are repressed in a p53-dependent manner. Taken together, this study identifies two novel functional p53RE in the HSV-1 genome and suggests a complex mechanism of viral gene regulation by p53 which may determine progression of the lytic viral replication cycle or the establishment of latency.

  9. Utilization of the human louse genome to study insecticide resistance and innate immune response

    PubMed Central

    Clark, J. Marshall; Yoon, Kyong Sup; Kim, Ju Hyeon; Lee, Si Hyeock; Pittendrigh, Barry R.

    2015-01-01

    Since sequencing the human body louse genome, substantial advances have occurred in the utilization of the information gathered from louse genomes and transcriptomes. Comparatively, the body louse genome contains far fewer genes involved in environmental response, such as xenobiotic detoxification and innate immune response. Additionally, the body louse maintains a primary bacterial endosymbiont, Candidatus Riesia pediculicola, and a number of bacterial pathogens that it vectors, which have genomes that are also reduced in size. Thus, human louse genomes offer unique information and tools for use in advancing our understanding of coevolution among vectors, endosymbionts and pathogens. In this review, we summarize the current literature on the extent of pediculicide resistance, the availability of new pediculicides and information establishing this organism as an efficient model to study how xenobiotic metabolism, which is involved in insecticide resistance, is induced and how insects modify their innate immune response upon bacterial challenge resulting in enhanced vector competence. PMID:25987230

  10. Implementation of responsiveness to intervention in early education settings.

    PubMed

    Justice, Laura M; McGinty, Anita; Guo, Ying; Moore, Douglas

    2009-05-01

    This article provides an overview of how response to intervention (RTI) may be used effectively within early childhood settings. Discussion is organized to address such issues regarding RTI implementation as (1) how to design and implement a high-quality Tier 1 learning environment that systematically improves children's language and literacy outcomes, (2) how to design and implement a high-quality Tier 2 supplemental learning intervention that systematically improves the language and literacy outcomes of children who are unresponsive to Tier 1, and (3) how to design and implement a comprehensive and cohesive assessment system that appropriately identifies children who show inadequate response to the Tier 1 and Tier 2 learning opportunities. A model for implementing RTI using the supplemental curriculum by Justice and McGinty, READ IT AGAIN-PREK! (2008), is presented. This tool was developed to meet the needs of early childhood programs as they seek to implement RIA in a cost-effective and scalable manner.

  11. Ancient genomes link early farmers from Atapuerca in Spain to modern-day Basques.

    PubMed

    Günther, Torsten; Valdiosera, Cristina; Malmström, Helena; Ureña, Irene; Rodriguez-Varela, Ricardo; Sverrisdóttir, Óddny Osk; Daskalaki, Evangelia A; Skoglund, Pontus; Naidoo, Thijessen; Svensson, Emma M; Bermúdez de Castro, José María; Carbonell, Eudald; Dunn, Michael; Storå, Jan; Iriarte, Eneko; Arsuaga, Juan Luis; Carretero, José-Miguel; Götherström, Anders; Jakobsson, Mattias

    2015-09-22

    The consequences of the Neolithic transition in Europe--one of the most important cultural changes in human prehistory--is a subject of great interest. However, its effect on prehistoric and modern-day people in Iberia, the westernmost frontier of the European continent, remains unresolved. We present, to our knowledge, the first genome-wide sequence data from eight human remains, dated to between 5,500 and 3,500 years before present, excavated in the El Portalón cave at Sierra de Atapuerca, Spain. We show that these individuals emerged from the same ancestral gene pool as early farmers in other parts of Europe, suggesting that migration was the dominant mode of transferring farming practices throughout western Eurasia. In contrast to central and northern early European farmers, the Chalcolithic El Portalón individuals additionally mixed with local southwestern hunter-gatherers. The proportion of hunter-gatherer-related admixture into early farmers also increased over the course of two millennia. The Chalcolithic El Portalón individuals showed greatest genetic affinity to modern-day Basques, who have long been considered linguistic and genetic isolates linked to the Mesolithic whereas all other European early farmers show greater genetic similarity to modern-day Sardinians. These genetic links suggest that Basques and their language may be linked with the spread of agriculture during the Neolithic. Furthermore, all modern-day Iberian groups except the Basques display distinct admixture with Caucasus/Central Asian and North African groups, possibly related to historical migration events. The El Portalón genomes uncover important pieces of the demographic history of Iberia and Europe and reveal how prehistoric groups relate to modern-day people.

  12. Ancient genomes link early farmers from Atapuerca in Spain to modern-day Basques

    PubMed Central

    Günther, Torsten; Valdiosera, Cristina; Malmström, Helena; Ureña, Irene; Rodriguez-Varela, Ricardo; Sverrisdóttir, Óddny Osk; Daskalaki, Evangelia A.; Skoglund, Pontus; Naidoo, Thijessen; Svensson, Emma M.; Bermúdez de Castro, José María; Carbonell, Eudald; Dunn, Michael; Storå, Jan; Iriarte, Eneko; Arsuaga, Juan Luis; Carretero, José-Miguel; Götherström, Anders; Jakobsson, Mattias

    2015-01-01

    The consequences of the Neolithic transition in Europe—one of the most important cultural changes in human prehistory—is a subject of great interest. However, its effect on prehistoric and modern-day people in Iberia, the westernmost frontier of the European continent, remains unresolved. We present, to our knowledge, the first genome-wide sequence data from eight human remains, dated to between 5,500 and 3,500 years before present, excavated in the El Portalón cave at Sierra de Atapuerca, Spain. We show that these individuals emerged from the same ancestral gene pool as early farmers in other parts of Europe, suggesting that migration was the dominant mode of transferring farming practices throughout western Eurasia. In contrast to central and northern early European farmers, the Chalcolithic El Portalón individuals additionally mixed with local southwestern hunter–gatherers. The proportion of hunter–gatherer-related admixture into early farmers also increased over the course of two millennia. The Chalcolithic El Portalón individuals showed greatest genetic affinity to modern-day Basques, who have long been considered linguistic and genetic isolates linked to the Mesolithic whereas all other European early farmers show greater genetic similarity to modern-day Sardinians. These genetic links suggest that Basques and their language may be linked with the spread of agriculture during the Neolithic. Furthermore, all modern-day Iberian groups except the Basques display distinct admixture with Caucasus/Central Asian and North African groups, possibly related to historical migration events. The El Portalón genomes uncover important pieces of the demographic history of Iberia and Europe and reveal how prehistoric groups relate to modern-day people. PMID:26351665

  13. Genomic regions of pufferfishes responsible for host specificity of a monogenean parasite, Heterobothrium okamotoi.

    PubMed

    Hosoya, Sho; Kido, Shinichi; Hirabayashi, Yo; Kai, Wataru; Kinami, Ryuhei; Yoshinaga, Tomoyoshi; Ogawa, Kazuo; Suetake, Hiroaki; Kikuchi, Kiyoshi; Suzuki, Yuzuru

    2013-10-01

    The genetic mechanisms underlying host specificity of parasitic infections are largely unknown. After hatching, the larvae of the monogenean parasite, Heterobothrium okamotoi, attach to the gill filaments of hosts and the post-larval worms develop there by consuming nutrients from the host. The susceptibility to H. okamotoi infection differs markedly among fish species. While this parasite can grow on tiger pufferfish (also called fugu), Takifugu rubripes, it appears to be rejected by a close congener, grass pufferfish, Takifugu niphobles, after initial attachment to the gills. To determine the genetic architecture of the pufferfish responsible for this host specificity, we performed genome-wide quantitative trait loci analysis. We raised second generation (F2) hybrids of the two pufferfish species and experimentally infected them with the monogenean in vivo. To assess possible differences in host mechanisms between early and later periods of infection, we sampled fish three h and 21days after exposure. Genome scanning of fish from the 3h infection trial revealed suggestive quantitative trait loci on linkage groups 2 and 14, which affected the number of parasites on the gill. However, analysis of fish 21days p.i. detected a significant quantitative trait locus on linkage group 9 and three other suggestive quantitative trait loci on linkage groups 7, 18 and 22. These results indicated the polygenic nature of the host mechanisms involved in the infection/rejection of H. okamotoi. Moreover the analyses suggested that host factors may play a more important role during the growth period of the parasite than during initial host recognition at the time of attachment. Within the 95% confidence interval of the linkage group 9 quantitative trait locus in the fugu genome, there were 214 annotated protein-coding genes, including immunity-related genes such as Irak4, Muc2 and Muc5ac.

  14. Divergence is focused on few genomic regions early in speciation: incipient speciation of sunflower ecotypes.

    PubMed

    Andrew, Rose L; Rieseberg, Loren H

    2013-09-01

    Early in speciation, as populations undergo the transition from local adaptation to incipient species, is when a number of transient, but potentially important, processes appear to be most easily detected. These include signatures of selective sweeps that can point to asymmetry in selection between habitats, divergence hitchhiking, and associations of adaptive genes with environments. In a genomic comparison of ecotypes of the prairie sunflower, Helianthus petiolaris, occurring at Great Sand Dunes National Park and Preserve (Colorado), we found that selective sweeps were mainly restricted to the dune ecotype and that there was variation across the genome in whether proximity to the nondune population constrained or promoted divergence. The major regions of divergence were few and large between ecotypes, in contrast with an interspecific comparison between H. petiolaris and a sympatric congener, Helianthus annuus. In general, the large regions of divergence observed in the ecotypic comparison swamped locus-specific associations with environmental variables. In both comparisons, regions of high divergence occurred in portions of the genetic map with high marker density, probably reflecting regions of low recombination. The difference in genomic distributions of highly divergent regions between ecotypic and interspecific comparisons highlights the value of studies spanning the spectrum of speciation in related taxa.

  15. Early responses of vascular endothelial cells to topographic cues.

    PubMed

    Dreier, Britta; Gasiorowski, Joshua Z; Morgan, Joshua T; Nealey, Paul F; Russell, Paul; Murphy, Christopher J

    2013-08-01

    Vascular endothelial cells in vivo are exposed to multiple biophysical cues provided by the basement membrane, a specialized extracellular matrix through which vascular endothelial cells are attached to the underlying stroma. The importance of biophysical cues has been widely reported, but the signaling pathways that mediate cellular recognition and response to these cues remain poorly understood. Anisotropic topographically patterned substrates with nano- through microscale feature dimensions were fabricated to investigate cellular responses to topographic cues. The present study focuses on early events following exposure of human umbilical vein endothelial cells (HUVECs) to these patterned substrates. In serum-free medium and on substrates without protein coating, HUVECs oriented parallel to the long axis of underlying ridges in as little as 30 min. Immunocytochemistry showed clear differences in the localization of the focal adhesion proteins Src, p130Cas, and focal adhesion kinase (FAK) in HUVECs cultured on topographically patterned surfaces and on planar surfaces, suggesting involvement of these proteins in mediating the response to topographic features. Knockdown experiments demonstrated that FAK was not necessary for HUVEC alignment in response to topographic cues, although FAK knockdown did modulate HUVEC migration. These data identify key events early in the cellular response to biophysical stimuli.

  16. Inferences of drug responses in cancer cells from cancer genomic features and compound chemical and therapeutic properties

    NASA Astrophysics Data System (ADS)

    Wang, Yongcui; Fang, Jianwen; Chen, Shilong

    2016-09-01

    Accurately predicting the response of a cancer patient to a therapeutic agent is a core goal of precision medicine. Existing approaches were mainly relied primarily on genomic alterations in cancer cells that have been treated with different drugs. Here we focus on predicting drug response based on integration of the heterogeneously pharmacogenomics data from both cell and drug sides. Through a systematical approach, named as PDRCC (Predict Drug Response in Cancer Cells), the cancer genomic alterations and compound chemical and therapeutic properties were incorporated to determine the chemotherapeutic response in cancer patients. Using the Cancer Cell Line Encyclopedia (CCLE) study as the benchmark dataset, all pharmacogenomics data exhibited their roles in inferring the relationships between cancer cells and drugs. When integrating both genomic resources and compound information, the prediction coverage was significantly increased. The validity of PDRCC was also supported by its effective in uncovering the unknown cell-drug associations with database and literature evidences. It set the stage for clinical testing of novel therapeutic strategies, such as the sensitive association between cancer cell ‘A549_LUNG’ and compound ‘Topotecan’. In conclusion, PDRCC offers the possibility for faster, safer, and cheaper the development of novel anti-cancer therapeutics in the early-stage clinical trails.

  17. Inferences of drug responses in cancer cells from cancer genomic features and compound chemical and therapeutic properties

    PubMed Central

    Wang, Yongcui; Fang, Jianwen; Chen, Shilong

    2016-01-01

    Accurately predicting the response of a cancer patient to a therapeutic agent is a core goal of precision medicine. Existing approaches were mainly relied primarily on genomic alterations in cancer cells that have been treated with different drugs. Here we focus on predicting drug response based on integration of the heterogeneously pharmacogenomics data from both cell and drug sides. Through a systematical approach, named as PDRCC (Predict Drug Response in Cancer Cells), the cancer genomic alterations and compound chemical and therapeutic properties were incorporated to determine the chemotherapeutic response in cancer patients. Using the Cancer Cell Line Encyclopedia (CCLE) study as the benchmark dataset, all pharmacogenomics data exhibited their roles in inferring the relationships between cancer cells and drugs. When integrating both genomic resources and compound information, the prediction coverage was significantly increased. The validity of PDRCC was also supported by its effective in uncovering the unknown cell-drug associations with database and literature evidences. It set the stage for clinical testing of novel therapeutic strategies, such as the sensitive association between cancer cell ‘A549_LUNG’ and compound ‘Topotecan’. In conclusion, PDRCC offers the possibility for faster, safer, and cheaper the development of novel anti-cancer therapeutics in the early-stage clinical trails. PMID:27645580

  18. Genome-scale transcriptomic insights into early-stage fruit development in woodland strawberry Fragaria vesca.

    PubMed

    Kang, Chunying; Darwish, Omar; Geretz, Aviva; Shahan, Rachel; Alkharouf, Nadim; Liu, Zhongchi

    2013-06-01

    Fragaria vesca, a diploid woodland strawberry with a small and sequenced genome, is an excellent model for studying fruit development. The strawberry fruit is unique in that the edible flesh is actually enlarged receptacle tissue. The true fruit are the numerous dry achenes dotting the receptacle's surface. Auxin produced from the achene is essential for the receptacle fruit set, a paradigm for studying crosstalk between hormone signaling and development. To investigate the molecular mechanism underlying strawberry fruit set, next-generation sequencing was employed to profile early-stage fruit development with five fruit tissue types and five developmental stages from floral anthesis to enlarged fruits. This two-dimensional data set provides a systems-level view of molecular events with precise spatial and temporal resolution. The data suggest that the endosperm and seed coat may play a more prominent role than the embryo in auxin and gibberellin biosynthesis for fruit set. A model is proposed to illustrate how hormonal signals produced in the endosperm and seed coat coordinate seed, ovary wall, and receptacle fruit development. The comprehensive fruit transcriptome data set provides a wealth of genomic resources for the strawberry and Rosaceae communities as well as unprecedented molecular insight into fruit set and early stage fruit development.

  19. Viral genome RNA serves as messenger early in the infectious cycle of murine leukemia virus.

    PubMed Central

    Shurtz, R; Dolev, S; Aboud, M; Salzberg, S

    1979-01-01

    When NIH/3T3 mouse fibroblasts were infected with the Moloney strain of murine leukemia virus, part of the viral genome RNA molecules were detected in polyribosomes of the infected cells early in the infectious cycle. The binding appears to be specific, since we could demonstrate the release of viral RNA from polyribosomes with EDTA. Moreover, when infection occurred in the presence of cycloheximide, most viral RNA molecules were detected in the free cytoplasm. Size analysis on polyribosomal viral RNA molecules indicated that two size class molecules, 38S and 23S, are present in polyribosomes at 3 h after infection. Analysis of the polyriboadenylate [poly(rA)] content of viral RNA extracted from infected polyribosomes demonstrated that such molecules bind with greatest abundance at 3 h after infection, as has been detected with total viral RNA. No molecules lacking poly(rA) stretches could be detected in polyribosomes. Furthermore, when a similar analysis was performed on unbound molecules present in the free cytoplasm, identical results were obtained. We conclude that no selection towards poly(rA)-containing viral molecules is evident on binding to polyribosomes. These findings suggest that the incoming viral genome of the Moloney strain of murine leukemia virus may serve as a messenger for the synthesis of one or more virus-specific proteins early after infection of mouse fibroblasts. PMID:117118

  20. Early life socioeconomic factors and genomic DNA methylation in mid-life.

    PubMed

    Tehranifar, Parisa; Wu, Hui-Chen; Fan, Xiaozhou; Flom, Julie D; Ferris, Jennifer S; Cho, Yoon Hee; Gonzalez, Karina; Santella, Regina M; Terry, Mary Beth

    2013-01-01

    Epigenetic modifications may be one mechanism linking early life factors, including parental socioeconomic status (SES), to adult onset disease risk. However, SES influences on DNA methylation patterns remain largely unknown. In a US birth cohort of women, we examined whether indicators of early life and adult SES were associated with white blood cell methylation of repetitive elements (Sat2, Alu and LINE-1) in adulthood. Low family income at birth was associated with higher Sat2 methylation (β = 19.7, 95% CI: 0.4, 39.0 for lowest vs. highest income quartile) and single parent family was associated with higher Alu methylation (β = 23.5, 95% CI: 2.6, 44.4), after adjusting for other early life factors. Lower adult education was associated with lower Sat2 methylation (β = -16.7, 95% CI: -29.0, -4.5). There were no associations between early life SES and LINE-1 methylation. Overall, our preliminary results suggest possible influences of SES across the life-course on genomic DNA methylation in adult women. However, these preliminary associations need to be replicated in larger prospective studies.

  1. Single-Genome Sequencing of Hepatitis C Virus in Donor-Recipient Pairs Distinguishes Modes and Models of Virus Transmission and Early Diversification

    PubMed Central

    Li, Hui; Stoddard, Mark B.; Wang, Shuyi; Giorgi, Elena E.; Blair, Lily M.; Learn, Gerald H.; Hahn, Beatrice H.; Alter, Harvey J.; Busch, Michael P.; Fierer, Daniel S.; Ribeiro, Ruy M.; Perelson, Alan S.; Bhattacharya, Tanmoy

    2015-01-01

    ABSTRACT Despite the recent development of highly effective anti-hepatitis C virus (HCV) drugs, the global burden of this pathogen remains immense. Control or eradication of HCV will likely require the broad application of antiviral drugs and development of an effective vaccine. A precise molecular identification of transmitted/founder (T/F) HCV genomes that lead to productive clinical infection could play a critical role in vaccine research, as it has for HIV-1. However, the replication schema of these two RNA viruses differ substantially, as do viral responses to innate and adaptive host defenses. These differences raise questions as to the certainty of T/F HCV genome inferences, particularly in cases where multiple closely related sequence lineages have been observed. To clarify these issues and distinguish between competing models of early HCV diversification, we examined seven cases of acute HCV infection in humans and chimpanzees, including three examples of virus transmission between linked donors and recipients. Using single-genome sequencing (SGS) of plasma vRNA, we found that inferred T/F sequences in recipients were identical to viral sequences in their respective donors. Early in infection, HCV genomes generally evolved according to a simple model of random evolution where the coalescent corresponded to the T/F sequence. Closely related sequence lineages could be explained by high multiplicity infection from a donor whose viral sequences had undergone a pretransmission bottleneck due to treatment, immune selection, or recent infection. These findings validate SGS, together with mathematical modeling and phylogenetic analysis, as a novel strategy to infer T/F HCV genome sequences. IMPORTANCE Despite the recent development of highly effective, interferon-sparing anti-hepatitis C virus (HCV) drugs, the global burden of this pathogen remains immense. Control or eradication of HCV will likely require the broad application of antiviral drugs and the

  2. The Early Endocrine Stress Response in Experimental Subarachnoid Hemorrhage

    PubMed Central

    Nyberg, Christoffer; Karlsson, Torbjörn; Hillered, Lars; Stridsberg, Mats; Ronne Engström, Elisabeth

    2016-01-01

    Introduction In patients with severe illness, such as aneurysmal subarachnoid hemorrhage (SAH), a physiologic stress response is triggered. This includes activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. The aim of this study was to investigate the very early responses of these systems. Methods A porcine animal model of aneurysmal SAH was used. In this model, blood is injected slowly to the basal cisterns above the anterior skull base until the cerebral perfusion pressure is 0 mm Hg. Sampling was done from blood and urine at -10, +15, +75 and +135 minutes from time of induction of SAH. Analyses of adrenocorticotropic hormone (ACTH), cortisol, aldosterone, catecholamines and chromogranin-A were performed. Results Plasma ACTH, serum cortisol and plasma aldosterone increased in the samples following induction of SAH, and started to decline after 75 minutes. Urine cortisol also increased after SAH. Urine catecholamines and their metabolites were found to increase after SAH. Many samples were however below detection level, not allowing for statistical analysis. Plasma chromogranin-A peaked at 15 minutes after SAH, and thereafter decreased. Conclusions The endocrine stress response after aneurysmal SAH was found to start within 15 minutes in the HPA axis with early peak values of ACTH, cortisol and aldosterone. The fact that the concentrations of the HPA axis hormones decreased 135 minutes after SAH may suggest that a similar pattern exists in SAH patients, thus making it difficult to catch these early peak values. There were also indications of early activation of the sympathetic nervous system, but the small number of valid samples made interpretation difficult. PMID:27007694

  3. The Complete Sequence of the Mitochondrial Genome of Butomus umbellatus – A Member of an Early Branching Lineage of Monocotyledons

    PubMed Central

    Cuenca, Argelia; Petersen, Gitte; Seberg, Ole

    2013-01-01

    In order to study the evolution of mitochondrial genomes in the early branching lineages of the monocotyledons, i.e., the Acorales and Alismatales, we are sequencing complete genomes from a suite of key taxa. As a starting point the present paper describes the mitochondrial genome of Butomus umbellatus (Butomaceae) based on next-generation sequencing data. The genome was assembled into a circular molecule, 450,826 bp in length. Coding sequences cover only 8.2% of the genome and include 28 protein coding genes, four rRNA genes, and 12 tRNA genes. Some of the tRNA genes and a 16S rRNA gene are transferred from the plastid genome. However, the total amount of recognized plastid sequences in the mitochondrial genome is only 1.5% and the amount of DNA transferred from the nucleus is also low. RNA editing is abundant and a total of 557 edited sites are predicted in the protein coding genes. Compared to the 40 angiosperm mitochondrial genomes sequenced to date, the GC content of the Butomus genome is uniquely high (49.1%). The overall similarity between the mitochondrial genomes of Butomus and Spirodela (Araceae), the closest relative yet sequenced, is low (less than 20%), and the two genomes differ in size by a factor 2. Gene order is also largely unconserved. However, based on its phylogenetic position within the core alismatids Butomus will serve as a good reference point for subsequent studies in the early branching lineages of the monocotyledons. PMID:23637852

  4. Stomatal Blue Light Response Is Present in Early Vascular Plants.

    PubMed

    Doi, Michio; Kitagawa, Yuki; Shimazaki, Ken-ichiro

    2015-10-01

    Light is a major environmental factor required for stomatal opening. Blue light (BL) induces stomatal opening in higher plants as a signal under the photosynthetic active radiation. The stomatal BL response is not present in the fern species of Polypodiopsida. The acquisition of a stomatal BL response might provide competitive advantages in both the uptake of CO2 and prevention of water loss with the ability to rapidly open and close stomata. We surveyed the stomatal opening in response to strong red light (RL) and weak BL under the RL with gas exchange technique in a diverse selection of plant species from euphyllophytes, including spermatophytes and monilophytes, to lycophytes. We showed the presence of RL-induced stomatal opening in most of these species and found that the BL responses operated in all euphyllophytes except Polypodiopsida. We also confirmed that the stomatal opening in lycophytes, the early vascular plants, is driven by plasma membrane proton-translocating adenosine triphosphatase and K(+) accumulation in guard cells, which is the same mechanism operating in stomata of angiosperms. These results suggest that the early vascular plants respond to both RL and BL and actively regulate stomatal aperture. We also found three plant species that absolutely require BL for both stomatal opening and photosynthetic CO2 fixation, including a gymnosperm, C. revoluta, and the ferns Equisetum hyemale and Psilotum nudum.

  5. Genomic Changes that May be Responsible for the Elevated UV Resistance of Bacillus Pumilus SAFR-032

    NASA Astrophysics Data System (ADS)

    Tirumalai, M. R.; Rastogi, R.; Venkateswaran, K.; Fox, G. E.

    2010-04-01

    The genomes of Bacillus pumilus SAFR-032 whose spores are highly resistant to UV and the closely related B. pumilus ATCC-7061 that lacks this resistance are compared. Candidate genes are identified that may be responsible for the elevated resistance.

  6. Barrier to Autointegration Factor (BANF1): interwoven roles in nuclear structure, genome integrity, innate immunity, stress responses and progeria.

    PubMed

    Jamin, Augusta; Wiebe, Matthew S

    2015-06-01

    The Barrier to Autointegration Factor (BAF or BANF1) is an abundant, highly conserved DNA binding protein. BAF is involved in multiple pathways including mitosis, nuclear assembly, viral infection, chromatin and gene regulation and the DNA damage response. BAF is also essential for early development in metazoans and relevant to human physiology; BANF1 mutations cause a progeroid syndrome, placing BAF within the laminopathy disease spectrum. This review summarizes previous knowledge about BAF in the context of recent discoveries about its protein partners, posttranslational regulation, dynamic subcellular localizations and roles in disease, innate immunity, transposable elements and genome integrity.

  7. Barrier to Autointegration Factor (BANF1): interwoven roles in nuclear structure, genome integrity, innate immunity, stress responses and progeria

    PubMed Central

    Jamin, Augusta; Wiebe, Matthew S.

    2015-01-01

    The Barrier to Autointegration Factor (BAF or BANF1) is an abundant, highly conserved DNA binding protein. BAF is involved in multiple pathways including mitosis, nuclear assembly, viral infection, chromatin and gene regulation and the DNA damage response. BAF is also essential for early development in metazoans and relevant to human physiology; BANF1 mutations cause a progeroid syndrome, placing BAF within the laminopathy disease spectrum. This review summarizes previous knowledge about BAF in the context of recent discoveries about its protein partners, posttranslational regulation, dynamic subcellular localizations and roles in disease, innate immunity, transposable elements and genome integrity. PMID:26072104

  8. Genomic analysis of the host response to nervous necrosis virus in Atlantic cod (Gadus morhua) brain.

    PubMed

    Krasnov, Aleksei; Kileng, Øyvind; Skugor, Stanko; Jørgensen, Sven Martin; Afanasyev, Sergey; Timmerhaus, Gerrit; Sommer, Ann-Inger; Jensen, Ingvill

    2013-07-01

    Genome sequencing combined with transcriptome profiling promotes exploration of defence against pathogens and discovery of immune genes. Based on sequences from the recently released genome of Atlantic cod, a genome-wide oligonucleotide microarray (ACIQ-1) was designed and used for analyses of gene expression in the brain during infection with nervous necrosis virus (NNV). A challenge experiment with NNV was performed with Atlantic cod juveniles and brain samples from virus infected and uninfected fish were used for microarray analysis. Expression of virus induced genes increased at 5 days post challenge and persisted at stable level to the last sampling at 25 days post challenge. A large fraction of the up-regulated genes (546 features) were known or expected to have immune functions and most of these have not previously been characterized in Atlantic cod. Transcriptomic changes induced by the virus involved strong activation of genes associated with interferon and tumour necrosis factor related responses and acute inflammation. Up-regulation of genes involved in adaptive immunity suggested a rapid recruitment of B and T lymphocytes to the NNV infected brain. QPCR analyses of 15 candidate genes of innate immunity showed rapid induction by poly(I:C) in Atlantic cod larvae cells suggesting an antiviral role. Earliest and greatest expression changes after poly I:C stimulation was observed for interferon regulatory factors IRF4 and IRF7. Comparative studies between teleost species provided new knowledge about the evolution of innate antiviral immunity in fish. A number of genes is present or responds to viruses only in fish. Innate immunity of Atlantic cod is characterized by selective expansion of several medium-sized multigene families with ribose binding domains. An interesting finding was the high representation of three large gene families among the early antiviral genes, including tripartite motif proteins (TRIM) and proteins with PRY-SPRY and NACHT domains. The

  9. Genome-wide association and genomic prediction for host response to porcine reproductive and respiratory syndrome virus infection

    PubMed Central

    2014-01-01

    Background Host genetics has been shown to play a role in porcine reproductive and respiratory syndrome (PRRS), which is the most economically important disease in the swine industry. A region on Sus scrofa chromosome (SSC) 4 has been previously reported to have a strong association with serum viremia and weight gain in pigs experimentally infected with the PRRS virus (PRRSV). The objective here was to identify haplotypes associated with the favorable phenotype, investigate additional genomic regions associated with host response to PRRSV, and to determine the predictive ability of genomic estimated breeding values (GEBV) based on the SSC4 region and based on the rest of the genome. Phenotypic data and 60 K SNP genotypes from eight trials of ~200 pigs from different commercial crosses were used to address these objectives. Results Across the eight trials, heritability estimates were 0.44 and 0.29 for viral load (VL, area under the curve of log-transformed serum viremia from 0 to 21 days post infection) and weight gain to 42 days post infection (WG), respectively. Genomic regions associated with VL were identified on chromosomes 4, X, and 1. Genomic regions associated with WG were identified on chromosomes 4, 5, and 7. Apart from the SSC4 region, the regions associated with these two traits each explained less than 3% of the genetic variance. Due to the strong linkage disequilibrium in the SSC4 region, only 19 unique haplotypes were identified across all populations, of which four were associated with the favorable phenotype. Through cross-validation, accuracies of EBV based on the SSC4 region were high (0.55), while the rest of the genome had little predictive ability across populations (0.09). Conclusions Traits associated with response to PRRSV infection in growing pigs are largely controlled by genomic regions with relatively small effects, with the exception of SSC4. Accuracies of EBV based on the SSC4 region were high compared to the rest of the genome

  10. Gene Expression Profiling Reveals Early Cellular Responses to Intracellular Magnetic Labeling with Superparamagnetic Iron Oxide Nanoparticles

    PubMed Central

    Kedziorek, Dorota A.; Muja, Naser; Walczak, Piotr; Ruiz-Cabello, Jesus; Gilad, Assaf A.; Jie, Chunfa C.; Bulte, Jeff W. M.

    2010-01-01

    With MRI (stem) cell tracking having entered the clinic, studies on the cellular genomic response toward labeling are warranted. Gene expression profiling was applied to C17.2 neural stem cells following superparamagnetic iron oxide/PLL (poly-L-lysine) labeling over the course of 1 week. Relative to unlabeled cells, less than 1% of genes (49 total) exhibited greater than 2-fold difference in expression in response to superparamagnetic iron oxide/PLL labeling. In particular, transferrin receptor 1 (Tfrc) and heme oxygenase 1 (Hmox1) expression was downregulated early, whereas genes involved in lysosomal function (Sulf1) and detoxification (Clu, Cp, Gstm2, Mgst1) were upregulated at later time points. Relative to cells treated with PLL only, cells labeled with superparamagnetic iron oxide/PLL complexes exhibited differential expression of 1399 genes. Though these differentially expressed genes exhibited altered expression over time, the overall extent was limited. Gene ontology analysis of differentially expressed genes showed that genes encoding zinc-binding proteins are enriched after superparamagnetic iron oxide/PLL labeling relative to PLL only treatment, whereas members of the apoptosis/ programmed cell death pathway did not display increased expression. Overexpression of the differentially expressed genes Rnf138 and Abcc4 were confirmed by quantitative real-time polymerase chain reaction. These results demonstrate that, although early reactions responsible for iron homeostasis are induced, overall neural stem cell gene expression remains largely unaltered following superparamagnetic iron oxide/PLL labeling. PMID:20373404

  11. Whole genome response in guinea pigs infected with the high virulence strain Mycobacterium tuberculosis TT372

    PubMed Central

    Aiyaz, Mohamed; Bipin, Chand; Pantulwar, Vinay; Mugasimangalam, Raja; Shanley, Crystal A.; Ordway, Diane J; Orme, Ian M.

    2014-01-01

    SUMMARY In this study we conducted a microarray-based whole genomic analysis of gene expression in the lungs after exposure of guinea pigs to a low dose aerosol of the Atypical Beijing Western Cape TT372 strain of Mycobacterium tuberculosis, after harvesting lung tissues three weeks after infection at a time that effector immunity is starting to peak. The infection resulted in a very large up-regulation of multiple genes at this time, particularly in the context of a “chemokine storm” in the lungs. Overall gene expression was considerably reduced in animals that had been vaccinated with BCG two months earlier, but in both cases strong signatures featuring gamma interferon [IFNγ] and tumor necrosis factor [TNFα] were observed indicating the potent TH1 response in these animals. Even though their effects are not seen until later in the infection, even at this early time point gene expression patterns associated with the potential emergence of regulatory T cells were observed. Genes involving lung repair, response to oxidative stress, and cell trafficking were strongly expressed, but interesting these gene patterns differed substantially between the infected and vaccinated/infected groups of animals. Given the importance of this species as a relevant and cost-effective small animal model of tuberculosis, this approach has the potential to provide new information regarding the effects of vaccination on control of the disease process. PMID:25621360

  12. Cytokine response after severe RSV bronchiolitis in early life

    PubMed Central

    Castro, Mario; Schweiger, Toni; Yin-DeClue, Huiquing; Ramkumar, Thiruvamoor P; Christie, Chandrika; Zheng, Jie; Cohen, Rebecca; Schechtman, Kenneth B; Strunk, Robert; Bacharier, Leonard B.

    2008-01-01

    Background Immune response following viral infection usually involves Th1-mediated response; however, severe respiratory syncytial virus (RSV) infection appears to be associated with the development of asthma, a Th2-predominant phenotype. Objective To understand the early and subsequent immunologic response to a serious RSV infection in children over time. Methods 206 previously healthy infants hospitalized with severe RSV bronchiolitis were enrolled in a prospective cohort called the RSV Bronchiolitis in Early Life (RBEL) study. Peripheral blood T cells were obtained immediately following RSV infection and at 2, 4 and 6 years of age, stimulated with PMA and ionomycin, and analyzed for interleukin (IL)-2, -4, and - 13 and interferon-γ (IFN-γ) by flow cytometry and real time PCR. Results 48% (n=97) of the children developed asthma (physician-diagnosed) and 48% (n=97) had eczema by age 6. 32% (n=48 of 150) developed allergic sensitization by 3 yrs of age. Children with asthma had lower IL-13 expression at 6 yrs of age than those without (p=0.001). IFN-γ, IL-2 and -4 levels did not differ by asthma or eczema status during follow-up (all p>0.05). Allergic sensitization was not associated with differences in cytokine levels during follow-up (all p>0.05). Conclusion Severe RSV infection early in life is associated with a high incidence of asthma and eczema. Contrary to expectations, subsequent immunologic development in those who developed asthma, eczema or allergic sensitization was not associated with a Th2 phenotype in the peripheral blood. PMID:18760461

  13. Moving through the Stressed Genome: Emerging Regulatory Roles for Transposons in Plant Stress Response

    PubMed Central

    Negi, Pooja; Rai, Archana N.; Suprasanna, Penna

    2016-01-01

    The recognition of a positive correlation between organism genome size with its transposable element (TE) content, represents a key discovery of the field of genome biology. Considerable evidence accumulated since then suggests the involvement of TEs in genome structure, evolution and function. The global genome reorganization brought about by transposon activity might play an adaptive/regulatory role in the host response to environmental challenges, reminiscent of McClintock's original ‘Controlling Element’ hypothesis. This regulatory aspect of TEs is also garnering support in light of the recent evidences, which project TEs as “distributed genomic control modules.” According to this view, TEs are capable of actively reprogramming host genes circuits and ultimately fine-tuning the host response to specific environmental stimuli. Moreover, the stress-induced changes in epigenetic status of TE activity may allow TEs to propagate their stress responsive elements to host genes; the resulting genome fluidity can permit phenotypic plasticity and adaptation to stress. Given their predominating presence in the plant genomes, nested organization in the genic regions and potential regulatory role in stress response, TEs hold unexplored potential for crop improvement programs. This review intends to present the current information about the roles played by TEs in plant genome organization, evolution, and function and highlight the regulatory mechanisms in plant stress responses. We will also briefly discuss the connection between TE activity, host epigenetic response and phenotypic plasticity as a critical link for traversing the translational bridge from a purely basic study of TEs, to the applied field of stress adaptation and crop improvement. PMID:27777577

  14. A genome triplication associated with early diversification of the core eudicots

    PubMed Central

    2012-01-01

    Background Although it is agreed that a major polyploidy event, gamma, occurred within the eudicots, the phylogenetic placement of the event remains unclear. Results To determine when this polyploidization occurred relative to speciation events in angiosperm history, we employed a phylogenomic approach to investigate the timing of gene set duplications located on syntenic gamma blocks. We populated 769 putative gene families with large sets of homologs obtained from public transcriptomes of basal angiosperms, magnoliids, asterids, and more than 91.8 gigabases of new next-generation transcriptome sequences of non-grass monocots and basal eudicots. The overwhelming majority (95%) of well-resolved gamma duplications was placed before the separation of rosids and asterids and after the split of monocots and eudicots, providing strong evidence that the gamma polyploidy event occurred early in eudicot evolution. Further, the majority of gene duplications was placed after the divergence of the Ranunculales and core eudicots, indicating that the gamma appears to be restricted to core eudicots. Molecular dating estimates indicate that the duplication events were intensely concentrated around 117 million years ago. Conclusions The rapid radiation of core eudicot lineages that gave rise to nearly 75% of angiosperm species appears to have occurred coincidentally or shortly following the gamma triplication event. Reconciliation of gene trees with a species phylogeny can elucidate the timing of major events in genome evolution, even when genome sequences are only available for a subset of species represented in the gene trees. Comprehensive transcriptome datasets are valuable complements to genome sequences for high-resolution phylogenomic analysis. PMID:22280555

  15. The Role of Early Growth Response 1 (EGR1) in Brain Plasticity and Neuropsychiatric Disorders

    PubMed Central

    Duclot, Florian; Kabbaj, Mohamed

    2017-01-01

    It is now clearly established that complex interactions between genes and environment are involved in multiple aspects of neuropsychiatric disorders, from determining an individual’s vulnerability to onset, to influencing its response to therapeutic intervention. In this perspective, it appears crucial to better understand how the organism reacts to environmental stimuli and provide a coordinated and adapted response. In the central nervous system, neuronal plasticity and neurotransmission are among the major processes integrating such complex interactions between genes and environmental stimuli. In particular, immediate early genes (IEGs) are critical components of these interactions as they provide the molecular framework for a rapid and dynamic response to neuronal activity while opening the possibility for a lasting and sustained adaptation through regulation of the expression of a wide range of genes. As a result, IEGs have been tightly associated with neuronal activity as well as a variety of higher order processes within the central nervous system such as learning, memory and sensitivity to reward. The immediate early gene and transcription factor early growth response 1 (EGR1) has thus been revealed as a major mediator and regulator of synaptic plasticity and neuronal activity in both physiological and pathological conditions. In this review article, we will focus on the role of EGR1 in the central nervous system. First, we will summarize the different factors influencing its activity. Then, we will analyze the amount of data, including genome-wide, that has emerged in the recent years describing the wide variety of genes, pathways and biological functions regulated directly or indirectly by EGR1. We will thus be able to gain better insights into the mechanisms underlying EGR1’s functions in physiological neuronal activity. Finally, we will discuss and illustrate the role of EGR1 in pathological states with a particular interest in cognitive functions

  16. Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features.

    PubMed

    Lessel, Davor; Vaz, Bruno; Halder, Swagata; Lockhart, Paul J; Marinovic-Terzic, Ivana; Lopez-Mosqueda, Jaime; Philipp, Melanie; Sim, Joe C H; Smith, Katherine R; Oehler, Judith; Cabrera, Elisa; Freire, Raimundo; Pope, Kate; Nahid, Amsha; Norris, Fiona; Leventer, Richard J; Delatycki, Martin B; Barbi, Gotthold; von Ameln, Simon; Högel, Josef; Degoricija, Marina; Fertig, Regina; Burkhalter, Martin D; Hofmann, Kay; Thiele, Holger; Altmüller, Janine; Nürnberg, Gudrun; Nürnberg, Peter; Bahlo, Melanie; Martin, George M; Aalfs, Cora M; Oshima, Junko; Terzic, Janos; Amor, David J; Dikic, Ivan; Ramadan, Kristijan; Kubisch, Christian

    2014-11-01

    Age-related degenerative and malignant diseases represent major challenges for health care systems. Elucidation of the molecular mechanisms underlying carcinogenesis and age-associated pathologies is thus of growing biomedical relevance. We identified biallelic germline mutations in SPRTN (also called C1orf124 or DVC1) in three patients from two unrelated families. All three patients are affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. SPRTN was recently proposed to have a function in translesional DNA synthesis and the prevention of mutagenesis. Our in vivo and in vitro characterization of identified mutations has uncovered an essential role for SPRTN in the prevention of DNA replication stress during general DNA replication and in replication-related G2/M-checkpoint regulation. In addition to demonstrating the pathogenicity of identified SPRTN mutations, our findings provide a molecular explanation of how SPRTN dysfunction causes accelerated aging and susceptibility toward carcinoma.

  17. Transcriptome analysis of silkworm, Bombyx mori, during early response to Beauveria bassiana challenges.

    PubMed

    Hou, Chengxiang; Qin, Guangxing; Liu, Ting; Geng, Tao; Gao, Kun; Pan, Zhonghua; Qian, Heying; Guo, Xijie

    2014-01-01

    Host-pathogen interactions are complex processes and it is a central challenge to reveal these interactions. Fungal infection of silkworm, Bombyx mori, may induce a variety of responsive reaction. However, little is known about the molecular mechanism of silkworm immune response against the fungal infection. To obtain an overview of the interaction between silkworm and an entomopathogenic fungus Beauveria bassiana, Digital Gene Expression profiling, a tag based high-throughput transcriptome sequencing method, was employed to screen and identify differentially expressed genes (DEGs, FDR ≤ 0.001, ∣log2ratio∣ ≥ 1) of silkworm larvae during early response against B. bassiana infection. Total 1430 DEGs including 960 up-regulated and 470 down-regulated ones were identified, of which 627 DEGs can be classified into GO categories by Gene Ontology (GO) analysis. KEGG pathways analysis of these DEGs suggested that many biological processes, such as defense and response, signal transduction, phagocytosis, regulation of gene expression, RNA splicing, biosynthesis and metabolism, protein transport etc. were involved in the interaction between the silkworm and B. bassiana. A number of differentially expressed fungal genes were also identified by mapping the sequencing tags to B. bassiana genome. These results provided new insights to the molecular mechanism of silkworm immune response to B. bassiana infection.

  18. Transcriptome Analysis of Silkworm, Bombyx mori, during Early Response to Beauveria bassiana Challenges

    PubMed Central

    Hou, Chengxiang; Qin, Guangxing; Liu, Ting; Geng, Tao; Gao, Kun; Pan, Zhonghua; Qian, Heying; Guo, Xijie

    2014-01-01

    Host–pathogen interactions are complex processes and it is a central challenge to reveal these interactions. Fungal infection of silkworm, Bombyx mori, may induce a variety of responsive reaction. However, little is known about the molecular mechanism of silkworm immune response against the fungal infection. To obtain an overview of the interaction between silkworm and an entomopathogenic fungus Beauveria bassiana, Digital Gene Expression profiling, a tag based high-throughput transcriptome sequencing method, was employed to screen and identify differentially expressed genes (DEGs, FDR≤0.001, ∣log2ratio∣≥1) of silkworm larvae during early response against B. bassiana infection. Total 1430 DEGs including 960 up-regulated and 470 down-regulated ones were identified, of which 627 DEGs can be classified into GO categories by Gene Ontology (GO) analysis. KEGG pathways analysis of these DEGs suggested that many biological processes, such as defense and response, signal transduction, phagocytosis, regulation of gene expression, RNA splicing, biosynthesis and metabolism, protein transport etc. were involved in the interaction between the silkworm and B. bassiana. A number of differentially expressed fungal genes were also identified by mapping the sequencing tags to B. bassiana genome. These results provided new insights to the molecular mechanism of silkworm immune response to B. bassiana infection. PMID:24618587

  19. Population genomics of a symbiont in the early stages of a pest invasion.

    PubMed

    Brown, Amanda M V; Huynh, Lynn Y; Bolender, Caitlin M; Nelson, Kelly G; McCutcheon, John P

    2014-03-01

    Invasive species often depend on microbial symbionts, but few studies have examined the evolutionary dynamics of symbionts during the early stages of an invasion. The insect Megacopta cribraria and its bacterial nutritional symbiont Candidatus Ishikawaella capsulata invaded the southeastern US in 2009. While M. cribraria was initially discovered on wild kudzu plants, it was found as a pest on soybeans within 1 year of infestation. Because prior research suggests Ishikawaella confers the pest status--that is, the ability to thrive on soybeans--in some Megacopta species, we performed a genomic study on Ishikawaella from US. Megacopta cribraria populations to understand the role of the symbiont in driving host plant preferences. We included Ishikawaella samples collected in the first days of the invasion in 2009 and from 23 locations across the insect's 2011 US range. The 0.75 Mb symbiont genome revealed only 47 fixed differences from the pest-conferring Ishikawaella in Japan, with only one amino acid change in a nutrition-provisioning gene. This similarity, along with a lack of fixed substitutions in the US symbiont population, indicates that Ishikawella likely arrived in the US capable of being a soybean pest. Analyses of allele frequency changes between 2009 and 2011 uncover signatures of both positive and negative selection and suggest that symbionts on soybeans and kudzu experience differential selection for genes related to nutrient provisioning. Our data reveal the evolutionary trajectory of an important insect-bacteria symbiosis in the early stages of an invasion, highlighting the role microbial symbionts may play in the spread of invasive species.

  20. A genome-wide association study of early spontaneous preterm delivery.

    PubMed

    Zhang, Heping; Baldwin, Don A; Bukowski, Radek K; Parry, Samuel; Xu, Yaji; Song, Chi; Andrews, William W; Saade, George R; Esplin, M Sean; Sadovsky, Yoel; Reddy, Uma M; Ilekis, John; Varner, Michael; Biggio, Joseph R

    2015-03-01

    Preterm birth is the leading cause of infant morbidity and mortality. Despite extensive research, the genetic contributions to spontaneous preterm birth (SPTB) are not well understood. Term controls were matched with cases by race/ethnicity, maternal age, and parity prior to recruitment. Genotyping was performed using Affymetrix SNP Array 6.0 assays. Statistical analyses utilized PLINK to compare allele occurrence rates between case and control groups, and incorporated quality control and multiple-testing adjustments. We analyzed DNA samples from mother-infant pairs from early SPTB cases (20(0/7)-33(6/7) weeks, 959 women and 979 neonates) and term delivery controls (39(0/7)-41(6/7) weeks, 960 women and 985 neonates). For validation purposes, we included an independent validation cohort consisting of early SPTB cases (293 mothers and 243 infants) and term controls (200 mothers and 149 infants). Clustering analysis revealed no population stratification. Multiple maternal SNPs were identified with association P-values between 10×10(-5) and 10×10(-6). The most significant maternal SNP was rs17053026 on chromosome 3 with an odds ratio (OR) 0.44 with a P-value of 1.0×10(-6). Two neonatal SNPs reached the genome-wide significance threshold, including rs17527054 on chromosome 6p22 with a P-value of 2.7×10(-12) and rs3777722 on chromosome 6q27 with a P-value of 1.4×10(-10). However, we could not replicate these findings after adjusting for multiple comparisons in a validation cohort. This is the first report of a genome-wide case-control study to identify single nucleotide polymorphisms (SNPs) that correlate with SPTB.

  1. The essential detail: the genetics and genomics of the primate immune response.

    PubMed

    Shen, Shu; Pyo, Chul-Woo; Vu, Quyen; Wang, Ruihan; Geraghty, Daniel E

    2013-01-01

    Next-generation sequencing technologies have led to rapid progress in the fields of human and nonhuman primate (NHP) genomics. The less expensive and more efficient technologies have enabled the sequencing of human genomes from multiple populations and the sequencing of many NHP species. NHP genomes have been sequenced for two main reasons: (1) their importance as animal models in biomedical research and (2) their phylogenetic relationship to humans and use in derivative evolutionary studies. NHPs are valuable animal models for a variety of diseases, most notably for human immunodeficiency virus/acquired immunodeficiency syndrome research, and for vaccine development. Knowledge about the variation in primate immune response loci can provide essential insights into relevant immune function. However, perhaps ironically considering their central role in infectious disease, the accumulation of sequence detail from genomic regions harboring immune response loci, such as the major histocompatibility complex and killer immunoglobulin-like receptors, has been slow. This deficiency is, at least in part, due to the highly repetitive and polymorphic nature of these regions and is being addressed by the application of special approaches to targeted sequencing of the immune response genomic regions. We discuss one such targeting approach that has successfully yielded complete phased genomic sequences from complex genomic regions and is now being used to resequence macaque and other primate major histocompatibility complex regions. The essential detail contained within the genomics of the NHP immune response is now being assembled, and the realization of precise comparisons between NHP and human immune genomics is close at hand, further enhancing the NHP animal model in the search for effective treatments for human disease.

  2. Responsiveness of the core set, response criteria, and utilities in early rheumatoid arthritis

    PubMed Central

    Verhoeven, A; Boers, M; van der Linden, S

    2000-01-01

    OBJECTIVE—Validation of responsiveness and discriminative power of the World Health Organisation/International League of Associations for Rheumatology (WHO/ILAR) core set, the American College of Rheumatology (ACR), and European League for Rheumatology (EULAR) criteria for improvement/response, and other single and combined measures (indices) in a trial in patients with early rheumatoid arthritis (RA).
METHODS—Ranking of measures by response (standardised response means and effect sizes) and between-group discrimination (unpaired t test and χ2 values) at two time points in the COBRA study. This study included 155 patients with early RA randomly allocated to two treatment groups with distinct levels of expected response: combined treatment, high response; sulfasalazine treatment, moderate response.
RESULTS—At week 16, standardised response means of core set measures ranged between 0.8 and 3.5 for combined treatment and between 0.4 and 1.2 for sulfasalazine treatment (95% confidence interval ±0.25). Performance of patient oriented measures (for example, pain, global assessment) was best when the questions were focused on the disease. The most responsive single measure was the patient's assessment of change in disease activity, at 3.5. Patient utility, a generic health status measure, was moderately (rating scale) to poorly (standard gamble) responsive. Response means of most indices (combined measures) exceeded 2.0, the simple count of core set measures improved by 20% was most responsive at 4.1. Discrimination performance yielded similar but not identical results: best discrimination between treatment groups was achieved by the EULAR response and ACR improvement criteria (at 20% and other percentage levels), the pooled index, and the disease activity score (DAS), but also by the Health Assessment Questionnaire (HAQ) and grip strength.
CONCLUSIONS—Responsiveness and discrimination between levels of response are not identical concepts, and

  3. Freedom and Responsibility in Synthetic Genomics: The Synthetic Yeast Project

    PubMed Central

    Sliva, Anna; Yang, Huanming; Boeke, Jef D.; Mathews, Debra J. H.

    2015-01-01

    First introduced in 2011, the Synthetic Yeast Genome (Sc2.0) Project is a large international synthetic genomics project that will culminate in the first eukaryotic cell (Saccharomyces cerevisiae) with a fully synthetic genome. With collaborators from across the globe and from a range of institutions spanning from do-it-yourself biology (DIYbio) to commercial enterprises, it is important that all scientists working on this project are cognizant of the ethical and policy issues associated with this field of research and operate under a common set of principles. In this commentary, we survey the current ethics and regulatory landscape of synthetic biology and present the Sc2.0 Statement of Ethics and Governance to which all members of the project adhere. This statement focuses on four aspects of the Sc2.0 Project: societal benefit, intellectual property, safety, and self-governance. We propose that such project-level agreements are an important, valuable, and flexible model of self-regulation for similar global, large-scale synthetic biology projects in order to maximize the benefits and minimize potential harms. PMID:26272997

  4. Insights into the dynamics of genome size and chromosome evolution in the early diverging angiosperm lineage Nymphaeales (water lilies).

    PubMed

    Pellicer, J; Kelly, L J; Magdalena, C; Leitch, I J

    2013-08-01

    Nymphaeales are the most species-rich lineage of the earliest diverging angiosperms known as the ANA grade (Amborellales, Nymphaeales, Austrobaileyales), and they have received considerable attention from morphological, physiological, and ecological perspectives. Although phylogenetic relationships between these three lineages of angiosperms are mainly well resolved, insights at the whole genome level are still limited because of a dearth of information. To address this, genome sizes and chromosome numbers in 34 taxa, comprising 28 species were estimated and analysed together with previously published data to provide an overview of genome size and chromosome diversity in Nymphaeales. Overall, genome sizes were shown to vary 10-fold and chromosome numbers and ploidy levels ranged from 2n = 2x = 18 to 2n = 16x = ∼224. Distinct patterns of genome diversity were apparent, reflecting the differential incidence of polyploidy, changes in repetitive DNA content, and chromosome rearrangements within and between genera. Using model-based approaches, ancestral genome size and basic chromosome numbers were reconstructed to provide insights into the dynamics of genome size and chromosome number evolution. Finally, by combining additional data from Amborellales and Austrobaileyales, a comprehensive overview of genome sizes and chromosome numbers in these early diverging angiosperms is presented.

  5. Evasion of early antiviral responses by herpes simplex viruses.

    PubMed

    Suazo, Paula A; Ibañez, Francisco J; Retamal-Díaz, Angello R; Paz-Fiblas, Marysol V; Bueno, Susan M; Kalergis, Alexis M; González, Pablo A

    2015-01-01

    Besides overcoming physical constraints, such as extreme temperatures, reduced humidity, elevated pressure, and natural predators, human pathogens further need to overcome an arsenal of antimicrobial components evolved by the host to limit infection, replication and optimally, reinfection. Herpes simplex virus-1 (HSV-1) and herpes simplex virus-2 (HSV-2) infect humans at a high frequency and persist within the host for life by establishing latency in neurons. To gain access to these cells, herpes simplex viruses (HSVs) must replicate and block immediate host antiviral responses elicited by epithelial cells and innate immune components early after infection. During these processes, infected and noninfected neighboring cells, as well as tissue-resident and patrolling immune cells, will sense viral components and cell-associated danger signals and secrete soluble mediators. While type-I interferons aim at limiting virus spread, cytokines and chemokines will modulate resident and incoming immune cells. In this paper, we discuss recent findings relative to the early steps taking place during HSV infection and replication. Further, we discuss how HSVs evade detection by host cells and the molecular mechanisms evolved by these viruses to circumvent early antiviral mechanisms, ultimately leading to neuron infection and the establishment of latency.

  6. Early growth response 3 (Egr-3) is induced by transforming growth factor-β and regulates fibrogenic responses.

    PubMed

    Fang, Feng; Shangguan, Anna J; Kelly, Kathleen; Wei, Jun; Gruner, Katherine; Ye, Boping; Wang, Wenxia; Bhattacharyya, Swati; Hinchcliff, Monique E; Tourtellotte, Warren G; Varga, John

    2013-10-01

    Members of the early growth response (Egr) gene family of transcription factors have nonredundant biological functions. Although Egr-3 is implicated primarily in neuromuscular development and immunity, its regulation and role in tissue repair and fibrosis has not been studied. We now show that in normal skin fibroblasts, Egr-3 was potently induced by transforming growth factor-β via canonical Smad3. Moreover, transient Egr-3 overexpression was sufficient to stimulate fibrotic gene expression, whereas deletion of Egr-3 resulted in substantially attenuated transforming growth factor-β responses. Genome-wide expression profiling in fibroblasts showed that genes associated with tissue remodeling and wound healing were prominently up-regulated by Egr-3. Notably, <5% of fibroblast genes regulated by Egr-1 or Egr-2 were found to be coregulated by Egr-3, revealing substantial functional divergence among these Egr family members. In a mouse model of scleroderma, development of dermal fibrosis was accompanied by accumulation of Egr-3-positive myofibroblasts in the lesional tissue. Moreover, skin biopsy samples from patients with scleroderma showed elevated Egr-3 levels in the dermis, and Egr-3 mRNA levels correlated with the extent of skin involvement. These results provide the first evidence that Egr-3, a functionally distinct member of the Egr family with potent effects on inflammation and immunity, is up-regulated in scleroderma and is necessary and sufficient for profibrotic responses, suggesting important and distinct roles in the pathogenesis of fibrosis.

  7. Genomic, transcriptomic and phenomic variation reveals the complex adaptation to stress response of modern maize breeding

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Early maize adaptation to different agricultural environments was an important process associated with the creation of a stable food supply that allowed the evolution of human civilization in the Americas. To explore the mechanisms of maize adaptation, genomic, transcriptomic and phenomic data were ...

  8. Detection of early plant stress responses in hyperspectral images

    NASA Astrophysics Data System (ADS)

    Behmann, Jan; Steinrücken, Jörg; Plümer, Lutz

    2014-07-01

    Early stress detection in crop plants is highly relevant, but hard to achieve. We hypothesize that close range hyperspectral imaging is able to uncover stress related processes non-destructively in the early stages which are invisible to the human eye. We propose an approach which combines unsupervised and supervised methods in order to identify several stages of progressive stress development from series of hyperspectral images. Stress of an entire plant is detected by stress response levels at pixel scale. The focus is on drought stress in barley (Hordeum vulgare). Unsupervised learning is used to separate hyperspectral signatures into clusters related to different stages of stress response and progressive senescence. Whereas all such signatures may be found in both, well watered and drought stressed plants, their respective distributions differ. Ordinal classification with Support Vector Machines (SVM) is used to quantify and visualize the distribution of progressive stages of senescence and to separate well watered from drought stressed plants. For each senescence stage a distinctive set of most relevant Vegetation Indices (VIs) is identified. The method has been applied on two experiments involving potted barley plants under well watered and drought stress conditions in a greenhouse. Drought stress is detected up to ten days earlier than using NDVI. Furthermore, it is shown that some VIs have overall relevance, while others are specific to particular senescence stages. The transferability of the method to the field is illustrated by an experiment on maize (Zea mays).

  9. Plasma-Sprayed Titanium Patterns for Enhancing Early Cell Responses

    NASA Astrophysics Data System (ADS)

    Shi, Yunqi; Xie, Youtao; Pan, Houhua; Zheng, Xuebin; Huang, Liping; Ji, Fang; Li, Kai

    2016-06-01

    Titanium coating has been widely used as a biocompatible metal in biomedical applications. However, the early cell responses and long-term fixation of titanium implants are not satisfied. To obviate these defects, in this paper, micro-post arrays with various widths (150-1000 μm) and intervals (100-300 μm) were fabricated on the titanium substrate by template-assisted plasma spraying technology. In vitro cell culture experiments showed that MC3T3-E1 cells exhibited significantly higher osteogenic differentiation as well as slightly improved adhesion and proliferation on the micro-patterned coatings compared with the traditional one. The cell number on the pattern with 1000 µm width reached 130% after 6 days of incubation, and the expressions of osteopontin (OPN) as well as osteocalcin (OC) were doubled. No obvious difference was found in cell adhesion on various size patterns. The present micro-patterned coatings proposed a new modification method for the traditional plasma spraying technology to enhance the early cell responses and convenience for the bone in-growth.

  10. Metagenomics, metatranscriptomics and single cell genomics reveal functional response of active Oceanospirillales to Gulf oil spill

    SciTech Connect

    Mason, Olivia U.; Hazen, Terry C.; Borglin, Sharon; Chain, Patrick S. G.; Dubinsky, Eric A.; Fortney, Julian L.; Han, James; Holman, Hoi-Ying N.; Hultman, Jenni; Lamendella, Regina; Mackelprang, Rachel; Malfatti, Stephanie; Tom, Lauren M.; Tringe, Susannah G.; Woyke, Tanja; Zhou, Jizhong; Rubin, Edward M.; Jansson, Janet K.

    2012-06-12

    The Deepwater Horizon oil spill in the Gulf of Mexico resulted in a deep-sea hydrocarbon plume that caused a shift in the indigenous microbial community composition with unknown ecological consequences. Early in the spill history, a bloom of uncultured, thus uncharacterized, members of the Oceanospirillales was previously detected, but their role in oil disposition was unknown. Here our aim was to determine the functional role of the Oceanospirillales and other active members of the indigenous microbial community using deep sequencing of community DNA and RNA, as well as single-cell genomics. Shotgun metagenomic and metatranscriptomic sequencing revealed that genes for motility, chemotaxis and aliphatic hydrocarbon degradation were significantly enriched and expressed in the hydrocarbon plume samples compared with uncontaminated seawater collected from plume depth. In contrast, although genes coding for degradation of more recalcitrant compounds, such as benzene, toluene, ethylbenzene, total xylenes and polycyclic aromatic hydrocarbons, were identified in the metagenomes, they were expressed at low levels, or not at all based on analysis of the metatranscriptomes. Isolation and sequencing of two Oceanospirillales single cells revealed that both cells possessed genes coding for n-alkane and cycloalkane degradation. Specifically, the near-complete pathway for cyclohexane oxidation in the Oceanospirillales single cells was elucidated and supported by both metagenome and metatranscriptome data. The draft genome also included genes for chemotaxis, motility and nutrient acquisition strategies that were also identified in the metagenomes and metatranscriptomes. These data point towards a rapid response of members of the Oceanospirillales to aliphatic hydrocarbons in the deep sea.

  11. Identification of a Genomic Signature Predicting for Recurrence in Early Stage Ovarian Cancer

    DTIC Science & Technology

    2013-10-01

    25 Patient information sheet You have previously been treated for early ovarian cancer at the Radium ...patients receiving chemotherapy does not need it. At the Radium Hospital we use a method with determination of the amount of DNA to identify patients...names. This code list will be kept at the Radium Hospital and only staff personnel responsible for this study will have access. All analyses will be

  12. Local Adaptation at the Transcriptome Level in Brown Trout: Evidence from Early Life History Temperature Genomic Reaction Norms

    PubMed Central

    Meier, Kristian; Hansen, Michael Møller; Normandeau, Eric; Mensberg, Karen-Lise D.; Frydenberg, Jane; Larsen, Peter Foged; Bekkevold, Dorte; Bernatchez, Louis

    2014-01-01

    Local adaptation and its underlying molecular basis has long been a key focus in evolutionary biology. There has recently been increased interest in the evolutionary role of plasticity and the molecular mechanisms underlying local adaptation. Using transcriptome analysis, we assessed differences in gene expression profiles for three brown trout (Salmo trutta) populations, one resident and two anadromous, experiencing different temperature regimes in the wild. The study was based on an F2 generation raised in a common garden setting. A previous study of the F1 generation revealed different reaction norms and significantly higher QST than FST among populations for two early life-history traits. In the present study we investigated if genomic reaction norm patterns were also present at the transcriptome level. Eggs from the three populations were incubated at two temperatures (5 and 8 degrees C) representing conditions encountered in the local environments. Global gene expression for fry at the stage of first feeding was analysed using a 32k cDNA microarray. The results revealed differences in gene expression between populations and temperatures and population × temperature interactions, the latter indicating locally adapted reaction norms. Moreover, the reaction norms paralleled those observed previously at early life-history traits. We identified 90 cDNA clones among the genes with an interaction effect that were differently expressed between the ecologically divergent populations. These included genes involved in immune- and stress response. We observed less plasticity in the resident as compared to the anadromous populations, possibly reflecting that the degree of environmental heterogeneity encountered by individuals throughout their life cycle will select for variable level of phenotypic plasticity at the transcriptome level. Our study demonstrates the usefulness of transcriptome approaches to identify genes with different temperature reaction norms. The

  13. Selection for early response to photostimulation in broiler breeders.

    PubMed

    Tyler, N C; Gous, R M

    2011-08-01

    1. To determine if selection for early response to photostimulation could be successful, 150 male broiler breeders were photostimulated at 8 weeks of age. The first 20 to produce a semen sample and have a reddened comb with an area > 10 cm2 were selected as responders (R) and 20 birds that did not show these signs of sexual development were chosen as non-responders (NR). Once sexually mature, 8 birds from each group that consistently produced a semen sample were mated with both egg-type hybrids and broiler breeder females to observe the response to 8-week photostimulation in the as-hatched offspring. 2. The AFE of the F1 females with NR or R paternity and egg-type hybrid layer maternity (F1L) were similar, but AFE was advanced in birds from R relative to NR paternity when they had broiler breeder maternity (F1B). 3. Date following a normal distribution of AFE were extracted from the overall data set. This group included offspring from both NR and R paternity, but AFE in F1L and F1B females with R paternity was advanced compared to those with NR paternity. 4. Mean testis weights, or age at most rapid testis growth predicted using parameters from Tyler and Gous (2009), of F1 males were not significantly different in birds with NR or R paternity. A strong correlation was found between predicted age at most rapid growth and AFE of full sibs and so it is likely that an advance in AFE in female offspring would also result in an advance in age of testis development of males. 5. There was no significant difference in 21-d body weight of F1B females of NR or R paternity, but the 21-d body weights of F1L females were higher from R than from NR sires, suggesting that although fertility and meat-type traits are often negatively correlated, there was no adverse effect of selection for responsiveness to early photostimulation and broiler growth rates to 21 d. 6. These findings showed that the response to early stimulation is heritable, and should be useful to the broiler breeder

  14. Novel Comparative Pattern Count Analysis Reveals a Chronic Ethanol-Induced Dynamic Shift in Immediate Early NF-κB Genome-wide Promoter Binding During Liver Regeneration

    PubMed Central

    Kuttippurathu, Lakshmi; Patra, Biswanath; Hoek, Jan B; Vadigepalli, Rajanikanth

    2016-01-01

    Liver regeneration after partial hepatectomy is a clinically important process that is impaired by adaptation to chronic alcohol intake. We focused on the initial time points following partial hepatectomy (PHx) to analyze genome-wide binding activity of NF-κB, a key immediate early regulator. We investigated the effect of chronic alcohol intake on immediate early NF-κB genome-wide localization, in the adapted state as well as in response to partial hepatectomy, using chromatin immunoprecipitation followed by promoter microarray analysis. We found many ethanol-specific NF-κB binding target promoters in the ethanol-adapted state, corresponding to regulation of biosynthetic processes, oxidation-reduction and apoptosis. Partial hepatectomy induced a diet-independent shift in NF-κB binding loci relative to the transcription start sites. We employed a novel pattern count analysis to exhaustively enumerate and compare the number of promoters corresponding to the temporal binding patterns in ethanol and pair-fed control groups. The highest pattern count corresponded to promoters with NF-κB binding exclusively in the ethanol group at 1h post PHx. This set was associated with regulation of cell death, response to oxidative stress, histone modification, mitochondrial function, and metabolic processes. Integration with the global gene expression profiles to identify putative transcriptional consequences of NF-κB binding patterns revealed that several of ethanol-specific 1h binding targets showed ethanol-specific differential expression through 6h post PHx. Motif analysis yielded co-incident binding loci for STAT3, AP-1, CREB, C/EBP-β, PPAR-γ and C/EBP-α, likely participating in co-regulatory modules with NF-κB in shaping the immediate early response to PHx. We conclude that adaptation to chronic ethanol intake disrupts the NF-κB promoter binding landscape with consequences for the immediate early gene regulatory response to the acute challenge of PHx. PMID:26847025

  15. Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer

    PubMed Central

    Tie, J.; Kinde, I.; Wang, Y.; Wong, H. L.; Roebert, J.; Christie, M.; Tacey, M.; Wong, R.; Singh, M.; Karapetis, C. S.; Desai, J.; Tran, B.; Strausberg, R. L.; Diaz, L. A.; Papadopoulos, N.; Kinzler, K. W.; Vogelstein, B.; Gibbs, P.

    2015-01-01

    Background Early indicators of treatment response in metastatic colorectal cancer (mCRC) could conceivably be used to optimize treatment. We explored early changes in circulating tumor DNA (ctDNA) levels as a marker of therapeutic efficacy. Patients and methods This prospective study involved 53 mCRC patients receiving standard first-line chemotherapy. Both ctDNA and CEA were assessed in plasma collected before treatment, 3 days after treatment and before cycle 2. Computed tomography (CT) scans were carried out at baseline and 8–10 weeks and were centrally assessed using RECIST v1.1 criteria. Tumors were sequenced using a panel of 15 genes frequently mutated in mCRC to identify candidate mutations for ctDNA analysis. For each patient, one tumor mutation was selected to assess the presence and the level of ctDNA in plasma samples using a digital genomic assay termed Safe-SeqS. Results Candidate mutations for ctDNA analysis were identified in 52 (98.1%) of the tumors. These patient-specific candidate tissue mutations were detectable in the cell-free DNA from the plasma of 48 of these 52 patients (concordance 92.3%). Significant reductions in ctDNA (median 5.7-fold; P < 0.001) levels were observed before cycle 2, which correlated with CT responses at 8–10 weeks (odds ratio = 5.25 with a 10-fold ctDNA reduction; P = 0.016). Major reductions (≥10-fold) versus lesser reductions in ctDNA precycle 2 were associated with a trend for increased progression-free survival (median 14.7 versus 8.1 months; HR = 1.87; P = 0.266). Conclusions ctDNA is detectable in a high proportion of treatment naïve mCRC patients. Early changes in ctDNA during first-line chemotherapy predict the later radiologic response. PMID:25851626

  16. Enhancing early child care quality and learning for toddlers at risk: the responsive early childhood program.

    PubMed

    Landry, Susan H; Zucker, Tricia A; Taylor, Heather B; Swank, Paul R; Williams, Jeffrey M; Assel, Michael; Crawford, April; Huang, Weihua; Clancy-Menchetti, Jeanine; Lonigan, Christopher J; Phillips, Beth M; Eisenberg, Nancy; Spinrad, Tracy L; de Villiers, Jill; de Villiers, Peter; Barnes, Marcia; Starkey, Prentice; Klein, Alice

    2014-02-01

    Despite reports of positive effects of high-quality child care, few experimental studies have examined the process of improving low-quality center-based care for toddler-age children. In this article, we report intervention effects on child care teachers' behaviors and children's social, emotional, behavioral, early literacy, language, and math outcomes as well as the teacher-child relationship. The intervention targeted the use of a set of responsive teacher practices, derived from attachment and sociocultural theories, and a comprehensive curriculum. Sixty-five childcare classrooms serving low-income 2- and 3-year-old children were randomized into 3 conditions: business-as-usual control, Responsive Early Childhood Curriculum (RECC), and RECC plus explicit social-emotional classroom activities (RECC+). Classroom observations showed greater gains for RECC and RECC+ teachers' responsive practices including helping children manage their behavior, establishing a predictable schedule, and use of cognitively stimulating activities (e.g., shared book reading) compared with controls; however, teacher behaviors did not differ for focal areas such as sensitivity and positive discipline supports. Child assessments demonstrated that children in the interventions outperformed controls in areas of social and emotional development, although children's performance in control and intervention groups was similar for cognitive skills (language, literacy, and math). Results support the positive impact of responsive teachers and environments providing appropriate support for toddlers' social and emotional development. Possible explanations for the absence of systematic differences in children's cognitive skills are considered, including implications for practice and future research targeting low-income toddlers.

  17. Broad CTL Response in Early HIV Infection Drives Multiple Concurrent CTL Escapes.

    PubMed

    Leviyang, Sivan; Ganusov, Vitaly V

    2015-10-01

    Recent studies have highlighted the ability of HIV to escape from cytotoxic T lymphocyte (CTL) responses that concurrently target multiple viral epitopes. Yet, the viral dynamics involved in such escape are incompletely understood. Previous analyses have made several strong assumptions regarding HIV escape from CTL responses such as independent or non-concurrent escape from individual CTL responses. Using experimental data from evolution of HIV half genomes in four patients we observe concurrent viral escape from multiple CTL responses during early infection (first 100 days of infection), providing confirmation of a recent result found in a study of one HIV-infected patient. We show that current methods of estimating CTL escape rates, based on the assumption of independent escapes, are biased and perform poorly when CTL escape proceeds concurrently at multiple epitopes. We propose a new method for analyzing longitudinal sequence data to estimate the rate of CTL escape across multiple epitopes; this method involves few parameters and performs well in simulation studies. By applying our novel method to experimental data, we find that concurrent multiple escapes occur at rates between 0.03 and 0.4 day(-1), a relatively broad range that reflects uncertainty due to sparse sampling and wide ranges of parameter values. However, we show that concurrent escape at rates 0.1-0.2 day(-1) across multiple epitopes is consistent with our patient datasets.

  18. State of the Art: Response Assessment in Lung Cancer in the Era of Genomic Medicine

    PubMed Central

    Hatabu, Hiroto; Johnson, Bruce E.; McLoud, Theresa C.

    2014-01-01

    Tumor response assessment has been a foundation for advances in cancer therapy. Recent discoveries of effective targeted therapy for specific genomic abnormalities in lung cancer and their clinical application have brought revolutionary advances in lung cancer therapy and transformed the oncologist’s approach to patients with lung cancer. Because imaging is a major method of response assessment in lung cancer both in clinical trials and practice, radiologists must understand the genomic alterations in lung cancer and the rapidly evolving therapeutic approaches to effectively communicate with oncology colleagues and maintain the key role in lung cancer care. This article describes the origin and importance of tumor response assessment, presents the recent genomic discoveries in lung cancer and therapies directed against these genomic changes, and describes how these discoveries affect the radiology community. The authors then summarize the conventional Response Evaluation Criteria in Solid Tumors and World Health Organization guidelines, which continue to be the major determinants of trial endpoints, and describe their limitations particularly in an era of genomic-based therapy. More advanced imaging techniques for lung cancer response assessment are presented, including computed tomography tumor volume and perfusion, dynamic contrast material–enhanced and diffusion-weighted magnetic resonance imaging, and positron emission tomography with fluorine 18 fluorodeoxyglucose and novel tracers. State-of-art knowledge of lung cancer biology, treatment, and imaging will help the radiology community to remain effective contributors to the personalized care of lung cancer patients. © RSNA, 2014 PMID:24661292

  19. DNA repair efficiency in germ cells and early mouse embryos and consequences for radiation-induced transgenerational genomic damage

    SciTech Connect

    Marchetti, Francesco; Wyrobek, Andrew J.

    2009-01-18

    Exposure to ionizing radiation and other environmental agents can affect the genomic integrity of germ cells and induce adverse health effects in the progeny. Efficient DNA repair during gametogenesis and the early embryonic cycles after fertilization is critical for preventing transmission of DNA damage to the progeny and relies on maternal factors stored in the egg before fertilization. The ability of the maternal repair machinery to repair DNA damage in both parental genomes in the fertilizing egg is especially crucial for the fertilizing male genome that has not experienced a DNA repair-competent cellular environment for several weeks prior to fertilization. During the DNA repair-deficient period of spermatogenesis, DNA lesions may accumulate in sperm and be carried into the egg where, if not properly repaired, could result in the formation of heritable chromosomal aberrations or mutations and associated birth defects. Studies with female mice deficient in specific DNA repair genes have shown that: (i) cell cycle checkpoints are activated in the fertilized egg by DNA damage carried by the sperm; and (ii) the maternal genotype plays a major role in determining the efficiency of repairing genomic lesions in the fertilizing sperm and directly affect the risk for abnormal reproductive outcomes. There is also growing evidence that implicates DNA damage carried by the fertilizing gamete as a mediator of postfertilization processes that contribute to genomic instability in subsequent generations. Transgenerational genomic instability most likely involves epigenetic mechanisms or error-prone DNA repair processes in the early embryo. Maternal and embryonic DNA repair processes during the early phases of mammalian embryonic development can have far reaching consequences for the genomic integrity and health of subsequent generations.

  20. The highest-copy repeats are methylated in the small genome of the early divergent vascular plant Selaginella moellendorffii

    PubMed Central

    Chan, Agnes P; Melake-Berhan, Admasu; O'Brien, Kimberly; Buckley, Stephanie; Quan, Hui; Chen, Dan; Lewis, Matthew; Banks, Jo Ann; Rabinowicz, Pablo D

    2008-01-01

    Background The lycophyte Selaginella moellendorffii is a vascular plant that diverged from the fern/seed plant lineage at least 400 million years ago. Although genomic information for S. moellendorffii is starting to be produced, little is known about basic aspects of its molecular biology. In order to provide the first glimpse to the epigenetic landscape of this early divergent vascular plant, we used the methylation filtration technique. Methylation filtration genomic libraries select unmethylated DNA clones due to the presence of the methylation-dependent restriction endonuclease McrBC in the bacterial host. Results We conducted a characterization of the DNA methylation patterns of the S. moellendorffii genome by sequencing a set of S. moellendorffii shotgun genomic clones, along with a set of methylation filtered clones. Chloroplast DNA, which is typically unmethylated, was enriched in the filtered library relative to the shotgun library, showing that there is DNA methylation in the extremely small S. moellendorffii genome. The filtered library also showed enrichment in expressed and gene-like sequences, while the highest-copy repeats were largely under-represented in this library. These results show that genes and repeats are differentially methylated in the S. moellendorffii genome, as occurs in other plants studied. Conclusion Our results shed light on the genome methylation pattern in a member of a relatively unexplored plant lineage. The DNA methylation data reported here will help understanding the involvement of this epigenetic mark in fundamental biological processes, as well as the evolutionary aspects of epigenetics in land plants. PMID:18549478

  1. Small cell ovarian carcinoma: genomic stability and responsiveness to therapeutics

    PubMed Central

    2013-01-01

    Background The biology of small cell ovarian carcinoma of the hypercalcemic type (SCCOHT), which is a rare and aggressive form of ovarian cancer, is poorly understood. Tumourigenicity, in vitro growth characteristics, genetic and genomic anomalies, and sensitivity to standard and novel chemotherapeutic treatments were investigated in the unique SCCOHT cell line, BIN-67, to provide further insight in the biology of this rare type of ovarian cancer. Method The tumourigenic potential of BIN-67 cells was determined and the tumours formed in a xenograft model was compared to human SCCOHT. DNA sequencing, spectral karyotyping and high density SNP array analysis was performed. The sensitivity of the BIN-67 cells to standard chemotherapeutic agents and to vesicular stomatitis virus (VSV) and the JX-594 vaccinia virus was tested. Results BIN-67 cells were capable of forming spheroids in hanging drop cultures. When xenografted into immunodeficient mice, BIN-67 cells developed into tumours that reflected the hypercalcemia and histology of human SCCOHT, notably intense expression of WT-1 and vimentin, and lack of expression of inhibin. Somatic mutations in TP53 and the most common activating mutations in KRAS and BRAF were not found in BIN-67 cells by DNA sequencing. Spectral karyotyping revealed a largely normal diploid karyotype (in greater than 95% of cells) with a visibly shorter chromosome 20 contig. High density SNP array analysis also revealed few genomic anomalies in BIN-67 cells, which included loss of heterozygosity of an estimated 16.7 Mb interval on chromosome 20. SNP array analyses of four SCCOHT samples also indicated a low frequency of genomic anomalies in the majority of cases. Although resistant to platinum chemotherapeutic drugs, BIN-67 cell viability in vitro was reduced by >75% after infection with oncolytic viruses. Conclusions These results show that SCCOHT differs from high-grade serous carcinomas by exhibiting few chromosomal anomalies and lacking TP53

  2. Early genetic responses in rat vascular tissue after simulated diving.

    PubMed

    Eftedal, Ingrid; Jørgensen, Arve; Røsbjørgen, Ragnhild; Flatberg, Arnar; Brubakk, Alf O

    2012-12-18

    Diving causes a transient reduction of vascular function, but the mechanisms behind this are largely unknown. The aim of this study was therefore to analyze genetic reactions that may be involved in acute changes of vascular function in divers. Rats were exposed to 709 kPa of hyperbaric air (149 kPa Po(2)) for 50 min followed by postdive monitoring of vascular bubble formation and full genome microarray analysis of the aorta from diving rats (n = 8) and unexposed controls (n = 9). Upregulation of 23 genes was observed 1 h after simulated diving. The differential gene expression was characteristic of cellular responses to oxidative stress, with functions of upregulated genes including activation and fine-tuning of stress-responsive transcription, cytokine/cytokine receptor signaling, molecular chaperoning, and coagulation. By qRT-PCR, we verified increased transcription of neuron-derived orphan receptor-1 (Nr4a3), plasminogen activator inhibitor 1 (Serpine1), cytokine TWEAK receptor FN14 (Tnfrsf12a), transcription factor class E basic helix-loop-helix protein 40 (Bhlhe40), and adrenomedullin (Adm). Hypoxia-inducible transcription factor HIF1 subunit HIF1-α was stabilized in the aorta 1 h after diving, and after 4 h there was a fivefold increase in total protein levels of the procoagulant plasminogen activator inhibitor 1 (PAI1) in blood plasma from diving rats. The study did not have sufficient power for individual assessment of effects of hyperoxia and decompression-induced bubbles on postdive gene expression. However, differential gene expression in rats without venous bubbles was similar to that of all the diving rats, indicating that elevated Po(2) instigated the observed genetic reactions.

  3. Human Macrophage Response to L. (Viannia) panamensis: Microarray Evidence for an Early Inflammatory Response

    PubMed Central

    Rojas, Ricardo; Ettinger, Nicholas A.; Tikhonova, Irina; Alexander, Neal D.; Valderrama, Liliana; Hager, Janet; Wilson, Mary E.; Lin, Aiping; Zhao, Hongyu; Saravia, Nancy G.; McMahon-Pratt, Diane

    2012-01-01

    Background Previous findings indicate that susceptibility to Leishmania (Viannia) panamensis infection of monocyte-derived macrophages from patients and asymptomatically infected individuals were associated with the adaptive immune response and clinical outcome. Methodology/Principal Findings To understand the basis for this difference we examined differential gene expression of human monocyte-derived macrophages following exposure to L. (V.) panamensis. Gene activation profiles were determined using macrophages from healthy volunteers cultured with or without stationary phase promastigotes of L. (V.) panamensis. Significant changes in expression (>1.5-fold change; p<0.05; up- or down-regulated) were identified at 0.5, 4 and 24 hours. mRNA abundance profiles varied over time, with the highest level of activation occurring at earlier time points (0.5 and 4 hrs). In contrast to observations for other Leishmania species, most significantly changed mRNAs were up- rather than down-regulated, especially at early time points. Up-regulated transcripts over the first 24 hours belonged to pathways involving eicosanoid metabolism, oxidative stress, activation of PKC through G protein coupled receptors, or mechanism of gene regulation by peroxisome proliferators via PPARα. Additionally, a marked activation of Toll-receptor mediated pathways was observed. Comparison with published microarray data from macrophages infected with L. (Leishmania) chagasi indicate differences in the regulation of genes involved in signaling, motility and the immune response. Conclusions Results show that the early (0.5 to 24 hours) human monocyte-derived macrophage response to L. (Viannia) panamensis is not quiescent, in contrast to published reports examining later response times (48–96 hours). Early macrophage responses are important for the developing cellular response at the site of infection. The kinetics and the mRNA abundance profiles induced by L. (Viannia) panamensis illustrate the

  4. Low residual proliferation after short-term letrozole therapy is an early predictive marker of response in high proliferative ER-positive breast cancer.

    PubMed

    Bedard, Philippe L; Singhal, Sandeep K; Ignatiadis, Michail; Bradbury, Ian; Haibe-Kains, Benjamin; Desmedt, Christine; Loi, Sherene; Evans, Dean B; Michiels, Stefan; Dixon, J Michael; Miller, William R; Piccart, Martine J; Sotiriou, Christos

    2011-12-01

    The gene expression grade index (GGI) is a 97-gene algorithm that measures proliferation and divides intermediate histological grade tumors into two distinct groups. We investigated the association between early changes in GGI and clinical response to neoadjuvant letrozole and compared this to Ki67 values. The paired gene expression data at the beginning and after 10-14 days of neoadjuvant letrozole treatment were available for 52 post-menopausal patients with estrogen receptor (ER)-positive breast cancer. Baseline values and changes in GGI, Ki67, and RNA expression modules representing oncogenic signaling pathways were compared to sonographic tumor volume changes after 3 months of treatment in the subsets of patients defined by high and low baseline GGI. The clinical response was observed in 80% genomic low-grade (24/30) and 59% genomic high-grade (13/22) tumors (P=0.10). Low residual proliferation after 10-14 days of neoadjuvant letrozole therapy, measured by either GGI or Ki67, was associated with sonographic response in genomic high-grade (GGI, P=0.003; Ki67, P=0.017) but not genomic low-grade (GGI, P=0.25; Ki67, P=1.0) tumors. The analysis of expression modules suggested that sonographic response to letrozole in genomic high-grade tumors was associated with an early reduction in IGF1 signaling (unadjusted P=0.018). The major conclusion of this study is that the early assessment of proliferation after short-term endocrine therapy may be useful to evaluate endocrine responsiveness, particularly in genomic high-grade ER-positive breast cancer.

  5. The early epigenetic response to ozone: impacts on DNA ...

    EPA Pesticide Factsheets

    Epigenetics have been increasingly recognized as a mechanism linking environment and gene expression. Despite awareness of the role of DNA methylation and hydroxymethylation as potential drivers of the response to air pollutants, very little work has been performed investigating the direct epigenetic effects following exposure to ambient air pollution. Thus the purpose of this study was to investigate the early epigenetic response to ozone in comparison to the epigenetic modifier 5-aza-2'-deoxycytidine (5-Aza) in rats. 12 week old, male Long-Evans rats (n=16) were exposed to 4 hours of whole-body 1.0 ppm ozone or air and immediately euthanized. A subset of animals were additionally treated with 5-Aza (n=16) to serve as an epigenetic control to ozone exposure. Neither 5-Aza nor ozone by itself induced changes to the global methylome or hydroxmethylome of the lung measured by ELISA. Despite this finding, ozone exposure induced a significant increase in the activity of the DNA methyltransferase enzymes in the lung which was reversed with 5-Aza treatment. Interestingly, a significant interaction between 5-Aza treatment and ozone exposure was found in a large array of data. The interaction between 5-Aza and ozone produced indicators of pulmonary edema and elevated lung damage. Along with these adverse changes, expression of major epigenetic enzymes (Tet 1-3, Dnmt3 a-b) were found to be perturbed in both the lung and hepatic tissues. While ozone exposure appears to in

  6. The early antibody-forming response to Salmonella antigens

    PubMed Central

    Russell, Pamela J.; Diener, E.

    1970-01-01

    This paper describes a new method for the morphological study of individual antibody-forming cells (AFC) on cell smears of the quality of normal haematological preparations. The early AFC response to polymerized flagellin of S. adelaide was studied in vivo using C57BL mice, which have very low background levels of AFC and in vitro using dispersed spleen cell cultures from CBA mice. AFC, arising as a result of in vivo or in vitro stimulation were found to comprise a heterogeneous population, including basophilic mononuclear cells, lymphocytes of most sizes, immature blast cells and occasional plasma cells. The earliest AFC detected comprised a high percentage (28 per cent in vivo, 31 per cent in vitro) of small lymphocyte-like cells. Studies of the incorporation of [3H]thymidine showed that most AFC arose by proliferation but that a proportion of AFC, the small lymphocyte-like cells, arose by differentiation of precursor cells not involving cell division. The effects of antigen concentration on the kinetics of AFC were investigated in vitro. Subtolerogenic antigen doses caused a delayed and decreased AFC response. ImagesFIG. 1FIG. 4 PMID:5529118

  7. Early transcriptional response to biotic stress in mixed starter fermentations involving Saccharomyces cerevisiae and Torulaspora delbrueckii.

    PubMed

    Tronchoni, Jordi; Curiel, Jose Antonio; Morales, Pilar; Torres-Pérez, Rafael; Gonzalez, Ramon

    2017-01-16

    Advances in microbial wine biotechnology have led to the recent commercialization of several non-Saccharomyces starter cultures. These are intended to be used in either simultaneous or sequential inoculation with Saccharomyces cerevisiae. The different types of microbial interactions that can be stablished during wine fermentation acquire an increased relevance in the context of these mixed-starter fermentations. We analysed the transcriptional response to co-cultivation of S. cerevisiae and Torulaspora delbrueckii. The study focused in the initial stages of wine fermentation, before S. cerevisiae completely dominates the mixed cultures. Both species showed a clear response to the presence of each other, even though the portion of the genome showing altered transcription levels was relatively small. Changes in the transcription pattern suggested a stimulation of metabolic activity and growth, as a consequence of the presence of competitors in the same medium. The response of S. cerevisiae seems to take place earlier, as compared to T. delbrueckii. Enhanced glycolytic activity of the mixed culture was confirmed by the CO2 production profile during these early stages of fermentation. Interestingly, HSP12 expression appeared induced by co-cultivation for both of S. cerevisiae and Torulaspora delbrueckii in the two time points studied. This might be related with a recently described role of Hsp12 in intercellular communication in yeast. Expression of S. cerevisiae PAU genes was also stimulated in mixed cultures.

  8. 1970s and 'Patient 0' HIV-1 genomes illuminate early HIV/AIDS history in North America.

    PubMed

    Worobey, Michael; Watts, Thomas D; McKay, Richard A; Suchard, Marc A; Granade, Timothy; Teuwen, Dirk E; Koblin, Beryl A; Heneine, Walid; Lemey, Philippe; Jaffe, Harold W

    2016-11-03

    The emergence of HIV-1 group M subtype B in North American men who have sex with men was a key turning point in the HIV/AIDS pandemic. Phylogenetic studies have suggested cryptic subtype B circulation in the United States (US) throughout the 1970s and an even older presence in the Caribbean. However, these temporal and geographical inferences, based upon partial HIV-1 genomes that postdate the recognition of AIDS in 1981, remain contentious and the earliest movements of the virus within the US are unknown. We serologically screened >2,000 1970s serum samples and developed a highly sensitive approach for recovering viral RNA from degraded archival samples. Here, we report eight coding-complete genomes from US serum samples from 1978-1979-eight of the nine oldest HIV-1 group M genomes to date. This early, full-genome 'snapshot' reveals that the US HIV-1 epidemic exhibited extensive genetic diversity in the 1970s but also provides strong evidence for its emergence from a pre-existing Caribbean epidemic. Bayesian phylogenetic analyses estimate the jump to the US at around 1970 and place the ancestral US virus in New York City with 0.99 posterior probability support, strongly suggesting this was the crucial hub of early US HIV/AIDS diversification. Logistic growth coalescent models reveal epidemic doubling times of 0.86 and 1.12 years for the US and Caribbean, respectively, suggesting rapid early expansion in each location. Comparisons with more recent data reveal many of these insights to be unattainable without archival, full-genome sequences. We also recovered the HIV-1 genome from the individual known as 'Patient 0' (ref. 5) and found neither biological nor historical evidence that he was the primary case in the US or for subtype B as a whole. We discuss the genesis and persistence of this belief in the light of these evolutionary insights.

  9. Filia is an ESC-specific regulator of DNA damage response and safeguards genomic stability

    PubMed Central

    Zhao, Bo; Zhang, Wei-dao; Duan, Ying-liang; Lu, Yong-qing; Cun, Yi-xian; Li, Chao-hui; Guo, Kun; Nie, Wen-hui; Li, Lei; Zhang, Rugang; Zheng, Ping

    2015-01-01

    Summary Pluripotent stem cells (PSCs) hold great promise in cell-based therapy, but the genomic instability seen in culture hampers full application. Greater understanding of the factors that regulate genomic stability in PSCs could help address this issue. Here we describe the identification of Filia as a specific regulator of genomic stability in mouse embryonic stem cells (ESCs). Filia expression is induced by genotoxic stress. Filia promotes centrosome integrity and regulates DNA damage response (DDR) through multiple pathways, including DDR signaling, cell cycle checkpoints and damage repair, ESC differentiation and apoptosis. Filia depletion causes ESC genomic instability, induces resistance to apoptosis and promotes malignant transformation. As part of its role in the DDR, Filia interacts with PARP1 and stimulates its enzymatic activity. Filia also constitutively resides on centrosomes and translocates to DNA damage sites and mitochondria, consistent with its multifaceted roles in regulating centrosome integrity, damage repair and apoptosis. PMID:25936915

  10. Facilitating a Culture of Responsible and Effective Sharing of Cancer Genome Data

    PubMed Central

    Siu, Lillian L.; Lawler, Mark; Haussler, David; Knoppers, Bartha Maria; Lewin, Jeremy; Vis, Daniel J.; Liao, Rachel G.; Andre, Fabrice; Banks, Ian; Barrett, J. Carl; Caldas, Carlos; Camargo, Anamaria Aranha; Fitzgerald, Rebecca C.; Mao, Mao; Mattison, John E.; Pao, William; Sellers, William R.; Sullivan, Patrick; Teh, Bin Tean; Ward, Robyn; ZenKlusen, Jean Claude; Sawyers, Charles L; Voest, Emile E.

    2016-01-01

    Rapid and affordable tumor molecular profiling has led to an explosion of clinical and genomic data poised to enhance diagnosis, prognostication and treatment of cancer. A critical point has now been reached where analysis and storage of annotated clinical and genomic information in unconnected silos will stall the advancement of precision cancer care. Information systems must be harmonized to overcome the multiple technical and logistical barriers for data sharing. Against this backdrop, the Global Alliance for Genomic Health (GA4GH) was established in 2013 to create a common framework that enables responsible, voluntary, and secure sharing of clinical and genomic data. This Perspective from the GA4GH Clinical Working Group Cancer Task Team highlights the data aggregation challenges faced by the field, suggests potential collaborative solutions, and describes how GA4GH can catalyze a harmonized data sharing culture. PMID:27149219

  11. The Drosophila early ovarian transcriptome provides insight to the molecular causes of recombination rate variation across genomes

    PubMed Central

    2013-01-01

    Background Evidence in yeast indicates that gene expression is correlated with recombination activity and double-strand break (DSB) formation in some hotspots. Studies of nucleosome occupancy in yeast and mice also suggest that open chromatin influences the formation of DSBs. In Drosophila melanogaster, high-resolution recombination maps show an excess of DSBs within annotated transcripts relative to intergenic sequences. The impact of active transcription on recombination landscapes, however, remains unexplored in a multicellular organism. We then investigated the transcription profile during early meiosis in D. melanogaster females to obtain a glimpse at the relevant transcriptional dynamics during DSB formation, and test the specific hypothesis that DSBs preferentially target transcriptionally active genomic regions. Results Our study of transcript profiles of early- and late-meiosis using mRNA-seq revealed, 1) significant differences in gene expression, 2) new genes and exons, 3) parent-of-origin effects on transcription in early-meiosis stages, and 4) a nonrandom genomic distribution of transcribed genes. Importantly, genomic regions that are more actively transcribed during early meiosis show higher rates of recombination, and we ruled out DSB preference for genic regions that are not transcribed. Conclusions Our results provide evidence in a multicellular organism that transcription during the initial phases of meiosis increases the likelihood of DSB and give insight into the molecular determinants of recombination rate variation across the D. melanogaster genome. We propose that a model where variation in gene expression plays a role altering the recombination landscape across the genome could provide a molecular, heritable and plastic mechanism to observed patterns of recombination variation, from the high level of intra-specific variation to the known influence of environmental factors and stress conditions. PMID:24228734

  12. Genomics of immune response to typhoid and cholera vaccines.

    PubMed

    Majumder, Partha P

    2015-06-19

    Considerable variation in antibody response (AR) was observed among recipients of an injectable typhoid vaccine and an oral cholera vaccine. We sought to find whether polymorphisms in genes of the immune system, both innate and adaptive, were associated with the observed variation in response. For both vaccines, we were able to discover and validate several polymorphisms that were significantly associated with immune response. For the typhoid vaccines, these polymorphisms were on genes that belonged to pathways of polysaccharide recognition, signal transduction, inhibition of T-cell proliferation, pro-inflammatory signalling and eventual production of antimicrobial peptides. For the cholera vaccine, the pathways included epithelial barrier integrity, intestinal homeostasis and leucocyte recruitment. Even though traditional wisdom indicates that both vaccines should act as T-cell-independent antigens, our findings reveal that the vaccines induce AR using different pathways.

  13. Defining the Genomic Signature of Totipotency and Pluripotency during Early Human Development

    PubMed Central

    Galan, Amparo; Diaz-Gimeno, Patricia; Poo, Maria Eugenia; Valbuena, Diana; Sanchez, Eva; Ruiz, Veronica; Dopazo, Joaquin; Montaner, David; Conesa, Ana; Simon, Carlos

    2013-01-01

    The genetic mechanisms governing human pre-implantation embryo development and the in vitro counterparts, human embryonic stem cells (hESCs), still remain incomplete. Previous global genome studies demonstrated that totipotent blastomeres from day-3 human embryos and pluripotent inner cell masses (ICMs) from blastocysts, display unique and differing transcriptomes. Nevertheless, comparative gene expression analysis has revealed that no significant differences exist between hESCs derived from blastomeres versus those obtained from ICMs, suggesting that pluripotent hESCs involve a new developmental progression. To understand early human stages evolution, we developed an undifferentiation network signature (UNS) and applied it to a differential gene expression profile between single blastomeres from day-3 embryos, ICMs and hESCs. This allowed us to establish a unique signature composed of highly interconnected genes characteristic of totipotency (61 genes), in vivo pluripotency (20 genes), and in vitro pluripotency (107 genes), and which are also proprietary according to functional analysis. This systems biology approach has led to an improved understanding of the molecular and signaling processes governing human pre-implantation embryo development, as well as enabling us to comprehend how hESCs might adapt to in vitro culture conditions. PMID:23614026

  14. Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features

    PubMed Central

    Lessel, Davor; Vaz, Bruno; Halder, Swagata; Lockhart, Paul J; Marinovic-Terzic, Ivana; Lopez-Mosqueda, Jaime; Philipp, Melanie; Sim, Joe C H; Smith, Katherine R; Oehler, Judith; Cabrera, Elisa; Freire, Raimundo; Pope, Kate; Nahid, Amsha; Norris, Fiona; Leventer, Richard J; Delatycki, Martin B; Barbi, Gotthold; von Ameln, Simon; Högel, Josef; Degoricija, Marina; Fertig, Regina; Burkhalter, Martin D; Hofmann, Kay; Thiele, Holger; Altmüller, Janine; Nürnberg, Gudrun; Nürnberg, Peter; Bahlo, Melanie; Martin, George M; Aalfs, Cora M; Oshima, Junko; Terzic, Janos; Amor, David J; Dikic, Ivan; Ramadan, Kristijan; Kubisch, Christian

    2015-01-01

    Age-related degenerative and malignant diseases represent major challenges for health care systems. Elucidation of the molecular mechanisms underlying carcinogenesis and age-associated pathologies is thus of growing biomedical relevance. We identified biallelic germline mutations in SPRTN (also called C1orf124 or DVC1)1–7 in three patients from two unrelated families. All three patients are affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. SPRTN was recently proposed to have a function in translesional DNA synthesis and the prevention of mutagenesis1–7. Our in vivo and in vitro characterization of identified mutations has uncovered an essential role for SPRTN in the prevention of DNA replication stress during general DNA replication and in replication-related G2/M-checkpoint regulation. In addition to demonstrating the pathogenicity of identified SPRTN mutations, our findings provide a molecular explanation of how SPRTN dysfunction causes accelerated aging and susceptibility toward carcinoma. PMID:25261934

  15. Cardenas receives, 2011 Early Career Hydrologic Sciences Award: Response

    NASA Astrophysics Data System (ADS)

    Cardenas, M. Bayani

    2012-06-01

    Meinhard Bayani Cardenas received the 2011 Early Career Hydrologic Sciences Award at the 2011 AGU Fall Meeting, held 5-9 December in San Francisco, Calif. The award is for significant early career contributions to hydrologic science.

  16. Responses to Developmental and Family Changes in Early Adolescence.

    ERIC Educational Resources Information Center

    Petersen, Anne C.; And Others

    Research has identified several factors which may be stressful in early adolescence, including school change, puberty, and family changes. This study used a longitudinal cohort sequential design to examine whether stressful changes in early adolescence have impact beyond early adolescence. Of the 335 sixth graders initially sampled, 169 were…

  17. Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus

    PubMed Central

    Baskin, Carole R.; Bielefeldt-Ohmann, Helle; Tumpey, Terrence M.; Sabourin, Patrick J.; Long, James P.; García-Sastre, Adolfo; Tolnay, Airn-E.; Albrecht, Randy; Pyles, John A.; Olson, Pam H.; Aicher, Lauri D.; Rosenzweig, Elizabeth R.; Murali-Krishna, Kaja; Clark, Edward A.; Kotur, Mark S.; Fornek, Jamie L.; Proll, Sean; Palermo, Robert E.; Sabourin, Carol L.; Katze, Michael G.

    2009-01-01

    The mechanisms responsible for the virulence of the highly pathogenic avian influenza (HPAI) and of the 1918 pandemic influenza virus in humans remain poorly understood. To identify crucial components of the early host response during these infections by using both conventional and functional genomics tools, we studied 34 cynomolgus macaques (Macaca fascicularis) to compare a 2004 human H5N1 Vietnam isolate with 2 reassortant viruses possessing the 1918 hemagglutinin (HA) and neuraminidase (NA) surface proteins, known conveyors of virulence. One of the reassortants also contained the 1918 nonstructural (NS1) protein, an inhibitor of the host interferon response. Among these viruses, HPAI H5N1 was the most virulent. Within 24 h, the H5N1 virus produced severe bronchiolar and alveolar lesions. Notably, the H5N1 virus targeted type II pneumocytes throughout the 7-day infection, and induced the most dramatic and sustained expression of type I interferons and inflammatory and innate immune genes, as measured by genomic and protein assays. The H5N1 infection also resulted in prolonged margination of circulating T lymphocytes and notable apoptosis of activated dendritic cells in the lungs and draining lymph nodes early during infection. While both 1918 reassortant viruses also were highly pathogenic, the H5N1 virus was exceptional for the extent of tissue damage, cytokinemia, and interference with immune regulatory mechanisms, which may help explain the extreme virulence of HPAI viruses in humans. PMID:19218453

  18. Is the Ultimate Treatment Response Predictable with Early Response in Major Depressive Episode?

    PubMed Central

    ÇİFTÇİ, Aslı; ULAŞ, Halis; TOPUZOĞLU, Ahmet; TUNCA, Zeliha

    2016-01-01

    Introduction New evidence suggests that the efficacy of antidepressants occurs within the first weeks of treatment and this early response predicts the later response. The purpose of the present study was to investigate if the partial response in the first week predicts the response at the end of treatment in patients with major depressive disorder who are treated with either antidepressant medication or electroconvulsive therapy. Methods Inpatients from Dokuz Eylül University Hospital with a major depressive episode, treated with antidepressant medication (n=52) or electroconvulsive therapy (ECT) (n=48), were recruited for the study. The data were retrospectively collected to decide whether a 25% decrease in the Hamilton Depression Rating Scale (HDRS) score at the first week of treatment predicts a 50% decrease at the third week using validity analysis. In addition, the effects of socio-demographic and clinical variables on the treatment response were assessed. Results A 25% decrease in the HDRS score in the first week of treatment predicted a 50% decrease in the HDRS score in the third week with a 78.3% positive predictive value, 62.1% negative predictive value, 62.1% sensitivity, and 78.3% specificity for antidepressant medications and an 88% positive predictive value, 52.2% negative predictive value, 66.7% sensitivity, and 80% specificity for ECT. The number of previous hospitalizations, comorbid medical illnesses, number of depressive episodes, duration of illness, and duration of the current episode were related to the treatment response. Conclusion Treatment response in the first week predicted the response in the third week with a high specificity and a high positive predictive value. Close monitoring of the response from the first week of treatment may thus help the clinician to predict the subsequent response. PMID:28373802

  19. Early Transcriptional Response of Soybean Contrasting Accessions to Root Dehydration

    PubMed Central

    Ferreira Neto, José Ribamar Costa; Pandolfi, Valesca; Guimaraes, Francismar Corrêa Marcelino; Benko-Iseppon, Ana Maria; Romero, Cynara; Silva, Roberta Lane de Oliveira; Rodrigues, Fabiana Aparecida; Abdelnoor, Ricardo Vilela; Nepomuceno, Alexandre Lima; Kido, Ederson Akio

    2013-01-01

    Drought is a significant constraint to yield increase in soybean. The early perception of water deprivation is critical for recruitment of genes that promote plant tolerance. DeepSuperSAGE libraries, including one control and a bulk of six stress times imposed (from 25 to 150 min of root dehydration) for drought-tolerant and sensitive soybean accessions, allowed to identify new molecular targets for drought tolerance. The survey uncovered 120,770 unique transcripts expressed by the contrasting accessions. Of these, 57,610 aligned with known cDNA sequences, allowing the annotation of 32,373 unitags. A total of 1,127 unitags were up-regulated only in the tolerant accession, whereas 1,557 were up-regulated in both as compared to their controls. An expression profile concerning the most representative Gene Ontology (GO) categories for the tolerant accession revealed the expression “protein binding” as the most represented for “Molecular Function”, whereas CDPK and CBL were the most up-regulated protein families in this category. Furthermore, particular genes expressed different isoforms according to the accession, showing the potential to operate in the distinction of physiological behaviors. Besides, heat maps comprising GO categories related to abiotic stress response and the unitags regulation observed in the expression contrasts covering tolerant and sensitive accessions, revealed the unitags potential for plant breeding. Candidate genes related to “hormone response” (LOX, ERF1b, XET), “water response” (PUB, BMY), “salt stress response” (WRKY, MYB) and “oxidative stress response” (PER) figured among the most promising molecular targets. Additionally, nine transcripts (HMGR, XET, WRKY20, RAP2-4, EREBP, NAC3, PER, GPX5 and BMY) validated by RT-qPCR (four different time points) confirmed their differential expression and pointed that already after 25 minutes a transcriptional reorganization started in response to the new condition, with

  20. BYSTANDER EFFECTS GENOMIC INSTABILITY, ADAPTIVE RESPONSE AND CANCER RISK ASSESSMENT FOR RADIAION AND CHEMICAL EXPOSURES

    EPA Science Inventory

    BYSTANDER EFFECTS, GENOMIC INSTABILITY, ADAPTIVE RESPONSE AND CANCER RISK ASSESSMENT FOR RADIATION AND CHEMICAL EXPOSURES

    R. Julian Preston
    Environmental Carcinogenesis Division, U.S. Environmental Protection Agency, Research Triangle Park, N.C. 27711, USA

    There ...

  1. Whole genome analysis using Bayesian models to identify candidate genes for immune response to vaccination

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study identified genome regions associated with variation in immune response to vaccination against bovine viral diarrhea virus type 2 (BVDV 2) in American Angus calves. Calves were born in the spring or fall of 2006-2008 (n = 620). Two doses of modified live vaccine were administered three wee...

  2. Genomic evaluation of oxalate-degrading transgenic soybean in response to Sclerotinia sclerotiorum infection

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Oxalate oxidases catalyze the degradation of oxalic acid (OA). Highly resistant transgenic soybean carrying an oxalate oxidase (OxO) gene and its susceptible parent soybean line, AC Colibri, were tested for genome-wide gene expression in response to the necrotrophic, OA producing pathogen Sclerotini...

  3. Language experience enhances early cortical pitch-dependent responses

    PubMed Central

    Krishnan, Ananthanarayan; Gandour, Jackson T.; Ananthakrishnan, Saradha; Vijayaraghavan, Venkatakrishnan

    2014-01-01

    Pitch processing at cortical and subcortical stages of processing is shaped by language experience. We recently demonstrated that specific components of the cortical pitch response (CPR) index the more rapidly-changing portions of the high rising Tone 2 of Mandarin Chinese, in addition to marking pitch onset and sound offset. In this study, we examine how language experience (Mandarin vs. English) shapes the processing of different temporal attributes of pitch reflected in the CPR components using stimuli representative of within-category variants of Tone 2. Results showed that the magnitude of CPR components (Na-Pb and Pb-Nb) and the correlation between these two components and pitch acceleration were stronger for the Chinese listeners compared to English listeners for stimuli that fell within the range of Tone 2 citation forms. Discriminant function analysis revealed that the Na-Pb component was more than twice as important as Pb-Nb in grouping listeners by language affiliation. In addition, a stronger stimulus-dependent, rightward asymmetry was observed for the Chinese group at the temporal, but not frontal, electrode sites. This finding may reflect selective recruitment of experience-dependent, pitch-specific mechanisms in right auditory cortex to extract more complex, time-varying pitch patterns. Taken together, these findings suggest that long-term language experience shapes early sensory level processing of pitch in the auditory cortex, and that the sensitivity of the CPR may vary depending on the relative linguistic importance of specific temporal attributes of dynamic pitch. PMID:25506127

  4. The Adaptive Response, Genetic Haplo-Insufficiency and Genomic Instability

    SciTech Connect

    Geard, Charles R.

    2014-12-12

    The linear no-threshold (LNT) hypothesis is the driving force in the establishment of radiation protection standards. However, the scientific basis for linearity has been brought into question, particularly due to the concerns about induced radiation resistance as it pertains to oxidative stress. Specifically, we investigated the observation that tumor hypoxia is associated with malignant progression, increased metastases, chemo- and radioresistance and poor prognosis. Experiments were conducted with non-malignant 3T3/NIH cells and normal human lung fibroblasts (NHLF) that were subjected to γ-irradiation under the levels of oxygen resembling those in growing tumors, and related our data to the concentrations of dissolved oxygen (DO), which is a better indicator of the amounts of residual oxygen inside the cells cultured in the hypoxic or anoxic atmosphere. We found that at DO levels about 0.5 mg/L cells subjected to both short-term (17 hours) and prolonged (48-72 hours) hypoxia continued to proliferate, and that apoptotic events were decreased at the early hours of hypoxic treatment. We showed that the short-term hypoxia up-regulated p53-binding protein 1 (53BP1) and resulted in facilitated 53BP1 nuclear foci formation and disappearance, thus indicating the higher efficiency of DNA double strand breaks repair processes. The latter was confirmed by the lower micronuclei incidence in irradiated hypoxic cells.

  5. Nucleotide sequence of a cluster of early and late genes in a conserved segment of the vaccinia virus genome.

    PubMed Central

    Plucienniczak, A; Schroeder, E; Zettlmeissl, G; Streeck, R E

    1985-01-01

    The nucleotide sequence of a 7.6 kb vaccinia DNA segment from a genomic region conserved among different orthopox virus has been determined. This segment contains a tight cluster of 12 partly overlapping open reading frames most of which can be correlated with previously identified early and late proteins and mRNAs. Regulatory signals used by vaccinia virus have been studied. Presumptive promoter regions are rich in A, T and carry the consensus sequences TATA and AATAA spaced at 20-24 base pairs. Tandem repeats of a CTATTC consensus sequence are proposed to be involved in the termination of early transcription. PMID:2987815

  6. Genomics-based early-phase clinical trials in oncology: recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies.

    PubMed

    Liu, Stephen V; Miller, Vincent A; Lobbezoo, Marinus W; Giaccone, Giuseppe

    2014-11-01

    The Methodology for the Development of Innovative Cancer Therapies (MDICT) task force discussed incorporation of genomic profiling into early (Phase I and II) clinical trials in oncology. The task force reviewed the challenges of standardising genomics data in a manner conducive to conducting clinical trials. Current barriers to successful and efficient implementation were identified and discussed, as well as the methods of genomic analysis, the proper setting for study and strategies to facilitate timely completion of genomics-based studies. The importance of properly capturing and cataloguing outcomes was also discussed. Several recommendations regarding the use of genomics in these trials are provided.

  7. Experimental evidence of genome-wide impact of ecological selection during early stages of speciation-with-gene-flow.

    PubMed

    Egan, Scott P; Ragland, Gregory J; Assour, Lauren; Powell, Thomas H Q; Hood, Glen R; Emrich, Scott; Nosil, Patrik; Feder, Jeffrey L

    2015-08-01

    Theory predicts that speciation-with-gene-flow is more likely when the consequences of selection for population divergence transitions from mainly direct effects of selection acting on individual genes to a collective property of all selected genes in the genome. Thus, understanding the direct impacts of ecologically based selection, as well as the indirect effects due to correlations among loci, is critical to understanding speciation. Here, we measure the genome-wide impacts of host-associated selection between hawthorn and apple host races of Rhagoletis pomonella (Diptera: Tephritidae), a model for contemporary speciation-with-gene-flow. Allele frequency shifts of 32 455 SNPs induced in a selection experiment based on host phenology were genome wide and highly concordant with genetic divergence between co-occurring apple and hawthorn flies in nature. This striking genome-wide similarity between experimental and natural populations of R. pomonella underscores the importance of ecological selection at early stages of divergence and calls for further integration of studies of eco-evolutionary dynamics and genome divergence.

  8. Genome-wide transcriptional responses of Nitrosomonas europaea to zinc.

    PubMed

    Park, Sunhwa; Ely, Roger L

    2008-06-01

    Nitrosomonas europaea, a Gram-negative obligate chemolithoautotroph, participates in global nitrogen cycling by carrying out nitrification and derives energy for growth through oxidation of ammonia. In this work, the physiological, proteomic, and transcriptional responses of N. europaea to zinc stress were studied. The nitrite production rate and ammonia-dependent oxygen uptake rate of the cells exposed to 3.4 microM ZnCl2 decreased about 61 and 69% within 30 min, respectively. Two proteins were notably up regulated in zinc treatment and the mRNA levels of their encoding genes started to increase by 1 h after the addition of zinc. A total of 27 genes were up regulated and 30 genes were down regulated. Up-regulated genes included mercury resistance genes (merTPCAD), inorganic ion transport genes, oxidative stress genes, toxin-antitoxin genes, and two-component signal transduction systems genes. merTPCAD was the highest up-regulated operon (46-fold). Down-regulated genes included the RubisCO operon (cbbO), biosynthesis (mrsA), and amino acid transporter.

  9. Molecular biology of the stress response in the early embryo and its stem cells.

    PubMed

    Puscheck, Elizabeth E; Awonuga, Awoniyi O; Yang, Yu; Jiang, Zhongliang; Rappolee, Daniel A

    2015-01-01

    to zygotic genome activation, the large mRNA program initiated at compaction, ion pumping required for cavitation, the differentiation of the first lineages, integration with the uterine environment at implantation, rapid proliferation of stem cells, and production of certain lineages which require the highest energy and are most sensitive to mitochondrial inhibition. Stress response mechanisms insure that stem cells for the early embryo and placenta survive at lower stress exposures, and that the organism survives through compensatory and prioritized stem cell differentiation, at higher stress exposures. These servomechanisms include a small set of stress enzymes from the 500 protein kinases in the kinome; the part of the genome coding for protein kinases that hierarchically regulate the activity of other proteins and enzymes. Important protein kinases that mediate the stress response of embryos and their stem cells are SAPK, p38MAPK, AMPK, PI3K, Akt, MEK1/2, MEKK4, PKA, IRE1 and PERK. These stress enzymes have cytosolic function in cell survival at low stress exposures and nuclear function in modifying transcription factor activity at higher stress exposures. Some of the transcription factors (TFs) that are most important in the stress response are JunC, JunB, MAPKAPs, ATF4, XBP1, Oct1, Oct4, HIFs, Nrf2/KEAP, NFKB, MT1, Nfat5, HSF1/2 and potency-maintaining factors Id2, Cdx2, Eomes, Sox2, Nanog, Rex1, and Oct4. Clearly the stress enzymes have a large number of cytosolic and nuclear substrates and the TFs regulate large numbers of genes. The interaction of stress enzymes and TFs in the early embryo and its stem cells are a continuing central focus of research. In vitro regulation of TFs by stress enzymes leads to reprogramming of the stem cell when stress diminishes stem cell accumulation. Since more differentiated product is produced by fewer cells, the process compensates for fewer cells. Coupled with stress-induced compensatory differentiation of stem cells is a

  10. Writ large: Genomic Dissection of the Effect of Cellular Environment on Immune Response

    PubMed Central

    Yosef, Nir; Regev, Aviv

    2016-01-01

    Cells of the immune system routinely respond to cues from their local environment and feedback to their surrounding through transient responses, choice of differentiation trajectories, plastic changes in cell state, and malleable adaptation to their tissue of residence. Genomic approaches have opened the way for comprehensive interrogation of such orchestrated responses. Focusing on genomic profiling of transcriptional and epigenetic cell state, we discuss how they are applied to investigate immune cells faced with various environmental cues. We highlight some of the emerging principles, on the role of dense regulatory circuitry, epigenetic memory, cell type fluidity, and reuse of regulatory modules, in achieving and maintaining appropriate responses to a changing environment. These provide a first step toward a systematic understanding of molecular circuits in complex tissues. PMID:27846493

  11. Genome-wide assessment of sequence-intrinsic enhancer responsiveness at single-base-pair resolution.

    PubMed

    Arnold, Cosmas D; Zabidi, Muhammad A; Pagani, Michaela; Rath, Martina; Schernhuber, Katharina; Kazmar, Tomáš; Stark, Alexander

    2017-02-01

    Gene expression is controlled by enhancers that activate transcription from the core promoters of their target genes. Although a key function of core promoters is to convert enhancer activities into gene transcription, whether and how strongly they activate transcription in response to enhancers has not been systematically assessed on a genome-wide level. Here we describe self-transcribing active core promoter sequencing (STAP-seq), a method to determine the responsiveness of genomic sequences to enhancers, and apply it to the Drosophila melanogaster genome. We cloned candidate fragments at the position of the core promoter (also called minimal promoter) in reporter plasmids with or without a strong enhancer, transfected the resulting library into cells, and quantified the transcripts that initiated from each candidate for each setup by deep sequencing. In the presence of a single strong enhancer, the enhancer responsiveness of different sequences differs by several orders of magnitude, and different levels of responsiveness are associated with genes of different functions. We also identify sequence features that predict enhancer responsiveness and discuss how different core promoters are employed for the regulation of gene expression.

  12. Early skin toxicity predicts better outcomes, and early tumor shrinkage predicts better response after cetuximab treatment in advanced colorectal cancer.

    PubMed

    Kogawa, T; Doi, A; Shimokawa, M; Fouad, T M; Osuga, T; Tamura, F; Mizushima, T; Kimura, T; Abe, S; Ihara, H; Kukitsu, T; Sumiyoshi, T; Yoshizaki, N; Hirayama, M; Sasaki, T; Kawarada, Y; Kitashiro, S; Okushiba, S; Kondo, H; Tsuji, Y

    2015-03-01

    Cetuximab-containing treatments for metastatic colorectal cancer have been shown to have higher overall response rates and longer progression-free and overall survival than other systemic therapies. Cetuximab-related manifestations, including severe skin toxicity and early tumor shrinkage, have been shown to be predictors of response to cetuximab. We hypothesized that early skin toxicity is a predictor of response and better outcomes in patients with advanced colorectal carcinoma. We retrospectively evaluated 62 patients with colorectal adenocarcinoma who had unresectable tumors and were treated with cetuximab in our institution. Skin toxicity grade was evaluated on each treatment day. Tumor size was evaluated using computed tomography prior to treatment and 4-8 weeks after the start of treatment with cetuximab.Patients with early tumor shrinkage after starting treatment with cetuximab had a significantly higher overall response rate (P = 0.0001). Patients with early skin toxicity showed significantly longer overall survival (P = 0.0305), and patients with higher skin toxicity grades had longer progression-free survival (P = 0.0168).We have shown that early tumor shrinkage, early onset of skin toxicity, and high skin toxicity grade are predictors of treatment efficacy and/or outcome in patients with advanced colorectal carcinoma treated with cetuximab.

  13. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.

    PubMed

    Postmus, Iris; Trompet, Stella; Deshmukh, Harshal A; Barnes, Michael R; Li, Xiaohui; Warren, Helen R; Chasman, Daniel I; Zhou, Kaixin; Arsenault, Benoit J; Donnelly, Louise A; Wiggins, Kerri L; Avery, Christy L; Griffin, Paula; Feng, QiPing; Taylor, Kent D; Li, Guo; Evans, Daniel S; Smith, Albert V; de Keyser, Catherine E; Johnson, Andrew D; de Craen, Anton J M; Stott, David J; Buckley, Brendan M; Ford, Ian; Westendorp, Rudi G J; Slagboom, P Eline; Sattar, Naveed; Munroe, Patricia B; Sever, Peter; Poulter, Neil; Stanton, Alice; Shields, Denis C; O'Brien, Eoin; Shaw-Hawkins, Sue; Chen, Y-D Ida; Nickerson, Deborah A; Smith, Joshua D; Dubé, Marie Pierre; Boekholdt, S Matthijs; Hovingh, G Kees; Kastelein, John J P; McKeigue, Paul M; Betteridge, John; Neil, Andrew; Durrington, Paul N; Doney, Alex; Carr, Fiona; Morris, Andrew; McCarthy, Mark I; Groop, Leif; Ahlqvist, Emma; Bis, Joshua C; Rice, Kenneth; Smith, Nicholas L; Lumley, Thomas; Whitsel, Eric A; Stürmer, Til; Boerwinkle, Eric; Ngwa, Julius S; O'Donnell, Christopher J; Vasan, Ramachandran S; Wei, Wei-Qi; Wilke, Russell A; Liu, Ching-Ti; Sun, Fangui; Guo, Xiuqing; Heckbert, Susan R; Post, Wendy; Sotoodehnia, Nona; Arnold, Alice M; Stafford, Jeanette M; Ding, Jingzhong; Herrington, David M; Kritchevsky, Stephen B; Eiriksdottir, Gudny; Launer, Leonore J; Harris, Tamara B; Chu, Audrey Y; Giulianini, Franco; MacFadyen, Jean G; Barratt, Bryan J; Nyberg, Fredrik; Stricker, Bruno H; Uitterlinden, André G; Hofman, Albert; Rivadeneira, Fernando; Emilsson, Valur; Franco, Oscar H; Ridker, Paul M; Gudnason, Vilmundur; Liu, Yongmei; Denny, Joshua C; Ballantyne, Christie M; Rotter, Jerome I; Adrienne Cupples, L; Psaty, Bruce M; Palmer, Colin N A; Tardif, Jean-Claude; Colhoun, Helen M; Hitman, Graham; Krauss, Ronald M; Wouter Jukema, J; Caulfield, Mark J

    2014-10-28

    Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

  14. Accuracy and responses of genomic selection on key traits in apple breeding

    PubMed Central

    Muranty, Hélène; Troggio, Michela; Sadok, Inès Ben; Rifaï, Mehdi Al; Auwerkerken, Annemarie; Banchi, Elisa; Velasco, Riccardo; Stevanato, Piergiorgio; van de Weg, W Eric; Di Guardo, Mario; Kumar, Satish; Laurens, François; Bink, Marco C A M

    2015-01-01

    The application of genomic selection in fruit tree crops is expected to enhance breeding efficiency by increasing prediction accuracy, increasing selection intensity and decreasing generation interval. The objectives of this study were to assess the accuracy of prediction and selection response in commercial apple breeding programmes for key traits. The training population comprised 977 individuals derived from 20 pedigreed full-sib families. Historic phenotypic data were available on 10 traits related to productivity and fruit external appearance and genotypic data for 7829 SNPs obtained with an Illumina 20K SNP array. From these data, a genome-wide prediction model was built and subsequently used to calculate genomic breeding values of five application full-sib families. The application families had genotypes at 364 SNPs from a dedicated 512 SNP array, and these genotypic data were extended to the high-density level by imputation. These five families were phenotyped for 1 year and their phenotypes were compared to the predicted breeding values. Accuracy of genomic prediction across the 10 traits reached a maximum value of 0.5 and had a median value of 0.19. The accuracies were strongly affected by the phenotypic distribution and heritability of traits. In the largest family, significant selection response was observed for traits with high heritability and symmetric phenotypic distribution. Traits that showed non-significant response often had reduced and skewed phenotypic variation or low heritability. Among the five application families the accuracies were uncorrelated to the degree of relatedness to the training population. The results underline the potential of genomic prediction to accelerate breeding progress in outbred fruit tree crops that still need to overcome long generation intervals and extensive phenotyping costs. PMID:26744627

  15. Archaeal Genome Guardians Give Insights into Eukaryotic DNA Replication and Damage Response Proteins

    PubMed Central

    Shin, David S.; Pratt, Ashley J.; Tainer, John A.

    2014-01-01

    As the third domain of life, archaea, like the eukarya and bacteria, must have robust DNA replication and repair complexes to ensure genome fidelity. Archaea moreover display a breadth of unique habitats and characteristics, and structural biologists increasingly appreciate these features. As archaea include extremophiles that can withstand diverse environmental stresses, they provide fundamental systems for understanding enzymes and pathways critical to genome integrity and stress responses. Such archaeal extremophiles provide critical data on the periodic table for life as well as on the biochemical, geochemical, and physical limitations to adaptive strategies allowing organisms to thrive under environmental stress relevant to determining the boundaries for life as we know it. Specifically, archaeal enzyme structures have informed the architecture and mechanisms of key DNA repair proteins and complexes. With added abilities to temperature-trap flexible complexes and reveal core domains of transient and dynamic complexes, these structures provide insights into mechanisms of maintaining genome integrity despite extreme environmental stress. The DNA damage response protein structures noted in this review therefore inform the basis for genome integrity in the face of environmental stress, with implications for all domains of life as well as for biomanufacturing, astrobiology, and medicine. PMID:24701133

  16. Lager yeasts possess dynamic genomes that undergo rearrangements and gene amplification in response to stress.

    PubMed

    James, Tharappel C; Usher, Jane; Campbell, Susan; Bond, Ursula

    2008-03-01

    A long-term goal of the brewing industry is to identify yeast strains with increased tolerance to the stresses experienced during the brewing process. We have characterised the genomes of a number of stress-tolerant mutants, derived from the lager yeast strain CMBS-33, that were selected for tolerance to high temperatures and to growth in high specific gravity wort. Our results indicate that the heat-tolerant strains have undergone a number of gross chromosomal rearrangements when compared to the parental strain. To determine if such rearrangements can spontaneously arise in response to exposure to stress conditions experienced during the brewing process, we examined the chromosome integrity of both the stress-tolerant strains and their parent during a single round of fermentation under a variety of environmental stresses. Our results show that the lager yeast genome shows tremendous plasticity during fermentation, especially when fermentations are carried out in high specific gravity wort and at higher than normal temperatures. Many localised regions of gene amplification were observed especially at the telomeres and at the rRNA gene locus on chromosome XII, and general chromosomal instability was evident. However, gross chromosomal rearrangements were not detected, indicating that continued selection in the stress conditions are required to obtain clonal isolates with stable rearrangements. Taken together, the data suggest that lager yeasts display a high degree of genomic plasticity and undergo genomic changes in response to environmental stress.

  17. Transcriptional regulatory network triggered by oxidative signals configures the early response mechanisms of japonica rice to chilling stress

    PubMed Central

    2010-01-01

    Background The transcriptional regulatory network involved in low temperature response leading to acclimation has been established in Arabidopsis. In japonica rice, which can only withstand transient exposure to milder cold stress (10°C), an oxidative-mediated network has been proposed to play a key role in configuring early responses and short-term defenses. The components, hierarchical organization and physiological consequences of this network were further dissected by a systems-level approach. Results Regulatory clusters responding directly to oxidative signals were prominent during the initial 6 to 12 hours at 10°C. Early events mirrored a typical oxidative response based on striking similarities of the transcriptome to disease, elicitor and wounding induced processes. Targets of oxidative-mediated mechanisms are likely regulated by several classes of bZIP factors acting on as1/ocs/TGA-like element enriched clusters, ERF factors acting on GCC-box/JAre-like element enriched clusters and R2R3-MYB factors acting on MYB2-like element enriched clusters. Temporal induction of several H2O2-induced bZIP, ERF and MYB genes coincided with the transient H2O2 spikes within the initial 6 to 12 hours. Oxidative-independent responses involve DREB/CBF, RAP2 and RAV1 factors acting on DRE/CRT/rav1-like enriched clusters and bZIP factors acting on ABRE-like enriched clusters. Oxidative-mediated clusters were activated earlier than ABA-mediated clusters. Conclusion Genome-wide, physiological and whole-plant level analyses established a holistic view of chilling stress response mechanism of japonica rice. Early response regulatory network triggered by oxidative signals is critical for prolonged survival under sub-optimal temperature. Integration of stress and developmental responses leads to modulated growth and vigor maintenance contributing to a delay of plastic injuries. PMID:20100339

  18. Early growth response 1 mediates the systemic and hepatic inflammatory response initiated by hemorrhagic shock.

    PubMed

    Prince, Jose M; Ming, Mei Jian; Levy, Ryan M; Liu, Shubing; Pinsky, David J; Vodovotz, Yoram; Billiar, Timothy R

    2007-02-01

    Hemorrhagic shock (HS) is a major cause of morbidity and mortality in trauma patients. The early growth response 1 (Egr-1) transcription factor is induced by a variety of cellular stresses, including hypoxia, and may function as a master switch to trigger the expression of numerous key inflammatory mediators. We hypothesized that HS would induce hepatic expression of Egr-1 and that Egr-1 upregulates the inflammatory response after HS. The Egr-1 mice and wild-type (WT) controls (n>or=5 for all groups) were subjected to HS alone or HS followed by resuscitation (HS/R). Other mice were subjected to a sham procedure which included general anesthesia and vessel cannulation but no shock (sham). After the HS, HS/R, or sham procedures, mice were euthanized for determination of serum concentrations of interleukin (IL) 6, IL-10, and alanine aminotransferase. Northern blot analysis was performed to evaluate Egr-1 messenger RNA (mRNA) expression. Liver whole cell lysates were evaluated for Egr-1 protein expression by Western blot analysis. Hepatic expression of IL-6, granulocyte colony-stimulating factor, and intracellular adhesion molecule 1 mRNA was determined by semiquantitative reverse transcriptase-polymerase chain reaction. The Egr-1 DNA binding was assessed using the electrophoretic mobility shift assay. Hemorrhagic shock results in a rapid and transient hepatic expression of Egr-1 mRNA in WT mice by 1 h, whereas protein and DNA binding activity was evident by 2.5 h. The Egr-1 mRNA expression diminished after 4 h of resuscitation, whereas Egr-1 protein expression and DNA binding activity persisted through resuscitation. The Egr-1 mice exhibited decreased levels of hepatic inflammatory mediators compared with WT controls with a decrease in hepatic mRNA levels of IL-6 by 42%, granulocyte colony-stimulating factor by 39%, and intracellular adhesion molecule 1 by 43%. Similarly, Egr-1 mice demonstrated a decreased systemic inflammatory response and hepatic injury after HS

  19. RNA from an immediate early region of the type 1 herpes simplex virus genome is present in the trigeminal ganglia of latently infected mice

    SciTech Connect

    Deatly, A.M.; Spivack, J.G.; Lavi, E.; Fraser, N.W.

    1987-05-01

    Transcription of the type 1 herpes simplex virus (HSV-1) genome in trigeminal ganglia of latently infected mice was studied using in situ hybridization. Probes representative of each temporal gene class were used to determine the regions of the genome that encode the transcripts present in latently infected cells. Probes encoding HSV-1 sequences of the five immediate early genes and representative early (thymidine kinase), early-late (major capsid protein), and late (glycoprotein C) genes were used in these experiments. Of the probes tested, only those encoding the immediate early gene product infected-cell polypeptide (ICP) 0 hybridized to RNA in latently infected tissues. Probes containing the other immediate early genes (ICP4, ICP22, ICP27, and ICP47) and the representative early, early-late, and late genes did not hybridize. Two probes covering approx. = 30% of the HSV-1 genome and encoding over 20 early and late transcripts also did not hybridize to RNA in latently infected tissues. These results, with probes spanning > 60% of the HSV-1 genome, suggest that transcription of the HSV-1 genome is restricted to one region in latently infected mouse trigeminal ganglia.

  20. Genome-Wide Identification and Expression Profiling Analysis of the Aux/IAA Gene Family in Medicago truncatula during the Early Phase of Sinorhizobium meliloti Infection

    PubMed Central

    Zhang, Lei; Sun, Tao; Xu, Luqin; Tie, Shuanggui; Wang, Huizhong

    2014-01-01

    Background Auxin/indoleacetic acid (Aux/IAA) genes, coding a family of short-lived nuclear proteins, play key roles in wide variety of plant developmental processes, including root system regulation and responses to environmental stimulus. However, how they function in auxin signaling pathway and symbiosis with rhizobial in Medicago truncatula are largely unknown. The present study aims at gaining deeper insight on distinctive expression and function features of Aux/IAA family genes in Medicago truncatula during nodule formation. Principal Findings Using the latest updated draft of the full Medicago truncatula genome, a comprehensive identification and analysis of IAA genes were performed. The data indicated that MtIAA family genes are distributed in all the M. truncatula chromosomes except chromosome 6. Most of MtIAA genes are responsive to exogenous auxin and express in tissues-specific manner. To understand the biological functions of MtIAA genes involved in nodule formation, quantitative real-time polymerase chain reaction (qRT-PCR) was used to test the expression profiling of MtIAA genes during the early phase of Sinorhizobium meliloti (S. meliloti) infection. The expression patterns of most MtIAA genes were down-regulated in roots and up-regulated in shoots by S. meliloti infection. The differences in expression responses between roots and shoots caused by S. meliloti infection were alleviated by 1-NOA application. Conclusion The genome-wide identification, evolution and expression pattern analysis of MtIAA genes were performed in this study. The data helps us to understand the roles of MtIAA-mediated auxin signaling in nodule formation during the early phase of S. meliloti infection. PMID:25226164

  1. Genome scale transcriptional response diversity among ten ecotypes of Arabidopsis thaliana during heat stress

    PubMed Central

    Barah, Pankaj; Jayavelu, Naresh D.; Mundy, John; Bones, Atle M.

    2013-01-01

    In the scenario of global warming and climate change, heat stress is a serious threat to crop production worldwide. Being sessile, plants cannot escape from heat. Plants have developed various adaptive mechanisms to survive heat stress. Several studies have focused on diversity of heat tolerance levels in divergent Arabidopsis thaliana (A. thaliana) ecotypes, but comprehensive genome scale understanding of heat stress response in plants is still lacking. Here we report the genome scale transcript responses to heat stress of 10 A. thaliana ecotypes (Col, Ler, C24, Cvi, Kas1, An1, Sha, Kyo2, Eri, and Kond) originated from different geographical locations. During the experiment, A. thaliana plants were subjected to heat stress (38°C) and transcript responses were monitored using Arabidopsis NimbleGen ATH6 microarrays. The responses of A. thaliana ecotypes exhibited considerable variation in the transcript abundance levels. In total, 3644 transcripts were significantly heat regulated (p < 0.01) in the 10 ecotypes, including 244 transcription factors and 203 transposable elements. By employing a systems genetics approach- Network Component Analysis (NCA), we have constructed an in silico transcript regulatory network model for 35 heat responsive transcription factors during cellular responses to heat stress in A. thaliana. The computed activities of the 35 transcription factors showed ecotype specific responses to the heat treatment. PMID:24409190

  2. 1970s and ‘Patient 0’ HIV-1 genomes illuminate early HIV/AIDS history in North America

    PubMed Central

    Worobey, Michael; Watts, Thomas D.; McKay, Richard A.; Suchard, Marc A.; Granade, Timothy; Teuwen, Dirk E.; Koblin, Beryl A.; Heneine, Walid; Lemey, Philippe; Jaffe, Harold W.

    2017-01-01

    The emergence of HIV-1 group M subtype B in North American men who have sex with men (MSM) was a key turning point in the HIV/AIDS pandemic. Phylogenetic studies have suggested cryptic subtype B circulation in the United States (US) throughout the 1970s2,3 and an even older presence in the Caribbean3. However, these timing and geographical inferences, based upon partial HIV-1 genomes that postdate the recognition of AIDS in 1981, remain contentious1,4 and the earliest movements of the virus within the US are unknown. We serologically screened >2000 1970s serum samples and developed a highly sensitive new approach for recovering viral RNA from degraded archival samples. Here, we report eight coding-complete genomes from US serum samples from 1978-79 – eight of the nine oldest HIV-1 group M genomes to date. This early, full-genome ‘snapshot’ reveals the US HIV-1 epidemic exhibited surprisingly extensive genetic diversity in the 1970s but also provides strong evidence of its emergence from a pre-existing Caribbean epidemic. Bayesian phylogenetic analyses estimate the jump to the US at ~1970 and place the ancestral US virus in New York City with 0.99 posterior probability support, strongly suggesting this was the crucial hub of early US HIV/AIDS diversification. Logistic growth coalescent models reveal epidemic doubling times of 0.86 and 1.12 years for the US and Caribbean, respectively, suggesting rapid early expansion in each location1. Comparisons with more recent data reveal many of these insights to be unattainable without archival, full-genome sequences. We also recovered the HIV-1 genome from the individual known as ‘Patient 0’5 and show there is neither biological nor historical evidence he was the primary case in the US or for subtype B as a whole. We discuss the genesis and persistence of this belief in the light of these evolutionary insights. PMID:27783600

  3. Altered Evoked Gamma-Band Responses Reveal Impaired Early Visual Processing in ADHD Children

    ERIC Educational Resources Information Center

    Lenz, Daniel; Krauel, Kerstin; Flechtner, Hans-Henning; Schadow, Jeanette; Hinrichs, Hermann; Herrmann, Christoph S.

    2010-01-01

    Neurophysiological studies yield contrary results whether attentional problems of patients with attention-deficit/hyperactivity disorder (ADHD) are related to early visual processing deficits or not. Evoked gamma-band responses (GBRs), being among the first cortical responses occurring as early as 90 ms after visual stimulation in human EEG, have…

  4. Complete Chloroplast Genome Sequence of the Early Diverging Green Alga Palmophyllum crassum

    PubMed Central

    Furukawa, Ryo; Kunugi, Motoshi; Ihara, Kunio; Tanaka, Ayumi

    2017-01-01

    ABSTRACT Palmophyllum crassum is a little-known green alga, with a unique evolutionary position and distinctive photosynthetic features. Here, we present the complete chloroplast genome sequence of Palmophyllum crassum. PMID:28280029

  5. Bivariate genomic analysis identifies a hidden locus associated with bacteria hypersensitive response in Arabidopsis thaliana

    PubMed Central

    Wang, Biao; Li, Zhuocheng; Xu, Weilin; Feng, Xiao; Wan, Qianhui; Zan, Yanjun; Sheng, Sitong; Shen, Xia

    2017-01-01

    Multi-phenotype analysis has drawn increasing attention to high-throughput genomic studies, whereas only a few applications have justified the use of multivariate techniques. We applied a recently developed multi-trait analysis method on a small set of bacteria hypersensitive response phenotypes and identified a single novel locus missed by conventional single-trait genome-wide association studies. The detected locus harbors a minor allele that elevates the risk of leaf collapse response to the injection of avrRpm1-modified Pseudomonas syringae (P = 1.66e-08). Candidate gene AT3G32930 with in the detected region and its co-expressed genes showed significantly reduced expression after P. syringae interference. Our results again emphasize that multi-trait analysis should not be neglected in association studies, as the power of specific multi-trait genotype-phenotype maps might only be tractable when jointly considering multiple phenotypes. PMID:28338080

  6. A Vitamin D Receptor/SMAD Genomic Circuit Gates Hepatic Fibrotic Response

    PubMed Central

    Ding, Ning; Yu, Ruth T.; Subramaniam, Nanthakumar; Sherman, Mara H.; Wilson, Caroline; Rao, Renuka; Leblanc, Mathias; Coulter, Sally; He, Mingxiao; Scott, Christopher; Lau, Sue L.; Atkins, Annette R.; Barish, Grant D.; Gunton, Jenny E.; Liddle, Christopher; Downes, Michael; Evans, Ronald M.

    2013-01-01

    SUMMARY Liver fibrosis is a reversible wound-healing response involving TGFβ1 activation of hepatic stellate cells (HSCs). Here we show that vitamin D receptor (VDR) ligands inhibit HSC activation and abrogate liver fibrosis, while Vdr knockout mice spontaneously developed hepatic fibrosis. Mechanistically, we describe a pronounced redistribution of genome wide VDR binding sites (VDR cistrome) in HSCs elicited by a TGFβ1 pro-fibrotic insult. This TGFβ1-induced VDR cistrome overlaps extensively with SMAD3 binding sites, with co-occupancy at numerous cis-regulatory elements identified on a large set of pro-fibrotic genes. Addition of VDR ligand reduces SMAD3 occupancy at co-regulated genes, revealing an intersecting VDR/SMAD genomic circuit that regulates hepatic fibrogenesis. These results define a role for VDR as a endocrine checkpoint to modulate the wound healing response in liver, and suggest VDR ligands as a potential therapy for liver fibrosis. PMID:23622244

  7. Analysis of an innovative survey platform: comparison of the public's responses to human health and salmon genomics surveys.

    PubMed

    Ahmad, Rana; Bailey, Jennifer; Danielson, Peter

    2010-03-01

    This paper presents the results of the first two surveys conducted using the innovative NERD (Norms Evolving in Response to Dilemmas) platform. The structure, results, and analysis of the first two NERD surveys on genomics and human health and salmon genomics are compared. This comparison demonstrates that NERD is a cost-effective and efficient public consultation and experimental tool that has provided insight on public acceptance of new technologies such as genomics.

  8. Genomic Microdiversity of Bifidobacterium pseudocatenulatum Underlying Differential Strain-Level Responses to Dietary Carbohydrate Intervention

    PubMed Central

    Wu, Guojun; Zhang, Chenhong; Wu, Huan; Wang, Ruirui; Shen, Jian; Wang, Linghua; Zhao, Yufeng; Pang, Xiaoyan; Zhang, Xiaojun; Zhao, Liping

    2017-01-01

    ABSTRACT The genomic basis of the response to dietary intervention of human gut beneficial bacteria remains elusive, which hinders precise manipulation of the microbiota for human health. After receiving a dietary intervention enriched with nondigestible carbohydrates for 105 days, a genetically obese child with Prader-Willi syndrome lost 18.4% of his body weight and showed significant improvement in his bioclinical parameters. We obtained five isolates (C1, C15, C55, C62, and C95) of one of the most abundantly promoted beneficial species, Bifidobacterium pseudocatenulatum, from a postintervention fecal sample. Intriguingly, these five B. pseudocatenulatum strains showed differential responses during the dietary intervention. Two strains were largely unaffected, while the other three were promoted to different extents by the changes in dietary carbohydrate resources. The differential responses of these strains were consistent with their functional clustering based on the COGs (Clusters of Orthologous Groups), including those involved with the ABC-type sugar transport systems, suggesting that the strain-specific genomic variations may have contributed to the niche adaption. Particularly, B. pseudocatenulatum C15, which had the most diverse types and highest gene copy numbers of carbohydrate-active enzymes targeting plant polysaccharides, had the highest abundance after the dietary intervention. These studies show the importance of understanding genomic diversity of specific members of the gut microbiota if precise nutrition approaches are to be realized. PMID:28196965

  9. Early Transcriptomic Response to LDL and oxLDL in Human Vascular Smooth Muscle Cells

    PubMed Central

    Damián-Zamacona, Salvador; Toledo-Ibelles, Paola; Ibarra-Abundis, Mabel Z.; Uribe-Figueroa, Laura; Hernández-Lemus, Enrique; Macedo-Alcibia, Karla Paola; Delgado–Coello, Blanca; Mas-Oliva, Jaime; Reyes-Grajeda, Juan Pablo

    2016-01-01

    Background Although nowadays it is well known that the human transcriptome can importantly vary according to external or environmental condition, the reflection of this concept when studying oxidative stress and its direct relationship with gene expression profiling during the process of atherogenesis has not been thoroughly achieved. Objective The ability to analyze genome-wide gene expression through transcriptomics has shown that the genome responds dynamically to diverse stimuli. Here, we describe the transcriptome of human vascular smooth muscle cells (hVSMC) stimulated by native and oxidized low-density lipoprotein (nLDL and oxLDL respectively), with the aim of assessing the early molecular changes that induce a response in this cell type resulting in a transcriptomic transformation. This expression has been demonstrated in atherosclerotic plaques in vivo and in vitro, particularly in the light of the oxidative modification hypothesis of atherosclerosis. Approach and Results Total RNA was isolated with TRIzol reagent (Life Technologies) and quality estimated using an Agilent 2100 bioanalyzer. The transcriptome of hVSMC under different experimental conditions (1,5 and 24 hours for nLDL and oxLDL) was obtained using the GeneChip Human Gene 1.0 ST (Affymetrix) designed to measure gene expression of 28,869 well-annotated genes. A fixed fold-change cut-off corresponding to ± 2 was used to identify genes exhibiting the most significant variation and statistical significance (P< 0.05), and 8 genes validated by qPCR using Taqman probes. Conclusions 10 molecular processes were significantly affected in hVSMC: Apoptosis and cell cycle, extracellular matrix remodeling, DNA repair, cholesterol efflux, cGMP biosynthesis, endocytic mechanisms, calcium homeostasis, redox balance, membrane trafficking and finally, the immune response to inflammation. The evidence we present supporting the hypothesis for the involvement of oxidative modification of several processes and

  10. SPOC1-Mediated Antiviral Host Cell Response Is Antagonized Early in Human Adenovirus Type 5 Infection

    PubMed Central

    Schreiner, Sabrina; Kinkley, Sarah; Bürck, Carolin; Mund, Andreas; Wimmer, Peter; Schubert, Tobias; Groitl, Peter; Will, Hans; Dobner, Thomas

    2013-01-01

    Little is known about immediate phases after viral infection and how an incoming viral genome complex counteracts host cell defenses, before the start of viral gene expression. Adenovirus (Ad) serves as an ideal model, since entry and onset of gene expression are rapid and highly efficient, and mechanisms used 24–48 hours post infection to counteract host antiviral and DNA repair factors (e.g. p53, Mre11, Daxx) are well studied. Here, we identify an even earlier host cell target for Ad, the chromatin-associated factor and epigenetic reader, SPOC1, recently found recruited to double strand breaks, and playing a role in DNA damage response. SPOC1 co-localized with viral replication centers in the host cell nucleus, interacted with Ad DNA, and repressed viral gene expression at the transcriptional level. We discovered that this SPOC1-mediated restriction imposed upon Ad growth is relieved by its functional association with the Ad major core protein pVII that enters with the viral genome, followed by E1B-55K/E4orf6-dependent proteasomal degradation of SPOC1. Mimicking removal of SPOC1 in the cell, knock down of this cellular restriction factor using RNAi techniques resulted in significantly increased Ad replication, including enhanced viral gene expression. However, depletion of SPOC1 also reduced the efficiency of E1B-55K transcriptional repression of cellular promoters, with possible implications for viral transformation. Intriguingly, not exclusive to Ad infection, other human pathogenic viruses (HSV-1, HSV-2, HIV-1, and HCV) also depleted SPOC1 in infected cells. Our findings provide a general model for how pathogenic human viruses antagonize intrinsic SPOC1-mediated antiviral responses in their host cells. A better understanding of viral entry and early restrictive functions in host cells should provide new perspectives for developing antiviral agents and therapies. Conversely, for Ad vectors used in gene therapy, counteracting mechanisms eradicating incoming

  11. Smooth Muscle Cell Genome Browser: Enabling the Identification of Novel Serum Response Factor Target Genes

    PubMed Central

    Lee, Moon Young; Park, Chanjae; Berent, Robyn M.; Park, Paul J.; Fuchs, Robert; Syn, Hannah; Chin, Albert; Townsend, Jared; Benson, Craig C.; Redelman, Doug; Shen, Tsai-wei; Park, Jong Kun; Miano, Joseph M.; Sanders, Kenton M.; Ro, Seungil

    2015-01-01

    Genome-scale expression data on the absolute numbers of gene isoforms offers essential clues in cellular functions and biological processes. Smooth muscle cells (SMCs) perform a unique contractile function through expression of specific genes controlled by serum response factor (SRF), a transcription factor that binds to DNA sites known as the CArG boxes. To identify SRF-regulated genes specifically expressed in SMCs, we isolated SMC populations from mouse small intestine and colon, obtained their transcriptomes, and constructed an interactive SMC genome and CArGome browser. To our knowledge, this is the first online resource that provides a comprehensive library of all genetic transcripts expressed in primary SMCs. The browser also serves as the first genome-wide map of SRF binding sites. The browser analysis revealed novel SMC-specific transcriptional variants and SRF target genes, which provided new and unique insights into the cellular and biological functions of the cells in gastrointestinal (GI) physiology. The SRF target genes in SMCs, which were discovered in silico, were confirmed by proteomic analysis of SMC-specific Srf knockout mice. Our genome browser offers a new perspective into the alternative expression of genes in the context of SRF binding sites in SMCs and provides a valuable reference for future functional studies. PMID:26241044

  12. Comprehensive genome and epigenome characterization of CHO cells in response to evolutionary pressures and over time

    PubMed Central

    Feichtinger, Julia; Hernández, Inmaculada; Fischer, Christoph; Hanscho, Michael; Auer, Norbert; Hackl, Matthias; Jadhav, Vaibhav; Baumann, Martina; Krempl, Peter M.; Schmidl, Christian; Farlik, Matthias; Schuster, Michael; Merkel, Angelika; Sommer, Andreas; Heath, Simon; Rico, Daniel; Bock, Christoph; Thallinger, Gerhard G.

    2016-01-01

    ABSTRACT The most striking characteristic of CHO cells is their adaptability, which enables efficient production of proteins as well as growth under a variety of culture conditions, but also results in genomic and phenotypic instability. To investigate the relative contribution of genomic and epigenetic modifications towards phenotype evolution, comprehensive genome and epigenome data are presented for six related CHO cell lines, both in response to perturbations (different culture conditions and media as well as selection of a specific phenotype with increased transient productivity) and in steady state (prolonged time in culture under constant conditions). Clear transitions were observed in DNA‐methylation patterns upon each perturbation, while few changes occurred over time under constant conditions. Only minor DNA‐methylation changes were observed between exponential and stationary growth phase; however, throughout a batch culture the histone modification pattern underwent continuous adaptation. Variation in genome sequence between the six cell lines on the level of SNPs, InDels, and structural variants is high, both upon perturbation and under constant conditions over time. The here presented comprehensive resource may open the door to improved control and manipulation of gene expression during industrial bioprocesses based on epigenetic mechanisms. Biotechnol. Bioeng. 2016;113: 2241–2253. © 2016 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc. PMID:27072894

  13. OxyGene: an innovative platform for investigating oxidative-response genes in whole prokaryotic genomes

    PubMed Central

    Thybert, David; Avner, Stéphane; Lucchetti-Miganeh, Céline; Chéron, Angélique; Barloy-Hubler, Frédérique

    2008-01-01

    Background Oxidative stress is a common stress encountered by living organisms and is due to an imbalance between intracellular reactive oxygen and nitrogen species (ROS, RNS) and cellular antioxidant defence. To defend themselves against ROS/RNS, bacteria possess a subsystem of detoxification enzymes, which are classified with regard to their substrates. To identify such enzymes in prokaryotic genomes, different approaches based on similarity, enzyme profiles or patterns exist. Unfortunately, several problems persist in the annotation, classification and naming of these enzymes due mainly to some erroneous entries in databases, mistake propagation, absence of updating and disparity in function description. Description In order to improve the current annotation of oxidative stress subsystems, an innovative platform named OxyGene has been developed. It integrates an original database called OxyDB, holding thoroughly tested anchor-based signatures associated to subfamilies of oxidative stress enzymes, and a new anchor-driven annotator, for ab initio detection of ROS/RNS response genes. All complete Bacterial and Archaeal genomes have been re-annotated, and the results stored in the OxyGene repository can be interrogated via a Graphical User Interface. Conclusion OxyGene enables the exploration and comparative analysis of enzymes belonging to 37 detoxification subclasses in 664 microbial genomes. It proposes a new classification that improves both the ontology and the annotation of the detoxification subsystems in prokaryotic whole genomes, while discovering new ORFs and attributing precise function to hypothetical annotated proteins. OxyGene is freely available at: PMID:19117520

  14. Genome-wide microarray analysis of human fibroblasts in response to γ radiation and the radiation-induced bystander effect.

    PubMed

    Kalanxhi, Erta; Dahle, Jostein

    2012-01-01

    Radiation-induced bystander effects have been studied extensively due to their potential implications for cancer therapy and radiation protection; however, a complete understanding of the molecular mechanisms remains to be elucidated. In this study, we monitored transcriptional responses to γ radiation in irradiated and bystander fibroblasts simultaneously employing a genome-wide microarray approach to determine factors that may be modulated in the generation or propagation of the bystander effect. For the microarray data we employed analysis at both the single-gene and gene-set level to place the findings in a biological context. Unirradiated bystander fibroblasts that were recipients of growth medium harvested from irradiated cultures 2 h after exposure to 2 Gy displayed transient enrichment in gene sets belonging to ribosome, oxidative phosphorylation and neurodegenerative disease pathways associated with mitochondrial dysfunctions. The response to direct irradiation was characterized by induction of signaling and apoptosis genes and the gradual formation of a cellular immune response. A set of 14 genes, many of which were regulated by p53, were found to be induced early after irradiation (prior to medium transfer) and may be important in the generation or propagation of the bystander effect.

  15. The complete mitochondrial genome of Pauropus longiramus (Myriapoda: Pauropoda): implications on early diversification of the myriapods revealed from comparative analysis.

    PubMed

    Dong, Yan; Sun, Hongying; Guo, Hua; Pan, Da; Qian, Changyuan; Hao, Sijing; Zhou, Kaiya

    2012-08-15

    Myriapods are among the earliest arthropods and may have evolved to become part of the terrestrial biota more than 400 million years ago. A noticeable lack of mitochondrial genome data from Pauropoda hampers phylogenetic and evolutionary studies within the subphylum Myriapoda. We sequenced the first complete mitochondrial genome of a microscopic pauropod, Pauropus longiramus (Arthropoda: Myriapoda), and conducted comprehensive mitogenomic analyses across the Myriapoda. The pauropod mitochondrial genome is a circular molecule of 14,487 bp long and contains the entire set of thirty-seven genes. Frequent intergenic overlaps occurred between adjacent tRNAs, and between tRNA and protein-coding genes. This is the first example of a mitochondrial genome with multiple intergenic overlaps and reveals a strategy for arthropods to effectively compact the mitochondrial genome by overlapping and truncating tRNA genes with neighbor genes, instead of only truncating tRNAs. Phylogenetic analyses based on protein-coding genes provide strong evidence that the sister group of Pauropoda is Symphyla. Additionally, approximately unbiased (AU) tests strongly support the Progoneata and confirm the basal position of Chilopoda in Myriapoda. This study provides an estimation of myriapod origins around 555 Ma (95% CI: 444-704 Ma) and this date is comparable with that of the Cambrian explosion and candidate myriapod-like fossils. A new time-scale suggests that deep radiations during early myriapod diversification occurred at least three times, not once as previously proposed. A Carboniferous origin of pauropods is congruent with the idea that these taxa are derived, rather than basal, progoneatans.

  16. Elevated Amygdala Response to Faces following Early Deprivation

    ERIC Educational Resources Information Center

    Tottenham, N.; Hare, T. A.; Millner, A.; Gilhooly, T.; Zevin, J. D.; Casey, B. J.

    2011-01-01

    A functional neuroimaging study examined the long-term neural correlates of early adverse rearing conditions in humans as they relate to socio-emotional development. Previously institutionalized (PI) children and a same-aged comparison group were scanned using functional magnetic resonance imaging (fMRI) while performing an Emotional Face Go/Nogo…

  17. Singaporean Early Childhood Teachers' Responses to Myths about Child Abuse

    ERIC Educational Resources Information Center

    Briggs, Freda; Potter, Gillian K.

    2004-01-01

    Prior to attending seminars on child abuse and domestic violence, 86 kindergarten and 64 special education (early childhood) teachers completed a questionnaire seeking views relating to the accuracy of statements relating to all forms of child abuse. This was designed to identify the accuracy of teachers' knowledge of child abuse and neglect…

  18. Investigating Early Years Teachers' Understanding and Response to Children's Preconceptions

    ERIC Educational Resources Information Center

    Kambouri, Maria

    2016-01-01

    This paper focuses on young children's scientific preconceptions and discusses teachers' identification of these preconceptions when teaching science in the early years, on which research is still limited. This paper is based on the theoretical framework of constructivism and it defines preconceptions as children's erroneous concepts prior to…

  19. Genomic Profiling of the Response of Candida albicans to Itraconazole Treatment Using a DNA Microarray

    PubMed Central

    De Backer, Marianne D.; Ilyina, Tatiana; Ma, Xiao-Jun; Vandoninck, Sandy; Luyten, Walter H. M. L.; Vanden Bossche, Hugo

    2001-01-01

    The application of genome-wide expression profiling to determine how drugs achieve their therapeutic effect has provided the pharmaceutical industry with an exciting new tool for drug mode-of-action studies. We used DNA chip technology to study cellular responses to perturbations of ergosterol biosynthesis caused by the broad-spectrum antifungal agent itraconazole. Simultaneous examination of over 6,600 Candida albicans gene transcript levels, representing the entire genome, upon treatment of cells with 10 μM itraconazole revealed that 296 genes were responsive. For 116 genes transcript levels were decreased at least 2.5-fold, while for 180 transcript levels were similarly increased. A global upregulation of ERG genes in response to azole treatment was observed. ERG11 and ERG5 were found to be upregulated approximately 12-fold. In addition, a significant upregulation was observed for ERG6, ERG1, ERG3, ERG4, ERG10, ERG9, ERG26, ERG25, ERG2, IDII, HMGS, NCP1, and FEN2, all of which are genes known to be involved in ergosterol biosynthesis. The effects of itraconazole on a wide variety of known metabolic processes are discussed. As over 140 proteins with unknown function were responsive to itraconazole, our analysis might provide—in combination with phenotypic data—first hints of their potential function. The present report is the first to describe the application of DNA chip technology to study the response of a major human fungal pathogen to drug treatment. PMID:11353609

  20. Whole-genome analyses resolve early branches in the tree of life of modern birds.

    PubMed

    Jarvis, Erich D; Mirarab, Siavash; Aberer, Andre J; Li, Bo; Houde, Peter; Li, Cai; Ho, Simon Y W; Faircloth, Brant C; Nabholz, Benoit; Howard, Jason T; Suh, Alexander; Weber, Claudia C; da Fonseca, Rute R; Li, Jianwen; Zhang, Fang; Li, Hui; Zhou, Long; Narula, Nitish; Liu, Liang; Ganapathy, Ganesh; Boussau, Bastien; Bayzid, Md Shamsuzzoha; Zavidovych, Volodymyr; Subramanian, Sankar; Gabaldón, Toni; Capella-Gutiérrez, Salvador; Huerta-Cepas, Jaime; Rekepalli, Bhanu; Munch, Kasper; Schierup, Mikkel; Lindow, Bent; Warren, Wesley C; Ray, David; Green, Richard E; Bruford, Michael W; Zhan, Xiangjiang; Dixon, Andrew; Li, Shengbin; Li, Ning; Huang, Yinhua; Derryberry, Elizabeth P; Bertelsen, Mads Frost; Sheldon, Frederick H; Brumfield, Robb T; Mello, Claudio V; Lovell, Peter V; Wirthlin, Morgan; Schneider, Maria Paula Cruz; Prosdocimi, Francisco; Samaniego, José Alfredo; Vargas Velazquez, Amhed Missael; Alfaro-Núñez, Alonzo; Campos, Paula F; Petersen, Bent; Sicheritz-Ponten, Thomas; Pas, An; Bailey, Tom; Scofield, Paul; Bunce, Michael; Lambert, David M; Zhou, Qi; Perelman, Polina; Driskell, Amy C; Shapiro, Beth; Xiong, Zijun; Zeng, Yongli; Liu, Shiping; Li, Zhenyu; Liu, Binghang; Wu, Kui; Xiao, Jin; Yinqi, Xiong; Zheng, Qiuemei; Zhang, Yong; Yang, Huanming; Wang, Jian; Smeds, Linnea; Rheindt, Frank E; Braun, Michael; Fjeldsa, Jon; Orlando, Ludovic; Barker, F Keith; Jønsson, Knud Andreas; Johnson, Warren; Koepfli, Klaus-Peter; O'Brien, Stephen; Haussler, David; Ryder, Oliver A; Rahbek, Carsten; Willerslev, Eske; Graves, Gary R; Glenn, Travis C; McCormack, John; Burt, Dave; Ellegren, Hans; Alström, Per; Edwards, Scott V; Stamatakis, Alexandros; Mindell, David P; Cracraft, Joel; Braun, Edward L; Warnow, Tandy; Jun, Wang; Gilbert, M Thomas P; Zhang, Guojie

    2014-12-12

    To better determine the history of modern birds, we performed a genome-scale phylogenetic analysis of 48 species representing all orders of Neoaves using phylogenomic methods created to handle genome-scale data. We recovered a highly resolved tree that confirms previously controversial sister or close relationships. We identified the first divergence in Neoaves, two groups we named Passerea and Columbea, representing independent lineages of diverse and convergently evolved land and water bird species. Among Passerea, we infer the common ancestor of core landbirds to have been an apex predator and confirm independent gains of vocal learning. Among Columbea, we identify pigeons and flamingoes as belonging to sister clades. Even with whole genomes, some of the earliest branches in Neoaves proved challenging to resolve, which was best explained by massive protein-coding sequence convergence and high levels of incomplete lineage sorting that occurred during a rapid radiation after the Cretaceous-Paleogene mass extinction event about 66 million years ago.

  1. Whole-genome sequencing of a malignant granular cell tumor with metabolic response to pazopanib

    PubMed Central

    Wei, Lei; Liu, Song; Conroy, Jeffrey; Wang, Jianmin; Papanicolau-Sengos, Antonios; Glenn, Sean T.; Murakami, Mitsuko; Liu, Lu; Hu, Qiang; Conroy, Jacob; Miles, Kiersten Marie; Nowak, David E.; Liu, Biao; Qin, Maochun; Bshara, Wiam; Omilian, Angela R.; Head, Karen; Bianchi, Michael; Burgher, Blake; Darlak, Christopher; Kane, John; Merzianu, Mihai; Cheney, Richard; Fabiano, Andrew; Salerno, Kilian; Talati, Chetasi; Khushalani, Nikhil I.; Trump, Donald L.; Johnson, Candace S.; Morrison, Carl D.

    2015-01-01

    Granular cell tumors are an uncommon soft tissue neoplasm. Malignant granular cell tumors comprise <2% of all granular cell tumors, are associated with aggressive behavior and poor clinical outcome, and are poorly understood in terms of tumor etiology and systematic treatment. Because of its rarity, the genetic basis of malignant granular cell tumor remains unknown. We performed whole-genome sequencing of one malignant granular cell tumor with metabolic response to pazopanib. This tumor exhibited a very low mutation rate and an overall stable genome with local complex rearrangements. The mutation signature was dominated by C>T transitions, particularly when immediately preceded by a 5′ G. A loss-of-function mutation was detected in a newly recognized tumor suppressor candidate, BRD7. No mutations were found in known targets of pazopanib. However, we identified a receptor tyrosine kinase pathway mutation in GFRA2 that warrants further evaluation. To the best of our knowledge, this is only the second reported case of a malignant granular cell tumor exhibiting a response to pazopanib, and the first whole-genome sequencing of this uncommon tumor type. The findings provide insight into the genetic basis of malignant granular cell tumors and identify potential targets for further investigation. PMID:27148567

  2. Genomic Selection Improves Response to Selection in Resilience by Exploiting Genotype by Environment Interactions

    PubMed Central

    Mulder, Han A.

    2016-01-01

    Genotype by environment interactions (GxE) are very common in livestock and hamper genetic improvement. On the other hand, GxE is a source of genetic variation: genetic variation in response to environment, e.g., environmental perturbations such as heat stress or disease. In livestock breeding, there is tendency to ignore GxE because of increased complexity of models for genetic evaluations and lack of accuracy in extreme environments. GxE, however, creates opportunities to increase resilience of animals toward environmental perturbations. The main aim of the paper is to investigate to which extent GxE can be exploited with traditional and genomic selection methods. Furthermore, we investigated the benefit of reaction norm (RN) models compared to conventional methods ignoring GxE. The questions were addressed with selection index theory. GxE was modeled according to a linear RN model in which the environmental gradient is the contemporary group mean. Economic values were based on linear and non-linear profit equations. Accuracies of environment-specific (G)EBV were highest in intermediate environments and lowest in extreme environments. RN models had higher accuracies of (G)EBV in extreme environments than conventional models ignoring GxE. Genomic selection always resulted in higher response to selection in all environments than sib or progeny testing schemes. The increase in response was with genomic selection between 9 and 140% compared to sib testing and between 11 and 114% compared to progeny testing when the reference population consisted of 1 million animals across all environments. When the aim was to decrease environmental sensitivity, the response in slope of the RN model with genomic selection was between 1.09 and 319 times larger than with sib or progeny testing and in the right direction in contrast to sib and progeny testing that still increased environmental sensitivity. This shows that genomic selection with large reference populations offers great

  3. Early transcriptomic response of Arabidopsis thaliana to polymetallic contamination: implications for the identification of potential biomarkers of metal exposure.

    PubMed

    Gómez-Sagasti, María T; Barrutia, Oihana; Ribas, Griselda; Garbisu, Carlos; Becerril, José M

    2016-05-01

    Heavy metal contaminated sites are frequently characterized by the simultaneous presence of several heavy metals. However, many studies report metal-induced plant responses after long-term exposure to just one metal. By contrast, whole genome expression microarrays were employed here to investigate the early (3 h) transcriptional responses of Arabidopsis thaliana plants exposed to polymetallic treatment (Pb, Hg, Cu, Cd, Co, Ni, Zn, and Mn) at low (L) and high (H) concentrations. After 3 h of exposure to polymetallic treatment, a total of 1315 noticeably (≥2-fold) and significantly (P < 0.05) differentially expressed genes were identified: 656 and 351 upregulated and 314 and 200 downregulated genes in L and H treatments, respectively. Functional analysis revealed that many genes involved in oxidative stress and perception/signalling/regulation systems were activated. Genes encoding proteins involved in hormone regulation (jasmonic acid, abscisic acid, ethylene, and auxins), glucosinolate metabolism and sulphur and nitrogen transport were also modulated. RT-qPCR analysis of four downregulated (AOP2, SAUR16, BBX31, and MTPC3) and upregulated genes (ASN1, DIN2, BT2, and EXL5), markedly responsive to both L and H treatments, validated our microarray data and suggested the potential of some of these genes (AOP2, SAUR16, ASN1, and DIN2) as early biomarkers of metal exposure. Relevant changes in gene expression occur as early as 3 h after exposure to polymetallic treatment. Four genes deserve further studies as novel putative biomarkers of early metal exposure and also owing to their potential implications in stress-related mechanisms: sulphur balance (AOP2), phytohormone regulation of plant growth and development (SAUR16), ammonium detoxification (ASN1) and senescence (DIN2).

  4. Comparative Genomics of Aspergillus flavus and A. oryzae: An Early View

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aspergillus flavus produces aflatoxins and is the second leading cause of aspergillosis in immunocompromised individuals. Aspergillus oryzae, on the other hand, has been used for centuries in Japan for the fermentation of food. The recently available whole genome sequences of Aspergillus flavus an...

  5. Genome Wide Analysis of Fatty Acid Desaturation and Its Response to Temperature1[OPEN

    PubMed Central

    Menard, Guillaume N.; Moreno, Jose Martin; Bryant, Fiona M.; Munoz-Azcarate, Olaya; Hassani-Pak, Keywan; Kurup, Smita

    2017-01-01

    Plants modify the polyunsaturated fatty acid content of their membrane and storage lipids in order to adapt to changes in temperature. In developing seeds, this response is largely controlled by the activities of the microsomal ω-6 and ω-3 fatty acid desaturases, FAD2 and FAD3. Although temperature regulation of desaturation has been studied at the molecular and biochemical levels, the genetic control of this trait is poorly understood. Here, we have characterized the response of Arabidopsis (Arabidopsis thaliana) seed lipids to variation in ambient temperature and found that heat inhibits both ω-6 and ω-3 desaturation in phosphatidylcholine, leading to a proportional change in triacylglycerol composition. Analysis of the 19 parental accessions of the multiparent advanced generation intercross (MAGIC) population showed that significant natural variation exists in the temperature responsiveness of ω-6 desaturation. A combination of quantitative trait locus (QTL) analysis and genome-wide association studies (GWAS) using the MAGIC population suggests that ω-6 desaturation is largely controlled by cis-acting sequence variants in the FAD2 5′ untranslated region intron that determine the expression level of the gene. However, the temperature responsiveness of ω-6 desaturation is controlled by a separate QTL on chromosome 2. The identity of this locus is unknown, but genome-wide association studies identified potentially causal sequence variants within ∼40 genes in an ∼450-kb region of the QTL. PMID:28108698

  6. Genetics of the immune response: identifying immune variation within the MHC and throughout the genome.

    PubMed

    Geraghty, Daniel E; Daza, Riza; Williams, Luke M; Vu, Quyen; Ishitani, Akiko

    2002-12-01

    With the advent of modern genomic sequencing technology the ability to obtain new sequence data and to acquire allelic polymorphism data from a broad range of samples has become routine. In this regard, our investigations have started with the most polymorphic of genetic regions fundamental to the immune response in the major histocompatibility complex (MHC). Starting with the completed human MHC genomic sequence, we have developed a resource of methods and information that provide ready access to a large portion of human and nonhuman primate MHCs. This resource consists of a set of primer pairs or amplicons that can be used to isolate about 15% of the 4.0 Mb MHC. Essentially similar studies are now being carried out on a set of immune response loci to broaden the usefulness of the data and tools developed. A panel of 100 genes involved in the immune response have been targeted for single nucleotide polymorphism (SNP) discovery efforts that will analyze 120 Mb of sequence data for the presence of immune-related SNPs. The SNP data provided from the MHC and from the immune response panel has been adapted for use in studies of evolution, MHC disease associations, and clinical transplantation.

  7. FANCD2 influences replication fork processes and genome stability in response to clustered DSBs.

    PubMed

    Zhu, Jiayun; Su, Fengtao; Mukherjee, Shibani; Mori, Eiichiro; Hu, Burong; Asaithamby, Aroumougame

    2015-01-01

    Fanconi Anemia (FA) is a cancer predisposition syndrome and the factors defective in FA are involved in DNA replication, DNA damage repair and tumor suppression. Here, we show that FANCD2 is critical for genome stability maintenance in response to high-linear energy transfer (LET) radiation. We found that FANCD2 is monoubiquitinated and recruited to the sites of clustered DNA double-stranded breaks (DSBs) specifically in S/G2 cells after high-LET radiation. Further, FANCD2 facilitated the repair of clustered DSBs in S/G2 cells and proper progression of S-phase. Furthermore, lack of FANCD2 led to a reduced rate of replication fork progression and elevated levels of both replication fork stalling and new origin firing in response to high-LET radiation. Mechanistically, FANCD2 is required for correct recruitment of RPA2 and Rad51 to the sites of clustered DSBs and that is critical for proper processing of clustered DSBs. Significantly, FANCD2-decifient cells exhibited defective chromosome segregation, elevated levels of chromosomal aberrations, and anchorage-independent growth in response to high-LET radiation. These findings establish FANCD2 as a key factor in genome stability maintenance in response to high-LET radiation and as a promising target to improve cancer therapy.

  8. Transient Genome-Wide Transcriptional Response to Low-Dose Ionizing Radiation In Vivo in Humans

    SciTech Connect

    Berglund, Susanne R.; Rocke, David M.; Dai Jian; Schwietert, Chad W.; Santana, Alison; Stern, Robin L.; Lehmann, Joerg; Hartmann Siantar, Christine L.; Goldberg, Zelanna

    2008-01-01

    Purpose: The in vivo effects of low-dose low linear energy transfer ionizing radiation on healthy human skin are largely unknown. Using a patient-based tissue acquisition protocol, we have performed a series of genomic analyses on the temporal dynamics over a 24-hour period to determine the radiation response after a single exposure of 10 cGy. Methods and Materials: RNA from each patient tissue sample was hybridized to an Affymetrix Human Genome U133 Plus 2.0 array. Data analysis was performed on selected gene groups and pathways. Results: Nineteen gene groups and seven gene pathways that had been shown to be radiation responsive were analyzed. Of these, nine gene groups showed significant transient transcriptional changes in the human tissue samples, which returned to baseline by 24 hours postexposure. Conclusions: Low doses of ionizing radiation on full-thickness human skin produce a definable temporal response out to 24 hours postexposure. Genes involved in DNA and tissue remodeling, cell cycle transition, and inflammation show statistically significant changes in expression, despite variability between patients. These data serve as a reference for the temporal dynamics of ionizing radiation response following low-dose exposure in healthy full-thickness human skin.

  9. Early and late mammalian responses to heavy charged particles

    NASA Technical Reports Server (NTRS)

    Ainsworth, E. J.

    1986-01-01

    This overview summarizes murine results on acute lethality responses, inactivation of marrow CFU-S and intestinal microcolonies, testes weight loss, life span shortening, and posterior lens opacification in mice irradiated with heavy charged particles. RBE-LET relationships for these mammalian responses are compared with results from in vitro studies. The trend is that the maximum RBE for in vivo responses tends to be lower and occurs at a lower LET than for inactivation of V79 and T-1 cells in culture. Based on inactivation cross sections, the response of CFU-S in vivo conforms to expectations from earlier studies with prokaryotic systems and mammalian cells in culture. Effects of heavy ions are compared with fission spectrum neutrons, and the results are consistent with the interpretation that RBEs are lower than for fission neutrons at about the same LET, probably due to differences in track structure.

  10. Genomic and transcriptomic predictors of response levels to endurance exercise training.

    PubMed

    Sarzynski, Mark A; Ghosh, Sujoy; Bouchard, Claude

    2016-05-28

    Predicting the responsiveness to regular exercise is a topic of great relevance due to its potential role in personalized exercise medicine applications. The present review focuses on cardiorespiratory fitness (commonly measured by maximal oxygen uptake, V̇O2 max ), a trait with wide-ranging impact on health and performance indicators. Gains in V̇O2 max demonstrate large inter-individual variation even in response to standardized exercise training programmes. The estimated ΔVO2 max heritability of 47% suggests that genomic-based predictors alone are insufficient to account for the total trainability variance. Candidate gene and genome-wide linkage studies have not significantly contributed to our understanding of the molecular basis of trainability. A genome-wide association study suggested that V̇O2 max trainability is influenced by multiple genes of small effects, but these findings still await rigorous replication. Valuable evidence, however, has been obtained by combining skeletal muscle transcript abundance profiles with common DNA variants for the prediction of the V̇O2 max response to exercise training. Although the physiological determinants of V̇O2 max measured at a given time are largely enunciated, what is poorly understood are the details of tissue-specific molecular mechanisms that limit V̇O2 max and related signalling pathways in response to exercise training. Bioinformatics explorations based on thousands of variants have been used to interrogate pathways and systems instead of single variants and genes, and the main findings, along with those from exercise experimental studies, have been summarized here in a working model of V̇O2 max trainability.

  11. Comparative Genomics Including the Early-Diverging Smut Fungus Ceraceosorus bombacis Reveals Signatures of Parallel Evolution within Plant and Animal Pathogens of Fungi and Oomycetes.

    PubMed

    Sharma, Rahul; Xia, Xiaojuan; Riess, Kai; Bauer, Robert; Thines, Marco

    2015-08-27

    Ceraceosorus bombacis is an early-diverging lineage of smut fungi and a pathogen of cotton trees (Bombax ceiba). To study the evolutionary genomics of smut fungi in comparison with other fungal and oomycete pathogens, the genome of C. bombacis was sequenced and comparative genomic analyses were performed. The genome of 26.09 Mb encodes for 8,024 proteins, of which 576 are putative-secreted effector proteins (PSEPs). Orthology analysis revealed 30 ortholog PSEPs among six Ustilaginomycotina genomes, the largest groups of which are lytic enzymes, such as aspartic peptidase and glycoside hydrolase. Positive selection analyses revealed the highest percentage of positively selected PSEPs in C. bombacis compared with other Ustilaginomycotina genomes. Metabolic pathway analyses revealed the absence of genes encoding for nitrite and nitrate reductase in the genome of the human skin pathogen Malassezia globosa, but these enzymes are present in the sequenced plant pathogens in smut fungi. Interestingly, these genes are also absent in cultivable oomycete animal pathogens, while nitrate reductase has been lost in cultivable oomycete plant pathogens. Similar patterns were also observed for obligate biotrophic and hemi-biotrophic fungal and oomycete pathogens. Furthermore, it was found that both fungal and oomycete animal pathogen genomes are lacking cutinases and pectinesterases. Overall, these findings highlight the parallel evolution of certain genomic traits, revealing potential common evolutionary trajectories among fungal and oomycete pathogens, shaping the pathogen genomes according to their lifestyle.

  12. Genome-wide characterisation and expression profile of the grapevine ATL ubiquitin ligase family reveal biotic and abiotic stress-responsive and development-related members

    PubMed Central

    Ariani, Pietro; Regaiolo, Alice; Lovato, Arianna; Giorgetti, Alejandro; Porceddu, Andrea; Camiolo, Salvatore; Wong, Darren; Castellarin, Simone; Vandelle, Elodie; Polverari, Annalisa

    2016-01-01

    The Arabidopsis Tóxicos en Levadura (ATL) protein family is a class of E3 ubiquitin ligases with a characteristic RING-H2 Zn-finger structure that mediates diverse physiological processes and stress responses in plants. We carried out a genome-wide survey of grapevine (Vitis vinifera L.) ATL genes and retrieved 96 sequences containing the canonical ATL RING-H2 domain. We analysed their genomic organisation, gene structure and evolution, protein domains and phylogenetic relationships. Clustering revealed several clades, as already reported in Arabidopsis thaliana and rice (Oryza sativa), with an expanded subgroup of grapevine-specific genes. Most of the grapevine ATL genes lacked introns and were scattered among the 19 chromosomes, with a high level of duplication retention. Expression profiling revealed that some ATL genes are expressed specifically during early or late development and may participate in the juvenile to mature plant transition, whereas others may play a role in pathogen and/or abiotic stress responses, making them key candidates for further functional analysis. Our data offer the first genome-wide overview and annotation of the grapevine ATL family, and provide a basis for investigating the roles of specific family members in grapevine physiology and stress responses, as well as potential biotechnological applications. PMID:27910910

  13. Genome-wide characterisation and expression profile of the grapevine ATL ubiquitin ligase family reveal biotic and abiotic stress-responsive and development-related members.

    PubMed

    Ariani, Pietro; Regaiolo, Alice; Lovato, Arianna; Giorgetti, Alejandro; Porceddu, Andrea; Camiolo, Salvatore; Wong, Darren; Castellarin, Simone; Vandelle, Elodie; Polverari, Annalisa

    2016-12-02

    The Arabidopsis Tóxicos en Levadura (ATL) protein family is a class of E3 ubiquitin ligases with a characteristic RING-H2 Zn-finger structure that mediates diverse physiological processes and stress responses in plants. We carried out a genome-wide survey of grapevine (Vitis vinifera L.) ATL genes and retrieved 96 sequences containing the canonical ATL RING-H2 domain. We analysed their genomic organisation, gene structure and evolution, protein domains and phylogenetic relationships. Clustering revealed several clades, as already reported in Arabidopsis thaliana and rice (Oryza sativa), with an expanded subgroup of grapevine-specific genes. Most of the grapevine ATL genes lacked introns and were scattered among the 19 chromosomes, with a high level of duplication retention. Expression profiling revealed that some ATL genes are expressed specifically during early or late development and may participate in the juvenile to mature plant transition, whereas others may play a role in pathogen and/or abiotic stress responses, making them key candidates for further functional analysis. Our data offer the first genome-wide overview and annotation of the grapevine ATL family, and provide a basis for investigating the roles of specific family members in grapevine physiology and stress responses, as well as potential biotechnological applications.

  14. Thompson Receives 2013 Early Career Hydrologic Science Award: Response

    NASA Astrophysics Data System (ADS)

    Thompson, Sally

    2014-08-01

    My most sincere thanks to AGU; the Hydrology section and its chair, Eric Wood; those who were kind enough to nominate me for this award; and, of course, the inimitable Gaby Katul for their support and for this recognition. Receiving the Early Career Hydrologic Science Award is an unexpected and humbling pleasure. After seven schizophrenic years of physical scientists accusing me of being an ecologist and ecologists telling me firmly that I'm an engineer, it's wonderful to be able to come to rest where I have always self-identified—as a hydrologist!

  15. Genomic Grade Index (GGI): Feasibility in Routine Practice and Impact on Treatment Decisions in Early Breast Cancer

    PubMed Central

    Metzger-Filho, Otto; Catteau, Aurélie; Michiels, Stefan; Buyse, Marc; Ignatiadis, Michail; Saini, Kamal S.; de Azambuja, Evandro; Fasolo, Virginie; Naji, Sihem; Canon, Jean Luc; Delrée, Paul; Coibion, Michel; Cusumano, Pino; Jossa, Veronique; Kains, Jean Pierre; Larsimont, Denis; Richard, Vincent; Faverly, Daniel; Cornez, Nathalie; Vuylsteke, Peter; Vanderschueren, Brigitte; Peyro-Saint-Paul, Hélène; Piccart, Martine; Sotiriou, Christos

    2013-01-01

    Purpose Genomic Grade Index (GGI) is a 97-gene signature that improves histologic grade (HG) classification in invasive breast carcinoma. In this prospective study we sought to evaluate the feasibility of performing GGI in routine clinical practice and its impact on treatment recommendations. Methods Patients with pT1pT2 or operable pT3, N0-3 invasive breast carcinoma were recruited from 8 centers in Belgium. Fresh surgical samples were sent at room temperature in the MapQuant Dx™ PathKit for centralized genomic analysis. Genomic profiles were determined using Affymetrix U133 Plus 2.0 and GGI calculated using the MapQuant Dx® protocol, which defines tumors as low or high Genomic Grade (GG-1 and GG-3 respectively). Results 180 pts were recruited and 155 were eligible. The MapQuant test was performed in 142 cases and GGI was obtained in 78% of cases (n=111). Reasons for failures were 15 samples with <30% of invasive tumor cells (11%), 15 with insufficient RNA quality (10%), and 1 failed hybridization (<1%). For tumors with an available representative sample (≥ 30% inv. tumor cells) (n=127), the success rate was 87.5%. GGI reclassified 69% of the 54 HG2 tumors as GG-1 (54%) or GG-3 (46%). Changes in treatment recommendations occurred mainly in the subset of HG2 tumors reclassified into GG-3, with increased use of chemotherapy in this subset. Conclusion The use of GGI is feasible in routine clinical practice and impacts treatment decisions in early-stage breast cancer. Trial Registration ClinicalTrials.gov NCT01916837, http://clinicaltrials.gov/ct2/show/NCT01916837 PMID:23990869

  16. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

    PubMed Central

    Postmus, Iris; Trompet, Stella; Deshmukh, Harshal A.; Barnes, Michael R.; Li, Xiaohui; Warren, Helen R.; Chasman, Daniel I.; Zhou, Kaixin; Arsenault, Benoit J.; Donnelly, Louise A.; Wiggins, Kerri L.; Avery, Christy L.; Griffin, Paula; Feng, QiPing; Taylor, Kent D.; Li, Guo; Evans, Daniel S.; Smith, Albert V.; de Keyser, Catherine E.; Johnson, Andrew D.; de Craen, Anton J. M.; Stott, David J.; Buckley, Brendan M.; Ford, Ian; Westendorp, Rudi G. J.; Eline Slagboom, P.; Sattar, Naveed; Munroe, Patricia B.; Sever, Peter; Poulter, Neil; Stanton, Alice; Shields, Denis C.; O’Brien, Eoin; Shaw-Hawkins, Sue; Ida Chen, Y.-D.; Nickerson, Deborah A.; Smith, Joshua D.; Pierre Dubé, Marie; Matthijs Boekholdt, S.; Kees Hovingh, G.; Kastelein, John J. P.; McKeigue, Paul M.; Betteridge, John; Neil, Andrew; Durrington, Paul N.; Doney, Alex; Carr, Fiona; Morris, Andrew; McCarthy, Mark I.; Groop, Leif; Ahlqvist, Emma; Bis, Joshua C.; Rice, Kenneth; Smith, Nicholas L.; Lumley, Thomas; Whitsel, Eric A.; Stürmer, Til; Boerwinkle, Eric; Ngwa, Julius S.; O’Donnell, Christopher J.; Vasan, Ramachandran S.; Wei, Wei-Qi; Wilke, Russell A.; Liu, Ching-Ti; Sun, Fangui; Guo, Xiuqing; Heckbert, Susan R; Post, Wendy; Sotoodehnia, Nona; Arnold, Alice M.; Stafford, Jeanette M.; Ding, Jingzhong; Herrington, David M.; Kritchevsky, Stephen B.; Eiriksdottir, Gudny; Launer, Leonore J.; Harris, Tamara B.; Chu, Audrey Y.; Giulianini, Franco; MacFadyen, Jean G.; Barratt, Bryan J.; Nyberg, Fredrik; Stricker, Bruno H.; Uitterlinden, André G.; Hofman, Albert; Rivadeneira, Fernando; Emilsson, Valur; Franco, Oscar H.; Ridker, Paul M.; Gudnason, Vilmundur; Liu, Yongmei; Denny, Joshua C.; Ballantyne, Christie M.; Rotter, Jerome I.; Adrienne Cupples, L.; Psaty, Bruce M.; Palmer, Colin N. A.; Tardif, Jean-Claude; Colhoun, Helen M.; Hitman, Graham; Krauss, Ronald M.; Wouter Jukema, J; Caulfield, Mark J.; Donnelly, Peter; Barroso, Ines; Blackwell, Jenefer M.; Bramon, Elvira; Brown, Matthew A.; Casas, Juan P.; Corvin, Aiden; Deloukas, Panos; Duncanson, Audrey; Jankowski, Janusz; Markus, Hugh S.; Mathew, Christopher G.; Palmer, Colin N. A.; Plomin, Robert; Rautanen, Anna; Sawcer, Stephen J.; Trembath, Richard C.; Viswanathan, Ananth C.; Wood, Nicholas W.; Spencer, Chris C. A.; Band, Gavin; Bellenguez, Céline; Freeman, Colin; Hellenthal, Garrett; Giannoulatou, Eleni; Pirinen, Matti; Pearson, Richard; Strange, Amy; Su, Zhan; Vukcevic, Damjan; Donnelly, Peter; Langford, Cordelia; Hunt, Sarah E.; Edkins, Sarah; Gwilliam, Rhian; Blackburn, Hannah; Bumpstead, Suzannah J.; Dronov, Serge; Gillman, Matthew; Gray, Emma; Hammond, Naomi; Jayakumar, Alagurevathi; McCann, Owen T.; Liddle, Jennifer; Potter, Simon C.; Ravindrarajah, Radhi; Ricketts, Michelle; Waller, Matthew; Weston, Paul; Widaa, Sara; Whittaker, Pamela; Barroso, Ines; Deloukas, Panos; Mathew, Christopher G.; Blackwell, Jenefer M.; Brown, Matthew A.; Corvin, Aiden; McCarthy, Mark I.; Spencer, Chris C. A.

    2014-01-01

    Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response. PMID:25350695

  17. Frameworks for Response to Intervention in Early Childhood: Description and Implications

    ERIC Educational Resources Information Center

    Communication Disorders Quarterly, 2014

    2014-01-01

    In February, 2013, the Division of Early Childhood, the National Association for the Education of Young Children, and the National Head Start Association released a collaborative paper to provide clarification and assistance regarding the relationship of response to intervention (RTI) with the field of early childhood (EC). In addition to…

  18. Response to therapy following retreatment of serofast early syphilis patients with benzathine penicillin.

    PubMed

    Seña, Arlene C; Wolff, Mark; Behets, Frieda; Van Damme, Kathleen; Martin, David H; Leone, Peter; McNeil, Linda; Hook, Edward W

    2013-02-01

    Persistent nontreponemal titers after treatment are common among patients with early syphilis. We retreated 82 human immunodeficiency virus-negative early syphilis participants who were serofast at 6 months using benzathine penicillin. Only 27% exhibited serological response after retreatment and after an additional 6 months of follow-up.

  19. Measuring Early Childhood Teacher Candidates' Conceptualizations of a Culturally Responsive Classroom Ecology

    ERIC Educational Resources Information Center

    Flores, Belinda Bustos; Riojas-Cortez, Mari

    2009-01-01

    With the increase of Latino preschoolers, it is pressing that early childhood teachers are prepared to create a high quality environment in which all children can succeed. Using the frameworks of cultural responsiveness and classroom management, we developed the Early Childhood Ecology Scale (ECES) as an observational and reflective tool to…

  20. Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting | Office of Cancer Genomics

    Cancer.gov

    The CRISPR/Cas9 system enables genome editing and somatic cell genetic screens in mammalian cells. We performed genome-scale loss-of-function screens in 33 cancer cell lines to identify genes essential for proliferation/survival and found a strong correlation between increased gene copy number and decreased cell viability after genome editing. Within regions of copy-number gain, CRISPR/Cas9 targeting of both expressed and unexpressed genes, as well as intergenic loci, led to significantly decreased cell proliferation through induction of a G2 cell-cycle arrest.

  1. Population genomics of early events in the ecological differentiation of bacteria

    SciTech Connect

    Shapiro, Jesse B.; Friedman, Jonatan; Cordero, Otto X.; Preheim, Sarah P..; Timberlake, Sonia C.; Szabo, Gitta; Polz, Martin F.; Alm, Eric J.

    2012-04-06

    Genetic exchange is common among bacteria, but its effect on population diversity during ecological differentiation remains controversial. A fundamental question is whether advantageous mutations lead to selection of clonal genomes or, as in sexual eukaryotes, sweep through populations on their own. Here, we show that in two recently diverged populations of ocean bacteria, ecological differentiation has occurred akin to a sexual mechanism: A few genome regions have swept through subpopulations in a habitat-specific manner, accompanied by gradual separation of gene pools as evidenced by increased habitat specificity of the most recent recombinations. These findings reconcile previous, seemingly contradictory empirical observations of the genetic structure of bacterial populations and point to a more unified process of differentiation in bacteria and sexual eukaryotes than previously thought.

  2. Genomic instability and DNA damage responses in progeria arising from defective maturation of prelamin A.

    PubMed

    Musich, Phillip R; Zou, Yue

    2009-01-01

    Progeria syndromes have in common a premature aging phenotype and increased genome instability. The susceptibility to DNA damage arises from a compromised repair system, either in the repair proteins themselves or in the DNA damage response pathways. The most severe progerias stem from mutations affecting lamin A production, a filamentous protein of the nuclear lamina. Hutchinson-Gilford progeria syndrome (HGPS) patients are heterozygous for aLMNA gene mutation while Restrictive Dermopathy (RD) individuals have a homozygous deficiency in the processing protease Zmpste24. These mutations generate the mutant lamin A proteins progerin and FC-lamina A, respectively, which cause nuclear deformations and chromatin perturbations. Genome instability is observed even though genome maintenance and repair genes appear normal. The unresolved question is what features of the DNA damage response pathways are deficient in HGPS and RD cells. Here we review and discuss recent findings which resolve some mechanistic details of how the accumulation of progerin/FC-lamin A proteins may disrupt DNA damage response pathways in HGPS and RD cells. As the mutant lamin proteins accumulate they sequester replication and repair factors, leading to stalled replication forks which collapse into DNA double-strand beaks (DSBs). In a reaction unique to HGPS and RD cells these accessible DSB termini bind Xeroderma pigmentosum group A (XPA) protein which excludes normal binding by DNA DSB repair proteins. The bound XPA also signals activation of ATM and ATR, arresting cell cycle progression, leading to arrested growth. In addition, the effective sequestration of XPA at these DSB damage sites makes HGPS and RD cells more sensitive to ultraviolet light and other mutagens normally repaired by the nucleotide excision repair pathway of which XPA is a necessary and specific component.

  3. Evaluation of Genomic Instability as an Early Event in the Progression of Breast Cancer

    DTIC Science & Technology

    2006-04-01

    dysfunctional telomeres and genomic instability implies that shortened telomeres are also associated with altered gene expression. The latter is a primary...2005;173:610-4. 29. Odagiri E, Kanada N, Jibiki K, Demura R, Aikawa E, Demura H. Reduction of telomeric length and c-erbB-2 gene amplification in human...loss or structural rearrangement of a critical gene or genes - occurs in virtually all cancers [6]. The phenotype of a tumor is a reflection of its

  4. DNA Microarray Analysis of Human Monocytes Early Response Genes upon Infection with Rickettsia rickettsii

    DTIC Science & Technology

    2004-11-15

    DNA Microarray Analysis of Human Monocytes Early Response Genes upon Infection with Rickettsia rickettsii Chien-Chung Chao Rickettsiae Diseases...TITLE AND SUBTITLE DNA Microarray Analysis of Human Monocytes Early Response Genes upon Infection with Rickettsia rickettsii 5a. CONTRACT NUMBER 5b...ANSI Std Z39-18 Rickettsiae • Gram negative coccobacillary bacteria • Obligate intracellular organisms • Arthropod-borne • Cause febrile diseases (mild

  5. Whole-genome analyses resolve early branches in the tree of life of modern birds

    PubMed Central

    Jarvis, Erich D.; Mirarab, Siavash; Aberer, Andre J.; Li, Bo; Houde, Peter; Li, Cai; Ho, Simon Y. W.; Faircloth, Brant C.; Nabholz, Benoit; Howard, Jason T.; Suh, Alexander; Weber, Claudia C.; da Fonseca, Rute R.; Li, Jianwen; Zhang, Fang; Li, Hui; Zhou, Long; Narula, Nitish; Liu, Liang; Ganapathy, Ganesh; Boussau, Bastien; Bayzid, Md. Shamsuzzoha; Zavidovych, Volodymyr; Subramanian, Sankar; Gabaldón, Toni; Capella-Gutiérrez, Salvador; Huerta-Cepas, Jaime; Rekepalli, Bhanu; Munch, Kasper; Schierup, Mikkel; Lindow, Bent; Warren, Wesley C.; Ray, David; Green, Richard E.; Bruford, Michael W.; Zhan, Xiangjiang; Dixon, Andrew; Li, Shengbin; Li, Ning; Huang, Yinhua; Derryberry, Elizabeth P.; Bertelsen, Mads Frost; Sheldon, Frederick H.; Brumfield, Robb T.; Mello, Claudio V.; Lovell, Peter V.; Wirthlin, Morgan; Schneider, Maria Paula Cruz; Prosdocimi, Francisco; Samaniego, José Alfredo; Velazquez, Amhed Missael Vargas; Alfaro-Núñez, Alonzo; Campos, Paula F.; Petersen, Bent; Sicheritz-Ponten, Thomas; Pas, An; Bailey, Tom; Scofield, Paul; Bunce, Michael; Lambert, David M.; Zhou, Qi; Perelman, Polina; Driskell, Amy C.; Shapiro, Beth; Xiong, Zijun; Zeng, Yongli; Liu, Shiping; Li, Zhenyu; Liu, Binghang; Wu, Kui; Xiao, Jin; Yinqi, Xiong; Zheng, Qiuemei; Zhang, Yong; Yang, Huanming; Wang, Jian; Smeds, Linnea; Rheindt, Frank E.; Braun, Michael; Fjeldsa, Jon; Orlando, Ludovic; Barker, F. Keith; Jønsson, Knud Andreas; Johnson, Warren; Koepfli, Klaus-Peter; O’Brien, Stephen; Haussler, David; Ryder, Oliver A.; Rahbek, Carsten; Willerslev, Eske; Graves, Gary R.; Glenn, Travis C.; McCormack, John; Burt, Dave; Ellegren, Hans; Alström, Per; Edwards, Scott V.; Stamatakis, Alexandros; Mindell, David P.; Cracraft, Joel; Braun, Edward L.; Warnow, Tandy; Jun, Wang; Gilbert, M. Thomas P.; Zhang, Guojie

    2015-01-01

    To better determine the history of modern birds, we performed a genome-scale phylogenetic analysis of 48 species representing all orders of Neoaves using phylogenomic methods created to handle genome-scale data. We recovered a highly resolved tree that confirms previously controversial sister or close relationships. We identified the first divergence in Neoaves, two groups we named Passerea and Columbea, representing independent lineages of diverse and convergently evolved land and water bird species. Among Passerea, we infer the common ancestor of core landbirds to have been an apex predator and confirm independent gains of vocal learning. Among Columbea, we identify pigeons and flamingoes as belonging to sister clades. Even with whole genomes, some of the earliest branches in Neoaves proved challenging to resolve, which was best explained by massive protein-coding sequence convergence and high levels of incomplete lineage sorting that occurred during a rapid radiation after the Cretaceous-Paleogene mass extinction event about 66 million years ago. PMID:25504713

  6. Functional genomic mapping of an early-activated centromeric mammalian origin of DNA replication.

    PubMed

    Pelletier, R; Price, G B; Zannis-Hadjopoulos, M

    1999-09-15

    Ors12, a mammalian autonomously replicating sequence (812 bp), was previously isolated by extrusion of African green monkey (CV-1 cells) nascent DNA from active replication bubbles. It contains a region of alpha-satellite extending 168-bp from the 5'-end, and a nonrepetitive portion extending from nucleotide position 169 to nucleotide 812 that is present in less than nine copies per haploid genome. Ors12 is capable of transient autonomous DNA replication in vivo and in vitro, associates with the nuclear matrix in a cell cycle-dependent manner, and hybridizes at the centromeric region of six CV-1 cell chromosomes as well as a marker chromosome. To demonstrate that DNA replication initiates at ors12 at a native chromosomal locus, a 14.2 kb African green monkey genomic clone was isolated and sequence information was obtained that allowed us to generate eight sets of PCR primers spanning a region of 8 kb containing ors12. One set of primers occurred inside ors12. These primers were used to amplify nascent DNA strands from asynchronously growing CV-1 and African green monkey kidney (AGMK) cells, using noncompetitive and competitive PCR-based mapping methodologies. Both assays showed that DNA replication in vivo initiates preferentially in a 2.3 kb region containing ors12, as well as at a second site located 1.7 kb upstream of ors12. This study provides the first demonstration of genomic function for a centromeric mammalian origin of DNA replication, originally isolated by nascent strand extrusion.

  7. Infectious diseases of marine molluscs and host responses as revealed by genomic tools

    PubMed Central

    Ford, Susan E.

    2016-01-01

    More and more infectious diseases affect marine molluscs. Some diseases have impacted commercial species including MSX and Dermo of the eastern oyster, QPX of hard clams, withering syndrome of abalone and ostreid herpesvirus 1 (OsHV-1) infections of many molluscs. Although the exact transmission mechanisms are not well understood, human activities and associated environmental changes often correlate with increased disease prevalence. For instance, hatcheries and large-scale aquaculture create high host densities, which, along with increasing ocean temperature, might have contributed to OsHV-1 epizootics in scallops and oysters. A key to understanding linkages between the environment and disease is to understand how the environment affects the host immune system. Although we might be tempted to downplay the role of immunity in invertebrates, recent advances in genomics have provided insights into host and parasite genomes and revealed surprisingly sophisticated innate immune systems in molluscs. All major innate immune pathways are found in molluscs with many immune receptors, regulators and effectors expanded. The expanded gene families provide great diversity and complexity in innate immune response, which may be key to mollusc's defence against diverse pathogens in the absence of adaptive immunity. Further advances in host and parasite genomics should improve our understanding of genetic variation in parasite virulence and host disease resistance. PMID:26880838

  8. Inflammatory response to isocyanates and onset of genomic instability in cultured human lung fibroblasts.

    PubMed

    Mishra, P K; Bhargava, A; Raghuram, G V; Gupta, S; Tiwari, S; Upadhyaya, R; Jain, S K; Maudar, K K

    2009-02-10

    Lungs comprise the primary organ exposed to environmental toxic chemicals, resulting in diverse respiratory ailments and other disorders, including carcinogenesis. Carcinogenesis is a multi-stage phenomenon, which involves a series of genetic alterations that begin with genomic instability provoked by certain factors such as inflammation and DNA damage and end with the development of cancer. Isocyanates such as methyl isocyanate are the chief metabolic intermediates in many industrial settings with diverse applications; exposure to them can lead to severe hypersensitive, mutagenic and genotoxic alterations. We examined the molecular mechanisms underlying isocyanate-mediated inflammatory responses and their probable role in the onset of genomic instability in cultured IMR-90 human lung fibroblasts. The isocyanates induced inflammation, resulting in extensive DNA damage, evidenced by increases in ATM, ATR, gammaH2AX, and p53 expression levels. The apoptotic index also increased. Chromosomal anomalies in treated cells included over-expression of centrosome protein and variable amplification of inter-simple sequence repeats, further demonstrating isocyanate-induced genomic instability. This information could be useful in the design of new approaches for risk assessment of potential industrial disasters.

  9. First genomic insights into members of a candidate bacterial phylum responsible for wastewater bulking.

    PubMed

    Sekiguchi, Yuji; Ohashi, Akiko; Parks, Donovan H; Yamauchi, Toshihiro; Tyson, Gene W; Hugenholtz, Philip

    2015-01-01

    Filamentous cells belonging to the candidate bacterial phylum KSB3 were previously identified as the causative agent of fatal filament overgrowth (bulking) in a high-rate industrial anaerobic wastewater treatment bioreactor. Here, we obtained near complete genomes from two KSB3 populations in the bioreactor, including the dominant bulking filament, using differential coverage binning of metagenomic data. Fluorescence in situ hybridization with 16S rRNA-targeted probes specific for the two populations confirmed that both are filamentous organisms. Genome-based metabolic reconstruction and microscopic observation of the KSB3 filaments in the presence of sugar gradients indicate that both filament types are Gram-negative, strictly anaerobic fermenters capable of non-flagellar based gliding motility, and have a strikingly large number of sensory and response regulator genes. We propose that the KSB3 filaments are highly sensitive to their surroundings and that cellular processes, including those causing bulking, are controlled by external stimuli. The obtained genomes lay the foundation for a more detailed understanding of environmental cues used by KSB3 filaments, which may lead to more robust treatment options to prevent bulking.

  10. Infectious diseases of marine molluscs and host responses as revealed by genomic tools.

    PubMed

    Guo, Ximing; Ford, Susan E

    2016-03-05

    More and more infectious diseases affect marine molluscs. Some diseases have impacted commercial species including MSX and Dermo of the eastern oyster, QPX of hard clams, withering syndrome of abalone and ostreid herpesvirus 1 (OsHV-1) infections of many molluscs. Although the exact transmission mechanisms are not well understood, human activities and associated environmental changes often correlate with increased disease prevalence. For instance, hatcheries and large-scale aquaculture create high host densities, which, along with increasing ocean temperature, might have contributed to OsHV-1 epizootics in scallops and oysters. A key to understanding linkages between the environment and disease is to understand how the environment affects the host immune system. Although we might be tempted to downplay the role of immunity in invertebrates, recent advances in genomics have provided insights into host and parasite genomes and revealed surprisingly sophisticated innate immune systems in molluscs. All major innate immune pathways are found in molluscs with many immune receptors, regulators and effectors expanded. The expanded gene families provide great diversity and complexity in innate immune response, which may be key to mollusc's defence against diverse pathogens in the absence of adaptive immunity. Further advances in host and parasite genomics should improve our understanding of genetic variation in parasite virulence and host disease resistance.

  11. DNA damage responses by human ELG1 in S phase are important to maintain genomic integrity.

    PubMed

    Sikdar, Nilabja; Banerjee, Soma; Lee, Kyoo-young; Wincovitch, Stephen; Pak, Evgenia; Nakanishi, Koji; Jasin, Maria; Dutra, Amalia; Myung, Kyungjae

    2009-10-01

    Genomic integrity depends on DNA replication, recombination and repair, particularly in S phase. We demonstrate that a human homologue of yeast Elg1 plays an important role in S phase to preserve genomic stability. The level of ELG1 is induced during recovery from a variety of DNA damage. In response to DNA damage, ELG1 forms distinct foci at stalled DNA replication forks that are different from DNA double strand break foci. Targeted gene knockdown of ELG1 resulted in spontaneous foci formation of gamma-H2AX, 53BP1 and phosphorylated-ATM that mark chromosomal breaks. Abnormal chromosomes including fusions, inversions and hypersensitivity to DNA damaging agents were also observed in cells expressing low level of ELG1 by targeted gene knockdown. Knockdown of ELG1 by siRNA reduced homologous recombination frequency in the I-SceI induced double strand break-dependent assay. In contrast, spontaneous homologous recombination frequency and sister chromatin exchange rate were upregulated when ELG1 was silenced by shRNA. Taken together, we propose that ELG1 would be a new member of proteins involved in maintenance of genomic integrity.

  12. Optimization of CRISPR/Cas9 genome editing to modify abiotic stress responses in plants

    PubMed Central

    Osakabe, Yuriko; Watanabe, Takahito; Sugano, Shigeo S; Ueta, Risa; Ishihara, Ryosuke; Shinozaki, Kazuo; Osakabe, Keishi

    2016-01-01

    Genome editing using the CRISPR/Cas9 system can be used to modify plant genomes, however, improvements in specificity and applicability are still needed in order for the editing technique to be useful in various plant species. Here, using genome editing mediated by a truncated gRNA (tru-gRNA)/Cas9 combination, we generated new alleles for OST2, a proton pump in Arabidopsis, with no off-target effects. By following expression of Cas9 and the tru-gRNAs, newly generated mutations in CRIPSR/Cas9 transgenic plants were detected with high average mutation rates of up to 32.8% and no off-target effects using constitutive promoter. Reducing nuclear localization signals in Cas9 decreased the mutation rate. In contrast, tru-gRNA Cas9 cassettes driven by meristematic- and reproductive-tissue-specific promoters increased the heritable mutation rate in Arabidopsis, showing that high expression in the germ line can produce bi-allelic mutations. Finally, the new mutant alleles obtained for OST2 exhibited altered stomatal closing in response to environmental conditions. These results suggest further applications in molecular breeding to improve plant function using optimized plant CRISPR/Cas9 systems. PMID:27226176

  13. First genomic insights into members of a candidate bacterial phylum responsible for wastewater bulking

    PubMed Central

    Ohashi, Akiko; Parks, Donovan H.; Yamauchi, Toshihiro; Tyson, Gene W.

    2015-01-01

    Filamentous cells belonging to the candidate bacterial phylum KSB3 were previously identified as the causative agent of fatal filament overgrowth (bulking) in a high-rate industrial anaerobic wastewater treatment bioreactor. Here, we obtained near complete genomes from two KSB3 populations in the bioreactor, including the dominant bulking filament, using differential coverage binning of metagenomic data. Fluorescence in situ hybridization with 16S rRNA-targeted probes specific for the two populations confirmed that both are filamentous organisms. Genome-based metabolic reconstruction and microscopic observation of the KSB3 filaments in the presence of sugar gradients indicate that both filament types are Gram-negative, strictly anaerobic fermenters capable of non-flagellar based gliding motility, and have a strikingly large number of sensory and response regulator genes. We propose that the KSB3 filaments are highly sensitive to their surroundings and that cellular processes, including those causing bulking, are controlled by external stimuli. The obtained genomes lay the foundation for a more detailed understanding of environmental cues used by KSB3 filaments, which may lead to more robust treatment options to prevent bulking. PMID:25650158

  14. Modular Transcriptional Networks of the Host Pulmonary Response during Early and Late Pneumococcal Pneumonia.

    PubMed

    Scicluna, Brendon P; van Lieshout, Miriam H; Blok, Dana C; Florquin, Sandrine; van der Poll, Tom

    2015-05-12

    Streptococcus pneumoniae (Spneu) remains the most lethal bacterial pathogen and the dominant agent of community-acquired pneumonia. Treatment has perennially focused on the use of antibiotics, albeit scrutinized due to the occurrence of antibiotic-resistant Spneu strains. Immunomodulatory strategies have emerged as potential treatment options. Although promising, immunomodulation can lead to improper tissue functions either at steady state or upon infectious challenge. This argues for the availability of tools to enable a detailed assessment of whole pulmonary functions during the course of infection, not only those functions biased to the defense response. Thus, through the use of an unbiased tissue microarray and bioinformatics approach, we aimed to construct a comprehensive map of whole-lung transcriptional activity and cellular pathways during the course of pneumococcal pneumonia. We performed genome-wide transcriptional analysis of whole lungs before and 6 and 48 h after Spneu infection in mice. The 4,000 most variable transcripts across all samples were used to assemble a gene coexpression network comprising 13 intercorrelating modules (clusters of genes). Fifty-four percent of this whole-lung transcriptional network was altered 6 and 48 h after Spneu infection. Canonical signaling pathway analysis uncovered known pathways imparting protection, including IL17A/IL17F signaling and previously undetected mechanisms that included lipid metabolism. Through in silico prediction of cell types, pathways were observed to enrich for distinct cell types such as a novel stromal cell lipid metabolism pathway. These cellular mechanisms were furthermore anchored at functional hub genes of cellular fate, differentiation, growth and transcription. Collectively, we provide a benchmark unsupervised map of whole-lung transcriptional relationships and cellular activity during early and late pneumococcal pneumonia.

  15. Using the Acropora digitifera genome to understand coral responses to environmental change.

    PubMed

    Shinzato, Chuya; Shoguchi, Eiichi; Kawashima, Takeshi; Hamada, Mayuko; Hisata, Kanako; Tanaka, Makiko; Fujie, Manabu; Fujiwara, Mayuki; Koyanagi, Ryo; Ikuta, Tetsuro; Fujiyama, Asao; Miller, David J; Satoh, Nori

    2011-07-24

    Despite the enormous ecological and economic importance of coral reefs, the keystone organisms in their establishment, the scleractinian corals, increasingly face a range of anthropogenic challenges including ocean acidification and seawater temperature rise. To understand better the molecular mechanisms underlying coral biology, here we decoded the approximately 420-megabase genome of Acropora digitifera using next-generation sequencing technology. This genome contains approximately 23,700 gene models. Molecular phylogenetics indicate that the coral and the sea anemone Nematostella vectensis diverged approximately 500 million years ago, considerably earlier than the time over which modern corals are represented in the fossil record (∼240 million years ago). Despite the long evolutionary history of the endosymbiosis, no evidence was found for horizontal transfer of genes from symbiont to host. However, unlike several other corals, Acropora seems to lack an enzyme essential for cysteine biosynthesis, implying dependency of this coral on its symbionts for this amino acid. Corals inhabit environments where they are frequently exposed to high levels of solar radiation, and analysis of the Acropora genome data indicates that the coral host can independently carry out de novo synthesis of mycosporine-like amino acids, which are potent ultraviolet-protective compounds. In addition, the coral innate immunity repertoire is notably more complex than that of the sea anemone, indicating that some of these genes may have roles in symbiosis or coloniality. A number of genes with putative roles in calcification were identified, and several of these are restricted to corals. The coral genome provides a platform for understanding the molecular basis of symbiosis and responses to environmental changes.

  16. Genomic analysis of between-cow variation in dermal fibroblast response to lipopolysaccharide

    PubMed Central

    Kandasamy, S.; Kerr, D. E.

    2014-01-01

    The innate immune response plays a major role in defense against mastitis causing pathogens. Identification of existing variation in innate immune signaling among cows and the underlying molecular causes for the variation may help in design of new mastitis control strategies. The dermal fibroblast has been used as a model cell type to explore between-cow variation in the ability of cells to produce IL-8 in response to lipopolysaccharide (LPS) treatment and this response appears related to an animal’s ability to respond to in vivo challenge with LPS or Escherichia coli mastitis. In this study, primary dermal fibroblast cultures of cows and microarray-based genomic analysis were used to investigate the cause(s) for the variable response to LPS. Fibroblast cultures from two cows, one with a low response phenotype (LRarray) and another with a high response phenotype (HRarray) were selected from our collection of fibroblast cultures established from 88 cows. The LR array fibroblast culture produces approximately five-fold less IL-8 as well as IL-6 proteins in response to 24 h LPS treatment than the HRarray fibroblast culture. Genomic analysis of RNA obtained from three replicates of the two cultures before and after 8 h LPS treatment revealed a combined LPS-induced differential expression of 321 transcripts indicating the robust response capability of the fibroblast cell. Under basal conditions, the microarray analysis revealed two-fold less TLR4 expression in the LR array fibroblasts as compared to the HRarray fibroblasts and this was associated with a marked reduction in expression of genes regulated by the TLR4-MyD88-dependent and TLR4-TRIF-dependent pathways (IL-8, IL-6, SAA3, CCL20, MX1, IRF1 and ISG20). The between-culture differential expression of TLR4 was confirmed and extended by quantitative PCR analysis (QPCR) that revealed a 33-fold lower expression of TLR4 in the LRarray fibroblast culture. After LPS treatment the difference in TLR4 expression increased

  17. Adaptive Response and Tolerance to Weak Acids in Saccharomyces cerevisiae: A Genome-Wide View

    PubMed Central

    Mira, Nuno P.; Teixeira, Miguel Cacho

    2010-01-01

    Abstract Weak acids are widely used as food preservatives (e.g., acetic, propionic, benzoic, and sorbic acids), herbicides (e.g., 2,4-dichlorophenoxyacetic acid), and as antimalarial (e.g., artesunic and artemisinic acids), anticancer (e.g., artesunic acid), and immunosuppressive (e.g., mycophenolic acid) drugs, among other possible applications. The understanding of the mechanisms underlying the adaptive response and resistance to these weak acids is a prerequisite to develop more effective strategies to control spoilage yeasts, and the emergence of resistant weeds, drug resistant parasites or cancer cells. Furthermore, the identification of toxicity mechanisms and resistance determinants to weak acid-based pharmaceuticals increases current knowledge on their cytotoxic effects and may lead to the identification of new drug targets. This review integrates current knowledge on the mechanisms of toxicity and tolerance to weak acid stress obtained in the model eukaryote Saccharomyces cerevisiae using genome-wide approaches and more detailed gene-by-gene analysis. The major features of the yeast response to weak acids in general, and the more specific responses and resistance mechanisms towards a specific weak acid or a group of weak acids, depending on the chemical nature of the side chain R group (R-COOH), are highlighted. The involvement of several transcriptional regulatory networks in the genomic response to different weak acids is discussed, focusing on the regulatory pathways controlled by the transcription factors Msn2p/Msn4p, War1p, Haa1p, Rim101p, and Pdr1p/Pdr3p, which are known to orchestrate weak acid stress response in yeast. The extrapolation of the knowledge gathered in yeast to other eukaryotes is also attempted. PMID:20955006

  18. Identification of genetic variants predictive of early onset pancreatic cancer through a population science analysis of functional genomic datasets.

    PubMed

    Chen, Jinyun; Wu, Xifeng; Huang, Yujing; Chen, Wei; Brand, Randall E; Killary, Ann M; Sen, Subrata; Frazier, Marsha L

    2016-08-30

    Biomarkers are critically needed for the early detection of pancreatic cancer (PC) are urgently needed. Our purpose was to identify a panel of genetic variants that, combined, can predict increased risk for early-onset PC and thereby identify individuals who should begin screening at an early age. Previously, we identified genes using a functional genomic approach that were aberrantly expressed in early pathways to PC tumorigenesis. We now report the discovery of single nucleotide polymorphisms (SNPs) in these genes associated with early age at diagnosis of PC using a two-phase study design. In silico and bioinformatics tools were used to examine functional relevance of the identified SNPs. Eight SNPs were consistently associated with age at diagnosis in the discovery phase, validation phase and pooled analysis. Further analysis of the joint effects of these 8 SNPs showed that, compared to participants carrying none of these unfavorable genotypes (median age at PC diagnosis 70 years), those carrying 1-2, 3-4, or 5 or more unfavorable genotypes had median ages at diagnosis of 64, 63, and 62 years, respectively (P = 3.0E-04). A gene-dosage effect was observed, with age at diagnosis inversely related to number of unfavorable genotypes (Ptrend = 1.0E-04). Using bioinformatics tools, we found that all of the 8 SNPs were predicted to play functional roles in the disruption of transcription factor and/or enhancer binding sites and most of them were expression quantitative trait loci (eQTL) of the target genes. The panel of genetic markers identified may serve as susceptibility markers for earlier PC diagnosis.

  19. Early tissue response to transscleral neodymium: YAG cyclophotocoagulation.

    PubMed

    Blasini, M; Simmons, R; Shields, M B

    1990-06-01

    Transscleral cyclophotocoagulation was performed with a neodymium: YAG laser on five patients 24-72 hr before enucleation for a blind, painful eye. The thermal mode at 20 ms and a maximum offset between aiming and therapeutic beams were kept constant. Variable parameters evaluated were energy levels between 2 and 8 J and distance from the limbus of 0.5-3.0 mm. Because of the underlying distortion in three of the eyes, meaningful interpretation by light microscopic evaluation was possible only in the other two. This suggested that the early histologic hallmark of the procedure is similar to that previously observed in human autopsy eyes with ciliary epithelial damage and elevation from underlying tissue. In addition, fibrin and scant inflammatory cells were seen in the space between ciliary epithelium and stroma. Minimal damage was observed in the ciliary muscle. These findings suggest that direct damage to the ciliary epithelium is the most likely mechanism of reduced aqueous production by this cyclodestructive procedure. The findings also support the concept that an anterior placement of approximately 1.0-1.5 mm posterior to the limbus is most likely to damage the ciliary epithelium of the pars plicata.

  20. Physiological, genomic and transcriptional diversity in responses to boron deficiency in rapeseed genotypes

    PubMed Central

    Hua, Yingpeng; Zhou, Ting; Ding, Guangda; Yang, Qingyong; Shi, Lei; Xu, Fangsen

    2016-01-01

    Allotetraploid rapeseed (Brassica napus L. AnAnCnCn, 2n=4x=38) is highly susceptible to boron (B) deficiency, a widespread limiting factor that causes severe losses in seed yield. The genetic variation in the sensitivity to B deficiency found in rapeseed genotypes emphasizes the complex response architecture. In this research, a B-inefficient genotype, ‘Westar 10’ (‘W10’), responded to B deficiencies during vegetative and reproductive development with an over-accumulation of reactive oxygen species, severe lipid peroxidation, evident plasmolysis, abnormal floral organogenesis, and widespread sterility compared to a B-efficient genotype, ‘Qingyou 10’ (‘QY10’). Whole-genome re-sequencing (WGS) of ‘QY10’ and ‘W10’ revealed a total of 1 605 747 single nucleotide polymorphisms and 218 755 insertions/deletions unevenly distributed across the allotetraploid rapeseed genome (~1130Mb). Digital gene expression (DGE) profiling identified more genes related to B transporters, antioxidant enzymes, and the maintenance of cell walls and membranes with higher transcript levels in the roots of ‘QY10’ than in ‘W10’ under B deficiency. Furthermore, based on WGS and bulked segregant analysis of the doubled haploid (DH) line pools derived from ‘QY10’ and ‘W10’, two significant quantitative trait loci (QTLs) for B efficiency were characterized on chromosome C2, and DGE-assisted QTL-seq analyses then identified a nodulin 26-like intrinsic protein gene and an ATP-binding cassette (ABC) transporter gene as the corresponding candidates regulating B efficiency. This research facilitates a more comprehensive understanding of the differential physiological and transcriptional responses to B deficiency and abundant genetic diversity in rapeseed genotypes, and the DGE-assisted QTL-seq analyses provide novel insights regarding the rapid dissection of quantitative trait genes in plant species with complex genomes. PMID:27639094

  1. Insect herbivory elicits genome-wide alternative splicing responses in Nicotiana attenuata.

    PubMed

    Ling, Zhihao; Zhou, Wenwu; Baldwin, Ian T; Xu, Shuqing

    2015-10-01

    Changes in gene expression and alternative splicing (AS) are involved in many responses to abiotic and biotic stresses in eukaryotic organisms. In response to attack and oviposition by insect herbivores, plants elicit rapid changes in gene expression which are essential for the activation of plant defenses; however, the herbivory-induced changes in AS remain unstudied. Using mRNA sequencing, we performed a genome-wide analysis on tobacco hornworm (Manduca sexta) feeding-induced AS in both leaves and roots of Nicotiana attenuata. Feeding by M. sexta for 5 h reduced total AS events by 7.3% in leaves but increased them in roots by 8.0% and significantly changed AS patterns in leaves and roots of existing AS genes. Feeding by M. sexta also resulted in increased (in roots) and decreased (in leaves) transcript levels of the serine/arginine-rich (SR) proteins that are involved in the AS machinery of plants and induced changes in SR gene expression that were jasmonic acid (JA)-independent in leaves but JA-dependent in roots. Changes in AS and gene expression elicited by M. sexta feeding were regulated independently in both tissues. This study provides genome-wide evidence that insect herbivory induces changes not only in the levels of gene expression but also in their splicing, which might contribute to defense against and/or tolerance of herbivory.

  2. Genome-Wide Analyses of Metal Responsive Genes in Caenorhabditis elegans

    PubMed Central

    Caito, Samuel; Fretham, Stephanie; Martinez-Finley, Ebany; Chakraborty, Sudipta; Avila, Daiana; Chen, Pan; Aschner, Michael

    2012-01-01

    Metals are major contaminants that influence human health. Many metals have physiologic roles, but excessive levels can be harmful. Advances in technology have made toxicogenomic analyses possible to characterize the effects of metal exposure on the entire genome. Much of what is known about cellular responses to metals has come from mammalian systems; however the use of non-mammalian species is gaining wider attention. Caenorhabditis elegans is a small round worm whose genome has been fully sequenced and its development from egg to adult is well characterized. It is an attractive model for high throughput screens due to its short lifespan, ease of genetic mutability, low cost, and high homology with humans. Research performed in C. elegans has led to insights in apoptosis, gene expression, and neurodegeneration, all of which can be altered by metal exposure. Additionally, by using worms one can potentially study mechanisms that underline differential responses to metals in nematodes and humans, allowing for identification of novel pathways and therapeutic targets. In this review, toxicogenomic studies performed in C. elegans exposed to various metals will be discussed, highlighting how this non-mammalian system can be utilized to study cellular processes and pathways induced by metals. Recent work focusing on neurodegeneration in Parkinson’s disease will be discussed as an example of the usefulness of genetic screens in C. elegans and the novel findings that can be produced. PMID:22514555

  3. TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism.

    PubMed

    Harley, Margaret E; Murina, Olga; Leitch, Andrea; Higgs, Martin R; Bicknell, Louise S; Yigit, Gökhan; Blackford, Andrew N; Zlatanou, Anastasia; Mackenzie, Karen J; Reddy, Kaalak; Halachev, Mihail; McGlasson, Sarah; Reijns, Martin A M; Fluteau, Adeline; Martin, Carol-Anne; Sabbioneda, Simone; Elcioglu, Nursel H; Altmüller, Janine; Thiele, Holger; Greenhalgh, Lynn; Chessa, Luciana; Maghnie, Mohamad; Salim, Mahmoud; Bober, Michael B; Nürnberg, Peter; Jackson, Stephen P; Hurles, Matthew E; Wollnik, Bernd; Stewart, Grant S; Jackson, Andrew P

    2016-01-01

    DNA lesions encountered by replicative polymerases threaten genome stability and cell cycle progression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism. We establish that TRAIP relocalizes to sites of DNA damage, where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to ultraviolet (UV) irradiation, as well as fork progression through UV-induced DNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP therefore limit cellular proliferation, providing a potential mechanism for microcephaly and dwarfism phenotypes. Human genetics thus identifies TRAIP as a component of the DNA damage response to replication-blocking DNA lesions.

  4. Storey building early monitoring based on rapid seismic response analysis

    NASA Astrophysics Data System (ADS)

    Julius, Musa, Admiral; Sunardi, Bambang; Rudyanto, Ariska

    2016-05-01

    Within the last decade, advances in the acquisition, processing and transmission of data from seismic monitoring has contributed to the growth in the number structures instrumented with such systems. An equally important factor for such growth can be attributed to the demands by stakeholders to find rapid answers to important questions related to the functionality or state of "health" of structures during and immediately of a seismic events. Consequently, this study aims to monitor the storey building based on seismic response i. e. earthquake and tremor analysis at short time lapse using accelerographs data. This study used one of storey building (X) in Jakarta city that suffered the effects of Kebumen earthquake January 25th 2014, Pandeglang earthquake July 9th 2014, and Lebak earthquake November 8th 2014. Tremors used in this study are tremors after the three following earthquakes. Data processing used to determine peak ground acceleration (PGA), peak ground velocity (PGV), peak ground displacement (PGD), spectral acceleration (SA), spectral velocity (SV), spectral displacement (SD), A/V ratio, acceleration amplification and effective duration (te). Then determine the natural frequency (f0) and peak of H/V ratio using H/V ratio method.The earthquakes data processing result shows the value of peak ground motion, spectrum response, A/V ratio and acceleration amplification increases with height, while the value of the effective duration give a different viewpoint of building dynamic because duration of Kebumen earthquake shows the highest energy in the highest floor but Pandeglang and Lebak earthquake in the lowest floor. Then, tremors data processing result one month after each earthquakes shows the natural frequency of building in constant value. Increasing of peak ground motion, spectrum response, A/V ratio, acceleration amplification, then decrease of effective duration following the increase of building floors shows that the building construction supports the

  5. Predictors of Responsiveness to Early Literacy Intervention: A 10-Year Update

    ERIC Educational Resources Information Center

    Lam, Elizabeth A.; McMaster, Kristen L.

    2014-01-01

    The purpose of this review was to update previous reviews on factors related to students' responsiveness to early literacy intervention. The 14 studies in this synthesis used experimental designs, provided small-group or one-on-one reading interventions, and analyzed factors related to responsiveness to those interventions. Participants were…

  6. Effect of the Responsive Environment Early Education Program for Low Birth Weight Children of Preschool Age.

    ERIC Educational Resources Information Center

    Askins, Billy E.; And Others

    This paper describes an external evaluation study of the Responsive Environment Early Education Program (formerly known as the Responsive Environment Program for Spanish American Children), an educational intervention program for "high risk" (low birth weight) 3-, 4-, and 5-year-old children in Clovis, New Mexico. Major goals of the…

  7. Response of Cross-biome Productivity to the Early 21st Century Drought

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The response of ecosystem productivity to contemporary drought coupled with record warming presents important challenges to predictive ecological modeling. In this study, we investigated the response of annual above-ground net primary production (ANPP) to precipitation variability during the early ...

  8. The Role Played by the Family in Shaping Early and Middle Adolescent Civic Responsibility

    ERIC Educational Resources Information Center

    Lenzi, Michela; Vieno, Alessio; Santinello, Massimo; Nation, Maury; Voight, Adam

    2014-01-01

    Adopting a multi-informant methodology, the current study examines the relative influence of multiple parental characteristics (civic responsibility, encouragement of civic action, parent-youth closeness) on adolescents' civic responsibility (local and global). The participants were 384 early and middle adolescents (47.9% male), randomly selected…

  9. Pharmacodynamic genome-wide association study identifies new responsive loci for glucocorticoid intervention in asthma.

    PubMed

    Wang, Y; Tong, C; Wang, Z; Wang, Z; Mauger, D; Tantisira, K G; Israel, E; Szefler, S J; Chinchilli, V M; Boushey, H A; Lazarus, S C; Lemanske, R F; Wu, R

    2015-10-01

    Asthma is a chronic lung disease that has a high prevalence. The therapeutic intervention of this disease can be made more effective if genetic variability in patients' response to medications is implemented. However, a clear picture of the genetic architecture of asthma intervention response remains elusive. We conducted a genome-wide association study (GWAS) to identify drug response-associated genes for asthma, in which 909 622 SNPs were genotyped for 120 randomized participants who inhaled multiple doses of glucocorticoids. By integrating pharmacodynamic properties of drug reactions, we implemented a mechanistic model to analyze the GWAS data, enhancing the scope of inference about the genetic architecture of asthma intervention. Our pharmacodynamic model observed associations of genome-wide significance between dose-dependent response to inhaled glucocorticoids (measured as %FEV1) and five loci (P=5.315 × 10(-7) to 3.924 × 10(-9)), many of which map to metabolic genes related to lung function and asthma risk. All significant SNPs detected indicate a recessive effect, at which the homozygotes for the mutant alleles drive variability in %FEV1. Significant associations were well replicated in three additional independent GWAS studies. Pooled together over these three trials, two SNPs, chr6 rs6924808 and chr11 rs1353649, display an increased significance level (P=6.661 × 10(-16) and 5.670 × 10(-11)). Our study reveals a general picture of pharmacogenomic control for asthma intervention. The results obtained help to tailor an optimal dose for individual patients to treat asthma based on their genetic makeup.

  10. A genome-wide association study of antidepressant response in Koreans.

    PubMed

    Myung, W; Kim, J; Lim, S-W; Shim, S; Won, H-H; Kim, Seonwoo; Kim, Sangha; Lee, M-S; Chang, H S; Kim, J-W; Carroll, B J; Kim, D K

    2015-09-08

    We conducted a three-stage genome-wide association study (GWAS) of response to antidepressant drugs in an ethnically homogeneous sample of Korean patients in untreated episodes of nonpsychotic unipolar depression, mostly of mature onset. Strict quality control was maintained in case selection, diagnosis, verification of adherence and outcome assessments. Analyzed cases completed 6 weeks of treatment with adequate plasma drug concentrations. The overall successful completion rate was 85.5%. Four candidate single-nucleotide polymorphisms (SNPs) on three chromosomes were identified by genome-wide search in the discovery sample of 481 patients who received one of four allowed selective serotonin reuptake inhibitor (SSRI) antidepressant drugs (Stage 1). In a focused replication study of 230 SSRI-treated patients, two of these four SNP candidates were confirmed (Stage 2). Analysis of the Stage 1 and Stage 2 samples combined (n = 711) revealed GWAS significance (P = 1.60 × 10(-8)) for these two SNP candidates, which were in perfect linkage disequilibrium. These two significant SNPs were confirmed also in a focused cross-replication study of 159 patients treated with the non-SSRI antidepressant drug mirtazapine (Stage 3). Analysis of the Stage 1, Stage 2 and Stage 3 samples combined (n = 870) also revealed GWAS significance for these two SNPs, which was sustained after controlling for gender, age, number of previous episodes, age at onset and baseline severity (P = 3.57 × 10(-8)). For each SNP, the response rate decreased (odds ratio=0.31, 95% confidence interval: 0.20-0.47) as a function of the number of minor alleles (non-response alleles). The two SNPs significantly associated with antidepressant response are rs7785360 and rs12698828 of the AUTS2 gene, located on chromosome 7 in 7q11.22. This gene has multiple known linkages to human psychological functions and neurobehavioral disorders. Rigorous replication efforts in other ethnic populations are recommended.

  11. DNA Methylation: A Mechanism for Embedding Early Life Experiences in the Genome

    ERIC Educational Resources Information Center

    Szyf, Moshe; Bick, Johanna

    2013-01-01

    Although epidemiological data provide evidence that early life experience plays a critical role in human development, the mechanism of how this works remains in question. Recent data from human and animal literature suggest that epigenetic changes, such as DNA methylation, are involved not only in cellular differentiation but also in the…

  12. Draft Genome Sequence of Cercospora arachidicola, Cause of Early Leaf Spot in Peanut

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cercospora arachidicola and Cercosporidium personatum, causal agents of early and late leaf spot, respectively, are important fungal pathogens of peanut. Leaf spot disease is a major contributor to the economic losses experienced by peanut farmers and the industry. Though peanut germplasms with so...

  13. Draft genome sequence of Cercospora arachidicola, causal agent of early leaf spot in peanuts

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cercospora arachidicola, an economically important pathogen of peanut, is the cause of early leaf spot disease. Despite its significance, insufficient genetic information is available for utilization. Understanding the genetic diversity of this pathogen is crucial for peanut breeding programs to d...

  14. Genome-wide transcriptional responses to a lipid hydroperoxide: adaptation occurs without induction of oxidant defenses.

    PubMed

    Alic, Nazif; Felder, Thomas; Temple, Mark D; Gloeckner, Christian; Higgins, Vincent J; Briza, Peter; Dawes, Ian W

    2004-07-01

    Free radicals can initiate the oxidation of polyunsaturated fatty acids in cells through the process of lipid peroxidation. The genome-wide transcriptional changes in Saccharomyces cerevisiae after treatment with the toxic lipid peroxidation product linoleic acid hydroperoxide (LoaOOH) were identified. High-dose treatment led to a switch in transcription from biosynthetic to protective functions. This response encompassed a set of genes stimulated predominantly by LoaOOH, and not by other oxidants or heat shock, which contained components of the pleiotropic drug resistance system. The dose dependence of the transcriptional response revealed that large and widespread changes occur only in response to higher doses. Pretreatment of cells with sublethal doses of LoaOOH induces resistance to an otherwise lethal dose through the process of adaptation. Adaptive doses elicited a more subtle transcriptional response affecting metabolic functions, including an increase in the capacity for detoxification and downregulation of the rate of protein synthesis. Surprisingly, the cellular response to adaptive doses did not include induction of oxidative-stress defense enzymes nor of transcripts involved in general cellular defense systems.

  15. Quantitative Models of the Mechanisms That Control Genome-Wide Patterns of Transcription Factor Binding during Early Drosophila Development

    PubMed Central

    Kaplan, Tommy; Li, Xiao-Yong; Sabo, Peter J.; Thomas, Sean; Stamatoyannopoulos, John A.; Biggin, Mark D.; Eisen, Michael B.

    2011-01-01

    Transcription factors that drive complex patterns of gene expression during animal development bind to thousands of genomic regions, with quantitative differences in binding across bound regions mediating their activity. While we now have tools to characterize the DNA affinities of these proteins and to precisely measure their genome-wide distribution in vivo, our understanding of the forces that determine where, when, and to what extent they bind remains primitive. Here we use a thermodynamic model of transcription factor binding to evaluate the contribution of different biophysical forces to the binding of five regulators of early embryonic anterior-posterior patterning in Drosophila melanogaster. Predictions based on DNA sequence and in vitro protein-DNA affinities alone achieve a correlation of ∼0.4 with experimental measurements of in vivo binding. Incorporating cooperativity and competition among the five factors, and accounting for spatial patterning by modeling binding in every nucleus independently, had little effect on prediction accuracy. A major source of error was the prediction of binding events that do not occur in vivo, which we hypothesized reflected reduced accessibility of chromatin. To test this, we incorporated experimental measurements of genome-wide DNA accessibility into our model, effectively restricting predicted binding to regions of open chromatin. This dramatically improved our predictions to a correlation of 0.6–0.9 for various factors across known target genes. Finally, we used our model to quantify the roles of DNA sequence, accessibility, and binding competition and cooperativity. Our results show that, in regions of open chromatin, binding can be predicted almost exclusively by the sequence specificity of individual factors, with a minimal role for protein interactions. We suggest that a combination of experimentally determined chromatin accessibility data and simple computational models of transcription factor binding may be

  16. Oxidative Stress and Heat-Shock Responses in Desulfovibrio vulgaris by Genome-Wide Transcriptomic Analysis

    SciTech Connect

    Zhang, Weiwen; Culley, David E.; Hogan, Mike; Vitiritti, Luigi; Brockman, Fred J.

    2006-05-30

    Abstract Sulfate-reducing bacteria, like Desulfovibrio vulgaris have developed a set of reactions allowing them to survive in environments. To obtain further knowledge of the protecting mechanisms employed in D. vulgaris against the oxidative stress and heat shock, we performed a genome-wide transcriptomic analysis to determine the cellular responses to both stimuli. The results showed that 130 genes were responsive to oxidative stress, while 427 genes responsive to heat-shock, respectively. Functional analyses suggested that the genes regulated were involved in a variety of cellular functions. Metabolic analysis showed that amino acid biosynthetic pathways were induced by both oxidative stress and heat shock treatments, while fatty acid metabolism, purine and cofactor biosynthesis were induced by heat shock only. Rubrerythrin gene (rbR) were upregulated by the oxidative stress, suggesting its important role in the oxidative resistance, whereas the expression of rubredoxin oxidoreductase (rbO), superoxide ismutase (sodB) and catalase (katA) genes were not subjected to regulation by oxidative stress in D. vulgaris. In addition, the results showed that thioredoxin reductase (trxB) was responsive to oxidative stress, suggesting the thiol-specific redox system might be involved in oxidative protection in D. vulgaris. Comparison of cellular responses to oxidative stress and heat-shock allowed the identification of 66 genes that showed a similar drastic response to both environmental stimuli, implying that they might be part of the general stress response (GSR) network in D. vulgaris, which was further supported by the finding of a conserved motif upstream these common-responsive genes.

  17. Prediction and set-dependent scaling of early postural responses in cerebellar patients.

    PubMed

    Timmann, D; Horak, F B

    1997-02-01

    We reported previously that patients with cerebellar deficits were unable to scale the magnitude of their early automatic postural responses to the predicted amplitudes of surface translations based on central set from prior experience. The present study investigated whether this deficit in set-dependent amplitude scaling was based predominantly on the cerebellar patient's disability (i) to predict perturbation amplitudes on the basis of prior experience, (ii) to scale the gain or magnitude of upcoming postural responses or (iii) to habituate postural responses. The increase in size of the early postural response when a larger than actual platform amplitude was expected and decrease when a smaller one was expected was defined as a measure of set-dependent amplitude prediction. The suppression of the postural response when the same platform velocity was repeated was used as a measure of habituation. The correlation between the size of early postural responses and platform amplitudes when presented serially, but not randomly, tested the ability to scale the gain of postural responses based on prior experience. Results show that although cerebellar patients could predict perturbation amplitudes based on prior experience, they could not use this prediction to modify precisely the gain of responses. The ability to habituate the magnitude of postural responses was not affected by cerebellar lesions. Thus, the cerebellum might not be critical for predicting upcoming events or for habituating to repeated postural stimuli, although it is important for accurate tuning of response gain based on prediction.

  18. Early immune response and regulation of IL-2 receptor subunits

    NASA Technical Reports Server (NTRS)

    Hughes-Fulford, Millie; Sugano, Eiko; Schopper, Thomas; Li, Chai-Fei; Boonyaratanakornkit, J. B.; Cogoli, Augusto

    2005-01-01

    MAPK pathways plays a role in early T-cell activation and induction of IL-2, IL-2R(alpha) and IFN(gamma) gene expression.

  19. Evolution of herbivore-induced early defense signaling was shaped by genome-wide duplications in Nicotiana

    PubMed Central

    Zhou, Wenwu; Brockmöller, Thomas; Ling, Zhihao; Omdahl, Ashton; Baldwin, Ian T; Xu, Shuqing

    2016-01-01

    Herbivore-induced defenses are widespread, rapidly evolving and relevant for plant fitness. Such induced defenses are often mediated by early defense signaling (EDS) rapidly activated by the perception of herbivore associated elicitors (HAE) that includes transient accumulations of jasmonic acid (JA). Analyzing 60 HAE-induced leaf transcriptomes from closely-related Nicotiana species revealed a key gene co-expression network (M4 module) which is co-activated with the HAE-induced JA accumulations but is elicited independently of JA, as revealed in plants silenced in JA signaling. Functional annotations of the M4 module were consistent with roles in EDS and a newly identified hub gene of the M4 module (NaLRRK1) mediates a negative feedback loop with JA signaling. Phylogenomic analysis revealed preferential gene retention after genome-wide duplications shaped the evolution of HAE-induced EDS in Nicotiana. These results highlight the importance of genome-wide duplications in the evolution of adaptive traits in plants. DOI: http://dx.doi.org/10.7554/eLife.19531.001 PMID:27813478

  20. Convergent Random Forest Predictor: Methodology for predicting drug response from genome-scale data applied to anti-TNF response

    PubMed Central

    Bienkowska, Jadwiga; Dagin, Gul; Batliwalla, Franak; Allaire, Normand; Roubenoff, Ronenn; Gregersen, Peter; Carulli, John

    2015-01-01

    Biomarker development for prediction of patient response to therapy is one of the goals of molecular profiling of human tissues. Due to the large number of transcripts, relatively limited number of samples, and high variability of data, identification of predictive biomarkers is a challenge for data analysis. Furthermore, many genes may be responsible for drug response differences, but often only a few are sufficient for accurate prediction. Here we present an analysis approach, the Convergent Random Forest (CRF) method, for the identification of highly predictive biomarkers. The aim is to select from genome-wide expression data a small number of non-redundant biomarkers that could be developed into a simple and robust diagnostic tool. Our method combines the Random Forest classifier and gene expression clustering to rank and select a small number of predictive genes. We evaluated the CRF approach by analyzing four different data sets. The first set contains transcript profiles of whole blood from rheumatoid arthritis patients, collected before anti-TNF treatment, and their subsequent response to the therapy. In this set, CRF identified 8 transcripts predicting response to therapy with 89% accuracy. We also applied the CRF to the analysis of three previously published expression data sets. For all sets, we have compared the CRF and recursive support vector machines (RSVM) approaches to feature selection and classification. In all cases the CRF selects much smaller number of features, five to eight genes, while achieving similar or better performance on both: training and independent testing sets of data. For both methods performance estimates using cross-validation is similar to performance on independent samples. The method has been implemented in R and is available from the authors upon request: Jadwiga.Bienkowska@biogenidec.com. PMID:19699293

  1. Genome-wide analysis of miRNAs and Tasi-RNAs in Zea mays in response to phosphate deficiency.

    PubMed

    Gupta, Saurabh; Kumari, Manju; Kumar, Himansu; Varadwaj, Pritish Kumar

    2017-01-09

    Globally important cereal crop maize provides important nutritions and starch in dietary foods. Low phosphate (LPi) availability in the soil frequently limits the maize quality and yield across the world. Small non-coding RNAs (Snc-RNAs) play crucial roles in growth and adaptation of plants to the environment. Snc-RNAs like microRNAs (miRs) and trans-acting small interfering RNAs (Tasi-Rs) play important functions in posttranscriptional regulation of gene expression, which controls plant development, reproduction, and biotic/abiotic stress responses. In order to identify the miR and Tasi-R alterations in leaf and root of maize in response to sufficient phosphate and LPi at 3LS and 4LS, the snc-RNA population libraries for 0th, 1st, 2nd, 4th, and 8th day were constructed. These libraries were used for genome-wide alignment and RNA-fold analysis for possible prediction of potential miRs and Tasi-Rs. This study reported 174 known and conserved differentially expressed miRs of 27 miR families of maize plant. In addition, leaf and root specific potential novel miRs representing 155 new families were also discovered. Differentially expressed conserved as well as novel miR functions in root and leaf during early stage of Pi starvation were extensively discussed. Leaf and root specific miRs as well as common miRs with their target genes, participating in different biological, cellular, and metabolic processes were explored. Further, four miR390-directed Tasi-Rs which belong to TAS3 gene family along with other orthologs of Tasi-Rs were also identified. Finally, the study provides an insight into the composite regulatory mechanism of miRs in maize in response to Pi deficiency.

  2. Genomics, microRNA, epigenetics, and proteomics for future diagnosis, treatment and monitoring response in upper GI cancers.

    PubMed

    Brücher, Björn L D M; Li, Yan; Schnabel, Philipp; Daumer, Martin; Wallace, Timothy J; Kube, Rainer; Zilberstein, Bruno; Steele, Scott; Voskuil, Jan L A; Jamall, Ijaz S

    2016-03-01

    One major objective for our evolving understanding in the treatment of cancers will be to address how a combination of diagnosis and treatment strategies can be used to integrate patient and tumor variables with an outcome-oriented approach. Such an approach, in a multimodal therapy setting, could identify those patients (1) who should undergo a defined treatment (personalized therapy) (2) in whom modifications of the multimodal therapy due to observed responses might lead to an improvement of the response and/or prognosis (individualized therapy), (3) who might not benefit from a particular toxic treatment regimen, and (4) who could be identified early on and thereby be spared the morbidity associated with such treatments. These strategies could lead in the direction of precision medicine and there is hope of integrating translational molecular data to improve cancer classifications. In order to achieve these goals, it is necessary to understand the key issues in different aspects of biotechnology to anticipate future directions of personalized and individualized diagnosis and multimodal treatment strategies. Providing an overview of translational data in cancers proved to be a challenge as different methods and techniques used to obtain molecular data are used and studies are based on different tumor entities with different tumor biology and prognoses as well as vastly different therapeutic approaches. The pros and cons of the available methodologies and the potential response data in genomics, microRNA, epigenetics and proteomics with a focus on upper gastrointestinal cancers are considered herein to allow for an understanding of where these technologies stand with respect to cancer diagnosis, prognosis and treatment.

  3. Genome-scale cold stress response regulatory networks in ten Arabidopsis thaliana ecotypes

    PubMed Central

    2013-01-01

    Background Low temperature leads to major crop losses every year. Although several studies have been conducted focusing on diversity of cold tolerance level in multiple phenotypically divergent Arabidopsis thaliana (A. thaliana) ecotypes, genome-scale molecular understanding is still lacking. Results In this study, we report genome-scale transcript response diversity of 10 A. thaliana ecotypes originating from different geographical locations to non-freezing cold stress (10°C). To analyze the transcriptional response diversity, we initially compared transcriptome changes in all 10 ecotypes using Arabidopsis NimbleGen ATH6 microarrays. In total 6061 transcripts were significantly cold regulated (p < 0.01) in 10 ecotypes, including 498 transcription factors and 315 transposable elements. The majority of the transcripts (75%) showed ecotype specific expression pattern. By using sequence data available from Arabidopsis thaliana 1001 genome project, we further investigated sequence polymorphisms in the core cold stress regulon genes. Significant numbers of non-synonymous amino acid changes were observed in the coding region of the CBF regulon genes. Considering the limited knowledge about regulatory interactions between transcription factors and their target genes in the model plant A. thaliana, we have adopted a powerful systems genetics approach- Network Component Analysis (NCA) to construct an in-silico transcriptional regulatory network model during response to cold stress. The resulting regulatory network contained 1,275 nodes and 7,720 connections, with 178 transcription factors and 1,331 target genes. Conclusions A. thaliana ecotypes exhibit considerable variation in transcriptome level responses to non-freezing cold stress treatment. Ecotype specific transcripts and related gene ontology (GO) categories were identified to delineate natural variation of cold stress regulated differential gene expression in the model plant A. thaliana. The predicted

  4. Comparative genome-scale analysis of niche-based stress-responsive genes in Lactobacillus helveticus strains.

    PubMed

    Senan, Suja; Prajapati, Jashbhai B; Joshi, Chaitanya G

    2014-04-01

    Next generation sequencing technologies with advanced bioinformatic tools present a unique opportunity to compare genomes from diverse niches. The identification of niche-specific stress-responsive genes can help in characterizing robust strains for multiple applications. In this study, we attempted to compare the stress-responsive genes of a potential probiotic strain, Lactobacillus helveticus MTCC 5463, and a cheese starter strain, Lactobacillus helveticus DPC 4571, from a gut and dairy niche, respectively. Sequencing of MTCC 5463 was done using 454 GS FLX, and contigs were assembled using GS Assembler software. Genome analysis was done using BLAST hits and the prokaryotic annotation server RAST. The MTCC 5463 genome carried multiple orthologs of genes governing stress responses, whereas the DPC 4571 genome lacked in the number of major stress-response proteins. The absence of the bile salt hydrolase gene in DPC 4571 and its presence in MTCC 5463 clearly indicated niche adaptation. Further, MTCC 5463 carried higher copy numbers of genes contributing towards heat, cold, osmotic, and oxidative stress resistance as compared with DPC 4571. Through comparative genomics, we could thus identify stress-responsive gene sets required to adapt to gut and dairy niches.

  5. Genome at Juncture of Early Human Migration: A Systematic Analysis of Two Whole Genomes and Thirteen Exomes from Kuwaiti Population Subgroup of Inferred Saudi Arabian Tribe Ancestry

    PubMed Central

    Alsmadi, Osama; Hebbar, Prashantha; Antony, Dinu; Behbehani, Kazem; Thanaraj, Thangavel Alphonse

    2014-01-01

    Population of the State of Kuwait is composed of three genetic subgroups of inferred Persian, Saudi Arabian tribe and Bedouin ancestry. The Saudi Arabian tribe subgroup traces its origin to the Najd region of Saudi Arabia. By sequencing two whole genomes and thirteen exomes from this subgroup at high coverage (>40X), we identify 4,950,724 Single Nucleotide Polymorphisms (SNPs), 515,802 indels and 39,762 structural variations. Of the identified variants, 10,098 (8.3%) exomic SNPs, 139,923 (2.9%) non-exomic SNPs, 5,256 (54.3%) exomic indels, and 374,959 (74.08%) non-exomic indels are ‘novel’. Up to 8,070 (79.9%) of the reported novel biallelic exomic SNPs are seen in low frequency (minor allele frequency <5%). We observe 5,462 known and 1,004 novel potentially deleterious nonsynonymous SNPs. Allele frequencies of common SNPs from the 15 exomes is significantly correlated with those from genotype data of a larger cohort of 48 individuals (Pearson correlation coefficient, 0.91; p <2.2×10−16). A set of 2,485 SNPs show significantly different allele frequencies when compared to populations from other continents. Two notable variants having risk alleles in high frequencies in this subgroup are: a nonsynonymous deleterious SNP (rs2108622 [19:g.15990431C>T] from CYP4F2 gene [MIM:*604426]) associated with warfarin dosage levels [MIM:#122700] required to elicit normal anticoagulant response; and a 3′ UTR SNP (rs6151429 [22:g.51063477T>C]) from ARSA gene [MIM:*607574]) associated with Metachromatic Leukodystrophy [MIM:#250100]. Hemoglobin Riyadh variant (identified for the first time in a Saudi Arabian woman) is observed in the exome data. The mitochondrial haplogroup profiles of the 15 individuals are consistent with the haplogroup diversity seen in Saudi Arabian natives, who are believed to have received substantial gene flow from Africa and eastern provenance. We present the first genome resource imperative for designing future genetic studies in Saudi Arabian

  6. A preliminary study of the whole-genome expression profile of sporadic and monogenic early-onset Alzheimer's disease.

    PubMed

    Antonell, Anna; Lladó, Albert; Altirriba, Jordi; Botta-Orfila, Teresa; Balasa, Mircea; Fernández, Manel; Ferrer, Isidre; Sánchez-Valle, Raquel; Molinuevo, José Luis

    2013-07-01

    Alzheimer's disease (AD) is the most common neurodegenerative dementia. Approximately 10% of cases present at an age of onset before 65 years old, which in turn can be monogenic familial AD (FAD) or sporadic early-onset AD (sEOAD). Mutations in PSEN1, PSEN2, and APP genes have been linked with FAD. The aim of our study is to describe the brain whole-genome RNA expression profile of the posterior cingulate area in sEOAD and FAD caused by PSEN1 mutations (FAD-PSEN1). Fourteen patients (7 sEOAD and 7 FAD-PSEN1) and 7 neurologically healthy control subjects were selected and whole-genome expression was measured using Affymetrix Human Gene 1.1 microarrays. We identified statistically significant expression changes in sEOAD and FAD-PSEN1 brains with respect to control subjects (3183 and 3350 differentially expressed genes [DEG] respectively, false discovery rate-corrected p < 0.05). Of them, 1916 DEG were common between the 2 comparisons. We did not identify DEG between sEOAD and FAD-PSEN1. Microarray data were validated through real-time quantitative polymerase chain reaction. In silico analysis of DEG revealed an alteration in biological pathways related to intracellular signaling pathways (particularly calcium signaling), neuroactive ligand-receptor interactions, axon guidance, and long-term potentiation in both groups of patients. In conclusion, the altered biological final pathways in sEOAD and FAD-PSEN1 are mainly related with cell signaling cascades, synaptic plasticity, and learning and memory processes. We hypothesize that these 2 groups of early-onset AD with distinct etiologies and likely different could present a neurodegenerative process with potential different pathways that might converge in a common and similar final stage of the disease.

  7. Modeling Innate Immune Response to Early Mycobacterium Infection

    PubMed Central

    Carvalho, Rafael V.; Kleijn, Jetty; Meijer, Annemarie H.

    2012-01-01

    In the study of complex patterns in biology, mathematical and computational models are emerging as important tools. In addition to experimental approaches, these modeling tools have recently been applied to address open questions regarding host-pathogen interaction dynamics, including the immune response to mycobacterial infection and tuberculous granuloma formation. We present an approach in which a computational model represents the interaction of the Mycobacterium infection with the innate immune system in zebrafish at a high level of abstraction. We use the Petri Net formalism to model the interaction between the key host elements involved in granuloma formation and infection dissemination. We define a qualitative model for the understanding and description of causal relations in this dynamic process. Complex processes involving cell-cell or cell-bacteria communication can be modeled at smaller scales and incorporated hierarchically into this main model; these are to be included in later elaborations. With the infection mechanism being defined on a higher level, lower-level processes influencing the host-pathogen interaction can be identified, modeled, and tested both quantitatively and qualitatively. This systems biology framework incorporates modeling to generate and test hypotheses, to perform virtual experiments, and to make experimentally verifiable predictions. Thereby it supports the unraveling of the mechanisms of tuberculosis infection. PMID:23365620

  8. Early IFN type I response: Learning from microbial evasion strategies.

    PubMed

    Coccia, Eliana M; Battistini, Angela

    2015-03-01

    Type I interferon (IFN) comprises a class of cytokines first discovered more than 50 years ago and initially characterized for their ability to interfere with viral replication and restrict locally viral propagation. As such, their induction downstream of germ-line encoded pattern recognition receptors (PRRs) upon recognition of pathogen-associated molecular patterns (PAMPs) is a hallmark of the host antiviral response. The acknowledgment that several PAMPs, not just of viral origin, may induce IFN, pinpoints at these molecules as a first line of host defense against a number of invading pathogens. Acting in both autocrine and paracrine manner, IFN interferes with viral replication by inducing hundreds of different IFN-stimulated genes with both direct anti-pathogenic as well as immunomodulatory activities, therefore functioning as a bridge between innate and adaptive immunity. On the other hand an inverse interference to escape the IFN system is largely exploited by pathogens through a number of tactics and tricks aimed at evading, inhibiting or manipulating the IFN pathway, that result in progression of infection or establishment of chronic disease. In this review we discuss the interplay between the IFN system and some selected clinically important and challenging viruses and bacteria, highlighting the wide array of pathogen-triggered molecular mechanisms involved in evasion strategies.

  9. Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study

    PubMed Central

    Davenport, Emma E; Burnham, Katie L; Radhakrishnan, Jayachandran; Humburg, Peter; Hutton, Paula; Mills, Tara C; Rautanen, Anna; Gordon, Anthony C; Garrard, Christopher; Hill, Adrian V S; Hinds, Charles J; Knight, Julian C

    2016-01-01

    Summary Background Effective targeted therapy for sepsis requires an understanding of the heterogeneity in the individual host response to infection. We investigated this heterogeneity by defining interindividual variation in the transcriptome of patients with sepsis and related this to outcome and genetic diversity. Methods We assayed peripheral blood leucocyte global gene expression for a prospective discovery cohort of 265 adult patients admitted to UK intensive care units with sepsis due to community-acquired pneumonia and evidence of organ dysfunction. We then validated our findings in a replication cohort consisting of a further 106 patients. We mapped genomic determinants of variation in gene transcription between patients as expression quantitative trait loci (eQTL). Findings We discovered that following admission to intensive care, transcriptomic analysis of peripheral blood leucocytes defines two distinct sepsis response signatures (SRS1 and SRS2). The presence of SRS1 (detected in 108 [41%] patients in discovery cohort) identifies individuals with an immunosuppressed phenotype that included features of endotoxin tolerance, T-cell exhaustion, and downregulation of human leucocyte antigen (HLA) class II. SRS1 was associated with higher 14 day mortality than was SRS2 (discovery cohort hazard ratio (HR) 2·4, 95% CI 1·3–4·5, p=0·005; validation cohort HR 2·8, 95% CI 1·5–5·1, p=0·0007). We found that a predictive set of seven genes enabled the classification of patients as SRS1 or SRS2. We identified cis-acting and trans-acting eQTL for key immune and metabolic response genes and sepsis response networks. Sepsis eQTL were enriched in endotoxin-induced epigenetic marks and modulated the individual host response to sepsis, including effects specific to SRS group. We identified regulatory genetic variants involving key mediators of gene networks implicated in the hypoxic response and the switch to glycolysis that occurs in sepsis, including HIF1α and

  10. Experimental infection of Newcastle disease virus in pigeons (Columba livia): humoral antibody response, contact transmission and viral genome shedding.

    PubMed

    de Oliveira Torres Carrasco, Adriano; Seki, Meire Christina; de Freitas Raso, Tânia; Paulillo, Antônio Carlos; Pinto, Aramis Augusto

    2008-05-25

    The aim of this study was to evaluate the humoral antibody response, the genome viral excretion and the contact transmission of pathogenic chicken origin Newcastle disease virus (NDV) from experimentally infected pigeons (Columba livia) to in-contact pigeon. The antibody response to infection was assessed by the hemagglutination inhibition (HI) test and the genome viral excretion was detected by RT-PCR. Viral strain induced high antibody levels, both in inoculated and in sentinel birds. The pathogenic viral strain for chickens was unable to produce clinical signs of the disease in experimentally infected pigeons, although it induced the humoral antibody response and produced NDV genome shedding. NDV genome was detected intermittently throughout the experimental period, from 5 days post-infection (dpi) to 24 dpi. Therefore, viral genome shedding occurred for 20 days. The viral genome was detected in all birds, between 11 and 13 dpi. Furthermore, the high infectivity of the virus was confirmed, as all non-inoculated sentinel pigeons showed antibody levels as high as those of inoculated birds.

  11. Question 7: Comparative Genomics and Early Cell Evolution: A Cautionary Methodological Note

    NASA Astrophysics Data System (ADS)

    Islas, Sara; Hernández-Morales, Ricardo; Lazcano, Antonio

    2007-10-01

    Inventories of the gene content of the last common ancestor (LCA), i.e., the cenancestor, include sequences that may have undergone horizontal transfer events, as well as sequences that have originated in different pre-cenancestral epochs. However, the universal distribution of highly conserved genes involved in RNA metabolism provide insights into early stages of cell evolution during which RNA played a much more conspicuous biological role, and is consistent with the hypothesis that extant living systems were preceded by an RNA/protein world. Insights into the traits of primitive entities from which the LCA evolved may be derived from the analysis of paralogous gene families, including those formed by sequences that resulted from internal elongation events. Three major types of paralogous gene families can be recognized. The importance of this grouping for understanding the traits of early cells is discussed.

  12. Genome-wide analysis of spatiotemporal gene expression patterns during early embryogenesis in rice.

    PubMed

    Itoh, Jun-Ichi; Sato, Yutaka; Sato, Yutaka; Hibara, Ken-Ichiro; Shimizu-Sato, Sae; Kobayashi, Hiromi; Takehisa, Hinako; Sanguinet, Karen A; Namiki, Nobukazu; Nagamura, Yoshiaki

    2016-04-01

    Embryogenesis in rice is different from that of most dicotolydonous plants in that it shows a non-stereotypic cell division pattern, formation of dorsal-ventral polarity, and endogenous initiation of the radicle. To reveal the transcriptional features associated with developmental events during rice early embryogenesis, we used microarray analysis coupled with laser microdissection to obtain both spatial and temporal transcription profiles. Our results allowed us to determine spatial expression foci for each expressed gene in the globular embryo, which revealed the importance of phytohormone-related genes and a suite of transcription factors to early embryogenesis. Our analysis showed the polarized expression of a small number of genes along the apical-basal and dorsal-ventral axes in the globular embryo, which tended to fluctuate in later developmental stages. We also analyzed gene expression patterns in the early globular embryo and how this relates to expression in embryonic organs at later stages. We confirmed the accuracy of the expression patterns found by microarray analysis of embryo subdomains using in situ hybridization. Our study identified homologous genes from Arabidopsis thaliana with known functions in embryogenesis in addition to unique and uncharacterized genes that show polarized expression patterns during embryogenesis. The results of this study are presented in a database to provide a framework for spatiotemporal gene expression during rice embryogenesis, to serve as a resource for future functional analysis of genes, and as a basis for comparative studies of plant embryogenesis.

  13. Genome-wide genetic and transcriptomic investigation of variation in antibody response to dietary antigens

    PubMed Central

    Rubicz, Rohina; Yolken, Robert; Alaedini, Armin; Drigalenko, Eugene; Charlesworth, Jac C.; Carless, Melanie A.; Severance, Emily G.; Krivogorsky, Bogdana; Dyer, Thomas D.; Kent, Jack W.; Curran, Joanne E.; Johnson, Matthew P.; Cole, Shelley A.; Almasy, Laura; Moses, Eric K.; Blangero, John; Göring, Harald H.H.

    2014-01-01

    Increased immunoglobulin G (IgG) response to dietary antigens can be associated with gastrointestinal dysfunction and autoimmunity. The underlying processes contributing to these adverse reactions remain largely unknown, and it is likely that genetic factors play a role. Here we estimate heritability and attempt to localize genetic factors influencing IgG antibody levels against food-derived antigens using an integrative genomics approach. IgG antibody levels were determined by ELISA in >1300 Mexican Americans for the following food antigens: wheat gliadin; bovine casein; and two forms of bovine serum albumin (BSA-a and BSA-b). Pedigree-based variance components methods were used to estimate additive genetic heritability (h2), perform genome-wide association analyses, and identify transcriptional signatures (based on 19,858 transcripts from peripheral blood lymphocytes). Heritability estimates were significant for all traits (0.15-0.53), and shared environment (based on shared residency among study participants) was significant for casein (0.09) and BSA-a (0.33). Genome-wide significant evidence of association was obtained only for antibody to gliadin (p=8.57×10-8), mapping to the human leukocyte antigen II region, with HLA-DRA and BTNL2 as the best candidate genes. Lack of association of known celiac disease risk alleles HLA-DQ2.5 and -DQ8 with anti-gliadin antibodies in the studied population suggests a separate genetic etiology. Significant transcriptional signatures were found for all IgG levels except BSA-b. These results demonstrate that individual genetic differences contribute to food antigen antibody measures in this population. Further investigations may elucidate the underlying immunological processes involved. PMID:24962563

  14. Genome-wide analysis for identification of salt-responsive genes in common wheat.

    PubMed

    Kawaura, Kanako; Mochida, Keiichi; Ogihara, Yasunari

    2008-08-01

    To identify salt-responsive genes in wheat, global expression analysis of transcripts was carried out using oligo-DNA microarrays. Microarrays have been designed from approximately 32,000 unique wheat genes classified from a large number of expressed sequence tags (ESTs). Two-week-old seedlings of wheat were treated with 150 mM NaCl for 1, 6, and 24 h, and their roots and shoots were separately subjected to analyses. Consequently, 5,996 genes showed changes in expression of more than twofold and were classified into 12 groups according to correlations in expression patterns. These salt-responsive genes were assigned functions using the Gene Ontology (GO). Genes assigned to transcription factor, transcription-regulator activity, and DNA-binding functions were preferentially classified into early response groups. On the other hand, those assigned transferase and transporter activity were classified into late response groups. These data suggest that multiple signal transduction pathways in response to salinity exist in wheat. Transcription factors (TFs) which have been reported as participants in salt-tolerant pathway changed their expression levels in response to salt treatment. Among them, only a few TFs show high sequence homologies to genes in rice. These investigations suggest that salt-responsive genes identified by this study are candidates for salt-stress tolerance uniquely in wheat.

  15. Molecular Mechanisms of Sulfur Mustard Vesicant-Induced Cell Death: Early and Late Cell Responses

    DTIC Science & Technology

    2005-10-01

    Mechanisms of Sulfur Mustard Vesicant-Induced Cell Death : Early and late cell responses 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6...It possess mutagenic, carcinogenic, cytotoxic, vesicating effects, and results in cell death . However, the biomedical mechanism of cell death induced... cell death via apoptosis: • In early stage, It induces JNK activity and then triggers apoptosis pathway. • In late stage, sulphur mustard attacks the

  16. Genome scan reveals selection acting on genes linked to stress response in wild pearl millet.

    PubMed

    Berthouly-Salazar, Cécile; Thuillet, Anne-Céline; Rhoné, Bénédicte; Mariac, Cédric; Ousseini, Issaka Salia; Couderc, Marie; Tenaillon, Maud I; Vigouroux, Yves

    2016-11-01

    Uncovering genomic regions involved in adaption is a major goal in evolutionary biology. High-throughput sequencing now makes it possible to tackle this challenge in nonmodel species. Yet, despite the increasing number of methods targeted to specifically detect genomic footprints of selection, the complex demography of natural populations often causes high rates of false positive in gene discoveries. The aim of this study was to identify climate adaptations in wild pearl millet populations, Cenchrus americanus ssp. monodii. We focused on two climate gradients, one in Mali and one in Niger. We used a two-step strategy to limit false-positive outliers. First, we considered gradients as biological replicates and performed RNA sequencing of four populations at the extremities. We combined four methods-three based on differentiation among populations and one based on diversity patterns within populations-to identify outlier SNPs from a set of 87 218 high-quality SNPs. Among 11 155 contigs of pearl millet reference transcriptome, 540 exhibited selection signals as evidenced by at least one of the four methods. In a second step, we genotyped 762 samples in 11 additional populations distributed along the gradients using SNPs from the detected contigs and random SNPs as control. We further assessed selection on this large data set using a differentiation-based method and a method based on correlations with environmental variables based. Four contigs displayed consistent signatures between the four extreme and 11 additional populations, two of which were linked to abiotic and biotic stress responses.

  17. Whole-genome transcriptional and physiological responses of Nitrosomonas europaea to cyanide: identification of cyanide stress response genes.

    PubMed

    Park, Sunhwa; Ely, Roger L

    2009-04-15

    Nitrosomonas europaea (ATCC 19718) is one of several nitrifying species that participate in the biological removal of nitrogen from wastewater by oxidizing ammonia to nitrite, the first step in nitrification. Because nitrification is quite sensitive to cyanide, a compound often encountered in wastewater treatment plants, we characterized the physiological and transcriptional responses of N. europaea cells to cyanide. The cells were extremely sensitive to low concentrations of cyanide, with NO-(2)production and ammonia-dependent oxygen uptake rates decreasing by 50% within 30 min of exposure to 1 microM NaCN. Whole-genome transcriptional responses of cells exposed to 1 microM NaCN were examined using Affymetrix microarrays to identify stress-induced genes. The transcript levels of 35 genes increased more than 2-fold while transcript levels of 29 genes decreased more than 20-fold. A gene cluster that included moeZ (NE2353), encoding a rhodanese homologue and thought to be involved in detoxification of cyanide, showed the highest up-regulation (7-fold). The down-regulated genes included genes encoding proteins involved in the sulfate reduction pathway, signal transduction mechanisms, carbohydrate transport, energy production, coenzyme metabolism, and amino acid transport.

  18. The pea aphid (Acyrthosiphon pisum) genome encodes two divergent early developmental programs.

    PubMed

    Duncan, Elizabeth J; Leask, Megan P; Dearden, Peter K

    2013-05-01

    The pea aphid (Acyrthosiphon pisum) can reproduce either sexually or asexually (parthenogenetically), giving rise, in each case, to almost identical adults. These two modes of reproduction are accompanied by differences in ovarian morphology and the developmental environment of the offspring, with sexual forms producing eggs that are laid, whereas asexual development occurs within the mother. Here we examine the effect each mode of reproduction has on the expression of key maternal and axis patterning genes; orthodenticle (otd), hunchback (hb), caudal (cad) and nanos (nos). We show that three of these genes (Ap-hb, Ap-otd and Ap-cad) are expressed differently between the sexually and asexually produced oocytes and embryos of the pea aphid. We also show, using immunohistochemistry and cytoskeletal inhibitors, that Ap-hb RNA is localized differently between sexually and asexually produced oocytes, and that this is likely due to differences in the 3' untranslated regions of the RNA. Furthermore, Ap-hb and Ap-otd have extensive expression domains in early sexually produced embryos, but are not expressed at equivalent stages in asexually produced embryos. These differences in expression likely correspond with substantial changes in the gene regulatory networks controlling early development in the pea aphid. These data imply that in the evolution of parthenogenesis a new program has evolved to control the development of asexually produced embryos, whilst retaining the existing, sexual, developmental program. The patterns of modification of these developmental processes mirror the changes that we see in developmental processes between species, in that early acting pathways in development are less constrained, and evolve faster, than later ones. We suggest that the evolution of the novel asexual development pathway in aphids is not a simple modification of an ancestral system, but the evolution of two very different developmental mechanisms occurring within a single

  19. Exposure to dim light at night during early development increases adult anxiety-like responses.

    PubMed

    Borniger, Jeremy C; McHenry, Zachary D; Abi Salloum, Bachir A; Nelson, Randy J

    2014-06-22

    Early experiences produce effects that may persist throughout life. Therefore, to understand adult phenotype, it is important to investigate the role of early environmental stimuli in adult behavior and health. Artificial light at night (LAN) is an increasingly common phenomenon throughout the world. However, animals, including humans, evolved under dark night conditions. Many studies have revealed affective, immune, and metabolic alterations provoked by aberrant light exposure and subsequent circadian disruption. Pups are receptive to entraining cues from the mother and then light early during development, raising the possibility that the early life light environment may influence subsequent behavior. Thus, to investigate potential influences of early life exposure to LAN on adult phenotype, we exposed mice to dim (~5 lux; full spectrum white light) or dark (~0 lux) nights pre- and/or postnatally. After weaning at 3 weeks of age, all mice were maintained in dark nights until adulthood (9 weeks of age) when behavior was assessed. Mice exposed to dim light in early life increased anxiety-like behavior and fearful responses on the elevated plus maze and passive avoidance tests. These mice also displayed reduced growth rates, which ultimately normalized during adolescence. mRNA expression of brain derived neurotrophic factor (BDNF), a neurotrophin previously linked to early life environment and adult phenotype, was not altered in the prefrontal cortex or hippocampus by early life LAN exposure. Serum corticosterone concentrations were similar between groups at weaning, suggesting that early life LAN does not elicit a long-term physiologic stress response. Dim light exposure did not influence behavior on the open field, novel object, sucrose anhedonia, or forced swim tests. Our data highlight the potential deleterious consequences of low levels of light during early life to development and subsequent behavior. Whether these changes are due to altered maternal behavior

  20. Cost effectiveness of responsive stimulation and nutrition interventions on early child development outcomes in Pakistan.

    PubMed

    Gowani, Saima; Yousafzai, Aisha K; Armstrong, Robert; Bhutta, Zulfiqar A

    2014-01-01

    Early childhood programs are heralded as a way to improve children's health and educational outcomes. However, few studies in developing countries calculate the effectiveness of quality early childhood interventions. Even fewer estimate the associated costs of such interventions. The study here looks at the costs and effectiveness of a cluster-randomized effectiveness trial on children from birth to 24 months in rural Sindh, Pakistan. Responsive stimulation and/or enhanced nutrition interventions were integrated in the Lady Health Worker program in Pakistan. Outcomes suggest that children who receive responsive stimulation had significantly better development outcomes at 24 months than those who only received enhanced nutrition intervention. A cost-effectiveness analysis of the results verifies that early childhood interventions that include responsive stimulation are more cost effective than a nutrition intervention alone in promoting children's early development. Costs of a responsive stimulation intervention integrated in an existing community-based service providing basic health and nutrition care is approximately US$4 per month per child. We discuss these findings and make recommendations about scaling up and costs for future early child development programs.

  1. Population genomic analyses of early-phase Atlantic Salmon (Salmo salar) domestication/captive breeding

    PubMed Central

    Mäkinen, Hannu; Vasemägi, Anti; McGinnity, Philip; Cross, Tom F; Primmer, Craig R

    2015-01-01

    Domestication can have adverse genetic consequences, which may reduce the fitness of individuals once released back into the wild. Many wild Atlantic salmon (Salmo salarL.) populations are threatened by anthropogenic influences, and they are supplemented with captively bred fish. The Atlantic salmon is also widely used in selective breeding programs to increase the mean trait values for desired phenotypic traits. We analyzed a genomewide set of SNPs in three domesticated Atlantic salmon strains and their wild conspecifics to identify loci underlying domestication. The genetic differentiation between domesticated strains and wild populations was low (FST < 0.03), and domesticated strains harbored similar levels of genetic diversity compared to their wild conspecifics. Only a few loci showed footprints of selection, and these loci were located in different linkage groups among the different wild population/hatchery strain comparisons. Simulated scenarios indicated that differentiation in quantitative trait loci exceeded that in neutral markers during the early phases of divergence only when the difference in the phenotypic optimum between populations was large. This study indicates that detecting selection using standard approaches in the early phases of domestication might be challenging unless selection is strong and the traits under selection show simple inheritance patterns. PMID:25667605

  2. Genome-Wide Transcription Profiling of the Early Phase of Biofilm Formation by Candida albicans†

    PubMed Central

    Murillo, Luis A.; Newport, George; Lan, Chung-Yu; Habelitz, Stefan; Dungan, Jan; Agabian, Nina M.

    2005-01-01

    The ability to adhere to surfaces and develop as a multicellular community is an adaptation used by most microorganisms to survive in changing environments. Biofilm formation proceeds through distinct developmental phases and impacts not only medicine but also industry and evolution. In organisms such as the opportunistic pathogen Candida albicans, the ability to grow as biofilms is also an important mechanism for persistence, facilitating its growth on different tissues and a broad range of abiotic surfaces used in medical devices. The early stage of C. albicans biofilm is characterized by the adhesion of single cells to the substratum, followed by the formation of an intricate network of hyphae and the beginning of a dense structure. Changes in the transcriptome begin within 30 min of contact with the substrate and include expression of genes related to sulfur metabolism, in particular MET3, and the equivalent gene homologues of the Ribi regulon in Saccharomyces cerevisiae. Some of these changes are initiated early and maintained throughout the process; others are restricted to the earliest stages of biofilm formation. We identify here a potential alternative pathway for cysteine metabolism and the biofilm-associated expression of genes involved in glutathione production in C. albicans. PMID:16151249

  3. Genome-wide chromatin remodeling modulates the Alu heat shock response.

    PubMed

    Kim, C; Rubin, C M; Schmid, C W

    2001-10-03

    During heat shock recovery in Hela cells, the level of Alu RNA transiently increases with kinetics that approximately parallel the transient expression of heat shock protein mRNAs. Coincidentally, there is a transient increase in the accessibility of Alu chromatin to restriction enzyme cleavage suggesting that an opening and re-closing of chromatin regulates the Alu stress response. Similar changes occur in alpha satellite and LINE1 chromatin showing that heat shock induces a genome-wide remodeling of chromatin structure which is independent of transcription. The increased accessibility of restriction sites within these repetitive sequences is inconsistent with a simple lengthening of the nucleosome linker region but instead suggests a scrambling of nucleosome positions. Chromatin structure and its dynamics account for many of the principal features of SINE transcriptional regulation potentially providing a functional rationale for the dispersion and high copy number of SINEs.

  4. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis.

    PubMed

    Martin, Hilary C; Kim, Grace E; Pagnamenta, Alistair T; Murakami, Yoshiko; Carvill, Gemma L; Meyer, Esther; Copley, Richard R; Rimmer, Andrew; Barcia, Giulia; Fleming, Matthew R; Kronengold, Jack; Brown, Maile R; Hudspith, Karl A; Broxholme, John; Kanapin, Alexander; Cazier, Jean-Baptiste; Kinoshita, Taroh; Nabbout, Rima; Bentley, David; McVean, Gil; Heavin, Sinéad; Zaiwalla, Zenobia; McShane, Tony; Mefford, Heather C; Shears, Deborah; Stewart, Helen; Kurian, Manju A; Scheffer, Ingrid E; Blair, Edward; Donnelly, Peter; Kaczmarek, Leonard K; Taylor, Jenny C

    2014-06-15

    In severe early-onset epilepsy, precise clinical and molecular genetic diagnosis is complex, as many metabolic and electro-physiological processes have been implicated in disease causation. The clinical phenotypes share many features such as complex seizure types and developmental delay. Molecular diagnosis has historically been confined to sequential testing of candidate genes known to be associated with specific sub-phenotypes, but the diagnostic yield of this approach can be low. We conducted whole-genome sequencing (WGS) on six patients with severe early-onset epilepsy who had previously been refractory to molecular diagnosis, and their parents. Four of these patients had a clinical diagnosis of Ohtahara Syndrome (OS) and two patients had severe non-syndromic early-onset epilepsy (NSEOE). In two OS cases, we found de novo non-synonymous mutations in the genes KCNQ2 and SCN2A. In a third OS case, WGS revealed paternal isodisomy for chromosome 9, leading to identification of the causal homozygous missense variant in KCNT1, which produced a substantial increase in potassium channel current. The fourth OS patient had a recessive mutation in PIGQ that led to exon skipping and defective glycophosphatidyl inositol biosynthesis. The two patients with NSEOE had likely pathogenic de novo mutations in CBL and CSNK1G1, respectively. Mutations in these genes were not found among 500 additional individuals with epilepsy. This work reveals two novel genes for OS, KCNT1 and PIGQ. It also uncovers unexpected genetic mechanisms and emphasizes the power of WGS as a clinical tool for making molecular diagnoses, particularly for highly heterogeneous disorders.

  5. Phylogenetic and evolutionary implications of complete chloroplast genome sequences of four early-diverging angiosperms: Buxus (Buxaceae), Chloranthus (Chloranthaceae), Dioscorea (Dioscoreaceae), and Illicium (Schisandraceae).

    PubMed

    Hansen, Debra R; Dastidar, Sayantani G; Cai, Zhengqiu; Penaflor, Cynthia; Kuehl, Jennifer V; Boore, Jeffrey L; Jansen, Robert K

    2007-11-01

    We have determined the complete chloroplast genome sequences of four early-diverging lineages of angiosperms, Buxus (Buxaceae), Chloranthus (Chloranthaceae), Dioscorea (Dioscoreaceae), and Illicium (Schisandraceae), to examine the organization and evolution of plastid genomes and to estimate phylogenetic relationships among angiosperms. For the most part, the organization of these plastid genomes is quite similar to the ancestral angiosperm plastid genome with a few notable exceptions. Dioscorea has lost one protein-coding gene, rps16; this gene loss has also happened independently in four other land plant lineages, liverworts, conifers, Populus, and legumes. There has also been a small expansion of the inverted repeat (IR) in Dioscorea that has duplicated trnH-GUG. This event has also occurred multiple times in angiosperms, including in monocots, and in the two basal angiosperms Nuphar and Drimys. The Illicium chloroplast genome is unusual by having a 10 kb contraction of the IR. The four taxa sequenced represent key groups in resolving phylogenetic relationships among angiosperms. Illicium is one of the basal angiosperms in the Austrobaileyales, Chloranthus (Chloranthales) remains unplaced in angiosperm classifications, and Buxus and Dioscorea are early-diverging eudicots and monocots, respectively. We have used sequences for 61 shared protein-coding genes from these four genomes and combined them with sequences from 35 other genomes to estimate phylogenetic relationships using parsimony, likelihood, and Bayesian methods. There is strong congruence among the trees generated by the three methods, and most nodes have high levels of support. The results indicate that Amborella alone is sister to the remaining angiosperms; the Nymphaeales represent the next-diverging clade followed by Illicium; Chloranthus is sister to the magnoliids and together this group is sister to a large clade that includes eudicots and monocots; and Dioscorea represents an early

  6. Genomic and genotoxic responses to controlled weathered-oil exposures confirm and extend field studies on impacts of the Deepwater Horizon oil spill on native killifish.

    PubMed

    Pilcher, Whitney; Miles, Scott; Tang, Song; Mayer, Greg; Whitehead, Andrew

    2014-01-01

    To understand the ecotoxicological impacts of the Deepwater Horizon oil spill, field studies provide a context for ecological realism but laboratory-based studies offer power for connecting biological effects with specific causes. As a complement to field studies, we characterized genome-wide gene expression responses of Gulf killifish (Fundulus grandis) to oil-contaminated waters in controlled laboratory exposures. Transcriptional responses to the highest concentrations of oiled water in the laboratory were predictive of field-observed responses that coincided with the timing and location of major oiling. The transcriptional response to the low concentration (∼ 10-fold lower than the high concentration) was distinct from the high concentration and was not predictive of major oiling in the field. The high concentration response was characterized by activation of the molecular signaling pathway that facilitates oil metabolism and oil toxicity. The high concentration also induced DNA damage. The low concentration invoked expression of genes that may support a compensatory response, including genes associated with regulation of transcription, cell cycle progression, RNA processing, DNA damage, and apoptosis. We conclude that the gene expression response detected in the field was a robust indicator of exposure to the toxic components of contaminating oil, that animals in the field were exposed to relatively high concentrations that are especially damaging to early life stages, and that such exposures can damage DNA.

  7. Genomic and Genotoxic Responses to Controlled Weathered-Oil Exposures Confirm and Extend Field Studies on Impacts of the Deepwater Horizon Oil Spill on Native Killifish

    PubMed Central

    Pilcher, Whitney; Miles, Scott; Tang, Song; Mayer, Greg; Whitehead, Andrew

    2014-01-01

    To understand the ecotoxicological impacts of the Deepwater Horizon oil spill, field studies provide a context for ecological realism but laboratory-based studies offer power for connecting biological effects with specific causes. As a complement to field studies, we characterized genome-wide gene expression responses of Gulf killifish (Fundulus grandis) to oil-contaminated waters in controlled laboratory exposures. Transcriptional responses to the highest concentrations of oiled water in the laboratory were predictive of field-observed responses that coincided with the timing and location of major oiling. The transcriptional response to the low concentration (∼10-fold lower than the high concentration) was distinct from the high concentration and was not predictive of major oiling in the field. The high concentration response was characterized by activation of the molecular signaling pathway that facilitates oil metabolism and oil toxicity. The high concentration also induced DNA damage. The low concentration invoked expression of genes that may support a compensatory response, including genes associated with regulation of transcription, cell cycle progression, RNA processing, DNA damage, and apoptosis. We conclude that the gene expression response detected in the field was a robust indicator of exposure to the toxic components of contaminating oil, that animals in the field were exposed to relatively high concentrations that are especially damaging to early life stages, and that such exposures can damage DNA. PMID:25208076

  8. Genome-wide association analysis of anti-TNF drug response in rheumatoid arthritis patients

    PubMed Central

    Mirkov, Maša Umiċeviċ; Cui, Jing; Vermeulen, Sita H; Stahl, Eli A.; Toonen, Erik JM; Makkinje, Remco R; Lee, Annette T; Huizinga, Tom WJ; Allaart, Renee; Barton, Anne; Mariette, Xavier; Miceli-Richard, Corinne; Criswell, Lindsey A; Tak, Paul P; de Vries, Niek; Saevarsdottir, Saedis; Padyukov, Leonid; Bridges, S. Louis; van Schaardenburg, Dirk-Jan; Jansen, Tim; Dutmer, Ellen AJ; van de Laar, Mart; Barrera, Pilar; Radstake, Timothy RDJ; van Riel, Piet LCM; Scheffer, Hans; Franke, Barbara; Brunner, Han G; Plenge, Robert M; Gregersen, Peter K; Guchelaar, Henk-Jan; Coenen, Marieke JH

    2014-01-01

    Background Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA). However, a significant subset of patients does not respond for unknown reasons. Currently there are no means of identifying these patients prior to treatment. This study was aimed at identifying genetic factors predicting anti-TNF treatment outcome in patient with RA using a genome-wide association approach. Methods We conducted a multi-stage, genome-wide association study with a primary analysis of 2,557,253 single nucleotide polymorphisms (SNPs) in 882 RA patients receiving anti-TNF therapy included through the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry and the database of Apotheekzorg. Linear regression analysis of changes in the Disease Activity Score in 28 joints after 14 weeks of treatment was performed using an additive model. Markers with a p<10−3 were selected for replication in 1,821 RA patients from three independent cohorts. Pathway analysis including all SNPs with a p-value < 10−3 was performed using Ingenuity. Results Seven hundred seventy two markers demonstrated evidence of association with treatment outcome in the initial stage. Eight genetic loci showed improved p-value in the overall meta-analysis compared to the first stage, three of which (rs1568885, rs1813443 and rs4411591) showed directional consistency over all four studied cohorts. We were unable to replicate markers previously reported to be associated with anti-TNF outcome. Network analysis indicated strong involvement of biological processes underlying inflammatory response and cell morphology. Conclusion Using a multi-stage strategy, we have identified 8 genetic loci associated with response to anti-TNF treatment. Further studies are required to validate these findings in additional patient collections. PMID:23233654

  9. Evolution of a Cellular Immune Response in Drosophila: A Phenotypic and Genomic Comparative Analysis

    PubMed Central

    Salazar-Jaramillo, Laura; Paspati, Angeliki; van de Zande, Louis; Vermeulen, Cornelis Joseph; Schwander, Tanja; Wertheim, Bregje

    2014-01-01

    Understanding the genomic basis of evolutionary adaptation requires insight into the molecular basis underlying phenotypic variation. However, even changes in molecular pathways associated with extreme variation, gains and losses of specific phenotypes, remain largely uncharacterized. Here, we investigate the large interspecific differences in the ability to survive infection by parasitoids across 11 Drosophila species and identify genomic changes associated with gains and losses of parasitoid resistance. We show that a cellular immune defense, encapsulation, and the production of a specialized blood cell, lamellocytes, are restricted to a sublineage of Drosophila, but that encapsulation is absent in one species of this sublineage, Drosophila sechellia. Our comparative analyses of hemopoiesis pathway genes and of genes differentially expressed during the encapsulation response revealed that hemopoiesis-associated genes are highly conserved and present in all species independently of their resistance. In contrast, 11 genes that are differentially expressed during the response to parasitoids are novel genes, specific to the Drosophila sublineage capable of lamellocyte-mediated encapsulation. These novel genes, which are predominantly expressed in hemocytes, arose via duplications, whereby five of them also showed signatures of positive selection, as expected if they were recruited for new functions. Three of these novel genes further showed large-scale and presumably loss-of-function sequence changes in D. sechellia, consistent with the loss of resistance in this species. In combination, these convergent lines of evidence suggest that co-option of duplicated genes in existing pathways and subsequent neofunctionalization are likely to have contributed to the evolution of the lamellocyte-mediated encapsulation in Drosophila. PMID:24443439

  10. Genome-Wide Association Study of Cell-Mediated Response in Dogs Naturally Infected by Leishmania infantum.

    PubMed

    Batista, Luís F S; Utsunomiya, Yuri T; Silva, Thaís B F; Dias, Raíssa A; Tomokane, Thaise Y; Pacheco, Acácio D; da Matta, Vânia L R; Silveira, Fernando T; Marcondes, Mary; Nunes, Cáris M; Laurenti, Márcia D

    2016-12-01

    A genome-wide association study (GWAS) could unravel the complexity of the cell-mediated immunity (CMI) to canine leishmaniasis (CanL). Therefore, we scanned 110,165 single-nucleotide polymorphisms (SNPs), aiming to identify chromosomal regions associated with the leishmanin skin test (LST), lymphocyte proliferation assay (LPA), and cytokine responses to further understand the role played by CMI in the outcome of natural Leishmania infantum infection in 189 dogs. Based on LST and LPA, four CMI profiles were identified (LST(-)/LPA(-), LST(+)/LPA(-), LST(-)/LPA(+), and LST(+)/LPA(+)), which were not associated with subclinically infected or diseased dogs. LST(+)/LPA(+) dogs showed increased interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) levels and mild parasitism in the lymph nodes, whereas LST(-)/LPA(+) dogs, in spite of increased IFN-γ, also showed increased interleukin-10 (IL-10) and transforming growth factor β (TGF-β) levels and the highest parasite load in lymph nodes. Low T cell proliferation under low parasite load suggested that L. infantum was not able to induce effective CMI in the early stage of infection. Altogether, genetic markers explained 87%, 16%, 15%, 11%, 0%, and 0% of phenotypic variance in TNF-α, TGF-β, LST, IL-10, IFN-γ, and LPA, respectively. GWAS showed that regions associated with TNF-α include the following genes: IL12RB1, JAK3, CCRL2, CCR2, CCR3, and CXCR6, involved in cytokine and chemokine signaling; regions associated with LST, including COMMD5 and SHARPIN, involved in regulation of NF-κB signaling; and regions associated with IL-10, including LTBP1 and RASGRP3, involved in T regulatory lymphocytes differentiation. These findings pinpoint chromosomic regions related to the cell-mediated response that potentially affect the clinical complexity and the parasite replication in canine L. infantum infection.

  11. Genome-Wide Transcriptional Response of Saccharomyces cerevisiae to Stress-Induced Perturbations

    PubMed Central

    Taymaz-Nikerel, Hilal; Cankorur-Cetinkaya, Ayca; Kirdar, Betul

    2016-01-01

    Cells respond to environmental and/or genetic perturbations in order to survive and proliferate. Characterization of the changes after various stimuli at different -omics levels is crucial to comprehend the adaptation of cells to the changing conditions. Genome-wide quantification and analysis of transcript levels, the genes affected by perturbations, extends our understanding of cellular metabolism by pointing out the mechanisms that play role in sensing the stress caused by those perturbations and related signaling pathways, and in this way guides us to achieve endeavors, such as rational engineering of cells or interpretation of disease mechanisms. Saccharomyces cerevisiae as a model system has been studied in response to different perturbations and corresponding transcriptional profiles were followed either statically or/and dynamically, short and long term. This review focuses on response of yeast cells to diverse stress inducing perturbations, including nutritional changes, ionic stress, salt stress, oxidative stress, osmotic shock, and to genetic interventions such as deletion and overexpression of genes. It is aimed to conclude on common regulatory phenomena that allow yeast to organize its transcriptomic response after any perturbation under different external conditions. PMID:26925399

  12. Transcriptional dynamics reveal critical roles for non-coding RNAs in the immediate-early response.

    PubMed

    Aitken, Stuart; Magi, Shigeyuki; Alhendi, Ahmad M N; Itoh, Masayoshi; Kawaji, Hideya; Lassmann, Timo; Daub, Carsten O; Arner, Erik; Carninci, Piero; Forrest, Alistair R R; Hayashizaki, Yoshihide; Khachigian, Levon M; Okada-Hatakeyama, Mariko; Semple, Colin A

    2015-04-01

    The immediate-early response mediates cell fate in response to a variety of extracellular stimuli and is dysregulated in many cancers. However, the specificity of the response across stimuli and cell types, and the roles of non-coding RNAs are not well understood. Using a large collection of densely-sampled time series expression data we have examined the induction of the immediate-early response in unparalleled detail, across cell types and stimuli. We exploit cap analysis of gene expression (CAGE) time series datasets to directly measure promoter activities over time. Using a novel analysis method for time series data we identify transcripts with expression patterns that closely resemble the dynamics of known immediate-early genes (IEGs) and this enables a comprehensive comparative study of these genes and their chromatin state. Surprisingly, these data suggest that the earliest transcriptional responses often involve promoters generating non-coding RNAs, many of which are produced in advance of canonical protein-coding IEGs. IEGs are known to be capable of induction without de novo protein synthesis. Consistent with this, we find that the response of both protein-coding and non-coding RNA IEGs can be explained by their transcriptionally poised, permissive chromatin state prior to stimulation. We also explore the function of non-coding RNAs in the attenuation of the immediate early response in a small RNA sequencing dataset matched to the CAGE data: We identify a novel set of microRNAs responsible for the attenuation of the IEG response in an estrogen receptor positive cancer cell line. Our computational statistical method is well suited to meta-analyses as there is no requirement for transcripts to pass thresholds for significant differential expression between time points, and it is agnostic to the number of time points per dataset.

  13. The genomic landscape of response to EGFR blockade in colorectal cancer.

    PubMed

    Bertotti, Andrea; Papp, Eniko; Jones, Siân; Adleff, Vilmos; Anagnostou, Valsamo; Lupo, Barbara; Sausen, Mark; Phallen, Jillian; Hruban, Carolyn A; Tokheim, Collin; Niknafs, Noushin; Nesselbush, Monica; Lytle, Karli; Sassi, Francesco; Cottino, Francesca; Migliardi, Giorgia; Zanella, Eugenia R; Ribero, Dario; Russolillo, Nadia; Mellano, Alfredo; Muratore, Andrea; Paraluppi, Gianluca; Salizzoni, Mauro; Marsoni, Silvia; Kragh, Michael; Lantto, Johan; Cassingena, Andrea; Li, Qing Kay; Karchin, Rachel; Scharpf, Robert; Sartore-Bianchi, Andrea; Siena, Salvatore; Diaz, Luis A; Trusolino, Livio; Velculescu, Victor E

    2015-10-08

    Colorectal cancer is the third most common cancer worldwide, with 1.2 million patients diagnosed annually. In late-stage colorectal cancer, the most commonly used targeted therapies are the monoclonal antibodies cetuximab and panitumumab, which prevent epidermal growth factor receptor (EGFR) activation. Recent studies have identified alterations in KRAS and other genes as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in colorectal cancer and little is known about determinants of sensitivity to this therapy. To examine the effect of somatic genetic changes in colorectal cancer on response to anti-EGFR antibody therapy, here we perform complete exome sequence and copy number analyses of 129 patient-derived tumour grafts and targeted genomic analyses of 55 patient tumours, all of which were KRAS wild-type. We analysed the response of tumours to anti-EGFR antibody blockade in tumour graft models and in clinical settings and functionally linked therapeutic responses to mutational data. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumours with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumour graft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluating response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and delineate new avenues for intervention in managing colorectal cancer.

  14. Genomic, genetic and functional dissection of bitter taste responses to artificial sweeteners.

    PubMed

    Roudnitzky, Natacha; Bufe, Bernd; Thalmann, Sophie; Kuhn, Christina; Gunn, Howard C; Xing, Chao; Crider, Bill P; Behrens, Maik; Meyerhof, Wolfgang; Wooding, Stephen P

    2011-09-01

    Bitter taste perception is initiated by TAS2R receptors, which respond to agonists by triggering depolarization of taste bud cells. Mutations in TAS2Rs are known to affect taste phenotypes by altering receptor function. Evidence that TAS2Rs overlap in ligand specificity suggests that they may also contribute joint effects. To explore this aspect of gustation, we examined bitter perception of saccharin and acesulfame K, widely used artificial sweeteners with aversive aftertastes. Both substances are agonists of TAS2R31 and -43, which belong to a five-member subfamily (TAS2R30-46) responsive to a diverse constellation of compounds. We analyzed sequence variation and linkage structure in the ∼140 kb genomic region encoding TAS2R30-46, taste responses to the two sweeteners in subjects, and functional characteristics of receptor alleles. Whole-gene sequences from TAS2R30-46 in 60 Caucasian subjects revealed extensive diversity including 34 missense mutations, two nonsense mutations and high-frequency copy-number variants. Thirty markers, including non-synonymous variants in all five genes, were associated (P< 0.001) with responses to saccharin and acesulfame K. However, linkage disequilibrium (LD) in the region was high (D', r(2) > 0.95). Haplotype analyses revealed that most associations were spurious, arising from LD with variants in TAS2R31. In vitro assays confirmed the functional importance of four TAS2R31 mutations, which had independent effects on receptor response. The existence of high LD spanning functionally distinct TAS2R loci predicts that bitter taste responses to many compounds will be strongly correlated even when they are mediated by different genes. Integrative approaches combining phenotypic, genetic and functional analysis will be essential in dissecting these complex relationships.

  15. Early Response of Prostate Carcinoma Xenografts to Docetaxel Chemotherapy Monitored With Diffusion MRI

    PubMed Central

    Jennings, Dominique; Hatton, B Nicholas; Guo, Jingyu; Galons, Jean-Philippe; Trouard, Theodore P; Raghunand, Natarajan; Marshall, James; Gillies, Robert J

    2002-01-01

    Abstract For many anticancer therapies, it would be desirable to accurately monitor and quantify tumor response early in the treatment regimen. This would allow oncologists to continue effective therapies or discontinue ineffective therapies early in the course of treatment, and hence, reduce morbidity. This is especially true for second-line therapies, which have reduced response rates and increased toxicities. Previous works by others and ourselves have shown that water mobility, measured by diffusion-weighted magnetic resonance imaging (DW-MRI), increases early in tumors destined to respond to therapies. In the current communication, we further characterize the utility of DW-MRI to predict response of prostate cancer xenografts to docetaxel in SCID mice in a preclinical setting. The current data illustrate that tumor volumes and secreted prostate-specific antigen both respond strongly to docetaxel in a dose-responsive manner, and the apparent diffusion coefficient of water (ADCw) increases significantly by 2 days even at the lowest doses (10 mg/kg). The ADCw data were parsed by histogram analyses. Our results indicate that DW-MRI can be used for early detection of prostate carcinoma xenograft response to docetaxel chemotherapy. PMID:11988845

  16. Toll-like receptor 7 mediates early innate immune responses to malaria.

    PubMed

    Baccarella, Alyssa; Fontana, Mary F; Chen, Eunice C; Kim, Charles C

    2013-12-01

    Innate immune recognition of malaria parasites is the critical first step in the development of the host response. At present, Toll-like receptor 9 (TLR9) is thought to play a central role in sensing malaria infection. However, we and others have observed that Tlr9(-/-) mice, in contrast to mice deficient in the downstream adaptor, Myeloid differentiation primary response gene 88 (MYD88), exhibit few deficiencies in immune function during early infection with the malaria parasite Plasmodium chabaudi, implying that another MYD88-dependent receptor also contributes to the antimalarial response. Here we use candidate-based screening to identify TLR7 as a key sensor of early P. chabaudi infection. We show that TLR7 mediates a rapid systemic response to infection through induction of cytokines such as type I interferons (IFN-I), interleukin 12, and gamma interferon. TLR7 is also required for induction of IFN-I by other species and strains of Plasmodium, including an etiological agent of human disease, P. falciparum, suggesting that malaria parasites harbor a common pathogen-associated molecular pattern (PAMP) recognized by TLR7. In contrast to the nonredundant requirement for TLR7 in early immune activation, sensing through both TLR7 and TLR9 was required for proinflammatory cytokine production and immune cell activation during the peak of parasitemia. Our findings indicate that TLR7 plays a central role in early immune activation during malaria infection, whereas TLR7 and TLR9 contribute combinatorially to immune responses as infection progresses.

  17. Real-time genomic profiling of histiocytoses identifies early-kinase domain BRAF alterations while improving treatment outcomes.

    PubMed

    Lee, Lynn H; Gasilina, Anjelika; Roychoudhury, Jayeeta; Clark, Jason; McCormack, Francis X; Pressey, Joseph; Grimley, Michael S; Lorsbach, Robert; Ali, Siraj; Bailey, Mark; Stephens, Philip; Ross, Jeffrey S; Miller, Vincent A; Nassar, Nicolas N; Kumar, Ashish R

    2017-02-09

    Many patients with histiocytic disorders such as Langerhans cell histiocytosis (LCH) or Erdheim-Chester disease (ECD) have treatment-refractory disease or suffer recurrences. Recent findings of gene mutations in histiocytoses have generated options for targeted therapies. We sought to determine the utility of prospective sequencing of select genes to further characterize mutations and identify targeted therapies for patients with histiocytoses. Biopsies of 72 patients with a variety of histiocytoses underwent comprehensive genomic profiling with targeted DNA and RNA sequencing. Fifteen patients (21%) carried the known BRAF V600E mutation, and 11 patients (15%) carried various mutations in MAP2K1, which we confirm induce constitutive activation of extracellular signal-regulated kinase (ERK) and were sensitive to inhibitors of mitogen-activated protein kinase kinase (MEK, the product of MAP2K1). We also identified recurring ALK rearrangements, and 4 LCH patients with an uncommon in-frame deletion in BRAF (N486_P490del or N486_T491>K), resulting in constitutive activation of ERK with resistance to V600E-specific inhibitors. We subsequently describe clinical cases where patients with aggressive multisystem LCH experience dramatic and sustained responses to monotherapy with either dabrafenib or trametinib. These findings support our conclusion that comprehensive genomic profiling should be regularly applied to these disorders at diagnosis, and can positively impact clinical care.

  18. Real-time genomic profiling of histiocytoses identifies early-kinase domain BRAF alterations while improving treatment outcomes

    PubMed Central

    Lee, Lynn H.; Gasilina, Anjelika; Roychoudhury, Jayeeta; McCormack, Francis X.; Pressey, Joseph; Lorsbach, Robert; Ali, Siraj; Bailey, Mark; Stephens, Philip; Ross, Jeffrey S.; Miller, Vincent A.; Nassar, Nicolas N.; Kumar, Ashish R.

    2017-01-01

    Many patients with histiocytic disorders such as Langerhans cell histiocytosis (LCH) or Erdheim-Chester disease (ECD) have treatment-refractory disease or suffer recurrences. Recent findings of gene mutations in histiocytoses have generated options for targeted therapies. We sought to determine the utility of prospective sequencing of select genes to further characterize mutations and identify targeted therapies for patients with histiocytoses. Biopsies of 72 patients with a variety of histiocytoses underwent comprehensive genomic profiling with targeted DNA and RNA sequencing. Fifteen patients (21%) carried the known BRAF V600E mutation, and 11 patients (15%) carried various mutations in MAP2K1, which we confirm induce constitutive activation of extracellular signal–regulated kinase (ERK) and were sensitive to inhibitors of mitogen-activated protein kinase kinase (MEK, the product of MAP2K1). We also identified recurring ALK rearrangements, and 4 LCH patients with an uncommon in-frame deletion in BRAF (N486_P490del or N486_T491>K), resulting in constitutive activation of ERK with resistance to V600E-specific inhibitors. We subsequently describe clinical cases where patients with aggressive multisystem LCH experience dramatic and sustained responses to monotherapy with either dabrafenib or trametinib. These findings support our conclusion that comprehensive genomic profiling should be regularly applied to these disorders at diagnosis, and can positively impact clinical care. PMID:28194436

  19. Auditory-neurophysiological responses to speech during early childhood: Effects of background noise.

    PubMed

    White-Schwoch, Travis; Davies, Evan C; Thompson, Elaine C; Woodruff Carr, Kali; Nicol, Trent; Bradlow, Ann R; Kraus, Nina

    2015-10-01

    Early childhood is a critical period of auditory learning, during which children are constantly mapping sounds to meaning. But this auditory learning rarely occurs in ideal listening conditions-children are forced to listen against a relentless din. This background noise degrades the neural coding of these critical sounds, in turn interfering with auditory learning. Despite the importance of robust and reliable auditory processing during early childhood, little is known about the neurophysiology underlying speech processing in children so young. To better understand the physiological constraints these adverse listening scenarios impose on speech sound coding during early childhood, auditory-neurophysiological responses were elicited to a consonant-vowel syllable in quiet and background noise in a cohort of typically-developing preschoolers (ages 3-5 yr). Overall, responses were degraded in noise: they were smaller, less stable across trials, slower, and there was poorer coding of spectral content and the temporal envelope. These effects were exacerbated in response to the consonant transition relative to the vowel, suggesting that the neural coding of spectrotemporally-dynamic speech features is more tenuous in noise than the coding of static features-even in children this young. Neural coding of speech temporal fine structure, however, was more resilient to the addition of background noise than coding of temporal envelope information. Taken together, these results demonstrate that noise places a neurophysiological constraint on speech processing during early childhood by causing a breakdown in neural processing of speech acoustics. These results may explain why some listeners have inordinate difficulties understanding speech in noise. Speech-elicited auditory-neurophysiological responses offer objective insight into listening skills during early childhood by reflecting the integrity of neural coding in quiet and noise; this paper documents typical response

  20. Recurrent Rare Genomic Copy Number Variants and Bicuspid Aortic Valve Are Enriched in Early Onset Thoracic Aortic Aneurysms and Dissections

    PubMed Central

    Prakash, Siddharth; Kuang, Shao-Qing; Regalado, Ellen; Guo, Dongchuan; Milewicz, Dianna

    2016-01-01

    Thoracic Aortic Aneurysms and Dissections (TAAD) are a major cause of death in the United States. The spectrum of TAAD ranges from genetic disorders, such as Marfan syndrome, to sporadic isolated disease of unknown cause. We hypothesized that genomic copy number variants (CNVs) contribute causally to early onset TAAD (ETAAD). We conducted a genome-wide SNP array analysis of ETAAD patients of European descent who were enrolled in the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC). Genotyping was performed on the Illumina Omni-Express platform, using PennCNV, Nexus and CNVPartition for CNV detection. ETAAD patients (n = 108, 100% European American, 28% female, average age 20 years, 55% with bicuspid aortic valves) were compared to 7013 dbGAP controls without a history of vascular disease using downsampled Omni 2.5 data. For comparison, 805 sporadic TAAD patients with late onset aortic disease (STAAD cohort) and 192 affected probands from families with at least two affected relatives (FTAAD cohort) from our institution were screened for additional CNVs at these loci with SNP arrays. We identified 47 recurrent CNV regions in the ETAAD, FTAAD and STAAD groups that were absent or extremely rare in controls. Nine rare CNVs that were either very large (>1 Mb) or shared by ETAAD and STAAD or FTAAD patients were also identified. Four rare CNVs involved genes that cause arterial aneurysms when mutated. The largest and most prevalent of the recurrent CNVs were at Xq28 (two duplications and two deletions) and 17q25.1 (three duplications). The percentage of individuals harboring rare CNVs was significantly greater in the ETAAD cohort (32%) than in the FTAAD (23%) or STAAD (17%) cohorts. We identified multiple loci affected by rare CNVs in one-third of ETAAD patients, confirming the genetic heterogeneity of TAAD. Alterations of candidate genes at these loci may contribute to the pathogenesis of TAAD. PMID:27092555

  1. Recurrent Rare Genomic Copy Number Variants and Bicuspid Aortic Valve Are Enriched in Early Onset Thoracic Aortic Aneurysms and Dissections.

    PubMed

    Prakash, Siddharth; Kuang, Shao-Qing; Regalado, Ellen; Guo, Dongchuan; Milewicz, Dianna

    2016-01-01

    Thoracic Aortic Aneurysms and Dissections (TAAD) are a major cause of death in the United States. The spectrum of TAAD ranges from genetic disorders, such as Marfan syndrome, to sporadic isolated disease of unknown cause. We hypothesized that genomic copy number variants (CNVs) contribute causally to early onset TAAD (ETAAD). We conducted a genome-wide SNP array analysis of ETAAD patients of European descent who were enrolled in the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC). Genotyping was performed on the Illumina Omni-Express platform, using PennCNV, Nexus and CNVPartition for CNV detection. ETAAD patients (n = 108, 100% European American, 28% female, average age 20 years, 55% with bicuspid aortic valves) were compared to 7013 dbGAP controls without a history of vascular disease using downsampled Omni 2.5 data. For comparison, 805 sporadic TAAD patients with late onset aortic disease (STAAD cohort) and 192 affected probands from families with at least two affected relatives (FTAAD cohort) from our institution were screened for additional CNVs at these loci with SNP arrays. We identified 47 recurrent CNV regions in the ETAAD, FTAAD and STAAD groups that were absent or extremely rare in controls. Nine rare CNVs that were either very large (>1 Mb) or shared by ETAAD and STAAD or FTAAD patients were also identified. Four rare CNVs involved genes that cause arterial aneurysms when mutated. The largest and most prevalent of the recurrent CNVs were at Xq28 (two duplications and two deletions) and 17q25.1 (three duplications). The percentage of individuals harboring rare CNVs was significantly greater in the ETAAD cohort (32%) than in the FTAAD (23%) or STAAD (17%) cohorts. We identified multiple loci affected by rare CNVs in one-third of ETAAD patients, confirming the genetic heterogeneity of TAAD. Alterations of candidate genes at these loci may contribute to the pathogenesis of TAAD.

  2. Viral evasion mechanisms of early antiviral responses involving regulation of ubiquitin pathways.

    PubMed

    Rajsbaum, Ricardo; García-Sastre, Adolfo

    2013-08-01

    Early innate and cell-intrinsic responses are essential to protect host cells against pathogens. In turn, viruses have developed sophisticated mechanisms to establish productive infections by counteracting host innate immune responses. Increasing evidence indicates that these antiviral factors may have a dual role by directly inhibiting viral replication as well as by sensing and transmitting signals to induce antiviral cytokines. Recent studies have pointed at new, unappreciated mechanisms of viral evasion of host innate protective responses including manipulating the host ubiquitin (Ub) system. Virus-mediated inhibition of antiviral factors by Ub-dependent degradation is emerging as a crucial mechanism for evading the antiviral response. In addition, recent studies have uncovered new mechanisms by which virus-encoded proteins inhibit Ub and Ub-like (Ubl) modification of host proteins involved in innate immune signaling pathways. Here we discuss recent findings and novel strategies that viruses have developed to counteract these early innate antiviral defenses.

  3. Population Response Profiles in Early Visual Cortex Are Biased in Favor of More Valuable Stimuli

    PubMed Central

    Saproo, Sameer

    2010-01-01

    Voluntary and stimulus-driven shifts of attention can modulate the representation of behaviorally relevant stimuli in early areas of visual cortex. In turn, attended items are processed faster and more accurately, facilitating the selection of appropriate behavioral responses. Information processing is also strongly influenced by past experience and recent studies indicate that the learned value of a stimulus can influence relatively late stages of decision making such as the process of selecting a motor response. However, the learned value of a stimulus can also influence the magnitude of cortical responses in early sensory areas such as V1 and S1. These early effects of stimulus value are presumed to improve the quality of sensory representations; however, the nature of these modulations is not clear. They could reflect nonspecific changes in response amplitude associated with changes in general arousal or they could reflect a bias in population responses so that high-value features are represented more robustly. To examine this issue, subjects performed a two-alternative forced choice paradigm with a variable-interval payoff schedule to dynamically manipulate the relative value of two stimuli defined by their orientation (one was rotated clockwise from vertical, the other counterclockwise). Activation levels in visual cortex were monitored using functional MRI and feature-selective voxel tuning functions while subjects performed the behavioral task. The results suggest that value not only modulates the relative amplitude of responses in early areas of human visual cortex, but also sharpens the response profile across the populations of feature-selective neurons that encode the critical stimulus feature (orientation). Moreover, changes in space- or feature-based attention cannot easily explain the results because representations of both the selected and the unselected stimuli underwent a similar feature-selective modulation. This sharpening in the population

  4. Evidence for an Early Origin of Vernalization Responsiveness in Temperate Pooideae Grasses.

    PubMed

    McKeown, Meghan; Schubert, Marian; Marcussen, Thomas; Fjellheim, Siri; Preston, Jill C

    2016-09-01

    The ability of plants to match their reproductive output with favorable environmental conditions has major consequences both for lifetime fitness and geographic patterns of diversity. In temperate ecosystems, some plant species have evolved the ability to use winter nonfreezing cold (vernalization) as a cue to ready them for spring flowering. However, it is unknown how important the evolution of vernalization responsiveness has been for the colonization and subsequent diversification of taxa within the northern and southern temperate zones. Grasses of subfamily Pooideae, including several important crops, such as wheat (Triticum aestivum), barley (Hordeum vulgare), and oats (Avena sativa), predominate in the northern temperate zone, and it is hypothesized that their radiation was facilitated by the early evolution of vernalization responsiveness. Predictions of this early origin hypothesis are that a response to vernalization is widespread within the subfamily and that the genetic basis of this trait is conserved. To test these predictions, we determined and reconstructed vernalization responsiveness across Pooideae and compared expression of wheat vernalization gene orthologs VERNALIZATION1 (VRN1) and VRN3 in phylogenetically representative taxa under cold and control conditions. Our results demonstrate that vernalization responsive Pooideae species are widespread, suggesting that this trait evolved early in the lineage and that at least part of the vernalization gene network is conserved throughout the subfamily. These results are consistent with the hypothesis that the evolution of vernalization responsiveness was important for the initial transition of Pooideae out of the tropics and into the temperate zone.

  5. Evidence for an Early Origin of Vernalization Responsiveness in Temperate Pooideae Grasses1[OPEN

    PubMed Central

    McKeown, Meghan; Fjellheim, Siri

    2016-01-01

    The ability of plants to match their reproductive output with favorable environmental conditions has major consequences both for lifetime fitness and geographic patterns of diversity. In temperate ecosystems, some plant species have evolved the ability to use winter nonfreezing cold (vernalization) as a cue to ready them for spring flowering. However, it is unknown how important the evolution of vernalization responsiveness has been for the colonization and subsequent diversification of taxa within the northern and southern temperate zones. Grasses of subfamily Pooideae, including several important crops, such as wheat (Triticum aestivum), barley (Hordeum vulgare), and oats (Avena sativa), predominate in the northern temperate zone, and it is hypothesized that their radiation was facilitated by the early evolution of vernalization responsiveness. Predictions of this early origin hypothesis are that a response to vernalization is widespread within the subfamily and that the genetic basis of this trait is conserved. To test these predictions, we determined and reconstructed vernalization responsiveness across Pooideae and compared expression of wheat vernalization gene orthologs VERNALIZATION1 (VRN1) and VRN3 in phylogenetically representative taxa under cold and control conditions. Our results demonstrate that vernalization responsive Pooideae species are widespread, suggesting that this trait evolved early in the lineage and that at least part of the vernalization gene network is conserved throughout the subfamily. These results are consistent with the hypothesis that the evolution of vernalization responsiveness was important for the initial transition of Pooideae out of the tropics and into the temperate zone. PMID:27474116

  6. Gram-positive pathogenic bacteria induce a common early response in human monocytes

    PubMed Central

    2010-01-01

    Background We infected freshly isolated human peripheral monocytes with live bacteria of three clinically important gram-positive bacterial species, Staphylococcus aureus, Streptococcus pneumoniae and Listeria monocytogenes and studied the ensuing early transcriptional response using expression microarrays. Thus the observed response was unbiased by signals originating from other helper and effector cells of the host and was not limited to induction by solitary bacterial constituents. Results Activation of monocytes was demonstrated by the upregulation of chemokine rather than interleukin genes except for the prominent expression of interleukin 23, marking it as the early lead cytokine. This activation was accompanied by cytoskeleton rearrangement signals and a general anti-oxidative stress and anti-apoptotic reaction. Remarkably, the expression profiles also provide evidence that monocytes participate in the regulation of angiogenesis and endothelial function in response to these pathogens. Conclusion Regardless of the invasion properties and survival mechanisms of the pathogens used, we found that the early response comprised of a consistent and common response. The common response was hallmarked by the upregulation of interleukin 23, a rather unexpected finding regarding Listeria infection, as this cytokine has been linked primarily to the control of extracellular bacterial dissemination. PMID:21044323

  7. Gene Transfer and the Reconstruction of Life's Early History from Genomic Data

    NASA Astrophysics Data System (ADS)

    Gogarten, J. Peter; Fournier, Gregory; Zhaxybayeva, Olga

    2008-03-01

    The metaphor of the unique and strictly bifurcating tree of life, suggested by Charles Darwin, needs to be replaced (or at least amended) to reflect and include processes that lead to the merging of and communication between independent lines of descent. Gene histories include and reflect processes such as gene transfer, symbioses and lineage fusion. No single molecule can serve as a proxy for the tree of life. Individual gene histories can be reconstructed from the growing molecular databases containing sequence and structural information. With some simplifications these gene histories can be represented by furcating trees; however, merging these gene histories into web-like organismal histories, including the transfer of metabolic pathways and cell biological innovations from now-extinct lineages, has yet to be accomplished. Because of these difficulties in interpreting the record retained in molecular sequences, correlations with biochemical fossils and with the geological record need to be interpreted with caution. Advances to detect and pinpoint transfer events promise to untangle at least a few of the intertwined histories of individual genes within organisms and trace them to the organismal ancestors. Furthermore, analysis of the shape of molecular phylogenetic trees may point towards organismal radiations that might reflect early mass extinction events that occurred on a planetary scale.

  8. Gene Transfer and the Reconstruction of Life's Early History from Genomic Data

    NASA Astrophysics Data System (ADS)

    Gogarten, J. Peter; Fournier, Gregory; Zhaxybayeva, Olga

    The metaphor of the unique and strictly bifurcating tree of life, suggested by Charles Darwin, needs to be replaced (or at least amended) to reflect and include processes that lead to the merging of and communication between independent lines of descent. Gene histories include and reflect processes such as gene transfer, symbioses and lineage fusion. No single molecule can serve as a proxy for the tree of life. Individual gene histories can be reconstructed from the growing molecular databases containing sequence and structural information. With some simplifications these gene histories can be represented by furcating trees; however, merging these gene histories into web-like organismal histories, including the transfer of metabolic pathways and cell biological innovations from now-extinct lineages, has yet to be accomplished. Because of these difficulties in interpreting the record retained in molecular sequences, correlations with biochemical fossils and with the geological record need to be interpreted with caution. Advances to detect and pinpoint transfer events promise to untangle at least a few of the intertwined histories of individual genes within organisms and trace them to the organismal ancestors. Furthermore, analysis of the shape of molecular phylogenetic trees may point towards organismal radiations that might reflect early mass extinction events that occurred on a planetary scale.

  9. Genome-wide transcriptional response of silkworm (Bombyx mori) to infection by the microsporidian Nosema bombycis.

    PubMed

    Ma, Zhengang; Li, Chunfeng; Pan, Guoqing; Li, Zhihong; Han, Bing; Xu, Jinshan; Lan, Xiqian; Chen, Jie; Yang, Donglin; Chen, Quanmei; Sang, Qi; Ji, Xiaocun; Li, Tian; Long, Mengxian; Zhou, Zeyang

    2013-01-01

    Microsporidia have attracted much attention because they infect a variety of species ranging from protists to mammals, including immunocompromised patients with AIDS or cancer. Aside from the study on Nosema ceranae, few works have focused on elucidating the mechanism in host response to microsporidia infection. Nosema bombycis is a pathogen of silkworm pébrine that causes great economic losses to the silkworm industry. Detailed understanding of the host (Bombyx mori) response to infection by N. bombycis is helpful for prevention of this disease. A genome-wide survey of the gene expression profile at 2, 4, 6 and 8 days post-infection by N. bombycis was performed and results showed that 64, 244, 1,328, 1,887 genes were induced, respectively. Up to 124 genes, which are involved in basal metabolism pathways, were modulated. Notably, B. mori genes that play a role in juvenile hormone synthesis and metabolism pathways were induced, suggesting that the host may accumulate JH as a response to infection. Interestingly, N. bombycis can inhibit the silkworm serine protease cascade melanization pathway in hemolymph, which may be due to the secretion of serpins in the microsporidia. N. bombycis also induced up-regulation of several cellular immune factors, in which CTL11 has been suggested to be involved in both spore recognition and immune signal transduction. Microarray and real-time PCR analysis indicated the activation of silkworm Toll and JAK/STAT pathways. The notable up-regulation of antimicrobial peptides, including gloverins, lebocins and moricins, strongly indicated that antimicrobial peptide defense mechanisms were triggered to resist the invasive microsporidia. An analysis of N. bombycis-specific response factors suggested their important roles in anti-microsporidia defense. Overall, this study primarily provides insight into the potential molecular mechanisms for the host-parasite interaction between B. mori and N. bombycis and may provide a foundation for

  10. Genome-wide microarray analysis of tomato roots showed defined responses to iron deficiency

    PubMed Central

    2012-01-01

    Background Plants react to iron deficiency stress adopting different kind of adaptive responses. Tomato, a Strategy I plant, improves iron uptake through acidification of rhizosphere, reduction of Fe3+ to Fe2+ and transport of Fe2+ into the cells. Large-scale transcriptional analyses of roots under iron deficiency are only available for a very limited number of plant species with particular emphasis for Arabidopsis thaliana. Regarding tomato, an interesting model species for Strategy I plants and an economically important crop, physiological responses to Fe-deficiency have been thoroughly described and molecular analyses have provided evidence for genes involved in iron uptake mechanisms and their regulation. However, no detailed transcriptome analysis has been described so far. Results A genome-wide transcriptional analysis, performed with a chip that allows to monitor the expression of more than 25,000 tomato transcripts, identified 97 differentially expressed transcripts by comparing roots of Fe-deficient and Fe-sufficient tomato plants. These transcripts are related to the physiological responses of tomato roots to the nutrient stress resulting in an improved iron uptake, including regulatory aspects, translocation, root morphological modification and adaptation in primary metabolic pathways, such as glycolysis and TCA cycle. Other genes play a role in flavonoid biosynthesis and hormonal metabolism. Conclusions The transcriptional characterization confirmed the presence of the previously described mechanisms to adapt to iron starvation in tomato, but also allowed to identify other genes potentially playing a role in this process, thus opening new research perspectives to improve the knowledge on the tomato root response to the nutrient deficiency. PMID:22433273

  11. The Impact of HIV Co-Infection on the Genomic Response to Sepsis

    PubMed Central

    Huson, Michaëla A. M.; Scicluna, Brendon P.; van Vught, Lonneke A.; Wiewel, Maryse A.; Hoogendijk, Arie J.; Cremer, Olaf L.; Bonten, Marc J. M.; Schultz, Marcus J.; Franitza, Marek; Toliat, Mohammad R.; Nürnberg, Peter; Grobusch, Martin P.; van der Poll, Tom

    2016-01-01

    HIV patients have an increased risk to develop sepsis and HIV infection affects several components of the immune system involved in sepsis pathogenesis. We hypothesized that HIV infection might aggrevate the aberrant immune response during sepsis, so we aimed to determine the impact of HIV infection on the genomic host response to sepsis. We compared whole blood leukocyte gene expression profiles among sepsis patients with or without HIV co-infection in the intensive care unit (ICU) and validated our findings in a cohort of patients admitted to the same ICUs in a different time frame. To examine the influence of HIV infection per se, we also determined the expression of genes of interest in a cohort of asymptomatic HIV patients. We identified a predominantly common host response in sepsis patients with or without HIV co-infection. HIV positive sepsis patients in both ICU cohorts showed overexpression of genes involved in granzyme signaling (GZMA, GZMB), cytotoxic T-cell signaling (CD8A, CD8B) and T-cell inhibitory signaling (LAG3), compared to HIV negative patients. Enhanced expression of CD8A, CD8B and LAG3 was also unmasked in asymptomatic HIV patients. Plasma levels of granzymes in sepsis patients were largely below detection limit, without differences according to HIV status. These results demonstrate that sepsis is characterized by a massive common response with few differences between HIV positive and HIV negative sepsis patients. Observed differences in granzyme signaling, cytotoxic T-cell signaling and T-cell inhibitory signaling appear to be changes commonly observed in asymptomatic HIV patients which persist during sepsis. PMID:26871709

  12. Genome-Wide Transcriptional Response of Silkworm (Bombyx mori) to Infection by the Microsporidian Nosema bombycis

    PubMed Central

    Pan, Guoqing; Li, Zhihong; Han, Bing; Xu, Jinshan; Lan, Xiqian; Chen, Jie; Yang, Donglin; Chen, Quanmei; Sang, Qi; Ji, Xiaocun; Li, Tian; Long, Mengxian; Zhou, Zeyang

    2013-01-01

    Microsporidia have attracted much attention because they infect a variety of species ranging from protists to mammals, including immunocompromised patients with AIDS or cancer. Aside from the study on Nosema ceranae, few works have focused on elucidating the mechanism in host response to microsporidia infection. Nosema bombycis is a pathogen of silkworm pébrine that causes great economic losses to the silkworm industry. Detailed understanding of the host (Bombyx mori) response to infection by N. bombycis is helpful for prevention of this disease. A genome-wide survey of the gene expression profile at 2, 4, 6 and 8 days post-infection by N. bombycis was performed and results showed that 64, 244, 1,328, 1,887 genes were induced, respectively. Up to 124 genes, which are involved in basal metabolism pathways, were modulated. Notably, B. mori genes that play a role in juvenile hormone synthesis and metabolism pathways were induced, suggesting that the host may accumulate JH as a response to infection. Interestingly, N. bombycis can inhibit the silkworm serine protease cascade melanization pathway in hemolymph, which may be due to the secretion of serpins in the microsporidia. N. bombycis also induced up-regulation of several cellular immune factors, in which CTL11 has been suggested to be involved in both spore recognition and immune signal transduction. Microarray and real-time PCR analysis indicated the activation of silkworm Toll and JAK/STAT pathways. The notable up-regulation of antimicrobial peptides, including gloverins, lebocins and moricins, strongly indicated that antimicrobial peptide defense mechanisms were triggered to resist the invasive microsporidia. An analysis of N. bombycis-specific response factors suggested their important roles in anti-microsporidia defense. Overall, this study primarily provides insight into the potential molecular mechanisms for the host-parasite interaction between B. mori and N. bombycis and may provide a foundation for

  13. Predicting Response to Histone Deacetylase Inhibitors Using High-Throughput Genomics

    PubMed Central

    Geeleher, Paul; Loboda, Andrey; Lenkala, Divya; Wang, Fan; LaCroix, Bonnie; Karovic, Sanja; Wang, Jacqueline; Nebozhyn, Michael; Chisamore, Michael; Hardwick, James; Maitland, Michael L.

    2015-01-01

    Background: Many disparate biomarkers have been proposed as predictors of response to histone deacetylase inhibitors (HDI); however, all have failed when applied clinically. Rather than this being entirely an issue of reproducibility, response to the HDI vorinostat may be determined by the additive effect of multiple molecular factors, many of which have previously been demonstrated. Methods: We conducted a large-scale gene expression analysis using the Cancer Genome Project for discovery and generated another large independent cancer cell line dataset across different cancers for validation. We compared different approaches in terms of how accurately vorinostat response can be predicted on an independent out-of-batch set of samples and applied the polygenic marker prediction principles in a clinical trial. Results: Using machine learning, the small effects that aggregate, resulting in sensitivity or resistance, can be recovered from gene expression data in a large panel of cancer cell lines. This approach can predict vorinostat response accurately, whereas single gene or pathway markers cannot. Our analyses recapitulated and contextualized many previous findings and suggest an important role for processes such as chromatin remodeling, autophagy, and apoptosis. As a proof of concept, we also discovered a novel causative role for CHD4, a helicase involved in the histone deacetylase complex that is associated with poor clinical outcome. As a clinical validation, we demonstrated that a common dose-limiting toxicity of vorinostat, thrombocytopenia, can be predicted (r = 0.55, P = .004) several days before it is detected clinically. Conclusion: Our work suggests a paradigm shift from single-gene/pathway evaluation to simultaneously evaluating multiple independent high-throughput gene expression datasets, which can be easily extended to other investigational compounds where similar issues are hampering clinical adoption. PMID:26296641

  14. The Impact of HIV Co-Infection on the Genomic Response to Sepsis.

    PubMed

    Huson, Michaëla A M; Scicluna, Brendon P; van Vught, Lonneke A; Wiewel, Maryse A; Hoogendijk, Arie J; Cremer, Olaf L; Bonten, Marc J M; Schultz, Marcus J; Franitza, Marek; Toliat, Mohammad R; Nürnberg, Peter; Grobusch, Martin P; van der Poll, Tom

    2016-01-01

    HIV patients have an increased risk to develop sepsis and HIV infection affects several components of the immune system involved in sepsis pathogenesis. We hypothesized that HIV infection might aggrevate the aberrant immune response during sepsis, so we aimed to determine the impact of HIV infection on the genomic host response to sepsis. We compared whole blood leukocyte gene expression profiles among sepsis patients with or without HIV co-infection in the intensive care unit (ICU) and validated our findings in a cohort of patients admitted to the same ICUs in a different time frame. To examine the influence of HIV infection per se, we also determined the expression of genes of interest in a cohort of asymptomatic HIV patients. We identified a predominantly common host response in sepsis patients with or without HIV co-infection. HIV positive sepsis patients in both ICU cohorts showed overexpression of genes involved in granzyme signaling (GZMA, GZMB), cytotoxic T-cell signaling (CD8A, CD8B) and T-cell inhibitory signaling (LAG3), compared to HIV negative patients. Enhanced expression of CD8A, CD8B and LAG3 was also unmasked in asymptomatic HIV patients. Plasma levels of granzymes in sepsis patients were largely below detection limit, without differences according to HIV status. These results demonstrate that sepsis is characterized by a massive common response with few differences between HIV positive and HIV negative sepsis patients. Observed differences in granzyme signaling, cytotoxic T-cell signaling and T-cell inhibitory signaling appear to be changes commonly observed in asymptomatic HIV patients which persist during sepsis.

  15. The Genomic Landscape of Response to EGFR Blockade in Colorectal Cancer

    PubMed Central

    Bertotti, Andrea; Papp, Eniko; Jones, Siân; Adleff, Vilmos; Anagnostou, Valsamo; Lupo, Barbara; Sausen, Mark; Phallen, Jillian; Hruban, Carolyn A.; Tokheim, Collin; Niknafs, Noushin; Nesselbush, Monica; Lytle, Karli; Sassi, Francesco; Cottino, Francesca; Migliardi, Giorgia; Zanella, Eugenia R.; Ribero, Dario; Russolillo, Nadia; Mellano, Alfredo; Muratore, Andrea; Paraluppi, Gianluca; Salizzoni, Mauro; Marsoni, Silvia; Kragh, Michael; Lantto, Johan; Cassingena, Andrea; Li, Qing Kay; Karchin, Rachel; Scharpf, Robert; Sartore-Bianchi, Andrea; Siena, Salvatore; Diaz, Luis A.; Trusolino, Livio; Velculescu, Victor E.

    2016-01-01

    Colorectal cancer (CRC) is the third most common cancer world-wide with 1.2 million patients diagnosed yearly. In late stage CRC, the most commonly used targeted therapies are monoclonal antibodies cetuximab and panitumumab, which inactivate EGFR1. Recent studies have identified alterations in KRAS2–4 and other genes5–13 as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in CRC and little is known about determinants of sensitivity to this therapy. To examine the effect of somatic genetic changes in CRC on response to anti-EGFR antibody therapy, we performed complete exome sequence and copy number analyses of 129 patient-derived tumorgrafts and targeted genomic analyses of 55 patient tumors, all of which were KRAS wild-type. We analyzed the response of tumors to anti-EGFR antibody blockade in tumorgraft models or in clinical settings. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumors with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumorgraft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluate response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and provide new avenues for intervention in the management of CRC. PMID:26416732

  16. Responsive Parenting: Establishing Early Foundations for Social, Communication, and Independent Problem-Solving Skills

    ERIC Educational Resources Information Center

    Landry, Susan H.; Smith, Karen E.; Swank, Paul R.

    2006-01-01

    Mothers whose infants varied in early biological characteristics (born at term, n = 120; born at very low birth weight [VLBW], n = 144) were randomized to a target group (n = 133) or developmental feedback comparison group (n = 131) to determine whether learning responsive behaviors would facilitate infant development. The target condition…

  17. Pre-Service Teacher Disposition Development: Cultural Reciprocity and Responsivity in Early Childhood Special Education Practica

    ERIC Educational Resources Information Center

    Van Steenberg, Vicki

    2012-01-01

    This qualitative Case Study explored the integrative process of pre-service teachers' disposition development for cultural reciprocity and responsiveness. Over the course of ten months, pre-service teachers completed two Early Childhood Special Education practica in diverse urban communities. The pre-service teachers were placed in public…

  18. Early Detection Rapid Response Program Targets New Noxious Weed Species in Washington State

    ERIC Educational Resources Information Center

    Andreas, Jennifer E.; Halpern, Alison D.; DesCamp, Wendy C.; Miller, Timothy W.

    2015-01-01

    Early detection, rapid response is a critical component of invasive plant management. It can be challenging, however, to detect new invaders before they become established if landowners cannot identify species of concern. In order to increase awareness, eye-catching postcards were developed in Washington State as part of a noxious weed educational…

  19. Designing a Measurement Framework for Response to Intervention in Early Childhood Programs

    ERIC Educational Resources Information Center

    McConnell, Scott R.; Wackerle-Hollman, Alisha K.; Roloff, Tracy A.; Rodriguez, Michael

    2014-01-01

    The overall architecture and major components of a measurement system designed and evaluated to support Response to Intervention (RTI) in the areas of language and literacy in early childhood programs are described. Efficient and reliable measurement is essential for implementing any viable RTI system, and implementing such a system in early…

  20. Unresectable Extraskeletal Myxoid Chondrosarcoma of the Neck: Early Tumor Response to Chemoradiotherapy

    PubMed Central

    Laszewski, Pam; Robinette, Natasha; Saleh, Husain; Raza, Naweed; Sukari, Ammar; Kim, Harold

    2015-01-01

    Extraskeletal myxoid chondrosarcoma (EMC) rarely occurs in the head and neck and is generally managed with primary surgery. To our knowledge, no cases of unresectable EMC of the neck have been reported. We present a case of an unresectable EMC treated with chemotherapy and radiation, and highlight the exceptional early response to therapy.  PMID:26848421

  1. Unresectable Extraskeletal Myxoid Chondrosarcoma of the Neck: Early Tumor Response to Chemoradiotherapy.

    PubMed

    Zaki, Mark; Laszewski, Pam; Robinette, Natasha; Saleh, Husain; Raza, Naweed; Sukari, Ammar; Kim, Harold

    2015-12-24

    Extraskeletal myxoid chondrosarcoma (EMC) rarely occurs in the head and neck and is generally managed with primary surgery. To our knowledge, no cases of unresectable EMC of the neck have been reported. We present a case of an unresectable EMC treated with chemotherapy and radiation, and highlight the exceptional early response to therapy.

  2. Caregiver Responsiveness during Preschool Supports Cooperation in Kindergarten: Moderation by Children's Early Compliance

    ERIC Educational Resources Information Center

    Pratt, Megan E.; Lipscomb, Shannon T.; McClelland, Megan M.

    2016-01-01

    Research Findings: The current study examined how children's parent-reported compliance at age 3 (36 months) moderated the effects of 2 dimensions of directly observed early care and education (ECE) process quality (positivity/responsivity and cognitive stimulation) during the prekindergarten year (54 months) on teacher reports of children's…

  3. Effectiveness of Community-Based Early Intervention Based on Pivotal Response Treatment

    ERIC Educational Resources Information Center

    Smith, Isabel M.; Flanagan, Helen E.; Garon, Nancy; Bryson, Susan E.

    2015-01-01

    Preschoolers (n = 118) with autism spectrum disorder (ASD) participated in this prospective effectiveness study of an early intervention program. Treatment entailed parent training and therapist-implemented components, incorporating Pivotal Response Treatment and Positive Behaviour Support. Standardized ability and behavioural measures were…

  4. An interaction between a neuropeptide Y gene polymorphism and early adversity modulates endocrine stress responses.

    PubMed

    Witt, Stephanie H; Buchmann, Arlette F; Blomeyer, Dorothea; Nieratschker, Vanessa; Treutlein, Jens; Esser, Günter; Schmidt, Martin H; Bidlingmaier, Martin; Wiedemann, Klaus; Rietschel, Marcella; Laucht, Manfred; Wüst, Stefan; Zimmermann, Ulrich S

    2011-08-01

    Interindividual variability in the regulation of the human stress system accounts for a part of the individual's liability to stress-related diseases. These differences are influenced by environmental and genetic factors. Early childhood adversity is a well-studied environmental factor affecting an individual's stress response which has been shown to be modulated by gene-environment interaction (GxE). Neuropeptide Y (NPY) plays a role in stress regulation and genetic variation in NPY may influence stress responses. In this study, we analyzed the association of a common variant in the NPY gene promoter, rs16147, with cortisol and ACTH responses to acute psychosocial stress in young adults from the Mannheim Study of Children at Risk (MARS), an ongoing epidemiological cohort study following the outcome of early adversity from birth into adulthood. We found evidence of a GxE interaction between rs16147 and early adversity significantly affecting HPA axis responses to acute psychosocial stress. These findings suggest that the neurobiological mechanisms linking early adverse experience and later neuroendocrine stress regulation are modulated by a gene variant whose functional relevance is documented by increasing convergent evidence from in vitro, animal and human studies.

  5. The Confluence of Adverse Early Experience and Puberty on the Cortisol Awakening Response

    ERIC Educational Resources Information Center

    Quevedo, Karina; Johnson, Anna E.; Loman, Michelle L.; LaFavor, Theresa L.; Gunnar, Megan

    2012-01-01

    Associations between early deprivation/neglect in the form of institutional care with the cortisol awakening response (CAR) were examined as a function of pubertal status among 12- and 13-year-old postinstitutionalized youth. CARs indexed hypothalamic-pituitary-adrenocortical reactivity. Postinstitutionalized youth were compared to youth adopted…

  6. Brad Ozenberger, Ph.D., Presents the Achievements of The Cancer Genome Atlas During its Early Years - TCGA

    Cancer.gov

    Dr. Brad Ozenberger, former TCGA Program Director for the National Human Genome Research Institute, describes the goals and achievements of TCGA during its pilot phase, which involved the genomic characterization of brain, ovarian, and lung cancers.

  7. Heterosis in early maize ear inflorescence development: a genome-wide transcription analysis for two maize inbred lines and their hybrid.

    PubMed

    Ding, Haiping; Qin, Cheng; Luo, Xirong; Li, Lujiang; Chen, Zhe; Liu, Hongjun; Gao, Jian; Lin, Haijian; Shen, Yaou; Zhao, Maojun; Lübberstedt, Thomas; Zhang, Zhiming; Pan, Guangtang

    2014-08-11

    Heterosis, or hybrid vigor, contributes to superior agronomic performance of hybrids compared to their inbred parents. Despite its importance, little is known about the genetic and molecular basis of heterosis. Early maize ear inflorescences formation affects grain yield, and are thus an excellent model for molecular mechanisms involved in heterosis. To determine the parental contributions and their regulation during maize ear-development-genesis, we analyzed genome-wide digital gene expression profiles in two maize elite inbred lines (B73 and Mo17) and their F1 hybrid using deep sequencing technology. Our analysis revealed 17,128 genes expressed in these three genotypes and 22,789 genes expressed collectively in the present study. Approximately 38% of the genes were differentially expressed in early maize ear inflorescences from heterotic cross, including many transcription factor genes and some presence/absence variations (PAVs) genes, and exhibited multiple modes of gene action. These different genes showing differential expression patterns were mainly enriched in five cellular component categories (organelle, cell, cell part, organelle part and macromolecular complex), five molecular function categories (structural molecule activity, binding, transporter activity, nucleic acid binding transcription factor activity and catalytic activity), and eight biological process categories (cellular process, metabolic process, biological regulation, regulation of biological process, establishment of localization, cellular component organization or biogenesis, response to stimulus and localization). Additionally, a significant number of genes were expressed in only one inbred line or absent in both inbred lines. Comparison of the differences of modes of gene action between previous studies and the present study revealed only a small number of different genes had the same modes of gene action in both maize seedlings and ear inflorescences. This might be an indication that in

  8. Comparative analysis of dioxin response elements in human, mouse and rat genomic sequences.

    PubMed

    Sun, Y V; Boverhof, D R; Burgoon, L D; Fielden, M R; Zacharewski, T R

    2004-01-01

    Comparative approaches were used to identify human, mouse and rat dioxin response elements (DREs) in genomic sequences unambiguously assigned to a nucleotide RefSeq accession number. A total of 13 bona fide DREs, all including the substitution intolerant core sequence (GCGTG) and adjacent variable sequences, were used to establish a position weight matrix and a matrix similarity (MS) score threshold to rank identified DREs. DREs with MS scores above the threshold were disproportionately distributed in close proximity to the transcription start site in all three species. Gene expression assays in hepatic mouse tissue confirmed the responsiveness of 192 genes possessing a putative DRE. Previously identified functional DREs in well-characterized AhR-regulated genes including Cyp1a1 and Cyp1b1 were corroborated. Putative DREs were identified in 48 out of 2437 human-mouse-rat orthologous genes between -1500 and the transcriptional start site, of which 19 of these genes possessed positionally conserved DREs as determined by multiple sequence alignment. Seven of these nineteen genes exhibited 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated regulation, although there were significant discrepancies between in vivo and in vitro results. Interestingly, of the mouse-rat orthologous genes with a DRE between -1500 and +1500, only 37% had an equivalent human ortholog. These results suggest that AhR-mediated gene expression may not be well conserved across species, which could have significant implications in human risk assessment.

  9. Comparative analysis of dioxin response elements in human, mouse and rat genomic sequences

    PubMed Central

    Sun, Y. V.; Boverhof, D. R.; Burgoon, L. D.; Fielden, M. R.; Zacharewski, T. R.

    2004-01-01

    Comparative approaches were used to identify human, mouse and rat dioxin response elements (DREs) in genomic sequences unambiguously assigned to a nucleotide RefSeq accession number. A total of 13 bona fide DREs, all including the substitution intolerant core sequence (GCGTG) and adjacent variable sequences, were used to establish a position weight matrix and a matrix similarity (MS) score threshold to rank identified DREs. DREs with MS scores above the threshold were disproportionately distributed in close proximity to the transcription start site in all three species. Gene expression assays in hepatic mouse tissue confirmed the responsiveness of 192 genes possessing a putative DRE. Previously identified functional DREs in well-characterized AhR-regulated genes including Cyp1a1 and Cyp1b1 were corroborated. Putative DREs were identified in 48 out of 2437 human–mouse–rat orthologous genes between −1500 and the transcriptional start site, of which 19 of these genes possessed positionally conserved DREs as determined by multiple sequence alignment. Seven of these nineteen genes exhibited 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated regulation, although there were significant discrepancies between in vivo and in vitro results. Interestingly, of the mouse–rat orthologous genes with a DRE between −1500 and +1500, only 37% had an equivalent human ortholog. These results suggest that AhR-mediated gene expression may not be well conserved across species, which could have significant implications in human risk assessment. PMID:15328365

  10. Genome-wide transcriptome analysis revealed organelle specific responses to temperature variations in algae

    PubMed Central

    Shin, HyeonSeok; Hong, Seong-Joo; Yoo, Chan; Han, Mi-Ae; Lee, Hookeun; Choi, Hyung-Kyoon; Cho, Suhyung; Lee, Choul-Gyun; Cho, Byung-Kwan

    2016-01-01

    Temperature is a critical environmental factor that affects microalgal growth. However, microalgal coping mechanisms for temperature variations are unclear. Here, we determined changes in transcriptome, total carbohydrate, total fatty acid methyl ester, and fatty acid composition of Tetraselmis sp. KCTC12432BP, a strain with a broad temperature tolerance range, to elucidate the tolerance mechanisms in response to large temperature variations. Owing to unavailability of genome sequence information, de novo transcriptome assembly coupled with BLAST analysis was performed using strand specific RNA-seq data. This resulted in 26,245 protein-coding transcripts, of which 83.7% could be annotated to putative functions. We identified more than 681 genes differentially expressed, suggesting an organelle-specific response to temperature variation. Among these, the genes related to the photosynthetic electron transfer chain, which are localized in the plastid thylakoid membrane, were upregulated at low temperature. However, the transcripts related to the electron transport chain and biosynthesis of phosphatidylethanolamine localized in mitochondria were upregulated at high temperature. These results show that the low energy uptake by repressed photosynthesis under low and high temperature conditions is compensated by different mechanisms, including photosystem I and mitochondrial oxidative phosphorylation, respectively. This study illustrates that microalgae tolerate different temperature conditions through organelle specific mechanisms. PMID:27883062

  11. Analysis of binary responses with outcome-specific misclassification probability in genome-wide association studies

    PubMed Central

    Rekaya, Romdhane; Smith, Shannon; Hay, El Hamidi; Farhat, Nourhene; Aggrey, Samuel E

    2016-01-01

    Errors in the binary status of some response traits are frequent in human, animal, and plant applications. These error rates tend to differ between cases and controls because diagnostic and screening tests have different sensitivity and specificity. This increases the inaccuracies of classifying individuals into correct groups, giving rise to both false-positive and false-negative cases. The analysis of these noisy binary responses due to misclassification will undoubtedly reduce the statistical power of genome-wide association studies (GWAS). A threshold model that accommodates varying diagnostic errors between cases and controls was investigated. A simulation study was carried out where several binary data sets (case–control) were generated with varying effects for the most influential single nucleotide polymorphisms (SNPs) and different diagnostic error rate for cases and controls. Each simulated data set consisted of 2000 individuals. Ignoring misclassification resulted in biased estimates of true influential SNP effects and inflated estimates for true noninfluential markers. A substantial reduction in bias and increase in accuracy ranging from 12% to 32% was observed when the misclassification procedure was invoked. In fact, the majority of influential SNPs that were not identified using the noisy data were captured using the proposed method. Additionally, truly misclassified binary records were identified with high probability using the proposed method. The superiority of the proposed method was maintained across different simulation parameters (misclassification rates and odds ratios) attesting to its robustness. PMID:27942229

  12. Regularization Method for Predicting an Ordinal Response Using Longitudinal High-dimensional Genomic Data

    PubMed Central

    Hou, Jiayi

    2015-01-01

    An ordinal scale is commonly used to measure health status and disease related outcomes in hospital settings as well as in translational medical research. In addition, repeated measurements are common in clinical practice for tracking and monitoring the progression of complex diseases. Classical methodology based on statistical inference, in particular, ordinal modeling has contributed to the analysis of data in which the response categories are ordered and the number of covariates (p) remains smaller than the sample size (n). With the emergence of genomic technologies being increasingly applied for more accurate diagnosis and prognosis, high-dimensional data where the number of covariates (p) is much larger than the number of samples (n), are generated. To meet the emerging needs, we introduce our proposed model which is a two-stage algorithm: Extend the Generalized Monotone Incremental Forward Stagewise (GMIFS) method to the cumulative logit ordinal model; and combine the GMIFS procedure with the classical mixed-effects model for classifying disease status in disease progression along with time. We demonstrate the efficiency and accuracy of the proposed models in classification using a time-course microarray dataset collected from the Inflammation and the Host Response to Injury study. PMID:25720102

  13. Genome-wide linkage using the Social Responsiveness Scale in Utah autism pedigrees

    PubMed Central

    2010-01-01

    Background Autism Spectrum Disorders (ASD) are phenotypically heterogeneous, characterized by impairments in the development of communication and social behaviour and the presence of repetitive behaviour and restricted interests. Dissecting the genetic complexity of ASD may require phenotypic data reflecting more detail than is offered by a categorical clinical diagnosis. Such data are available from the Social Responsiveness Scale (SRS) which is a continuous, quantitative measure of social ability giving scores that range from significant impairment to above average ability. Methods We present genome-wide results for 64 multiplex and extended families ranging from two to nine generations. SRS scores were available from 518 genotyped pedigree subjects, including affected and unaffected relatives. Genotypes from the Illumina 6 k single nucleotide polymorphism panel were provided by the Center for Inherited Disease Research. Quantitative and qualitative analyses were done using MCLINK, a software package that uses Markov chain Monte Carlo (MCMC) methods to perform multilocus linkage analysis on large extended pedigrees. Results When analysed as a qualitative trait, linkage occurred in the same locations as in our previous affected-only genome scan of these families, with findings on chromosomes 7q31.1-q32.3 [heterogeneity logarithm of the odds (HLOD) = 2.91], 15q13.3 (HLOD = 3.64), and 13q12.3 (HLOD = 2.23). Additional positive qualitative results were seen on chromosomes 6 and 10 in regions that may be of interest for other neuropsychiatric disorders. When analysed as a quantitative trait, results replicated a peak found in an independent sample using quantitative SRS scores on chromosome 11p15.1-p15.4 (HLOD = 2.77). Additional positive quantitative results were seen on chromosomes 7, 9, and 19. Conclusions The SRS linkage peaks reported here substantially overlap with peaks found in our previous affected-only genome scan of clinical diagnosis. In addition, we

  14. The cellular and genomic response of rat dopaminergic neurons (N27) to coated nanosilver.

    PubMed

    Chorley, Brian; Ward, William; Simmons, Steven O; Vallanat, Beena; Veronesi, Bellina

    2014-12-01

    This study examined if nanosilver (nanoAg) of different sizes and coatings were differentially toxic to oxidative stress-sensitive neurons. N27 rat dopaminergic neurons were exposed (0.5-5 ppm) to a set of nanoAg of different sizes (10nm, 75 nm) and coatings (PVP, citrate) and their physicochemical, cellular and genomic response measured. Both coatings retained their manufactured sizes in culture media, however, the zeta potentials of both sizes of PVP-coated nanoAg were significantly less electronegative than those of their citrate-coated counterparts. Markers of oxidative stress, measured at 0.5-5 ppm exposure concentrations, indicated that caspase 3/7 activity and glutathione levels were significantly increased by both sizes of PVP-coated nanoAg and by the 75 nm citrate-coated nanoAg. Both sizes of PVP-coated nanoAg also increased intra-neuronal nitrite levels and activated ARE/NRF2, a reporter gene for the oxidative stress-protection pathway. Global gene expression on N27 neurons, exposed to 0.5 ppm for 8h, indicated a dominant effect by PVP-coated nanoAg over citrate. The 75 nm PVP-coated material altered 196 genes that were loosely associated with mitochondrial dysfunction. In contrast, the 10nm PVP-coated nanoAg altered 82 genes that were strongly associated with NRF2 oxidative stress pathways. Less that 20% of the affected genes were shared by both sizes of PVP-coated nanoAg. These cellular and genomic findings suggest that PVP-coated nanoAg is more bioactive than citrate-coated nanoAg. Although both sizes of PVP-coated nanoAg altered the genomic expression of N27 neurons along oxidative stress pathways, exposure to the 75 nm nanoAg favored pathways associated with mitochondrial dysfunction, whereas the 10nm PVP-coated nanoAg affected NRF2 neuronal protective pathways.

  15. Genome-wide analysis of the response to nitric oxide in uropathogenic Escherichia coli CFT073

    PubMed Central

    Mehta, Heer H.; Liu, Yuxuan

    2015-01-01

    Uropathogenic Escherchia coli (UPEC) is the causative agent of urinary tract infections. Nitric oxide (NO) is a toxic water-soluble gas that is encountered by UPEC in the urinary tract. Therefore, UPEC probably requires mechanisms to detoxify NO in the host environment. Thus far, flavohaemoglobin (Hmp), an NO denitrosylase, is the only demonstrated NO detoxification system in UPEC. Here we show that, in E. coli strain CFT073, the NADH-dependent NO reductase flavorubredoxin (FlRd) also plays a major role in NO scavenging. We generated a mutant that lacks all known and candidate NO detoxification pathways (Hmp, FlRd and the respiratory nitrite reductase, NrfA). When grown and assayed anaerobically, this mutant expresses an NO-inducible NO scavenging activity, pointing to the existence of a novel detoxification mechanism. Expression of this activity is inducible by both NO and nitrate, and the enzyme is membrane-associated. Genome-wide transcriptional profiling of UPEC grown under anaerobic conditions in the presence of nitrate (as a source of NO) highlighted various aspects of the response of the pathogen to nitrate and NO. Several virulence-associated genes are upregulated, suggesting that host-derived NO is a potential regulator of UPEC virulence. Chromatin immunoprecipitation and sequencing was used to evaluate the NsrR regulon in CFT073. We identified 49 NsrR binding sites in promoter regions in the CFT073 genome, 29 of which were not previously identified in E. coli K-12. NsrR may regulate some CFT073 genes that do not have homologues in E. coli K-12. PMID:28348816

  16. [Health threats and health system crises. An approach to early warning and response. 2008 SESPAS Report].

    PubMed

    Simón Soria, Fernando; Guillén Enríquez, Francisco Javier

    2008-04-01

    The world is changing more and faster than ever before. New diseases are coming to light each year, controlled diseases are reemerging as potential threats, and natural or man-made disasters are increasingly affecting human health. The "International Health Regulations (2005)" reflect the changes in the response of public health to this new situation. Surveillance of specific diseases and predefined control measures have been replaced by surveillance of public health events of international concern and control measures adapted to each situation. The public health events of international interest are characterized by their seriousness, predictability, the risk of international spread and potential for travel or trade restrictions. The development of the European Early Warning and Response System in 1998 and the creation of the European Center for Disease Prevention and Control in 2005 demonstrate political commitment in Europe, with early detection of and response to public health threats. However, timely risk evaluation and response at a national level requires improved data digitalization and accessibility, automatic notification processes, data analysis and dissemination of information, the combination of information from multiple sources and adaptation of public health services. The autonomous regions in Spain are initiating this adaptation process, but interoperability between systems and the development of guidelines for a coordinated response should be steered by the National Interregional Health Council and coordinated by the Ministry of Health. Efficient early warning systems of health threats that allow for a timely response and reduce uncertainty about information would help to minimize the risk of public health crises. The profile of public health threats is nonspecific. Early detection of threats requires access to information from multiple sources and efficient risk assessment. Key factors for improving the response to public health threats are the

  17. Coordinate regulation of two cytoplasmic RNA species transcribed from early region 2 of the adenovirus 2 genome.

    PubMed

    Goldenberg, C J; Rosenthal, R; Bhaduri, S; Raskas, H

    1981-06-01

    Early region 2 (E2) of the adenovirus 2 genome specifies a 72,000-dalton DNA-binding protein that is required for viral DNA replication. Electron microscopy studies have detected two major forms of 20S E2 mRNA, one species with a 5' leader from map position 75 and a second form having a leader from position 72 (Chow et al., J. Mol. Biol. 134:265-303, 1979). Only the species with a leader from position 75 was detected at early times; however, both forms were found at late times. We have analyzed the temporal regulation of E2 expression by documenting mRNA accumulation in the cytoplasm. Kinetic studies of pulse-labeled RNAs demonstrated a peak of E2 cytoplasmic RNa synthesis at 10 to 12 h, coinciding with the time of maximal synthesis of the 72,000-dalton DNA binding protein and viral DNA. To estimate the relative abundances of the two major E2 RNA species at various times during infection, total E2 cytoplasmic and polysomal 20S RNAs were isolated by hybridization-selection with specific DNA probes. The leader sequences in the selected RNAs were then quantitated by further RNA-DNA hybridization. We found that the elevated accumulation rate for E2 cytoplasmic RNA at late times reflected an increase in formation of both major species. Moreover, for all time points examined 66% of the mRNA species had a 5' end from map position 75, and 33% had a 5' terminus from position 72. Continuous labeling experiments provided evidence that both RNA forms have comparable half-lives. The results suggest that the two major species encoded by E2 are regulated in a coordinate fashion late in infection.

  18. Genome-Wide Study of the Adaptation of Saccharomyces cerevisiae to the Early Stages of Wine Fermentation

    PubMed Central

    Novo, Maite; Mangado, Ana; Quirós, Manuel; Morales, Pilar; Salvadó, Zoel; Gonzalez, Ramon

    2013-01-01

    This work was designed to identify yeast cellular functions specifically affected by the stress factors predominating during the early stages of wine fermentation, and genes required for optimal growth under these conditions. The main experimental method was quantitative fitness analysis by means of competition experiments in continuous culture of whole genome barcoded yeast knockout collections. This methodology allowed the identification of haploinsufficient genes, and homozygous deletions resulting in growth impairment in synthetic must. However, genes identified as haploproficient, or homozygous deletions resulting in fitness advantage, were of little predictive power concerning optimal growth in this medium. The relevance of these functions for enological performance of yeast was assessed in batch cultures with single strains. Previous studies addressing yeast adaptation to winemaking conditions by quantitative fitness analysis were not specifically focused on the proliferative stages. In some instances our results highlight the importance of genes not previously linked to winemaking. In other cases they are complementary to those reported in previous studies concerning, for example, the relevance of some genes involved in vacuolar, peroxisomal, or ribosomal functions. Our results indicate that adaptation to the quickly changing growth conditions during grape must fermentation require the function of different gene sets in different moments of the process. Transport processes and glucose signaling seem to be negatively affected by the stress factors encountered by yeast in synthetic must. Vacuolar activity is important for continued growth during the transition to stationary phase. Finally, reduced biogenesis of peroxisomes also seems to be advantageous. However, in contrast to what was described for later stages, reduced protein synthesis is not advantageous for the early (proliferative) stages of the fermentation process. Finally, we found adenine and lysine

  19. Early HLA-B*57-Restricted CD8+ T Lymphocyte Responses Predict HIV-1 Disease Progression

    PubMed Central

    Ibarrondo, F. Javier; Sugar, Catherine A.; Hausner, Mary Ann; Shih, Roger; Ng, Hwee L.; Detels, Roger; Margolick, Joseph B.; Rinaldo, Charles R.; Phair, John; Jacobson, Lisa P.; Yang, Otto O.

    2012-01-01

    Although HLA-B*57 (B57) is associated with slow progression to disease following HIV-1 infection, B57 heterozygotes display a wide spectrum of outcomes, including rapid progression, viremic slow progression, and elite control. Efforts to identify differences between B57-positive (B57+) slow progressors and B57+ rapid progressors have largely focused on cytotoxic T lymphocyte (CTL) phenotypes and specificities during chronic stages of infection. Although CTL responses in the early months of infection are likely to be the most important for the long-term rate of HIV-1 disease progression, few data on the early CTL responses of eventual slow progressors have been available. Utilizing the Multicenter AIDS Cohort Study (MACS), we retrospectively examined the early HIV-1-specific CTL responses of 14 B57+ individuals whose time to development of disease ranged from 3.5 years to longer than 25 years after infection. In general, a greater breadth of targeting of epitopes from structural proteins, especially Gag, as well as of highly conserved epitopes from any HIV-1 protein, correlated with longer times until disease. The single elite controller in the cohort was an outlier on several correlations of CTL targeting and time until disease, consistent with reports that elite control is typically not achieved solely by protective HLA-mediated CTLs. When targeting of individual epitopes was analyzed, we found that early CTL responses to the IW9 (ISPRTLNAW) epitope of Gag, while generally subdominant, correlated with delayed progression to disease. This is the first study to identify early CTL responses to IW9 as a correlate of protection in persons with HLA-B*57. PMID:22811521

  20. Relationship of smoking status to genomic profile, chemotherapy response and clinical outcome in patients with advanced urothelial carcinoma

    PubMed Central

    Joshi, Monika; Vasekar, Monali; Grivas, Petros; Emamekhoo, Hamid; Hsu, JoAnn; Miller, Vincent A.; Stephens, Philip J.; Ali, Siraj M.; Ross, Jeffrey S.; Zhu, Junjia; Warrick, Joshua; Drabick, Joseph J.; Holder, Sheldon L.; Kaag, Matthew; Li, Min; Pal, Sumanta Kumar

    2016-01-01

    Smoking has been linked to urothelial carcinoma (UC), but the implications on genomic profile and therapeutic response are poorly understood. To determine how smoking history impacts genomic profile and chemotherapy response, clinicopathologic data was collected for patients with metastatic UC (mUC) across 3 academic medical centers and comprehensive genomic profiling (CGP) was performed through a CLIA-certified lab. Unsupervised hierarchical clustering based on smoking status was used to categorize the frequency of genomic alterations (GAs) amongst current smokers (CS), ex-smokers (ES) and non-smokers (NS), and survival was compared in these subsets. Fisher's exact test identified significant associations between GAs and smoking status. Amongst 83 patients, 23%, 55% and 22% were CS, ES, and NS, respectively, and 95% of patients had stage IV disease. With a median follow up of 14.4 months, the median overall survival (OS) was significantly higher in NS and ES (combined) as compared to CS (51.6 vs 15.6 months; P = 0.04). Of 315 cancer-related genes and 31 genes often related to rearrangement tested, heatmaps show some variations amongst the subsets. GAs in NSD1 were more frequent in CS as compared to other groups (P < 0.001). CS status negatively impacts OS in patients with mUC and is associated with genomic alterations that could have therapeutic implications. PMID:27213592

  1. Genomic heritability estimation for the early life-history transition related to propensity to migrate in wild rainbow and steelhead trout populations

    PubMed Central

    Hu, Guo; Wang, Chunkao; Da, Yang

    2014-01-01

    A previous genomewide association study (GWAS) identified SNP markers associated with propensity to migrate of rainbow and steelhead trout (Oncorhynchus mykiss) in a connected population with free access to the ocean in Upper Yakima River (UYR) and a population in Upper Mann Creek (UMC) that has been sequestered from its access to the ocean for more than 50 years. Applying genomic heritability estimation using the same dataset, we found that smoltification in the UYR population were almost completely determined by additive effects, with 95.5% additive heritability and 4.5% dominance heritability, whereas smoltification in the UMC population had substantial dominance effects, with 0% additive heritability and 39.3% dominance heritability. Dominance test detected one SNP marker (R30393) with significant dominance effect on smoltification (P = 1.98 × 10−7). Genomic-predicted additive effects completely separated migratory and nonmigratory fish in the UYR population, whereas genomic-predicted dominance effects achieved such complete separation in the UMC population. The UMC population had higher genomic additive and dominance correlations than the UYR population, and fish between these two populations had the least genomic correlations. These results suggested that blocking the free access to the ocean may have reduced genetic diversity and increased genomic similarity associated with the early life-history transition related to propensity to migrate. PMID:24834334

  2. Cell-Type Specific Responses to DNA Replication Stress in Early C. elegans Embryos

    PubMed Central

    Stevens, Holly; Williams, Ashley B.

    2016-01-01

    To better understand how the cellular response to DNA replication stress is regulated during embryonic development, we and others have established the early C. elegans embryo as a model system to study this important problem. As is the case in most eukaryotic cell types, the replication stress response is controlled by the ATR kinase in early worm embryos. In this report we use RNAi to systematically characterize ATR pathway components for roles in promoting cell cycle delay during a replication stress response, and we find that these genetic requirements vary, depending on the source of stress. We also examine how individual cell types within the embryo respond to replication stress, and we find that the strength of the response, as defined by duration of cell cycle delay, varies dramatically within blastomeres of the early embryo. Our studies shed light on how the replication stress response is managed in the context of embryonic development and show that this pathway is subject to developmental regulation. PMID:27727303

  3. Tris(1,3-dichloro-2-propyl)phosphate Induces Genome-Wide Hypomethylation within Early Zebrafish Embryos

    PubMed Central

    2016-01-01

    Tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) is a high-production volume organophosphate-based plasticizer and flame retardant widely used within the United States. Using zebrafish as a model, the objectives of this study were to determine whether (1) TDCIPP inhibits DNA methyltransferase (DNMT) within embryonic nuclear extracts; (2) uptake of TDCIPP from 0.75 h postfertilization (hpf, 2-cell) to 2 hpf (64-cell) or 6 hpf (shield stage) leads to impacts on the early embryonic DNA methylome; and (3) TDCIPP-induced impacts on cytosine methylation are localized to CpG islands within intergenic regions. Within this study, 5-azacytidine (5-azaC, a DNMT inhibitor) was used as a positive control. Although 5-azaC significantly inhibited zebrafish DNMT, TDCIPP did not affect DNMT activity in vitro at concentrations as high as 500 μM. However, rapid embryonic uptake of 5-azaC and TDCIPP from 0.75 to 2 hpf resulted in chemical- and chromosome-specific alterations in cytosine methylation at 2 hpf. Moreover, TDCIPP exposure predominantly resulted in hypomethylation of positions outside of CpG islands and within intragenic (exon) regions of the zebrafish genome. Overall, these findings provide the foundation for monitoring DNA methylation dynamics within zebrafish as well as identifying potential associations among TDCIPP exposure, adverse health outcomes, and DNA methylation status within human populations. PMID:27574916

  4. The genetic and genomic background of multiple myeloma patients achieving complete response after induction therapy with bortezomib, thalidomide and dexamethasone (VTD)

    PubMed Central

    Terragna, Carolina; Remondini, Daniel; Martello, Marina; Zamagni, Elena; Pantani, Lucia; Patriarca, Francesca; Pezzi, Annalisa; Levi, Giuseppe; Offidani, Massimo; Proserpio, Ilaria; De Sabbata, Giovanni; Tacchetti, Paola; Cangialosi, Clotilde; Ciambelli, Fabrizio; Viganò, Clara Virginia; Dico, Flores Angela; Santacroce, Barbara; Borsi, Enrica; Brioli, Annamaria; Marzocchi, Giulia; Castellani, Gastone; Martinelli, Giovanni; Palumbo, Antonio; Cavo, Michele

    2016-01-01

    The prime focus of the current therapeutic strategy for Multiple Myeloma (MM) is to obtain an early and deep tumour burden reduction, up to the level of complete response (CR). To date, no description of the characteristics of the plasma cells (PC) prone to achieve CR has been reported. This study aimed at the molecular characterization of PC obtained at baseline from MM patients in CR after bortezomib-thalidomide-dexamethasone (VTD) first line therapy. One hundred and eighteen MM primary tumours obtained from homogeneously treated patients were profiled both for gene expression and for single nucleotide polymorphism genotype. Genomic results were used to obtain a predictor of sensitivity to VTD induction therapy, as well as to describe both the transcription and the genomic profile of PC derived from MM with subsequent optimal response to primary induction therapy. By analysing the gene profiles of CR patients, we identified a 5-gene signature predicting CR with an overall median accuracy of 75% (range: 72%–85%). In addition, we highlighted the differential expression of a series of genes, whose deregulation might explain patients' sensitivity to VTD therapy. We also showed that a small copy number loss, covering 606Kb on chromosome 1p22.1 was the most significantly associated with CR patients. PMID:26575327

  5. Early redox, Src family kinase, and calcium signaling integrate wound responses and tissue regeneration in zebrafish.

    PubMed

    Yoo, Sa Kan; Freisinger, Christina M; LeBert, Danny C; Huttenlocher, Anna

    2012-10-15

    Tissue injury can lead to scar formation or tissue regeneration. How regenerative animals sense initial tissue injury and transform wound signals into regenerative growth is an unresolved question. Previously, we found that the Src family kinase (SFK) Lyn functions as a redox sensor in leukocytes that detects H(2)O(2) at wounds in zebrafish larvae. In this paper, using zebrafish larval tail fins as a model, we find that wounding rapidly activated SFK and calcium signaling in epithelia. The immediate SFK and calcium signaling in epithelia was important for late epimorphic regeneration of amputated fins. Wound-induced activation of SFKs in epithelia was dependent on injury-generated H(2)O(2). A SFK member, Fynb, was responsible for fin regeneration. This work provides a new link between early wound responses and late regeneration and suggests that redox, SFK, and calcium signaling are immediate "wound signals" that integrate early wound responses and late epimorphic regeneration.

  6. Effect of Dietary Conjugated Linoleic Acid Supplementation on Early Inflammatory Responses during Cutaneous Wound Healing

    PubMed Central

    Park, Na-Young; Valacchi, Giuseppe; Lim, Yunsook

    2010-01-01

    Inflammatory response is considered the most important period that regulates the entire healing process. Conjugated linoleic acid (CLA), a class of linoleic acid positional and geometric isomers, is well known for its antioxidant and anti-inflammatory properties. We hypothesized that dietary CLA supplementation accelerates cutaneous wound healing by regulating antioxidant and anti-inflammatory functions. To investigate wound closure rates and inflammatory responses, we used a full-thickness excisional wound model after 2-week treatments with control, 0.5%, or 1% CLA-supplemented diet. Mice fed dietary CLA supplementation had reduced levels of oxidative stress and inflammatory markers. Moreover, the wound closure rate was improved significantly in mice fed a 1% CLA-supplemented diet during early stage of wound healing (inflammatory stage). We conclude that dietary CLA supplementation enhances the early stage of cutaneous wound healing as a result of modulating oxidative stress and inflammatory responses. PMID:20871865

  7. Genome-Wide Expression Profiling Identifies Type 1 Interferon Response Pathways in Active Tuberculosis

    PubMed Central

    Ottenhoff, Tom H. M.; Zhang, Mingzi M.; Wong, Hazel E. E.; Sahiratmadja, Edhyana; Khor, Chiea Chuen; Alisjahbana, Bachti; van Crevel, Reinout; Marzuki, Sangkot; Seielstad, Mark; van de Vosse, Esther; Hibberd, Martin L.

    2012-01-01

    Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), remains the leading cause of mortality from a single infectious agent. Each year around 9 million individuals newly develop active TB disease, and over 2 billion individuals are latently infected with M.tb worldwide, thus being at risk of developing TB reactivation disease later in life. The underlying mechanisms and pathways of protection against TB in humans, as well as the dynamics of the host response to M.tb infection, are incompletely understood. We carried out whole-genome expression profiling on a cohort of TB patients longitudinally sampled along 3 time-points: during active infection, during treatment, and after completion of curative treatment. We identified molecular signatures involving the upregulation of type-1 interferon (α/β) mediated signaling and chronic inflammation during active TB disease in an Indonesian population, in line with results from two recent studies in ethnically and epidemiologically different populations in Europe and South Africa. Expression profiles were captured in neutrophil-depleted blood samples, indicating a major contribution of lymphocytes and myeloid cells. Expression of type-1 interferon (α/β) genes mediated was also upregulated in the lungs of M.tb infected mice and in infected human macrophages. In patients, the regulated gene expression-signature normalized during treatment, including the type-1 interferon mediated signaling and a concurrent opposite regulation of interferon-gamma. Further analysis revealed IL15RA, UBE2L6 and GBP4 as molecules involved in the type-I interferon response in all three experimental models. Our data is highly suggestive that the innate immune type-I interferon signaling cascade could be used as a quantitative tool for monitoring active TB disease, and provide evidence that components of the patient’s blood gene expression signature bear similarities to the pulmonary and macrophage response to mycobacterial infection

  8. Early COPD patients with lung hyperinflation associated with poorer lung function but better bronchodilator responsiveness

    PubMed Central

    Chen, Chunlan; Jian, Wenhua; Gao, Yi; Xie, Yanqing; Song, Yan; Zheng, Jinping

    2016-01-01

    Background It is unknown whether aggressive medication strategies should be used for early COPD with or without lung hyperinflation. We aimed to explore the characteristics and bronchodilator responsiveness of early COPD patients (stages I and II) with/without lung hyperinflation. Methods Four hundred and six patients with COPD who performed both lung volume and bronchodilation tests were retrospectively analyzed. Residual volume to total lung capacity >120% of predicted values indicated lung hyperinflation. The characteristics and bronchodilator responsiveness were compared between the patients with and without lung hyperinflation across all stages of COPD. Results The percentages of patients with lung hyperinflation were 72.7% in the entire cohort, 19.4% in stage I, 68.5% in stage II, 95.3% in stage III, and 100.0% in stage IV. The patients with lung hyperinflation exhibited poorer lung function but better bronchodilator responsiveness of both forced expiratory volume in 1 second and forced vital capacity than those without lung hyperinflation during early COPD (t=2.21–5.70, P=0.000–0.029), especially in stage I, while age, body mass index, smoking status, smoking history, and disease duration were similar between the two subgroups in the same stages. From stages I to IV of subgroups with lung hyperinflation, stage I patients had the best bronchodilator responsiveness. Use of bronchodilator responsiveness of forced vital capacity to detect the presence of lung hyperinflation in COPD patients showed relatively high sensitivities (69.5%–75.3%) and specificities (70.3%–75.7%). Conclusion We demonstrated the novel finding that early COPD patients with lung hyperinflation are associated with poorer lung function but better bronchodilator responsiveness and established a simple method for detecting lung hyperinflation. PMID:27785008

  9. Early changes in emotional processing as a marker of clinical response to SSRI treatment in depression.

    PubMed

    Godlewska, B R; Browning, M; Norbury, R; Cowen, P J; Harmer, C J

    2016-11-22

    Antidepressant treatment reduces behavioural and neural markers of negative emotional bias early in treatment and has been proposed as a mechanism of antidepressant drug action. Here, we provide a critical test of this hypothesis by assessing whether neural markers of early emotional processing changes predict later clinical response in depression. Thirty-five unmedicated patients with major depression took the selective serotonin re-uptake inhibitor (SSRI), escitalopram (10 mg), over 6 weeks, and were classified as responders (22 patients) versus non-responders (13 patients), based on at least a 50% reduction in symptoms by the end of treatment. The neural response to fearful and happy emotional facial expressions was assessed before and after 7 days of treatment using functional magnetic resonance imaging. Changes in the neural response to these facial cues after 7 days of escitalopram were compared in patients as a function of later clinical response. A sample of healthy controls was also assessed. At baseline, depressed patients showed greater activation to fear versus happy faces than controls in the insula and dorsal anterior cingulate. Depressed patients who went on to respond to the SSRI had a greater reduction in neural activity to fearful versus happy facial expressions after just 7 days of escitalopram across a network of regions including the anterior cingulate, insula, amygdala and thalamus. Mediation analysis confirmed that the direct effect of neural change on symptom response was not mediated by initial changes in depressive symptoms. These results support the hypothesis that early changes in emotional processing with antidepressant treatment are the basis of later clinical improvement. As such, early correction of negative bias may be a key mechanism of antidepressant drug action and a potentially useful predictor of therapeutic response.

  10. Early changes in emotional processing as a marker of clinical response to SSRI treatment in depression

    PubMed Central

    Godlewska, B R; Browning, M; Norbury, R; Cowen, P J; Harmer, C J

    2016-01-01

    Antidepressant treatment reduces behavioural and neural markers of negative emotional bias early in treatment and has been proposed as a mechanism of antidepressant drug action. Here, we provide a critical test of this hypothesis by assessing whether neural markers of early emotional processing changes predict later clinical response in depression. Thirty-five unmedicated patients with major depression took the selective serotonin re-uptake inhibitor (SSRI), escitalopram (10 mg), over 6 weeks, and were classified as responders (22 patients) versus non-responders (13 patients), based on at least a 50% reduction in symptoms by the end of treatment. The neural response to fearful and happy emotional facial expressions was assessed before and after 7 days of treatment using functional magnetic resonance imaging. Changes in the neural response to these facial cues after 7 days of escitalopram were compared in patients as a function of later clinical response. A sample of healthy controls was also assessed. At baseline, depressed patients showed greater activation to fear versus happy faces than controls in the insula and dorsal anterior cingulate. Depressed patients who went on to respond to the SSRI had a greater reduction in neural activity to fearful versus happy facial expressions after just 7 days of escitalopram across a network of regions including the anterior cingulate, insula, amygdala and thalamus. Mediation analysis confirmed that the direct effect of neural change on symptom response was not mediated by initial changes in depressive symptoms. These results support the hypothesis that early changes in emotional processing with antidepressant treatment are the basis of later clinical improvement. As such, early correction of negative bias may be a key mechanism of antidepressant drug action and a potentially useful predictor of therapeutic response. PMID:27874847

  11. Genomic copy number imbalances associated with bone and non-bone metastasis of early-stage breast cancer.

    PubMed

    Liu, Yanhong; Zhou, Renke; Baumbusch, Lars O; Tsavachidis, Spyros; Brewster, Abenaa M; Do, Kim-Anh; Sahin, Aysegul; Hortobagyi, Gabriel N; Taube, Joseph H; Mani, Sendurai A; Aarøe, Jørgen; Wärnberg, Fredrik; Børresen-Dale, Anne-Lise; Mills, Gordon B; Thompson, Patricia A; Bondy, Melissa L

    2014-01-01

    The aim of this study is to identify and validate copy number aberrations in early-stage primary breast tumors associated with bone or non-bone metastasis. Whole-genome molecular inversion probe arrays were used to evaluate copy number imbalances (CNIs) in breast tumors from 960 early-stage patients with information about site of metastasis. The CoxBoost algorithm was used to select metastasis site-related CNIs and to fit a Cox proportional hazards model. Gains at 1q41 and 1q42.12 and losses at 1p13.3, 8p22, and Xp11.3 were significantly associated with bone metastasis. Gains at 2p11.2, 3q21.3-22.2, 3q27.1, 10q23.1, and 14q13.2-3 and loss at 7q21.11 were associated with non-bone metastasis. To examine the joint effect of CNIs and clinical predictors, patients were stratified into three risk groups (low, intermediate, and high) based on the sum of predicted linear hazard ratios. For bone metastasis, the hazard (95 % confidence interval) for the low-risk group was 0.32 (0.11-0.92) compared to the intermediate-risk group and 2.99 (1.74-5.11) for the high-risk group. For non-bone metastasis, the hazard for the low-risk group was 0.34 (0.17-0.66) and 2.33 (1.59-3.43) for the high-risk group. The prognostic value of loss at 8p22 for bone metastasis and gains at 10q23.1 for non-bone metastasis, and gain at 11q13.5 for both bone and non-bone metastases were externally validated in 335 breast tumors pooled from four independent cohorts. Distinct CNIs are independently associated with bone and non-bone metastasis for early-stage breast cancer patients across cohorts. These data warrant consideration for tailoring surveillance and management of metastasis risk.

  12. A Multiplexed Single-Cell CRISPR Screening Platform Enables Systematic Dissection of the Unfolded Protein Response. | Office of Cancer Genomics

    Cancer.gov

    Functional genomics efforts face tradeoffs between number of perturbations examined and complexity of phenotypes measured. We bridge this gap with Perturb-seq, which combines droplet-based single-cell RNA-seq with a strategy for barcoding CRISPR-mediated perturbations, allowing many perturbations to be profiled in pooled format. We applied Perturb-seq to dissect the mammalian unfolded protein response (UPR) using single and combinatorial CRISPR perturbations. Two genome-scale CRISPR interference (CRISPRi) screens identified genes whose repression perturbs ER homeostasis.

  13. Immune adjuvants in early life: targeting the innate immune system to overcome impaired adaptive response.

    PubMed

    de Brito, Cyro Alves; Goldoni, Adriana Letícia; Sato, Maria Notomi

    2009-09-01

    The neonatal phase is a transitory period characterized by an absence of memory cells, favoring a slow adaptive response prone to tolerance effects and the development of Th2-type responses. However, when appropriately stimulated, neonates may achieve an immune response comparable with adult counterparts. One strategy to stimulate the immunological response of neonates or children in early infancy has been to explore natural or synthetic ligands of cell receptors to stimulate innate immunity. The use of adjuvants for activating different cell receptors may be the key to enhancing neonatal adaptive immunity. This review highlights recent advances in the emerging field of molecular adjuvants of innate immune response and their implications for the development of immunotherapies, with particular focus on the neonatal period.

  14. Image-guided genomic analysis of tissue response to laser-induced thermal stress

    PubMed Central

    Mackanos, Mark A.; Helms, Mike; Kalish, Flora; Contag, Christopher H.

    2011-01-01

    The cytoprotective response to thermal injury is characterized by transcriptional activation of “heat shock proteins” (hsp) and proinflammatory proteins. Expression of these proteins may predict cellular survival. Microarray analyses were performed to identify spatially distinct gene expression patterns responding to thermal injury. Laser injury zones were identified by expression of a transgene reporter comprised of the 70 kD hsp gene and the firefly luciferase coding sequence. Zones included the laser spot, the surrounding region where hsp70-luc expression was increased, and a region adjacent to the surrounding region. A total of 145 genes were up-regulated in the laser irradiated region, while 69 were up-regulated in the adjacent region. At 7 hours the chemokine Cxcl3 was the highest expressed gene in the laser spot (24 fold) and adjacent region (32 fold). Chemokines were the most common up-regulated genes identified. Microarray gene expression was successfully validated using qRT- polymerase chain reaction for selected genes of interest. The early response genes are likely involved in cytoprotection and initiation of the healing response. Their regulatory elements will benefit creating the next generation reporter mice and controlling expression of therapeutic proteins. The identified genes serve as drug development targets that may prevent acute tissue damage and accelerate healing. PMID:21639585

  15. Image-guided genomic analysis of tissue response to laser-induced thermal stress

    NASA Astrophysics Data System (ADS)

    Mackanos, Mark A.; Helms, Mike; Kalish, Flora; Contag, Christopher H.

    2011-05-01

    The cytoprotective response to thermal injury is characterized by transcriptional activation of ``heat shock proteins'' (hsp) and proinflammatory proteins. Expression of these proteins may predict cellular survival. Microarray analyses were performed to identify spatially distinct gene expression patterns responding to thermal injury. Laser injury zones were identified by expression of a transgene reporter comprised of the 70 kD hsp gene and the firefly luciferase coding sequence. Zones included the laser spot, the surrounding region where hsp70-luc expression was increased, and a region adjacent to the surrounding region. A total of 145 genes were up-regulated in the laser irradiated region, while 69 were up-regulated in the adjacent region. At 7 hours the chemokine Cxcl3 was the highest expressed gene in the laser spot (24 fold) and adjacent region (32 fold). Chemokines were the most common up-regulated genes identified. Microarray gene expression was successfully validated using qRT- polymerase chain reaction for selected genes of interest. The early response genes are likely involved in cytoprotection and initiation of the healing response. Their regulatory elements will benefit creating the next generation reporter mice and controlling expression of therapeutic proteins. The identified genes serve as drug development targets that may prevent acute tissue damage and accelerate healing.

  16. Genome-wide association study of response to cognitive–behavioural therapy in children with anxiety disorders

    PubMed Central

    Coleman, Jonathan R. I.; Lester, Kathryn J.; Keers, Robert; Roberts, Susanna; Curtis, Charles; Arendt, Kristian; Bögels, Susan; Cooper, Peter; Creswell, Cathy; Dalgleish, Tim; Hartman, Catharina A.; Heiervang, Einar R.; Hötzel, Katrin; Hudson, Jennifer L.; In-Albon, Tina; Lavallee, Kristen; Lyneham, Heidi J.; Marin, Carla E.; Meiser-Stedman, Richard; Morris, Talia; Nauta, Maaike H.; Rapee, Ronald M.; Schneider, Silvia; Schneider, Sophie C.; Silverman, Wendy K.; Thastum, Mikael; Thirlwall, Kerstin; Waite, Polly; Wergeland, Gro Janne; Breen, Gerome; Eley, Thalia C.

    2016-01-01

    Background Anxiety disorders are common, and cognitive–behavioural therapy (CBT) is a first-line treatment. Candidate gene studies have suggested a genetic basis to treatment response, but findings have been inconsistent. Aims To perform the first genome-wide association study (GWAS) of psychological treatment response in children with anxiety disorders (n = 980). Method Presence and severity of anxiety was assessed using semi-structured interview at baseline, on completion of treatment (post-treatment), and 3 to 12 months after treatment completion (follow-up). DNA was genotyped using the Illumina Human Core Exome-12v1.0 array. Linear mixed models were used to test associations between genetic variants and response (change in symptom severity) immediately post-treatment and at 6-month follow-up. Results No variants passed a genome-wide significance threshold (P = 5 × 10−8) in either analysis. Four variants met criteria for suggestive significance (P<5 × 10−6) in association with response post-treatment, and three variants in the 6-month follow-up analysis. Conclusions This is the first genome-wide therapygenetic study. It suggests no common variants of very high effect underlie response to CBT. Future investigations should maximise power to detect single-variant and polygenic effects by using larger, more homogeneous cohorts. PMID:26989097

  17. Girls’ Challenging Social Experiences in Early Adolescence Predict Neural Response to Rewards and Depressive Symptoms1

    PubMed Central

    Casement, Melynda D.; Guyer, Amanda E.; Hipwell, Alison; McAloon, Rose L.; Hoffmann, Amy M.; Keenan, Kathryn; Forbes, Erika E.

    2014-01-01

    Developmental models of psychopathology posit that exposure to social stressors may confer risk for depression in adolescent girls by disrupting neural reward circuitry. The current study tested this hypothesis by examining the relationship between early adolescent social stressors and later neural reward processing and depressive symptoms. Participants were 120 girls from an ongoing longitudinal study of precursors to depression across adolescent development. Low parental warmth, peer victimization, and depressive symptoms were assessed when the girls were 11 and 12 years old, and participants completed a monetary reward guessing fMRI task and assessment of depressive symptoms at age 16. Results indicate that low parental warmth was associated with increased response to potential rewards in the medial prefrontal cortex (mPFC), striatum, and amygdala, whereas peer victimization was associated with decreased response to potential rewards in the mPFC. Furthermore, concurrent depressive symptoms were associated with increased reward anticipation response in mPFC and striatal regions that were also associated with early adolescent psychosocial stressors, with mPFC and striatal response mediating the association between social stressors and depressive symptoms. These findings are consistent with developmental models that emphasize the adverse impact of early psychosocial stressors on neural reward processing and risk for depression in adolescence. PMID:24397999

  18. Apparent Motion Suppresses Responses in Early Visual Cortex: A Population Code Model

    PubMed Central

    Van Humbeeck, Nathalie; Putzeys, Tom; Wagemans, Johan

    2016-01-01

    Two stimuli alternately presented at different locations can evoke a percept of a stimulus continuously moving between the two locations. The neural mechanism underlying this apparent motion (AM) is thought to be increased activation of primary visual cortex (V1) neurons tuned to locations along the AM path, although evidence remains inconclusive. AM masking, which refers to the reduced detectability of stimuli along the AM path, has been taken as evidence for AM-related V1 activation. AM-induced neural responses are thought to interfere with responses to physical stimuli along the path and as such impair the perception of these stimuli. However, AM masking can also be explained by predictive coding models, predicting that responses to stimuli presented on the AM path are suppressed when they match the spatio-temporal prediction of a stimulus moving along the path. In the present study, we find that AM has a distinct effect on the detection of target gratings, limiting the maximum performance at high contrast levels. This masking is strongest when the target orientation is identical to the orientation of the inducers. We developed a V1-like population code model of early visual processing, based on a standard contrast normalization model. We find that AM-related activation in early visual cortex is too small to either cause masking or to be perceived as motion. Our model instead predicts strong suppression of early sensory responses during AM, consistent with the theoretical framework of predictive coding. PMID:27783622

  19. Quantitative Proteomic Profiling of Early and Late Responses to Salicylic Acid in Cucumber Leaves

    PubMed Central

    Li, Liang; Shang, Qing-Mao

    2016-01-01

    Salicylic acid (SA) is an important phytohormone that plays vital regulatory roles in plant growth, development, and stress responses. However, studies on the molecular mechanism of SA, especially during the early SA responses, are lagging behind. In this study, we initiated a comprehensive isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomic analysis to explore the early and late SA-responsive proteins in leaves of cucumber (Cucumis sativus L.) seedlings. Upon SA application through the roots, endogenous SA accumulated in cucumber leaves. By assaying the changes in marker gene expression and photosynthetic rate, we collected samples at 12 h and 72 h post treatment (hpt) to profile the early and late SA responsiveness, respectively. The iTRAQ assay followed by tandem mass spectrometry revealed 135 differentially expressed proteins (DEPs) at 12 hpt and 301 DEPs at 72 hpt. The functional categories for these SA-responsive proteins included in a variety of biochemical processes, including photosynthesis, redox homeostasis, carbohydrate and energy metabolism, lipid metabolism, transport, protein folding and modification, proteolysis, cell wall organization, and the secondary phenylpropanoid pathway. Conclusively, based on the abundant changes of these DEPs, together with their putative functions, we proposed a possible SA-responsive protein network. It appears that SA could elicit reactive oxygen species (ROS) production via enhancing the photosynthetic electron transferring, and then confer some growth-promoting and stress-priming effects on cells during the late phase, including enhanced photosynthesis and ROS scavenging, altered carbon metabolic flux for the biosynthesis of amino acids and nucleotides, and cell wall reorganization. Overall, the present iTRAQ assay provides higher proteome coverage and deepened our understanding of the molecular basis of SA-responses. PMID:27551830

  20. Incomplete immune response to coxsackie B viruses associates with early autoimmunity against insulin

    PubMed Central

    Ashton, Michelle P.; Eugster, Anne; Walther, Denise; Daehling, Natalie; Riethausen, Stephanie; Kuehn, Denise; Klingel, Karin; Beyerlein, Andreas; Zillmer, Stephanie; Ziegler, Anette-Gabriele; Bonifacio, Ezio

    2016-01-01

    Viral infections are associated with autoimmunity in type 1 diabetes. Here, we asked whether this association could be explained by variations in host immune response to a putative type 1 etiological factor, namely coxsackie B viruses (CVB). Heterogeneous antibody responses were observed against CVB capsid proteins. Heterogeneity was largely defined by different binding to VP1 or VP2. Antibody responses that were anti-VP2 competent but anti-VP1 deficient were unable to neutralize CVB, and were characteristic of children who developed early insulin-targeting autoimmunity, suggesting an impaired ability to clear CVB in early childhood. In contrast, children who developed a GAD-targeting autoimmunity had robust VP1 and VP2 antibody responses to CVB. We further found that 20% of memory CD4+ T cells responding to the GAD65247-266 peptide share identical T cell receptors to T cells responding to the CVB4 p2C30-51 peptide, thereby providing direct evidence for the potential of molecular mimicry as a mechanism for GAD autoimmunity. Here, we highlight functional immune response differences between children who develop insulin-targeting and GAD-targeting autoimmunity, and suggest that children who lose B cell tolerance to insulin within the first years of life have a paradoxical impaired ability to mount humoral immune responses to coxsackie viruses. PMID:27604323

  1. Early immune responses and development of pathogenesis of avian infectious bronchitis viruses with different virulence profiles

    PubMed Central

    Mores, Marcos Antônio Zanella; Trevisol, Iara Maria; Coldebella, Arlei; Montassier, Hélio José; Brentano, Liana

    2017-01-01

    Avian infectious bronchitis virus (IBV) primarily replicates in epithelial cells of the upper respiratory tract of chickens, inducing both morphological and immune modulatory changes. However, the association between the local immune responses induced by IBV and the mechanisms of pathogenesis has not yet been completely elucidated. This study compared the expression profile of genes related to immune responses in tracheal samples after challenge with two Brazilian field isolates (A and B) of IBV from the same genotype, associating these responses with viral replication and with pathological changes in trachea and kidney. We detected a suppressive effect on the early activation of TLR7 pathway, followed by lower expression levels of inflammatory related genes induced by challenge with the IBV B isolate when compared to the challenge with to the IBV A isolate. Cell-mediated immune (CMI) related genes presented also lower levels of expression in tracheal samples from birds challenged with B isolate at 1dpi. Increased viral load and a higher percentage of birds with relevant lesions were observed in both tracheal and renal samples from chickens exposed to challenge with IBV B isolate. This differential pattern of early immune responses developed after challenge with IBV B isolate, related to the downregulation of TLR7, leading to insufficient pro-inflammatory response and lower CMI responses, seem to have an association with a most severe renal lesion and an enhanced capability of replication of this isolate in chicken. PMID:28199419

  2. Early response mechanisms of perennial ryegrass (Lolium perenne) to phosphorus deficiency

    PubMed Central

    Byrne, Stephen L.; Foito, Alexandre; Hedley, Pete E.; Morris, Jenny A.; Stewart, Derek; Barth, Susanne

    2011-01-01

    Background and Aims Improving phosphorus (P) nutrient efficiency in Lolium perenne (perennial ryegrass) is likely to result in considerable economic and ecological benefits. To date, research into the molecular and biochemical response of perennial ryegrass to P deficiency has been limited, particularly in relation to the early response mechanisms. This study aimed to identify molecular mechanisms activated in response to the initial stages of P deficiency. Methods A barley microarray was successfully used to study gene expression in perennial ryegrass and this was complemented with gas chromatography-mass spectrometry metabolic profiling to obtain an overview of the plant response to early stages of P deficiency. Key Results After 24 h of P deficiency, internal phosphate concentrations were reduced and significant alterations were detected in the metabolome and transcriptome of two perennial ryegrass genotypes. Results indicated a replacement of phospholipids with sulfolipids and the utilization of glycolytic bypasses in response to P deficiency in perennial ryegrass. Conclusions The transcriptome and metabolome of perennial ryegrass undergo changes in response to reductions in P supply after 24 h. PMID:21148585

  3. Implementation of an alert and response system in Haiti during the early stage of the response to the cholera epidemic.

    PubMed

    Santa-Olalla, Patricia; Gayer, Michelle; Magloire, Roc; Barrais, Robert; Valenciano, Marta; Aramburu, Carmen; Poncelet, Jean Luc; Gustavo Alonso, Juan Carlos; Van Alphen, Dana; Heuschen, Florence; Andraghetti, Roberta; Lee, Robert; Drury, Patrick; Aldighieri, Sylvain

    2013-10-01

    The start of the cholera epidemic in Haiti quickly highlighted the necessity of the implementation of an Alert and Response (A&R) System to complement the existing national surveillance system. The national system had been able to detect and confirm the outbreak etiology but required external support to monitor the spread of cholera and coordinate response, because much of the information produced was insufficiently timely for real-time monitoring and directing of a rapid, targeted response. The A&R System was designed by the Pan American Health Organization/World Health Organization in collaboration with the Haiti Ministry of Health, and it was based on a network of partners, including any institution, structure, or individual that could identify, verify, and respond to alerts. The defined objectives were to (1) save lives through early detection and treatment of cases and (2) control the spread through early intervention at the community level. The operational structure could be broken down into three principle categories: (1) alert (early warning), (2) verification and assessment of the information, and (3) efficient and timely response in coordination with partners to avoid duplication. Information generated by the A&R System was analyzed and interpreted, and the qualitative information was critical in qualifying the epidemic and defining vulnerable areas, particularly because the national surveillance system reported incomplete data for more than one department. The A&R System detected a number of alerts unrelated to cholera and facilitated rapid access to that information. The sensitivity of the system and its ability to react quickly was shown in May of 2011, when an abnormal increase in alerts coming from several communes in the Sud-Est Department in epidemiological weeks (EWs) 17 and 18 were noted and disseminated network-wide and response activities were implemented. The national cholera surveillance system did not register the increase until EWs 21 and

  4. Implementation of an Alert and Response System in Haiti during the Early Stage of the Response to the Cholera Epidemic

    PubMed Central

    Santa-Olalla, Patricia; Gayer, Michelle; Magloire, Roc; Barrais, Robert; Valenciano, Marta; Aramburu, Carmen; Poncelet, Jean Luc; Gustavo Alonso, Juan Carlos; Van Alphen, Dana; Heuschen, Florence; Andraghetti, Roberta; Lee, Robert; Drury, Patrick; Aldighieri, Sylvain

    2013-01-01

    The start of the cholera epidemic in Haiti quickly highlighted the necessity of the implementation of an Alert and Response (A&R) System to complement the existing national surveillance system. The national system had been able to detect and confirm the outbreak etiology but required external support to monitor the spread of cholera and coordinate response, because much of the information produced was insufficiently timely for real-time monitoring and directing of a rapid, targeted response. The A&R System was designed by the Pan American Health Organization/World Health Organization in collaboration with the Haiti Ministry of Health, and it was based on a network of partners, including any institution, structure, or individual that could identify, verify, and respond to alerts. The defined objectives were to (1) save lives through early detection and treatment of cases and (2) control the spread through early intervention at the community level. The operational structure could be broken down into three principle categories: (1) alert (early warning), (2) verification and assessment of the information, and (3) efficient and timely response in coordination with partners to avoid duplication. Information generated by the A&R System was analyzed and interpreted, and the qualitative information was critical in qualifying the epidemic and defining vulnerable areas, particularly because the national surveillance system reported incomplete data for more than one department. The A&R System detected a number of alerts unrelated to cholera and facilitated rapid access to that information. The sensitivity of the system and its ability to react quickly was shown in May of 2011, when an abnormal increase in alerts coming from several communes in the Sud-Est Department in epidemiological weeks (EWs) 17 and 18 were noted and disseminated network-wide and response activities were implemented. The national cholera surveillance system did not register the increase until EWs 21 and

  5. Characterization of the low-pH responses of Helicobacter pylori using genomic DNA arrays.

    PubMed

    Allan, E; Clayton, C L; McLaren, A; Wallace, D M; Wren, B W

    2001-08-01

    Helicobacter pylori is unique among bacterial pathogens in its ability to persist in the acidic environment of the human stomach. To identify H. pylori genes responsive to low pH, the authors assembled a high-density array of PCR-amplified random genomic DNA. Hybridization of radiolabelled cDNA probes, prepared using total RNA from bacteria exposed to buffer at either pH 4.0 or pH 7.0, allowed both qualitative and quantitative information on differential gene expression to be obtained. A previously described low-pH-induced gene, cagA, was identified together with several novel genes that may have relevance to the survival and persistence of H. pylori in the gastric environment. These include genes encoding enzymes involved in LPS and phospholipid synthesis and secF, encoding a component of the protein export machinery. A hypothetical protein unique to H. pylori (HP0681) was also found to be acid induced. Genes down-regulated at pH 4.0 include those encoding a sugar nucleotide biosynthesis protein, a flagellar protein and an outer-membrane protein. Differential gene expression was confirmed by total RNA slot-blot hybridization.

  6. Genome-wide mapping of nucleosome positions in Saccharomyces cerevisiae in response to different nitrogen conditions

    PubMed Central

    Zhang, Peng; Du, Guocheng; Zou, Huijun; Xie, Guangfa; Chen, Jian; Shi, Zhongping; Zhou, Jingwen

    2016-01-01

    Well-organized chromatin is involved in a number of various transcriptional regulation and gene expression. We used genome-wide mapping of nucleosomes in response to different nitrogen conditions to determine both nucleosome profiles and gene expression events in Saccharomyces cerevisiae. Nitrogen conditions influence general nucleosome profiles and the expression of nitrogen catabolite repression (NCR) sensitive genes. The nucleosome occupancy of TATA-containing genes was higher compared to TATA-less genes. TATA-less genes in high or low nucleosome occupancy, showed a significant change in gene coding regions when shifting cells from glutamine to proline as the sole nitrogen resource. Furthermore, a correlation between the expression of nucleosome occupancy induced NCR sensitive genes or TATA containing genes in NCR sensitive genes, and nucleosome prediction were found when cells were cultured in proline or shifting from glutamine to proline as the sole nitrogen source compared to glutamine. These results also showed that variation of nucleosome occupancy accompany with chromatin-dependent transcription factor could influence the expression of a series of genes involved in the specific regulation of nitrogen utilization. PMID:27659668

  7. Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma.

    PubMed

    Hugo, Willy; Zaretsky, Jesse M; Sun, Lu; Song, Chunying; Moreno, Blanca Homet; Hu-Lieskovan, Siwen; Berent-Maoz, Beata; Pang, Jia; Chmielowski, Bartosz; Cherry, Grace; Seja, Elizabeth; Lomeli, Shirley; Kong, Xiangju; Kelley, Mark C; Sosman, Jeffrey A; Johnson, Douglas B; Ribas, Antoni; Lo, Roger S

    2016-03-24

    PD-1 immune checkpoint blockade provides significant clinical benefits for melanoma patients. We analyzed the somatic mutanomes and transcriptomes of pretreatment melanoma biopsies to identify factors that may influence innate sensitivity or resistance to anti-PD-1 therapy. We find that overall high mutational loads associate with improved survival, and tumors from responding patients are enriched for mutations in the DNA repair gene BRCA2. Innately resistant tumors display a transcriptional signature (referred to as the IPRES, or innate anti-PD-1 resistance), indicating concurrent up-expression of genes involved in the regulation of mesenchymal transition, cell adhesion, extracellular matrix remodeling, angiogenesis, and wound healing. Notably, mitogen-activated protein kinase (MAPK)-targeted therapy (MAPK inhibitor) induces similar signatures in melanoma, suggesting that a non-genomic form of MAPK inhibitor resistance mediates cross-resistance to anti-PD-1 therapy. Validation of the IPRES in other independent tumor cohorts defines a transcriptomic subset across distinct types of advanced cancer. These findings suggest that attenuating the biological processes that underlie IPRES may improve anti-PD-1 response in melanoma and other cancer types.

  8. Genome-wide transcriptional response of a Saccharomyces cerevisiae strain with an altered redox metabolism.

    PubMed

    Bro, Christoffer; Regenberg, Birgitte; Nielsen, Jens

    2004-02-05

    The genome-wide transcriptional response of a Saccharomyces cerevisiae strain deleted in GDH1 that encodes a NADP(+)-dependent glutamate dehydrogenase was compared to a wild-type strain under anaerobic steady-state conditions. The GDH1-deleted strain has a significantly reduced NADPH requirement, and therefore, an altered redox metabolism. Identification of genes with significantly changed expression using a t-test and a Bonferroni correction yielded only 16 transcripts when accepting two false-positives, and 7 of these were Open Reading Frames (ORFs) with unknown function. Among the 16 transcripts the only one with a direct link to redox metabolism was GND1, encoding phosphogluconate dehydrogenase. To extract additional information we analyzed the transcription data for a gene subset consisting of all known genes encoding metabolic enzymes that use NAD(+) or NADP(+). The subset was analyzed for genes with significantly changed expression again with a t-test and correction for multiple testing. This approach was found to enrich the analysis since GND1, ZWF1 and ALD6, encoding the most important enzymes for regeneration of NADPH under anaerobic conditions, were down-regulated together with eight other genes encoding NADP(H)-dependent enzymes. This indicates a possible common redox-dependent regulation of these genes. Furthermore, we showed that it might be necessary to analyze the expression of a subset of genes to extract all available information from global transcription analysis.

  9. Expression and comparative genomics of two serum response factor genes in zebrafish.

    PubMed

    Davis, Jody L; Long, Xiaochun; Georger, Mary A; Scott, Ian C; Rich, Adam; Miano, Joseph M

    2008-01-01

    Serum response factor (SRF) is a single copy, highly conserved transcription factor that governs the expression of hundreds of genes involved with actin cytoskeletal organization, cellular growth and signaling, neuronal circuitry and muscle differentiation. Zebrafish have emerged as a facile and inexpensive vertebrate model to delineate gene expression, regulation, and function, and yet the study of SRF in this animal has been virtually unexplored. Here, we report the existence of two srf genes in zebrafish, with partially overlapping patterns of expression in 3 and 7 day old developing animals. The mammalian ortholog (srf1) encodes for a 520 amino acid protein expressed in adult vascular and visceral smooth muscle cells, cardiac and skeletal muscle, as well as neuronal cells. The second zebrafish srf gene (srf2), encoding for a presumptive protein of only 314 amino acids, is transcribed at lower levels and appears to be less widely expressed across adult tissues. Both srf genes are induced by the SRF coactivator myocardin and attenuated with a short hairpin RNA to mammalian SRF. Promoter studies with srf1 reveal conserved CArG boxes that are the targets of SRF-myocardin in embryonic zebrafish cells. These results reveal that SRF was duplicated in the zebrafish genome and that its protein expression in all three muscle cell types is highly conserved across vertebrate animals suggesting an ancient code for transcriptional regulation of genes unique to muscle cell lineages.

  10. Comparative functional genomics and the bovine macrophage response to strains of the mycobacterium genus.

    PubMed

    Rue-Albrecht, Kévin; Magee, David A; Killick, Kate E; Nalpas, Nicolas C; Gordon, Stephen V; MacHugh, David E

    2014-01-01

    Mycobacterial infections are major causes of morbidity and mortality in cattle and are also potential zoonotic agents with implications for human health. Despite the implementation of comprehensive animal surveillance programs, many mycobacterial diseases have remained recalcitrant to eradication in several industrialized countries. Two major mycobacterial pathogens of cattle are Mycobacterium bovis and Mycobacterium avium subspecies paratuberculosis (MAP), the causative agents of bovine tuberculosis (BTB) and Johne's disease (JD), respectively. BTB is a chronic, granulomatous disease of the respiratory tract that is spread via aerosol transmission, while JD is a chronic granulomatous disease of the intestines that is transmitted via the fecal-oral route. Although these diseases exhibit differential tissue tropism and distinct complex etiologies, both M. bovis and MAP infect, reside, and replicate in host macrophages - the key host innate immune cell that encounters mycobacterial pathogens after initial exposure and mediates the subsequent immune response. The persistence of M. bovis and MAP in macrophages relies on a diverse series of immunomodulatory mechanisms, including the inhibition of phagosome maturation and apoptosis, generation of cytokine-induced necrosis enabling dissemination of infection through the host, local pathology, and ultimately shedding of the pathogen. Here, we review the bovine macrophage response to infection with M. bovis and MAP. In particular, we describe how recent advances in functional genomics are shedding light on the host macrophage-pathogen interactions that underlie different mycobacterial diseases. To illustrate this, we present new analyses of previously published bovine macrophage transcriptomics data following in vitro infection with virulent M. bovis, the attenuated vaccine strain M. bovis BCG, and MAP, and discuss our findings with respect to the differing etiologies of BTB and JD.

  11. Genome-Wide Transcriptional Response of the Archaeon Thermococcus gammatolerans to Cadmium

    PubMed Central

    Lagorce, Arnaud; Fourçans, Aude; Dutertre, Murielle; Bouyssiere, Brice; Zivanovic, Yvan; Confalonieri, Fabrice

    2012-01-01

    Thermococcus gammatolerans, the most radioresistant archaeon known to date, is an anaerobic and hyperthermophilic sulfur-reducing organism living in deep-sea hydrothermal vents. Knowledge of mechanisms underlying archaeal metal tolerance in such metal-rich ecosystem is still poorly documented. We showed that T. gammatolerans exhibits high resistance to cadmium (Cd), cobalt (Co) and zinc (Zn), a weaker tolerance to nickel (Ni), copper (Cu) and arsenate (AsO4) and that cells exposed to 1 mM Cd exhibit a cellular Cd concentration of 67 µM. A time-dependent transcriptomic analysis using microarrays was performed at a non-toxic (100 µM) and a toxic (1 mM) Cd dose. The reliability of microarray data was strengthened by real time RT-PCR validations. Altogether, 114 Cd responsive genes were revealed and a substantial subset of genes is related to metal homeostasis, drug detoxification, re-oxidization of cofactors and ATP production. This first genome-wide expression profiling study of archaeal cells challenged with Cd showed that T. gammatolerans withstands induced stress through pathways observed in both prokaryotes and eukaryotes but also through new and original strategies. T. gammatolerans cells challenged with 1 mM Cd basically promote: 1) the induction of several transporter/permease encoding genes, probably to detoxify the cell; 2) the upregulation of Fe transporters encoding genes to likely compensate Cd damages in iron-containing proteins; 3) the induction of membrane-bound hydrogenase (Mbh) and membrane-bound hydrogenlyase (Mhy2) subunits encoding genes involved in recycling reduced cofactors and/or in proton translocation for energy production. By contrast to other organisms, redox homeostasis genes appear constitutively expressed and only a few genes encoding DNA repair proteins are regulated. We compared the expression of 27 Cd responsive genes in other stress conditions (Zn, Ni, heat shock, γ-rays), and showed that the Cd transcriptional pattern is

  12. Comparative mapping, genomic structure, and expression analysis of eight pseudo-response regulator genes in Brassica rapa.

    PubMed

    Kim, Jin A; Kim, Jung Sun; Hong, Joon Ki; Lee, Yeon-Hee; Choi, Beom-Soon; Seol, Young-Joo; Jeon, Chang Hoo

    2012-05-01

    Circadian clocks regulate plant growth and development in response to environmental factors. In this function, clocks influence the adaptation of species to changes in location or climate. Circadian-clock genes have been subject of intense study in models such as Arabidopsis thaliana but the results may not necessarily reflect clock functions in species with polyploid genomes, such as Brassica species, that include multiple copies of clock-related genes. The triplicate genome of Brassica rapa retains high sequence-level co-linearity with Arabidopsis genomes. In B. rapa we had previously identified five orthologs of the five known Arabidopsis pseudo-response regulator (PRR) genes that are key regulators of the circadian clock in this species. Three of these B. rapa genes, BrPRR1, BrPPR5, and BrPPR7, are present in two copies each in the B. rapa genome, for a total of eight B. rapa PRR (BrPRR) orthologs. We have now determined sequences and expression characteristics of the eight BrPRR genes and mapped their positions in the B. rapa genome. Although both members of each paralogous pair exhibited the same expression pattern, some variation in their gene structures was apparent. The BrPRR genes are tightly linked to several flowering genes. The knowledge about genome location, copy number variation and structural diversity of these B. rapa clock genes will improve our understanding of clock-related functions in this important crop. This will facilitate the development of Brassica crops for optimal growth in new environments and under changing conditions.

  13. Innate immune gene expression differentiates the early avian intestinal response between Salmonella and Campylobacter.

    PubMed

    Shaughnessy, Ronan G; Meade, Kieran G; Cahalane, Sarah; Allan, Brenda; Reiman, Carla; Callanan, John J; O'Farrelly, Cliona

    2009-12-15

    Salmonella enterica serovar Typhimurium and Campylobacter jejuni are major human pathogens, yet colonise chickens without causing pathology. The aim of this study was to compare intestinal innate immune responses to both bacterial species, in a 4-week-old broiler chicken model. Challenged and control birds were sacrificed and tissue samples taken for histopathology and RNA extraction. No significant clinical or pathological changes were observed in response to infection with either bacterial species. Expression of selected genes involved in pathogen detection and the innate immune response were profiled in caecal tissues by quantitative real-time PCR. TLR4 and TLR21 gene expression was transiently increased in response to both bacterial species (P<0.05). Significant increases in TLR5 and TLR15 gene expression were detected in response to S. Typhimurium but not to C. jejuni. Transient increases of proinflammatory cytokine (IL6 and IFNG) and chemokine (IL8 and K60) genes increased as early as 6h in response to S. Typhimurium. Minimal cytokine gene expression was detected in response to C. jejuni after 20h. IL8 gene expression however, was significantly increased by 24-fold (P<0.01). The differential expression profiles of innate immune genes in both infection models shed light on the tailored responses of the host immune system to specific microbes. It is further evidence that innate regulation of these responses is an important prerequisite to preventing development of disease.

  14. Immune response profiling in early rheumatoid arthritis: discovery of a novel interaction of treatment response with viral immunity

    PubMed Central

    2013-01-01

    Introduction It remains challenging to predict the outcomes of therapy in patients with rheumatoid arthritis (RA). The objective of this study was to identify immune response signatures that correlate with clinical treatment outcomes in patients with RA. Methods A cohort of 71 consecutive patients with early RA starting treatment with disease-modifying antirheumatic drugs (DMARDs) was recruited. Disease activity at baseline and after 21 to 24 weeks of follow-up was measured using the Disease Activity Score in 28 joints (DAS28). Immune response profiling was performed by analyzing multi-cytokine production from peripheral blood cells following incubation with a panel of stimuli, including a mixture of human cytomegalovirus (CMV) and Epstein-Barr virus (EBV) lysates. Profiles identified via principal components analysis (PCA) for each stimulus were then correlated with the ΔDAS28 from baseline to follow-up. A clinically meaningful improvement in the DAS28 was defined as a decrease of ≥1.2. Results A profile of T-cell cytokines (IL-13, IL-4, IL-5, IL-2, IL-12, and IFN-γ) produced in response to CMV/EBV was found to correlate with the ΔDAS28 from baseline to follow-up. At baseline, a higher magnitude of the CMV/EBV immune response profile predicted inadequate DAS28 improvement (mean PCA-1 scores: 65.6 versus 50.2; P = 0.029). The baseline CMV/EBV response was particularly driven by IFN-γ (P = 0.039) and IL-4 (P = 0.027). Among patients who attained clinically meaningful DAS28 improvement, the CMV/EBV PCA-1 score increased from baseline to follow-up (mean +11.6, SD 25.5), whereas among patients who responded inadequately to DMARD therapy, the CMV/EBV PCA-1 score decreased (mean -12.8, SD 25.4; P = 0.002). Irrespective of the ΔDAS28, methotrexate use was associated with up-regulation of the CMV/EBV response. The CMV/EBV profile was associated with positive CMV IgG (P <0.001), but not EBV IgG (P = 0.32), suggesting this response was related to

  15. Cortisol Stress Response Variability in Early Adolescence: Attachment, Affect and Sex.

    PubMed

    Cameron, Catherine Ann; McKay, Stacey; Susman, Elizabeth J; Wynne-Edwards, Katherine; Wright, Joan M; Weinberg, Joanne

    2017-01-01

    Attachment, affect, and sex shape responsivity to psychosocial stress. Concurrent social contexts influence cortisol secretion, a stress hormone and biological marker of hypothalamic-pituitary-adrenal axis activity. Patterns of attachment, emotion status, and sex were hypothesized to relate to bifurcated, that is, accentuated and attenuated, cortisol reactivity. The theoretical framework for this study posits that multiple individual differences mediate a cortisol stress response. The effects of two psychosocial stress interventions, a modified Trier Social Stress Test for Teens and the Frustration Social Stressor for Adolescents were developed and investigated with early adolescents. Both of these protocols induced a significant stress reaction and evoked predicted bifurcation in cortisol responses; an increase or decrease from baseline to reactivity. In Study I, 120 predominantly middle-class, Euro-Canadian early adolescents with a mean age of 13.43 years were studied. The girls' attenuated cortisol reactivity to the public performance stressor related significantly to their self-reported lower maternal-attachment and higher trait-anger. In Study II, a community sample of 146 predominantly Euro-Canadian middle-class youth, with an average age of 14.5 years participated. Their self-reports of higher trait-anger and trait-anxiety, and lower parental attachment by both sexes related differentially to accentuated and attenuated cortisol reactivity to the frustration stressor. Thus, attachment, affect, sex, and the stressor contextual factors were associated with the adrenal-cortical responses of these adolescents through complex interactions. Further studies of individual differences in physiological responses to stress are called for in order to clarify the identities of concurrent protective and risk factors in the psychosocial stress and physiological stress responses of early adolescents.

  16. Differential Host Response, Rather Than Early Viral Replication Efficiency, Correlates with Pathogenicity Caused by Influenza Viruses

    PubMed Central

    Askovich, Peter S.; Sanders, Catherine J.; Rosenberger, Carrie M.; Diercks, Alan H.; Dash, Pradyot; Navarro, Garnet; Vogel, Peter; Doherty, Peter C.; Thomas, Paul G.; Aderem, Alan

    2013-01-01

    Influenza viruses exhibit large, strain-dependent differences in pathogenicity in mammalian hosts. Although the characteristics of severe disease, including uncontrolled viral replication, infection of the lower airway, and highly inflammatory cytokine responses have been extensively documented, the specific virulence mechanisms that distinguish highly pathogenic strains remain elusive. In this study, we focused on the early events in influenza infection, measuring the growth rate of three strains of varying pathogenicity in the mouse airway epithelium and simultaneously examining the global host transcriptional response over the first 24 hours. Although all strains replicated equally rapidly over the first viral life-cycle, their growth rates in both lung and tracheal tissue strongly diverged at later times, resulting in nearly 10-fold differences in viral load by 24 hours following infection. We identified separate networks of genes in both the lung and tracheal tissues whose rapid up-regulation at early time points by specific strains correlated with a reduced viral replication rate of those strains. The set of early-induced genes in the lung that led to viral growth restriction is enriched for both NF-κB binding site motifs and members of the TREM1 and IL-17 signaling pathways, suggesting that rapid, NF-κB –mediated activation of these pathways may contribute to control of viral replication. Because influenza infection extending into the lung generally results in severe disease, early activation of these pathways may be one factor distinguishing high- and low-pathogenicity strains. PMID:24073225

  17. Bcl-2 Inhibits the Innate Immune Response during Early Pathogenesis of Murine Congenital Muscular Dystrophy

    PubMed Central

    Jeudy, Sheila; Wardrop, Katherine E.; Alessi, Amy; Dominov, Janice A.

    2011-01-01

    Laminin α2 (LAMA2)-deficient congenital muscular dystrophy is a severe, early-onset disease caused by abnormal levels of laminin 211 in the basal lamina leading to muscle weakness, transient inflammation, muscle degeneration and impaired mobility. In a Lama2-deficient mouse model for this disease, animal survival is improved by muscle-specific expression of the apoptosis inhibitor Bcl-2, conferred by a MyoD-hBcl-2 transgene. Here we investigated early disease stages in this model to determine initial pathological events and effects of Bcl-2 on their progression. Using quantitative immunohistological and mRNA analyses we show that inflammation occurs very early in Lama2-deficient muscle, some aspects of which are reduced or delayed by the MyoD-hBcl-2 transgene. mRNAs for innate immune response regulators, including multiple Toll-like receptors (TLRs) and the inflammasome component NLRP3, are elevated in diseased muscle compared with age-matched controls expressing Lama2. MyoD-hBcl-2 inhibits induction of TLR4, TLR6, TLR7, TLR8 and TLR9 in Lama2-deficient muscle compared with non-transgenic controls, and leads to reduced infiltration of eosinophils, which are key death effector cells. This congenital disease model provides a new paradigm for investigating cell death mechanisms during early stages of pathogenesis, demonstrating that interactions exist between Bcl-2, a multifunctional regulator of cell survival, and the innate immune response. PMID:21850221

  18. In vivo chemical exchange saturation transfer imaging allows early detection of a therapeutic response in glioblastoma.

    PubMed

    Sagiyama, Koji; Mashimo, Tomoyuki; Togao, Osamu; Vemireddy, Vamsidhara; Hatanpaa, Kimmo J; Maher, Elizabeth A; Mickey, Bruce E; Pan, Edward; Sherry, A Dean; Bachoo, Robert M; Takahashi, Masaya

    2014-03-25

    Glioblastoma multiforme (GBM), which account for more than 50% of all gliomas, is among the deadliest of all human cancers. Given the dismal prognosis of GBM, it would be advantageous to identify early biomarkers of a response to therapy to avoid continuing ineffective treatments and to initiate other therapeutic strategies. The present in vivo longitudinal study in an orthotopic mouse model demonstrates quantitative assessment of early treatment response during short-term chemotherapy with temozolomide (TMZ) by amide proton transfer (APT) imaging. In a GBM line, only one course of TMZ (3 d exposure and 4 d rest) at a dose of 80 mg/kg resulted in substantial reduction in APT signal compared with untreated control animals, in which the APT signal continued to increase. Although there were no detectable differences in tumor volume, cell density, or apoptosis rate between groups, levels of Ki67 (index of cell proliferation) were substantially reduced in treated tumors. In another TMZ-resistant GBM line, the APT signal and levels of Ki67 increased despite the same course of TMZ treatment. As metabolite changes are known to occur early in the time course of chemotherapy and precede morphologic changes, these results suggest that the APT signal in glioma may be a useful functional biomarker of treatment response or degree of tumor progression. Thus, APT imaging may serve as a sensitive biomarker of early treatment response and could potentially replace invasive biopsies to provide a definitive diagnosis. This would have a major impact on the clinical management of patients with glioma.

  19. The effects of early weaning on innate immune responses of Holstein calves

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objectives of this study were to compare innate immune responses of calves weaned early (EW; n = 23; weaned at 23.7 ± 2.3 d of age) to conventionally-weaned calves (CW; n = 22; weaned at 44.7 ± 2.3 d of age). All calves were fed 3.8 L of colostrum within 12 h of birth and were subsequently fed m...

  20. Early Student Support for a Process Study of Oceanic Responses to Typhoons

    DTIC Science & Technology

    2015-06-21

    responses to tropical cyclone forcing are surface waves, wind -driven currents, shear and turbulence, and inertial currents. Quantifying the effect...uncertainties in air–sea flux parameterizations in extreme wind regimes. A graduate student, Andy Hsu, is supported by the ONR Early Student Support...on the estimates of surface wind stress and drag coefficients under tropical cyclones in the western Pacific and Atlantic oceans using direct

  1. Early developmental gene regulation in Strongylocentrotus purpuratus embryos in response to elevated CO₂ seawater conditions.

    PubMed

    Hammond, LaTisha M; Hofmann, Gretchen E

    2012-07-15

    Ocean acidification, or the increased uptake of CO(2) by the ocean due to elevated atmospheric CO(2) concentrations, may variably impact marine early life history stages, as they may be especially susceptible to changes in ocean chemistry. Investigating the regulatory mechanisms of early development in an environmental context, or ecological development, will contribute to increased understanding of potential organismal responses to such rapid, large-scale environmental changes. We examined transcript-level responses to elevated seawater CO(2) during gastrulation and the initiation of spiculogenesis, two crucial developmental processes in the purple sea urchin, Strongylocentrotus purpuratus. Embryos were reared at the current, accepted oceanic CO(2) concentration of 380 microatmospheres (μatm), and at the elevated levels of 1000 and 1350 μatm, simulating predictions for oceans and upwelling regions, respectively. The seven genes of interest comprised a subset of pathways in the primary mesenchyme cell gene regulatory network (PMC GRN) shown to be necessary for the regulation and execution of gastrulation and spiculogenesis. Of the seven genes, qPCR analysis indicated that elevated CO(2) concentrations only had a significant but subtle effect on two genes, one important for early embryo patterning, Wnt8, and the other an integral component in spiculogenesis and biomineralization, SM30b. Protein levels of another spicule matrix component, SM50, demonstrated significant variable responses to elevated CO(2). These data link the regulation of crucial early developmental processes with the environment that these embryos would be developing within, situating the study of organismal responses to ocean acidification in a developmental context.

  2. The Early Humoral Immune Response to Bacillus anthracis Toxins in Patients Infected with Cutaneous Anthrax

    DTIC Science & Technology

    2011-01-01

    RESEARCH ARTICLE The early humoral immune response to Bacillus anthracis toxins in patients infected with cutaneous anthrax Karen E. Brenneman 1•2...Editor: Patrick Brennan Keywords anthrax; lethal factor; edema factor; protective antigen. Introduction Abstract Bacillus anthracis, the...Anthrax is a zoonotic disease caused by Bacillus anthracis, a Gram-positive spore-forming microorganism whose mani- festations in humans depend on the

  3. Speciation genomics and a role for the Z chromosome in the early stages of divergence between Mexican ducks and mallards.

    PubMed

    Lavretsky, Philip; Dacosta, Jeffrey M; Hernández-Baños, Blanca E; Engilis, Andrew; Sorenson, Michael D; Peters, Jeffrey L

    2015-11-01

    Speciation is a continuous and dynamic process, and studying organisms during the early stages of this process can aid in identifying speciation mechanisms. The mallard (Anas platyrhynchos) and Mexican duck (A. [p.] diazi) are two recently diverged taxa with a history of hybridization and controversial taxonomy. To understand their evolutionary history, we conducted genomic scans to characterize patterns of genetic diversity and divergence across the mitochondrial DNA (mtDNA) control region, 3523 autosomal loci and 172 Z-linked sex chromosome loci. Between the two taxa, Z-linked loci (ΦST  = 0.088) were 5.2 times more differentiated than autosomal DNA (ΦST  = 0.017) but comparable to mtDNA (ΦST  = 0.092). This elevated Z differentiation deviated from neutral expectations inferred from simulated data that incorporated demographic history and differences in effective population sizes between marker types. Furthermore, 3% of Z-linked loci, compared to <0.1% of autosomal loci, were detected as outlier loci under divergent selection with elevated relative (ΦST ) and absolute (dXY ) estimates of divergence. In contrast, the ratio of Z-linked and autosomal differentiation among the seven Mexican duck sampling locations was close to 1:1 (ΦST  = 0.018 for both markers). We conclude that between mallards and Mexican ducks, divergence at autosomal markers is largely neutral, whereas greater divergence on the Z chromosome (or some portions thereof) is likely the product of selection that has been important in speciation. Our results contribute to a growing body of literature indicating elevated divergence on the Z chromosome and its likely importance in avian speciation.

  4. Pharmacogenomic Genome-Wide Meta-Analysis of Blood Pressure Response to β-Blockers in Hypertensive African Americans.

    PubMed

    Gong, Yan; Wang, Zhiying; Beitelshees, Amber L; McDonough, Caitrin W; Langaee, Taimour Y; Hall, Karen; Schmidt, Siegfried O F; Curry, Robert W; Gums, John G; Bailey, Kent R; Boerwinkle, Eric; Chapman, Arlene B; Turner, Stephen T; Cooper-DeHoff, Rhonda M; Johnson, Julie A

    2016-03-01

    African Americans suffer a higher prevalence of hypertension compared with other racial/ethnic groups. In this study, we performed a pharmacogenomic genome-wide association study of blood pressure (BP) response to β-blockers in African Americans with uncomplicated hypertension. Genome-wide meta-analysis was performed in 318 African American hypertensive participants in the 2 Pharmacogenomic Evaluation of Antihypertensive Responses studies: 150 treated with atenolol monotherapy and 168 treated with metoprolol monotherapy. The analysis adjusted for age, sex, baseline BP and principal components for ancestry. Genome-wide significant variants with P<5×10(-8) and suggestive variants with P<5×10(-7) were evaluated in an additional cohort of 141 African Americans treated with the addition of atenolol to hydrochlorothiazide treatment. The validated variants were then meta-analyzed in these 3 groups of African Americans. Two variants discovered in the monotherapy meta-analysis were validated in the add-on therapy. African American participants heterozygous for SLC25A31 rs201279313 deletion versus wild-type genotype had better diastolic BP response to atenolol monotherapy, metoprolol monotherapy, and atenolol add-on therapy: -9.3 versus -4.6, -9.6 versus -4.8, and -9.7 versus -6.4 mm Hg, respectively (3-group meta-analysis P=2.5×10(-8), β=-4.42 mm Hg per variant allele). Similarly, LRRC15 rs11313667 was validated for systolic BP response to β-blocker therapy with 3-group meta-analysis P=7.2×10(-8) and β=-3.65 mm Hg per variant allele. In this first pharmacogenomic genome-wide meta-analysis of BP response to β-blockers in African Americans, we identified novel variants that may provide valuable information for personalized antihypertensive treatment in this group.

  5. Depressive symptoms and immune response to meningococcal conjugate vaccine in early adolescence.

    PubMed

    O'Connor, Thomas G; Moynihan, Jan A; Wyman, Peter A; Carnahan, Jennifer; Lofthus, Gerry; Quataert, Sally A; Bowman, Melissa; Caserta, Mary T

    2014-11-01

    Research findings in psychoneuroimmunology document reliable, bidirectional linkages among psychological processes, the nervous system, and the immune system. However, available data are based almost entirely on animal and adult human studies; the application to children and adolescents is uncertain. We capitalized on the experimental leverage provided by a routine vaccination to examine the link between mood symptoms and the immune response to a vaccine challenge in early adolescence. One hundred twenty-six 11-year-olds for whom vaccine response data were available were assessed at prevaccination and 4 weeks, 3 months, and 6 months following vaccination; self-report ratings of depression and anxiety as well as measures of psychosocial and somatic risk were assessed prior to vaccine response. Analyses indicated that children's internalizing mood symptoms were associated with elevated and persistently higher antibody responses, with evidence extending to two of the four serogroups. The associations remained after controlling for multiple possible confounders (social class, body mass index, sleep, psychosocial risk, and pubertal status). The observed enhanced vaccine response associated with depressive and anxious symptoms in early adolescence may reflect an important developmental difference in immune system-brain interplay between adults and children, and it underscores the need for further developmental studies of psychoneuroimmunology.

  6. Early response predicts subsequent response to olanzapine long-acting injection in a randomized, double-blind clinical trial of treatment for schizophrenia

    PubMed Central

    2011-01-01

    Background In patients with schizophrenia, early non-response to oral antipsychotic therapy robustly predicts subsequent non-response to continued treatment with the same medication. This study assessed whether early response predicted later response when using a long-acting injection (LAI) antipsychotic. Methods Data were taken from an 8-week, randomized, double-blind, placebo-controlled study of olanzapine LAI in acutely ill patients with schizophrenia (n = 233). Early response was defined as ≥30% improvement from baseline to Week 4 in Positive and Negative Syndrome Scale (PANSS0-6) Total score. Subsequent response was defined as ≥40% baseline-to-endpoint improvement in PANSS0-6 Total score. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and predictive accuracy were calculated. Clinical and functional outcomes were compared between Early Responders and Early Non-responders. Results Early response/non-response to olanzapine LAI predicted later response/non-response with high sensitivity (85%), specificity (72%), PPV (78%), NPV (80%), and overall accuracy (79%). Compared to Early Non-responders, Early Responders had significantly greater improvement in PANSS0-6 Total scores at all time points and greater baseline-to-endpoint improvement in PANSS subscale scores, Quality of Life Scale scores, and Short Form-36 Health Survey scores (all p ≤ .01). Among Early Non-responders, 20% demonstrated response by Week 8. Patients who lacked early improvement (at Week 4) in Negative Symptoms and Disorganized Thoughts were more likely to continue being non-responders at Week 8. Conclusions Among acutely ill patients with schizophrenia, early response predicted subsequent response to olanzapine LAI. Early Responders experienced significantly better clinical and functional outcomes than Early Non-responders. Findings are consistent with previous research on oral antipsychotics. Clinical Trials Registry F1D-MC-HGJZ: Comparison of

  7. Sexually Dimorphic Responses to Early Adversity: Implications for Affective Problems and Autism Spectrum Disorder

    PubMed Central

    Davis, Elysia Poggi; Pfaff, Donald

    2014-01-01

    During gestation, development proceeds at a pace that is unmatched by any other stage of the lifecycle. For these reason the human fetus is particularly susceptible not only to organizing influences, but also to pathogenic disorganizing influences. Growing evidence suggests that exposure to prenatal adversity leads to neurological changes that underlie lifetime risks for mental illness. Beginning early in gestation, males and females show differential developmental trajectories and responses to stress. It is likely that sex-dependent organization of neural circuits during the fetal period influences differential vulnerability to mental health problems. We consider in this review evidence that sexually dimorphic responses to early life stress are linked to two developmental disorders: affective problems (greater female prevalence) and autism spectrum disorder (greater male prevalence). Recent prospective studies illustrating the neurodevelopmental consequences of fetal exposure to stress and stress hormones for males and females are considered here. Plausible biological mechanisms including the role of the sexually differentiated placenta are discussed. We consider in this review evidence that sexually dimorphic responses to early life stress are linked to two sets of developmental disorders: affective problems (greater female prevalence) and autism spectrum disorders (greater male prevalence). PMID:25038479

  8. Genomic instability in quartz dust exposed rat lungs: Is inflammation responsible?

    NASA Astrophysics Data System (ADS)

    Albrecht, C.; Knaapen, A. M.; Cakmak Demircigil, G.; Coskun, Erdem; van Schooten, F. J.; Borm, P. J. A.; Schins, R. P. F.

    2009-02-01

    Exposure to quartz dusts has been associated with lung cancer and fibrosis. Although the responsible mechanisms are not completely understood, progressive inflammation with associated induction of persistent oxidative stress has been discussed as a key event for these diseases. Previously we have evaluated the kinetics of pulmonary inflammation in the rat model following a single intratracheal instillation of 2mg DQ12 quartz, either in its native form or upon its surface modification with polyvinylpyridine-N-oxide or aluminium lactate. This model has been applied now to evaluate the role of inflammation in the kinetics of induction of DNA damage and response at 3, 7, 28, and 90 days after treatment. Bronchoalveolar lavage (BAL) cell counts and differentials as well as BAL fluid myeloperoxidase activity were used as markers of inflammation. Whole lung homogenate was investigated to determine the induction of the oxidative and pre-mutagenic DNA lesion 8-hydroxy-2-deoxy-guanosine (8-OHdG) by HPLC/ECD, while mRNA and protein expression of oxidative stress and DNA damage response genes including hemeoxygenase-1 (HO-1) and apurinic/apyrimidinic endonuclease (APE/Ref-1) were evaluated using Western blotting and real time PCR. Isolated lung epithelial cells from the treated rats were used for DNA strand breakage analysis using the alkaline comet assay as well as for micronucleus scoring in May-Gruenwald-Giemsa stained cytospin preparations. In the rats that were treated with quartz, no increased 8-OHdG levels were observed, despite the presence of a marked and persistent inflammation. However, DNA strand breakage in the lung epithelial cells of the quartz treated rats was significantly enhanced at 3 days, but not at 28 days. Moreover, significantly enhanced micronucleus frequencies were observed for all four time points investigated. In the animals that were treated with the PVNO modified quartz, micronuclei scores did not differ from controls, while in those treated with

  9. Sleep Moderates the Association Between Response Inhibition and Self-Regulation in Early Childhood

    PubMed Central

    Schumacher, Allyson M.; Miller, Alison L.; Watamura, Sarah E.; Kurth, Salome; Lassonde, Jonathan M.; LeBourgeois, Monique K.

    2017-01-01

    Early childhood is a time of rapid developmental changes in sleep, cognitive control processes, and the regulation of emotion and behavior. This experimental study examined sleep-dependent effects on response inhibition and self-regulation, as well as whether acute sleep restriction moderated the association between these processes. Preschool children (N = 19; 45.6 ± 2.2 months; 11 female) followed a strict sleep schedule for at least 3 days before each of 2 morning behavior assessments: baseline (habitual nap/night sleep) and sleep restriction (missed nap/delayed bedtime). Response inhibition was evaluated via a go/no-go task. Twelve self-regulation strategies were coded from videotapes of children while attempting an unsolvable puzzle. We then created composite variables representing adaptive and maladaptive self-regulation strategies. Although we found no sleep-dependent effects on response inhibition or self-regulation measures, linear mixed-effects regression showed that acute sleep restriction moderated the relationship between these processes. At baseline, children with better response inhibition were more likely to use adaptive self-regulation strategies (e.g., self-talk, alternate strategies), and those with poorer response inhibition showed increased use of maladaptive self-regulation strategies (e.g., perseveration, fidgeting); however, response inhibition was not related to self-regulation strategies following sleep restriction. Our results showing a sleep-dependent effect on the associations between response inhibition and self-regulation strategies indicate that adequate sleep facilitates synergy between processes supporting optimal social-emotional functioning in early childhood. Although replication studies are needed, findings suggest that sleep may alter connections between maturing emotional and cognitive systems, which have important implications for understanding risk for or resilience to developmental psychopathology. PMID:27652491

  10. The immune response in the CNS in Theiler's virus induced demyelinating disease switches from an early adaptive response to a chronic innate-like response.

    PubMed

    Gilli, Francesca; Li, Libin; Pachner, Andrew R

    2016-02-01

    Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is an important model of the progressive disability caused by irreversible CNS tissue injury, and provides an example of how a CNS pathogen can cause inflammation, demyelination, and neuronal damage. We were interested in which molecules, especially inflammatory mediators, might be upregulated in the CNS throughout TMEV-IDD. We quantitated by a real-time RT-PCR multi-gene system the expression of a pathway-focused panel of genes at 30 and 165 days post infection, characterizing both the early inflammatory and the late neurodegenerative stages of TMEV-IDD. Also, we measured 32 cytokines/chemokines by multiplex Luminex analysis in CSF specimens from early and late TMEV-IDD as well as sham-treated mice. Results indicate that, in the later stage of TMEV-IDD, activation of the innate immune response is most prominent: TLRs, type I IFN response genes, and innate immunity-associated cytokines were highly expressed in late TMEV-IDD compared to sham (p ≤ 0.0001) and early TMEV-IDD (p < 0.05). Conversely, several molecular mediators of adaptive immune response were highly expressed in early TMEV-IDD (all p ≤ 0.001). Protein detection in the CSF was broadly concordant with mRNA abundance of the corresponding gene measured by real-time RT-PCR in the spinal cord, since several cytokines/chemokines were increased in the CSF of TMEV-IDD mice. Results show a clear shift from adaptive to innate immunity from early to late TMEV-IDD, indicating that adaptive and innate immune pathways are likely involved in the development and progression of the disease to different extents. CSF provides an optimal source of biomarkers of CNS neuroinflammation.

  11. The genome-wide transcriptional response to neonatal hyperoxia identifies Ahr as a key regulator

    PubMed Central

    Bhattacharya, Soumyaroop; Zhou, Zhongyang; Yee, Min; Chu, Chin-Yi; Lopez, Ashley M.; Lunger, Valerie A.; Solleti, Siva Kumar; Resseguie, Emily; Buczynski, Bradley; O'Reilly, Michael A.

    2014-01-01

    Premature infants requiring supplemental oxygen are at increased risk for developing bronchopulmonary dysplasia (BPD). Rodent models involving neonatal exposure to excessive oxygen concentrations (hyperoxia) have helped to identify mechanisms of BPD-associated pathology. Genome-wide assessments of the effects of hyperoxia in neonatal mouse lungs could identify novel BPD-related genes and pathways. Newborn C57BL/6 mice were exposed to 100% oxygen for 10 days, and whole lung tissue RNA was used for high-throughput, sequencing-based transcriptomic analysis (RNA-Seq). Significance Analysis of Microarrays and Ingenuity Pathway Analysis were used to identify genes and pathways affected. Expression patterns for selected genes were validated by qPCR. Mechanistic relationships between genes were further tested in cultured mouse lung epithelial cells. We identified 300 genes significantly and substantially affected following acute neonatal hyperoxia. Canonical pathways dysregulated in hyperoxia lungs included nuclear fctor (erythryoid-derived-2)-like 2-mediated oxidative stress signaling, p53 signaling, eNOS signaling, and aryl hydrocarbon receptor (Ahr) pathways. Cluster analysis identified Ccnd1, Cdkn1a, and Ahr as critical regulatory nodes in the response to hyperoxia, with Ahr serving as the major effector node. A mechanistic role for Ahr was assessed in lung epithelial cells, and we confirmed its ability to regulate the expression of multiple hyperoxia markers, including Cdkn1a, Pdgfrb, and A2m. We conclude that a global assessment of gene regulation in the acute neonatal hyperoxia model of BPD-like pathology has identified Ahr as one driver of gene dysregulation. PMID:25150061

  12. MORC1 exhibits cross-species differential methylation in association with early life stress as well as genome-wide association with MDD

    PubMed Central

    Nieratschker, V; Massart, R; Gilles, M; Luoni, A; Suderman, M J; Krumm, B; Meier, S; Witt, S H; Nöthen, M M; Suomi, S J; Peus, V; Scharnholz, B; Dukal, H; Hohmeyer, C; Wolf, I A-C; Cirulli, F; Gass, P; Sütterlin, M W; Filsinger, B; Laucht, M; Riva, M A; Rietschel, M; Deuschle, M; Szyf, M

    2014-01-01

    Early life stress (ELS) is associated with increased vulnerability for diseases in later life, including psychiatric disorders. Animal models and human studies suggest that this effect is mediated by epigenetic mechanisms. In humans, epigenetic studies to investigate the influence of ELS on psychiatric phenotypes are limited by the inaccessibility of living brain tissue. Due to the tissue-specific nature of epigenetic signatures, it is impossible to determine whether ELS induced epigenetic changes in accessible peripheral cells, for example, blood lymphocytes, reflect epigenetic changes in the brain. To overcome these limitations, we applied a cross-species approach involving: (i) the analysis of CD34+ cells from human cord blood; (ii) the examination of blood-derived CD3+ T cells of newborn and adolescent nonhuman primates (Macaca mulatta); and (iii) the investigation of the prefrontal cortex of adult rats. Several regions in MORC1 (MORC family CW-type zinc finger 1; previously known as: microrchidia (mouse) homolog) were differentially methylated in response to ELS in CD34+ cells and CD3+ T cells derived from the blood of human and monkey neonates, as well as in CD3+ T cells derived from the blood of adolescent monkeys and in the prefrontal cortex of adult rats. MORC1 is thus the first identified epigenetic marker of ELS to be present in blood cell progenitors at birth and in the brain in adulthood. Interestingly, a gene-set-based analysis of data from a genome-wide association study of major depressive disorder (MDD) revealed an association of MORC1 with MDD. PMID:25158004

  13. Ancestry trumps experience: Transgenerational but not early life stress affects the adult physiological stress response.

    PubMed

    McCormick, Gail L; Robbins, Travis R; Cavigelli, Sonia A; Langkilde, Tracy

    2017-01-01

    Exposure to stressors can affect an organism's physiology and behavior as well as that of its descendants (e.g. through maternal effects, epigenetics, and/or selection). We examined the relative influence of early life vs. transgenerational stress exposure on adult stress physiology in a species that has populations with and without ancestral exposure to an invasive predator. We raised offspring of eastern fence lizards (Sceloporus undulatus) from sites historically invaded (high stress) or uninvaded (low stress) by predatory fire ants (Solenopsis invicta) and determined how this different transgenerational exposure to stress interacted with the effects of early life stress exposure to influence the physiological stress response in adulthood. Offspring from these high- and low-stress populations were exposed weekly to either sub-lethal attack by fire ants (an ecologically relevant stressor), topical treatment with a physiologically-appropriate dose of the stress-relevant hormone, corticosterone (CORT), or a control treatment from 2 to 43weeks of age. Several months after treatments ended, we quantified plasma CORT concentrations at baseline and following restraint, exposure to fire ants, and adrenocorticotropic hormone (ACTH) injection. Exposure to fire ants or CORT during early life did not affect lizard stress physiology in adulthood. However, offspring of lizards from populations that had experienced multiple generations of fire ant-invasion exhibited more robust adult CORT responses to restraint and ACTH-injection compared to offspring from uninvaded populations. Together, these results indicate that transgenerational stress history may be at least as important, if not more important, than early life stress in affecting adult physiological stress responses.

  14. Early responses to deep brain stimulation in depression are modulated by anti-inflammatory drugs.

    PubMed

    Perez-Caballero, L; Pérez-Egea, R; Romero-Grimaldi, C; Puigdemont, D; Molet, J; Caso, J-R; Mico, J-A; Pérez, V; Leza, J-C; Berrocoso, E

    2014-05-01

    Deep brain stimulation (DBS) in the subgenual cingulated gyrus (SCG) is a promising new technique that may provide sustained remission in resistant major depressive disorder (MDD). Initial studies reported a significant early improvement in patients, followed by a decline within the first month of treatment, an unexpected phenomenon attributed to potential placebo effects or a physiological response to probe insertion that remains poorly understood. Here we characterized the behavioural antidepressant-like effect of DBS in the rat medial prefrontal cortex, focusing on modifications to rodent SCG correlate (prelimbic and infralimbic (IL) cortex). In addition, we evaluated the early outcome of DBS in the SCG of eight patients with resistant MDD involved in a clinical trial. We found similar antidepressant-like effects in rats implanted with electrodes, irrespective of whether they received electrical brain stimulation or not. This effect was due to regional inflammation, as it was temporally correlated with an increase of glial-fibrillary-acidic-protein immunoreactivity, and it was blocked by anti-inflammatory drugs. Indeed, inflammatory mediators and neuronal p11 expression also changed. Furthermore, a retrospective study indicated that the early response of MDD patients subjected to DBS was poorer when they received anti-inflammatory drugs. Our study demonstrates that electrode implantation up to the IL cortex is sufficient to produce an antidepressant-like effect of a similar magnitude to that observed in rats receiving brain stimulation. Moreover, both preclinical and clinical findings suggest that the use of anti-inflammatory drugs after electrode implantation may attenuate the early anti-depressive response in patients who are subjected to DBS.

  15. Prediction and Early Evaluation of Anticancer Therapy Response: From Imaging of Drug Efflux Pumps to Targeted Therapy Response.

    PubMed

    Meng, Qingqing; Li, Zheng; Li, Shaoshun

    2016-01-01

    Multidrug resistance (MDR) describes the resistance of tumor cells to chemotherapy and has been ascribed to the overexpression of drug efflux pumps. Molecular imaging of drug efflux pumps is helpful to identify the patients who may be resistant to the chemotherapy and thus will avoid the unnecessary treatment and increase the therapeutic effectiveness. Imaging probes targeting drug efflux pumps can non-invasively evaluate the Pgp function and play an important role in identification of MDR, prediction of response, and monitoring MDR modulation. On the other hand, new anticancer agents based on molecular targets such as epidermal growth factor receptor (EGFR) and angiogenic factor receptor may potentially be combined with chemotherapeutic drugs to overcome the MDR. Imaging of molecular targets visualize treatment response of patients at molecular level vividly and help to select right patients for certain targeted anticancer therapy. Among all the imaging modalities, nuclear imaging including positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging has the greatest promise for rapid translation to the clinic and can realize quantitative visualization of biochemical processes in vivo. In this review, we will summarize the nuclear imaging probes utilized for predicting and evaluating the early anticancer therapy response.99mTc labeled agents and PET based radiopharmaceuticals like 18F-Paclitaxel, 11C-Verapamil for drug efflux pumps imaging will be discussed here. Moreover, molecular imaging probes used for targeted therapy response evaluation like 18F-Tamoxifen,89Zr-Trastuzumab will also be introduced in this review.

  16. Temperament and Parenting Styles in Early Childhood Differentially Influence Neural Response to Peer Evaluation in Adolescence

    PubMed Central

    Guyer, Amanda E.; Jarcho, Johanna M.; Pérez-Edgar, Koraly; Degnan, Kathryn A.; Pine, Daniel S.; Fox, Nathan A.; Nelson, Eric E.

    2015-01-01

    Behavioral inhibition (BI) is a temperament characterized by social reticence and withdrawal from unfamiliar or novel contexts and conveys risk for social anxiety disorder. Developmental outcomes associated with this temperament can be influenced by children’s caregiving context. The convergence of a child’s temperamental disposition and rearing environment is ultimately expressed at both the behavioral and neural levels in emotional and cognitive response patterns to social challenges. The present study used functional neuroimaging to assess the moderating effects of different parenting styles on neural response to peer rejection in two groups of adolescents characterized by their early childhood temperament (Mage = 17.89 years, N= 39, 17 males, 22 females; 18 with BI; 21 without BI). The moderating effects of authoritarian and authoritative parenting styles were examined in three brain regions linked with social anxiety: ventrolateral prefrontal cortex (vlPFC), striatum, and amygdala. In youth characterized with BI in childhood, but not in those without BI, diminished responses to peer rejection in vlPFC were associated with higher levels of authoritarian parenting. In contrast, all youth showed decreased caudate response to peer rejection at higher levels of authoritative parenting. These findings indicate that BI in early life relates to greater neurobiological sensitivity to variance in parenting styles, particularly harsh parenting, in late adolescence. These results are discussed in relation to biopsychosocial models of development. PMID:25588884

  17. Early neuronal responses in right limbic structures mediate harmony incongruity processing in musical experts.

    PubMed

    James, Clara E; Britz, Juliane; Vuilleumier, Patrik; Hauert, Claude-Alain; Michel, Christoph M

    2008-10-01

    In western tonal music, musical phrases end with an explicit harmonic consequent which is highly expected. As such expectation is a consequence of musical background, cerebral processing of incongruities of musical grammar might be a function of expertise. We hypothesized that a subtle incongruity of standard closure should evoke a profound and rapid reaction in an expert's brain. If such a reaction is due to neuroplasticity as a consequence of musical training, it should be correlated with distinctive activations in sensory, motor and/or cognitive function related brain areas in response to the incongruent closure. Using event related potential (ERP) source imaging, we determined the temporal dynamics of neuronal activity in highly trained pianists and musical laymen in response to syntactic harmonic incongruities in expressive music, which were easily detected by the experts but not by the laymen. Our results revealed that closure incongruity evokes a selective early response in musical experts, characterized by a strong, right lateralized negative ERP component. Statistical source analysis could demonstrate putative contribution to the generation of this component in right temporal-limbic areas, encompassing hippocampal complex and amygdala, and in right insula. Its early onset (approximately 200 ms) preceded responses in frontal areas that may reflect more conscious processing. These results go beyond previous work demonstrating that musical training can change activity of sensory and motor areas during musical or audio-motor tasks, and suggest that functional plasticity in right medial-temporal structures and insula also modulates processing of subtle harmonic incongruities.

  18. Stomatal Blue Light Response Is Present in Early Vascular Plants1[OPEN

    PubMed Central

    Doi, Michio; Kitagawa, Yuki; Shimazaki, Ken-ichiro

    2015-01-01

    Light is a major environmental factor required for stomatal opening. Blue light (BL) induces stomatal opening in higher plants as a signal under the photosynthetic active radiation. The stomatal BL response is not present in the fern species of Polypodiopsida. The acquisition of a stomatal BL response might provide competitive advantages in both the uptake of CO2 and prevention of water loss with the ability to rapidly open and close stomata. We surveyed the stomatal opening in response to strong red light (RL) and weak BL under the RL with gas exchange technique in a diverse selection of plant species from euphyllophytes, including spermatophytes and monilophytes, to lycophytes. We showed the presence of RL-induced stomatal opening in most of these species and found that the BL responses operated in all euphyllophytes except Polypodiopsida. We also confirmed that the stomatal opening in lycophytes, the early vascular plants, is driven by plasma membrane proton-translocating adenosine triphosphatase and K+ accumulation in guard cells, which is the same mechanism operating in stomata of angiosperms. These results suggest that the early vascular plants respond to both RL and BL and actively regulate stomatal aperture. We also found three plant species that absolutely require BL for both stomatal opening and photosynthetic CO2 fixation, including a gymnosperm, C. revoluta, and the ferns Equisetum hyemale and Psilotum nudum. PMID:26307440

  19. Temperament and Parenting Styles in Early Childhood Differentially Influence Neural Response to Peer Evaluation in Adolescence.

    PubMed

    Guyer, Amanda E; Jarcho, Johanna M; Pérez-Edgar, Koraly; Degnan, Kathryn A; Pine, Daniel S; Fox, Nathan A; Nelson, Eric E

    2015-07-01

    Behavioral inhibition (BI) is a temperament characterized by social reticence and withdrawal from unfamiliar or novel contexts and conveys risk for social anxiety disorder. Developmental outcomes associated with this temperament can be influenced by children's caregiving context. The convergence of a child's temperamental disposition and rearing environment is ultimately expressed at both the behavioral and neural levels in emotional and cognitive response patterns to social challenges. The present study used functional neuroimaging to assess the moderating effects of different parenting styles on neural response to peer rejection in two groups of adolescents characterized by their early childhood temperament (M(age) = 17.89 years, N = 39, 17 males, 22 females; 18 with BI; 21 without BI). The moderating effects of authoritarian and authoritative parenting styles were examined in three brain regions linked with social anxiety: ventrolateral prefrontal cortex (vlPFC), striatum, and amygdala. In youth characterized with BI in childhood, but not in those without BI, diminished responses to peer rejection in vlPFC were associated with higher levels of authoritarian parenting. In contrast, all youth showed decreased caudate response to peer rejection at higher levels of authoritative parenting. These findings indicate that BI in early life relates to greater neurobiological sensitivity to variance in parenting styles, particularly harsh parenting, in late adolescence. These results are discussed in relation to biopsychosocial models of development.

  20. The genomic response of the ipsilateral and contralateral cortex to stroke in aged rats

    PubMed Central

    Buga, A-M; Sascau, M; Pisoschi, C; Herndon, J G; Kessler, C; Popa-Wagner, A

    2008-01-01

    Aged rats recover poorly after unilateral stroke, whereas young rats recover readily possibly with the help from the contralateral, healthy hemisphere. In this study we asked whether anomalous, age-related changes in the transcriptional activity in the brains of aged rats could be one underlying factor contributing to reduced functional recovery. We analysed gene expression in the periinfarct and contralateral areas of 3-month- and 18-month-old Sprague Dawley rats. Our experimental end-points were cDNA arrays containing genes related to hypoxia signalling, DNA damage and apoptosis, cellular response to injury, axonal damage and re-growth, cell lineage differentiation, dendritogenesis and neurogenesis. The major transcriptional events observed were: (i) Early up-regulation of DNA damage and down-regulation of anti-apoptosis-related genes in the periinfarct region of aged rats after stroke; (ii) Impaired neurogenesis in the periinfarct area, especially in aged rats; (iii) Impaired neurogenesis in the contralateral (unlesioned) hemisphere of both young and aged rats at all times after stroke and (iv) Marked up-regulation, in aged rats, of genes associated with inflammation and scar formation. These results were confirmed with quantitative real-time PCR. We conclude that reduced transcriptional activity in the healthy, contralateral hemisphere of aged rats in conjunction with an early up-regulation of DNA damage-related genes and pro-apoptotic genes and down-regulation of axono- and neurogenesis in the periinfarct area are likely to account for poor neurorehabilitation after stroke in old rats. PMID:18266980

  1. Whole Genome Pathway Analysis Identifies an Association of Cadmium Response Gene Loss with Copy Number Variation in Mutant p53 Bearing Uterine Endometrial Carcinomas

    PubMed Central

    Stupack, Dwayne G

    2016-01-01

    Background Massive chromosomal aberrations are a signature of advanced cancer, although the factors promoting the pervasive incidence of these copy number alterations (CNAs) are poorly understood. Gatekeeper mutations, such as p53, contribute to aneuploidy, yet p53 mutant tumors do not always display CNAs. Uterine Corpus Endometrial Carcinoma (UCEC) offers a unique system to begin to evaluate why some cancers acquire high CNAs while others evolve another route to oncogenesis, since about half of p53 mutant UCEC tumors have a relatively flat CNA landscape and half have 20–90% of their genome altered in copy number. Methods We extracted copy number information from 68 UCEC genomes mutant in p53 by the GISTIC2 algorithm. GO term pathway analysis, via GOrilla, was used to identify suppressed pathways. Genes within these pathways were mapped for focal or wide distribution. Deletion hotspots were evaluated for temporal incidence. Results Multiple pathways contributed to the development of pervasive CNAs, including developmental, metabolic, immunological, cell adhesion and cadmium response pathways. Surprisingly, cadmium response pathway genes are predicted as the earliest loss events within these tumors: in particular, the metallothionein genes involved in heavy metal sequestration. Loss of cadmium response genes were associated with copy number changes and poorer prognosis, contrasting with 'copy number flat' tumors which instead exhibited substantive mutation. Conclusion Metallothioneins are lost early in the development of high CNA endometrial cancer, providing a potential mechanism and biological rationale for increased incidence of endometrial cancer with cadmium exposure. Developmental and metabolic pathways are altered later in tumor progression. PMID:27391266

  2. Complete Genome Sequence and Transcriptomic Analysis of the Novel Pathogen Elizabethkingia anophelis in Response to Oxidative Stress.

    PubMed

    Li, Yingying; Liu, Yang; Chew, Su Chuen; Tay, Martin; Salido, May Margarette Santillan; Teo, Jeanette; Lauro, Federico M; Givskov, Michael; Yang, Liang

    2015-05-26

    Elizabethkingia anophelis is an emerging pathogen that can cause life-threatening infections in neonates, severely immunocompromised and postoperative patients. The lack of genomic information on E. anophelis hinders our understanding of its mechanisms of pathogenesis. Here, we report the first complete genome sequence of E. anophelis NUHP1 and assess its response to oxidative stress. Elizabethkingia anophelis NUHP1 has a circular genome of 4,369,828 base pairs and 4,141 predicted coding sequences. Sequence analysis indicates that E. anophelis has well-developed systems for scavenging iron and stress response. Many putative virulence factors and antibiotic resistance genes were identified, underscoring potential host-pathogen interactions and antibiotic resistance. RNA-sequencing-based transcriptome profiling indicates that expressions of genes involved in synthesis of an yersiniabactin-like iron siderophore and heme utilization are highly induced as a protective mechanism toward oxidative stress caused by hydrogen peroxide treatment. Chrome azurol sulfonate assay verified that siderophore production of E. anophelis is increased in the presence of oxidative stress. We further showed that hemoglobin facilitates the growth, hydrogen peroxide tolerance, cell attachment, and biofilm formation of E. anophelis NUHP1. Our study suggests that siderophore production and heme uptake pathways might play essential roles in stress response and virulence of the emerging pathogen E. anophelis.

  3. Complete Genome Sequence and Transcriptomic Analysis of the Novel Pathogen Elizabethkingia anophelis in Response to Oxidative Stress

    PubMed Central

    Li, Yingying; Liu, Yang; Chew, Su Chuen; Tay, Martin; Salido, May Margarette Santillan; Teo, Jeanette; Lauro, Federico M.; Givskov, Michael; Yang, Liang

    2015-01-01

    Elizabethkingia anophelis is an emerging pathogen that can cause life-threatening infections in neonates, severely immunocompromised and postoperative patients. The lack of genomic information on E. anophelis hinders our understanding of its mechanisms of pathogenesis. Here, we report the first complete genome sequence of E. anophelis NUHP1 and assess its response to oxidative stress. Elizabethkingia anophelis NUHP1 has a circular genome of 4,369,828 base pairs and 4,141 predicted coding sequences. Sequence analysis indicates that E. anophelis has well-developed systems for scavenging iron and stress response. Many putative virulence factors and antibiotic resistance genes were identified, underscoring potential host–pathogen interactions and antibiotic resistance. RNA-sequencing-based transcriptome profiling indicates that expressions of genes involved in synthesis of an yersiniabactin-like iron siderophore and heme utilization are highly induced as a protective mechanism toward oxidative stress caused by hydrogen peroxide treatment. Chrome azurol sulfonate assay verified that siderophore production of E. anophelis is increased in the presence of oxidative stress. We further showed that hemoglobin facilitates the growth, hydrogen peroxide tolerance, cell attachment, and biofilm formation of E. anophelis NUHP1. Our study suggests that siderophore production and heme uptake pathways might play essential roles in stress response and virulence of the emerging pathogen E. anophelis. PMID:26019164

  4. Genome-Wide Host-Pathogen Interaction Unveiled by Transcriptomic Response of Diamondback Moth to Fungal Infection

    PubMed Central

    Chu, Zhen-Jian; Wang, Yu-Jun; Ying, Sheng-Hua; Wang, Xiao-Wei; Feng, Ming-Guang

    2016-01-01

    Genome-wide insight into insect pest response to the infection of Beauveria bassiana (fungal insect pathogen) is critical for genetic improvement of fungal insecticides but has been poorly explored. We constructed three pairs of transcriptomes of Plutella xylostella larvae at 24, 36 and 48 hours post treatment of infection (hptI) and of control (hptC) for insight into the host-pathogen interaction at genomic level. There were 2143, 3200 and 2967 host genes differentially expressed at 24, 36 and 48 hptI/hptC respectively. These infection-responsive genes (~15% of the host genome) were enriched in various immune processes, such as complement and coagulation cascades, protein digestion and absorption, and drug metabolism-cytochrome P450. Fungal penetration into cuticle and host defense reaction began at 24 hptI, followed by most intensive host immune response at 36 hptI and attenuated immunity at 48 hptI. Contrastingly, 44% of fungal genes were differentially expressed in the infection course and enriched in several biological processes, such as antioxidant activity, peroxidase activity and proteolysis. There were 1636 fungal genes co-expressed during 24–48 hptI, including 116 encoding putative secretion proteins. Our results provide novel insights into the insect-pathogen interaction and help to probe molecular mechanisms involved in the fungal infection to the global pest. PMID:27043942

  5. Salinity- and population-dependent genome regulatory response during osmotic acclimation in the killifish (Fundulus heteroclitus) gill.

    PubMed

    Whitehead, Andrew; Roach, Jennifer L; Zhang, Shujun; Galvez, Fernando

    2012-04-15

    The killifish Fundulus heteroclitus is abundant in osmotically dynamic estuaries and it can quickly adjust to extremes in environmental salinity. We performed a comparative osmotic challenge experiment to track the transcriptomic and physiological responses to two salinities throughout a time course of acclimation, and to explore the genome regulatory mechanisms that enable extreme osmotic acclimation. One southern and one northern coastal population, known to differ in their tolerance to hypo-osmotic exposure, were used as our comparative model. Both populations could maintain osmotic homeostasis when transferred from 32 to 0.4 p.p.t., but diverged in their compensatory abilities when challenged down to 0.1 p.p.t., in parallel with divergent transformation of gill morphology. Genes involved in cell volume regulation, nucleosome maintenance, ion transport, energetics, mitochondrion function, transcriptional regulation and apoptosis showed population- and salinity-dependent patterns of expression during acclimation. Network analysis confirmed the role of cytokine and kinase signaling pathways in coordinating the genome regulatory response to osmotic challenge, and also posited the importance of signaling coordinated through the transcription factor HNF-4α. These genome responses support hypotheses of which regulatory mechanisms are particularly relevant for enabling extreme physiological flexibility.

  6. Genome-Wide Host-Pathogen Interaction Unveiled by Transcriptomic Response of Diamondback Moth to Fungal Infection.

    PubMed

    Chu, Zhen-Jian; Wang, Yu-Jun; Ying, Sheng-Hua; Wang, Xiao-Wei; Feng, Ming-Guang

    2016-01-01

    Genome-wide insight into insect pest response to the infection of Beauveria bassiana (fungal insect pathogen) is critical for genetic improvement of fungal insecticides but has been poorly explored. We constructed three pairs of transcriptomes of Plutella xylostella larvae at 24, 36 and 48 hours post treatment of infection (hptI) and of control (hptC) for insight into the host-pathogen interaction at genomic level. There were 2143, 3200 and 2967 host genes differentially expressed at 24, 36 and 48 hptI/hptC respectively. These infection-responsive genes (~15% of the host genome) were enriched in various immune processes, such as complement and coagulation cascades, protein digestion and absorption, and drug metabolism-cytochrome P450. Fungal penetration into cuticle and host defense reaction began at 24 hptI, followed by most intensive host immune response at 36 hptI and attenuated immunity at 48 hptI. Contrastingly, 44% of fungal genes were differentially expressed in the infection course and enriched in several biological processes, such as antioxidant activity, peroxidase activity and proteolysis. There were 1636 fungal genes co-expressed during 24-48 hptI, including 116 encoding putative secretion proteins. Our results provide novel insights into the insect-pathogen interaction and help to probe molecular mechanisms involved in the fungal infection to the global pest.

  7. Very rapid virologic response and early HCV response kinetics, as quick measures to compare efficacy and guide a personalized response-guided therapy

    PubMed Central

    Yakoot, Mostafa; Abdo, Alaa M; Yousry, Ahmed; Helmy, Sherine

    2016-01-01

    Background This is the second and final report for our study designed to compare two generic sofosbuvir products for the degree and speed of virologic response to a dual anti-hepatitis C virus (HCV) treatment protocol. We aimed to test the applicability of the early virus response kinetics and the very rapid virologic response (vRVR) rate as quick outcome measures for accelerated comparative efficacy studies and as a foundation for a personalized response-guided therapy. Methods Fifty eligible chronic HCV patients were randomized to either one of two generic sofosbuvir products (Gratisovir or Grateziano) at a daily dose of one 400 mg tablet plus a weight-based ribavirin dose. Data were compared between the groups for early virus response kinetics and vRVR rates in relation to the rates of final sustained virologic response at week 12 posttreatment (SVR12). Results The Log10 transformed virus load (Log polymerase chain reaction) curves showed fairly similar rapid decline during the first 2 weeks, with no significant difference between the groups at four analysis points throughout the study by repeated-measures factorial analysis of variance test (P=0.48). The SVR12 rates were 96% (95% confidence interval, 79.6%–99.9%) in Gratisovir group (24/25) and 95.7% (95% confidence interval, 78%–99.9%) in Grateziano group (22/23). There was no statistically significant difference found by exact test (P>0.999). There was a significant association between the vRVR and the SVR12, with 100% positive predictive value (38/38 of those who had vRVR, achieved a final SVR12) and 82.6% sensitivity (among the total 46 with SVR12, 38 were having vRVR). Conclusion We can conclude from our study that the early HCV response kinetics and the vRVR rates could be used as sensitive quick markers for efficacy (with a very high positive predictive value for SVR12), based on our accelerated comparative efficacy research model. This might open the way for new models of accelerated equivalence

  8. Dermoscopic hemorrhagic dots: an early predictor of response of psoriasis to biologic agents

    PubMed Central

    Lallas, Aimilios; Argenziano, Giuseppe; Zalaudek, Iris; Apalla, Zoe; Ardigo, Marco; Chellini, Patricia; Cordeiro, Natalia; Guimaraes, Mariana; Kyrgidis, Athanassios; Lazaridou, Elizabeth; Longo, Caterina; Moscarella, Elvira; Papadimitriou, Ilias; Pellacani, Giovanni; Sotiriou, Elena; Vakirlis, Efstratios; Ioannides, Dimitrios

    2016-01-01

    Background Biologic agents are routinely used in the treatment of severe psoriasis. The evaluation of treatment response is mainly based on the physician’s global clinical assessment. Objective To investigate whether dermoscopy might enhance the assessment of response of psoriasis to treatment with biologic agents. Methods Patients with severe psoriasis scheduled to receive a biologic agent were enrolled in the study. A target lesion from each patient was clinically and dermoscopically documented at baseline and after one, two and six months. The clinical response was evaluated by the recruiting clinicians at all visits, while dermoscopic images were evaluated by two independent investigators, blinded to the clinical information. Chi Square test was used for cross-tabulation comparisons, while odds ratios, 95% confidence intervals and p values were calculated using univariate logistic regression. Results Overall, there was a significant correlation between clinical response and vessel distribution at all time points: a regular vessel distribution correlated with no response, a clustered distribution with partial response, and the dermoscopic absence of vessels with complete response. The presence of dermoscopic hemorrhagic dots was a potent predictor of favorable clinical response at the subsequent visit at all time points. Among lesions initially clinically responding and later recurring, 87.5% displayed dermoscopic dotted vessels despite the macroscopic remission. Conclusion Dermoscopy might be a useful additional tool for evaluating the response of psoriatic patients to biologic agents. Hemorrhagic dots represent an early predictor of clinical response, while the persistence or reappearance of dotted vessels might predict clinical persistence or recurrence, respectively. PMID:27867739

  9. Genome-wide association study identifies SESTD1 as a novel risk gene for lithium-responsive bipolar disorder

    PubMed Central

    Song, J; Bergen, S E; Di Florio, A; Karlsson, R; Charney, A; Ruderfer, D M; Stahl, E A; Chambert, K D; Moran, J L; Gordon-Smith, K; Forty, L; Green, E K; Jones, I; Jones, L; Scolnick, E M; Sklar, P; Smoller, J W; Lichtenstein, P; Hultman, C; Craddock, N; Landén, M; Smoller, Jordan W; Perlis, Roy H; Lee, Phil Hyoun; Castro, Victor M; Hoffnagle, Alison G; Sklar, Pamela; Stahl, Eli A; Purcell, Shaun M; Ruderfer, Douglas M; Charney, Alexander W; Roussos, Panos; Michele Pato, Carlos Pato; Medeiros, Helen; Sobel, Janet; Craddock, Nick; Jones, Ian; Forty, Liz; Florio, Arianna Di; Green, Elaine; Jones, Lisa; Gordon-Smith, Katherine; Landen, Mikael; Hultman, Christina; Jureus, Anders; Bergen, Sarah; McCarroll, Steven; Moran, Jennifer; Smoller, Jordan W; Chambert, Kimberly; Belliveau, Richard A

    2016-01-01

    Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10−8). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants (‘SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD. PMID:26503763

  10. Genome-wide association study identifies SESTD1 as a novel risk gene for lithium-responsive bipolar disorder.

    PubMed

    Song, J; Bergen, S E; Di Florio, A; Karlsson, R; Charney, A; Ruderfer, D M; Stahl, E A; Chambert, K D; Moran, J L; Gordon-Smith, K; Forty, L; Green, E K; Jones, I; Jones, L; Scolnick, E M; Sklar, P; Smoller, J W; Lichtenstein, P; Hultman, C; Craddock, N; Landén, M; Smoller, Jordan W; Perlis, Roy H; Lee, Phil Hyoun; Castro, Victor M; Hoffnagle, Alison G; Sklar, Pamela; Stahl, Eli A; Purcell, Shaun M; Ruderfer, Douglas M; Charney, Alexander W; Roussos, Panos; Michele Pato, Carlos Pato; Medeiros, Helen; Sobel, Janet; Craddock, Nick; Jones, Ian; Forty, Liz; Florio, Arianna Di; Green, Elaine; Jones, Lisa; Gordon-Smith, Katherine; Landen, Mikael; Hultman, Christina; Jureus, Anders; Bergen, Sarah; McCarroll, Steven; Moran, Jennifer; Smoller, Jordan W; Chambert, Kimberly; Belliveau, Richard A

    2016-09-01

    Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10(-8)). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.

  11. Genome-Wide Analysis of MicroRNA Responses to the Phytohormone Abscisic Acid in Populus euphratica

    PubMed Central

    Duan, Hui; Lu, Xin; Lian, Conglong; An, Yi; Xia, Xinli; Yin, Weilun

    2016-01-01

    MicroRNA (miRNA) is a type of non-coding small RNA with a regulatory function at the posttranscriptional level in plant growth development and in response to abiotic stress. Previous studies have not reported on miRNAs responses to the phytohormone abscisic acid (ABA) at a genome-wide level in Populus euphratica, a model tree for studying abiotic stress responses in woody plants. Here we analyzed the miRNA response to ABA at a genome-wide level in P. euphratica utilizing high-throughput sequencing. To systematically perform a genome-wide analysis of ABA-responsive miRNAs in P. euphratica, nine sRNA libraries derived from three groups (control, treated with ABA for 1 day and treated with ABA for 4 days) were constructed. Each group included three libraries from three individual plantlets as biological replicate. In total, 151 unique mature sequences belonging to 75 conserved miRNA families were identified, and 94 unique sequences were determined to be novel miRNAs, including 56 miRNAs with miRNA* sequences. In all, 31 conserved miRNAs and 31 novel miRNAs response to ABA significantly differed among the groups. In addition, 4132 target genes were predicted for the conserved and novel miRNAs. Confirmed by real-time qPCR, expression changes of miRNAs were inversely correlated with the expression profiles of their putative targets. The Populus special or novel miRNA-target interactions were predicted might be involved in some biological process related stress tolerance. Our analysis provides a comprehensive view of how P. euphratica miRNA respond to ABA, and moreover, different temporal dynamics were observed in different ABA-treated libraries. PMID:27582743

  12. Population responses to contour integration: early encoding of discrete elements and late perceptual grouping.

    PubMed

    Gilad, Ariel; Meirovithz, Elhanan; Slovin, Hamutal

    2013-04-24

    The neuronal mechanisms underlying perceptual grouping of discrete, similarly oriented elements are not well understood. To investigate this, we measured neural population responses using voltage-sensitive dye imaging in V1 of monkeys trained on a contour-detection task. By mapping the contour and background elements onto V1, we could study their neural processing. Population response early in time showed activation patches corresponding to the contour/background individual elements. However, late increased activity in the contour elements, along with suppressed activity in the background elements, enabled us to visualize in single trials a salient continuous contour "popping out" from a suppressed background. This modulated activity in the contour and in background extended beyond the cortical representation of individual contour or background elements. Finally, the late modulation was correlated with behavioral performance of contour saliency and the monkeys' perceptual report. Thus, opposing responses in the contour and background may underlie perceptual grouping in V1.

  13. Disclosing early steps of protein-primed genome replication of the Gram-positive tectivirus Bam35

    PubMed Central

    Berjón-Otero, Mónica; Villar, Laurentino; Salas, Margarita; Redrejo-Rodríguez, Modesto

    2016-01-01

    Protein-primed replication constitutes a generalized mechanism to initiate DNA or RNA synthesis in a number of linear genomes of viruses, linear plasmids and mobile elements. By this mechanism, a so-called terminal protein (TP) primes replication and becomes covalently linked to the genome ends. Bam35 belongs to a group of temperate tectiviruses infecting Gram-positive bacteria, predicted to replicate their genomes by a protein-primed mechanism. Here, we characterize Bam35 replication as an alternative model of protein-priming DNA replication. First, we analyze the role of the protein encoded by the ORF4 as the TP and characterize the replication mechanism of the viral genome (TP-DNA). Indeed, full-length Bam35 TP-DNA can be replicated using only the viral TP and DNA polymerase. We also show that DNA replication priming entails the TP deoxythymidylation at conserved tyrosine 194 and that this reaction is directed by the third base of the template strand. We have also identified the TP tyrosine 172 as an essential residue for the interaction with the viral DNA polymerase. Furthermore, the genetic information of the first nucleotides of the genome can be recovered by a novel single-nucleotide jumping-back mechanism. Given the similarities between genome inverted terminal repeats and the genes encoding the replication proteins, we propose that related tectivirus genomes can be replicated by a similar mechanism. PMID:27466389

  14. Expanded roles of leucine-responsive regulatory protein in transcription regulation of the Escherichia coli genome: Genomic SELEX screening of the regulation targets

    PubMed Central

    Saito, Natsumi; Maeda, Michihisa; Tanaka, Kan; Ishihama, Akira

    2015-01-01

    Leucine-responsive regulatory protein (Lrp) is a transcriptional regulator for the genes involved in transport, biosynthesis and catabolism of amino acids in Escherichia coli. In order to identify the whole set of genes under the direct control of Lrp, we performed Genomic SELEX screening and identified a total of 314 Lrp-binding sites on the E. coli genome. As a result, the regulation target of Lrp was predicted to expand from the hitherto identified genes for amino acid metabolism to a set of novel target genes for utilization of amino acids for protein synthesis, including tRNAs, aminoacyl-tRNA synthases and rRNAs. Northern blot analysis indicated alteration of mRNA levels for at least some novel targets, including the aminoacyl-tRNA synthetase genes. Phenotype MicroArray of the lrp mutant indicated significant alteration in utilization of amino acids and peptides, whilst metabolome analysis showed variations in the concentration of amino acids in the lrp mutant. From these two datasets we realized a reverse correlation between amino acid levels and cell growth rate: fast-growing cells contain low-level amino acids, whilst a high level of amino acids exists in slow-growing cells. Taken together, we propose that Lrp is a global regulator of transcription of a large number of the genes involved in not only amino acid transport and metabolism, but also amino acid utilization. PMID:28348809

  15. Comparative responses to endocrine disrupting compounds in early life stages of Atlantic salmon, Salmo salar

    USGS Publications Warehouse

    Duffy, Tara A.; Iwanowicz, Luke R.; McCormick, Stephen D.

    2014-01-01

    Atlantic salmon (Salmo salar) are endangered anadromous fish that may be exposed to feminizing endocrine disrupting compounds (EDCs) during early development, potentially altering physiological capacities, survival and fitness. To assess differential life stage sensitivity to common EDCs, we carried out short-term (four day) exposures using three doses each of 17α-ethinylestradiol (EE2), 17β-estradiol (E2), and nonylphenol (NP) on four early life stages; embryos, yolk-sac larvae, feeding fry and one year old smolts. Differential response was compared using vitellogenin (Vtg, a precursor egg protein) gene transcription. Smolts were also examined for impacts on plasma Vtg, cortisol, thyroid hormones (T4/T3) and hepatosomatic index (HSI). Compound-related mortality was not observed in any life stage, but Vtg mRNA was elevated in a dose-dependent manner in yolk-sac larvae, fry and smolts but not in embyos. The estrogens EE2 and E2 were consistently stronger inducers of Vtg than NP. Embryos responded significantly to the highest concentration of EE2 only, while older life stages responded to the highest doses of all three compounds, as well as intermediate doses of EE2 and E2. Maximal transcription was greater for fry among the three earliest life stages, suggesting fry may be the most responsive life stage in early development. Smolt plasma Vtg was also significantly increased, and this response was observed at lower doses of each compound than was detected by gene transcription suggesting this is a more sensitive indicator at this life stage. HSI was increased at the highest doses of EE2 and E2 and plasma T3 decreased at the highest dose of EE2. Our results indicate that all life stages after hatching are potentially sensitive to endocrine disruption by estrogenic compounds and that physiological responses were altered over a short window of exposure, indicating the potential for these compounds to impact fish in the wild.

  16. Jasmonate signaling is activated in the very early stages of iron deficiency responses in rice roots.

    PubMed

    Kobayashi, Takanori; Itai, Reiko Nakanishi; Senoura, Takeshi; Oikawa, Takaya; Ishimaru, Yasuhiro; Ueda, Minoru; Nakanishi, Hiromi; Nishizawa, Naoko K

    2016-07-01

    Under low iron availability, plants induce the expression of various genes involved in iron uptake and translocation at the transcriptional level. This iron deficiency response is affected by various plant hormones, but the roles of jasmonates in this response are not well-known. We investigated the involvement of jasmonates in rice iron deficiency responses. High rates of jasmonate-inducible genes were induced during the very early stages of iron deficiency treatment in rice roots. Many jasmonate-inducible genes were also negatively regulated by the ubiquitin ligases OsHRZ1 and OsHRZ2 and positively regulated by the transcription factor IDEF1. Ten out of 35 genes involved in jasmonate biosynthesis and signaling were rapidly induced at 3 h of iron deficiency treatment, and this induction preceded that of known iron deficiency-inducible genes involved in iron uptake and translocation. Twelve genes involved in jasmonate biosynthesis and signaling were also upregulated in HRZ-knockdown roots. Endogenous concentrations of jasmonic acid and jasmonoyl isoleucine tended to be rapidly increased in roots in response to iron deficiency treatment, whereas these concentrations were higher in HRZ-knockdown roots under iron-sufficient conditions. Analysis of the jasmonate-deficient cpm2 mutant revealed that jasmonates repress the expression of many iron deficiency-inducible genes involved in iron uptake and translocation under iron sufficiency, but this repression is partly canceled under an early stage of iron deficiency. These results indicate that jasmonate signaling is activated during the very early stages of iron deficiency, which is partly regulated by IDEF1 and OsHRZs.

  17. Different clustering of genomes across life using the A-T-C-G and degenerate R-Y alphabets: early and late signaling on genome evolution?

    PubMed

    Kirzhner, V; Paz, A; Volkovich, Z; Nevo, E; Korol, A

    2007-04-01

    In this study, we have calculated distances between genomes based on our previously developed compositional spectra (CS) analysis. The study was conducted using genomes of 39 species of Eukarya, Eubacteria, and Archaea. Based on CS distances, we produced two different consensus dendrograms for four- and two-letter (purine-pyrimidine) alphabets. A comparison of the obtained structure using purine-pyrimidine alphabet with the standard three-kingdom (3K) scheme reveals substantial similarity. Surprisingly, this is not the case when the same procedure is based on the four-letter alphabet. In this situation, we also found three main clusters-but different from those in the 3K scheme. In particular, one of the clusters includes Eukarya and thermophilic bacteria and a part of the considered Archaea species. We speculate that the key factor in the last classification (based on the A-T-G-C alphabet) is related to ecology: two ecological parameters, temperature and oxygen, distinctly explain the clustering revealed by compositional spectra in the four-letter alphabet. Therefore, we assume that this result reflects two interdependent processes: evolutionary divergence and superimposed ecological convergence of the genomes, albeit another process, horizontal transfer, cannot be excluded as an important contributing factor.

  18. Tumor interstitial fluid pressure as an early-response marker for anticancer therapeutics.

    PubMed

    Ferretti, Stephane; Allegrini, Peter R; Becquet, Mike M; McSheehy, Paul Mj

    2009-09-01

    Solid tumors have a raised interstitial fluid pressure (IFP) due to high vessel permeability, low lymphatic drainage, poor perfusion, and high cell density around the blood vessels. To investigate tumor IFP as an early-response biomarker, we have tested the effect of seven anticancer chemotherapeutics including cytotoxics and targeted cytostatics in 13 experimental tumor models. IFP was recorded with the wick-in-needle method. Models were either ectopic or orthotopic and included mouse and rat syngeneic as well as human xenografts in nude mice. The mean basal IFP was between 4.4 and 15.2mm Hg; IFP was lowest in human tumor xenografts and highest in rat syngeneic models. Where measured, basal IFP correlated positively with relative tumor blood volume (rTBV) determined by dynamic contrast-enhanced magnetic resonance imaging. Most chemotherapeutics sooner (2 or 3 days) or later (6 or 7 days) lowered tumor IFP significantly, and the cytotoxic patupilone caused the greatest decrease in IFP. In rat mammary orthotopic BN472 tumors, significant drug-induced decreases in IFP and rTBV correlated positively with each other for both patupilone and the cytostatic vatalanib. In the two orthotopic models studied, early decreases in IFP were significantly (P < or = .005) correlated with late changes in tumor volume. Thus, drug-induced decreases in tumor IFP are an early marker of response to therapy, which could aid clinical development.

  19. Energy input and response from prompt and early optical afterglow emission in gamma-ray bursts.

    PubMed

    Vestrand, W T; Wren, J A; Wozniak, P R; Aptekar, R; Golentskii, S; Pal'shin, V; Sakamoto, T; White, R R; Evans, S; Casperson, D; Fenimore, E

    2006-07-13

    The taxonomy of optical emission detected during the critical first few minutes after the onset of a gamma-ray burst (GRB) defines two broad classes: prompt optical emission correlated with prompt gamma-ray emission, and early optical afterglow emission uncorrelated with the gamma-ray emission. The standard theoretical interpretation attributes prompt emission to internal shocks in the ultra-relativistic outflow generated by the internal engine; early afterglow emission is attributed to shocks generated by interaction with the surrounding medium. Here we report on observations of a bright GRB that, for the first time, clearly show the temporal relationship and relative strength of the two optical components. The observations indicate that early afterglow emission can be understood as reverberation of the energy input measured by prompt emission. Measurements of the early afterglow reverberations therefore probe the structure of the environment around the burst, whereas the subsequent response to late-time impulsive energy releases reveals how earlier flaring episodes have altered the jet and environment parameters. Many GRBs are generated by the death of massive stars that were born and died before the Universe was ten per cent of its current age, so GRB afterglow reverberations provide clues about the environments around some of the first stars.

  20. Early Traumatic Stress Responses in Parents Following a Serious Illness in Their Child: A Systematic Review.

    PubMed

    Woolf, Claudia; Muscara, Frank; Anderson, Vicki A; McCarthy, Maria C

    2016-03-01

    A systematic review of the literature investigating the early traumatic stress responses in parents of children diagnosed with a serious illness/injury. A literature review was conducted (September 2013) using Medline, PsycINFO, and CINAHL databases. Twenty-four studies related to parents of children hospitalized due to diagnosis of cancer, type 1 diabetes, meningococcal disease, trauma or serious injury, preterm birth and other serious illnesses requiring admission to intensive care were included. Parents were assessed for early traumatic stress symptoms within 3 months of their child's diagnosis/hospitalization. Prevalence rates of acute stress disorder in parents ranged from 12 to 63%. Prevalence of posttraumatic stress disorder ranged from 8 to 68%. Variability was related to methodological factors including differences in study design, timing of assessments, measurement tools, and scoring protocols. Psychosocial factors rather than medical factors predicted parent distress. This review integrates and compares early traumatic reactions in parents with children suffering a range of serious illnesses. Findings suggest a high prevalence of acute and posttraumatic stress symptoms in parents. Methodological inconsistencies made comparison of early traumatic stress prevalence rates difficult. Risk factors associated with traumati