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Sample records for lineage progression potential

  1. Lineage factors and differentiation states in lung cancer progression.

    PubMed

    Cheung, W K C; Nguyen, D X

    2015-11-19

    Lung cancer encompasses a heterogeneous group of malignancies. Here we discuss how the remarkable diversity of major lung cancer subtypes is manifested in their transforming cell of origin, oncogenic dependencies, phenotypic plasticity, metastatic competence and response to therapy. More specifically, we review the increasing evidence that links this biological heterogeneity to the deregulation of cell lineage-specific pathways and the transcription factors that ultimately control them. As determinants of pulmonary epithelial differentiation, these poorly characterized transcriptional networks may underlie the etiology and biological progression of distinct lung cancers, while providing insight into innovative therapeutic strategies. PMID:25823023

  2. Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression

    PubMed Central

    Ferrarese, Roberto; Harsh, Griffith R.; Yadav, Ajay K.; Bug, Eva; Maticzka, Daniel; Reichardt, Wilfried; Dombrowski, Stephen M.; Miller, Tyler E.; Masilamani, Anie P.; Dai, Fangping; Kim, Hyunsoo; Hadler, Michael; Scholtens, Denise M.; Yu, Irene L.Y.; Beck, Jürgen; Srinivasasainagendra, Vinodh; Costa, Fabrizio; Baxan, Nicoleta; Pfeifer, Dietmar; von Elverfeldt, Dominik; Backofen, Rolf; Weyerbrock, Astrid; Duarte, Christine W.; He, Xiaolin; Prinz, Marco; Chandler, James P.; Vogel, Hannes; Chakravarti, Arnab; Rich, Jeremy N.; Carro, Maria S.; Bredel, Markus

    2014-01-01

    Tissue-specific alternative splicing is critical for the emergence of tissue identity during development, yet the role of this process in malignant transformation is undefined. Tissue-specific splicing involves evolutionarily conserved, alternative exons that represent only a minority of the total alternative exons identified. Many of these conserved exons have functional features that influence signaling pathways to profound biological effect. Here, we determined that lineage-specific splicing of a brain-enriched cassette exon in the membrane-binding tumor suppressor annexin A7 (ANXA7) diminishes endosomal targeting of the EGFR oncoprotein, consequently enhancing EGFR signaling during brain tumor progression. ANXA7 exon splicing was mediated by the ribonucleoprotein PTBP1, which is normally repressed during neuronal development. PTBP1 was highly expressed in glioblastomas due to loss of a brain-enriched microRNA (miR-124) and to PTBP1 amplification. The alternative ANXA7 splicing trait was present in precursor cells, suggesting that glioblastoma cells inherit the trait from a potential tumor-initiating ancestor and that these cells exploit this trait through accumulation of mutations that enhance EGFR signaling. Our data illustrate that lineage-specific splicing of a tissue-regulated alternative exon in a constituent of an oncogenic pathway eliminates tumor suppressor functions and promotes glioblastoma progression. This paradigm may offer a general model as to how tissue-specific regulatory mechanisms can reprogram normal developmental processes into oncogenic ones. PMID:24865424

  3. Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression.

    PubMed

    Ferrarese, Roberto; Harsh, Griffith R; Yadav, Ajay K; Bug, Eva; Maticzka, Daniel; Reichardt, Wilfried; Dombrowski, Stephen M; Miller, Tyler E; Masilamani, Anie P; Dai, Fangping; Kim, Hyunsoo; Hadler, Michael; Scholtens, Denise M; Yu, Irene L Y; Beck, Jürgen; Srinivasasainagendra, Vinodh; Costa, Fabrizio; Baxan, Nicoleta; Pfeifer, Dietmar; von Elverfeldt, Dominik; Backofen, Rolf; Weyerbrock, Astrid; Duarte, Christine W; He, Xiaolin; Prinz, Marco; Chandler, James P; Vogel, Hannes; Chakravarti, Arnab; Rich, Jeremy N; Carro, Maria S; Bredel, Markus

    2014-07-01

    Tissue-specific alternative splicing is critical for the emergence of tissue identity during development, yet the role of this process in malignant transformation is undefined. Tissue-specific splicing involves evolutionarily conserved, alternative exons that represent only a minority of the total alternative exons identified. Many of these conserved exons have functional features that influence signaling pathways to profound biological effect. Here, we determined that lineage-specific splicing of a brain-enriched cassette exon in the membrane-binding tumor suppressor annexin A7 (ANXA7) diminishes endosomal targeting of the EGFR oncoprotein, consequently enhancing EGFR signaling during brain tumor progression. ANXA7 exon splicing was mediated by the ribonucleoprotein PTBP1, which is normally repressed during neuronal development. PTBP1 was highly expressed in glioblastomas due to loss of a brain-enriched microRNA (miR-124) and to PTBP1 amplification. The alternative ANXA7 splicing trait was present in precursor cells, suggesting that glioblastoma cells inherit the trait from a potential tumor-initiating ancestor and that these cells exploit this trait through accumulation of mutations that enhance EGFR signaling. Our data illustrate that lineage-specific splicing of a tissue-regulated alternative exon in a constituent of an oncogenic pathway eliminates tumor suppressor functions and promotes glioblastoma progression. This paradigm may offer a general model as to how tissue-specific regulatory mechanisms can reprogram normal developmental processes into oncogenic ones. PMID:24865424

  4. Data defining markers of human neural stem cell lineage potential.

    PubMed

    Oikari, Lotta E; Okolicsanyi, Rachel K; Griffiths, Lyn R; Haupt, Larisa M

    2016-06-01

    Neural stem cells (NSCs) and neural progenitor cells (NPCs) are self-renewing and multipotent cells, however, NPCs are considered to be more lineage-restricted with a reduced self-renewing capacity. We present data comparing the expression of 21 markers encompassing pluripotency, self-renewal (NSC) as well as neuronal and glial (astrocyte and oligodendrocyte) lineage specification and 28 extracellular proteoglycan (PG) genes and their regulatory enzymes between embryonic stem cell (ESC)-derived human NSCs (hNSC H9 cells, Thermo Fisher) and human cortex-derived normal human NPCs (nhNPCs, Lonza). The data demonstrates expression differences of multiple lineage and proteoglycan-associated genes between hNSC H9 cells and nhNPCs. Data interpretation of markers and proteoglycans defining NSC and neural cell lineage characterisation can be found in "Cell surface heparan sulfate proteoglycans as novel markers of human neural stem cell fate determination" (Oikari et al. 2015) [1]. PMID:26958640

  5. Data defining markers of human neural stem cell lineage potential

    PubMed Central

    Oikari, Lotta E.; Okolicsanyi, Rachel K.; Griffiths, Lyn R.; Haupt, Larisa M.

    2016-01-01

    Neural stem cells (NSCs) and neural progenitor cells (NPCs) are self-renewing and multipotent cells, however, NPCs are considered to be more lineage-restricted with a reduced self-renewing capacity. We present data comparing the expression of 21 markers encompassing pluripotency, self-renewal (NSC) as well as neuronal and glial (astrocyte and oligodendrocyte) lineage specification and 28 extracellular proteoglycan (PG) genes and their regulatory enzymes between embryonic stem cell (ESC)-derived human NSCs (hNSC H9 cells, Thermo Fisher) and human cortex-derived normal human NPCs (nhNPCs, Lonza). The data demonstrates expression differences of multiple lineage and proteoglycan-associated genes between hNSC H9 cells and nhNPCs. Data interpretation of markers and proteoglycans defining NSC and neural cell lineage characterisation can be found in “Cell surface heparan sulfate proteoglycans as novel markers of human neural stem cell fate determination” (Oikari et al. 2015) [1]. PMID:26958640

  6. Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential.

    PubMed

    Bolton, Helen; Graham, Sarah J L; Van der Aa, Niels; Kumar, Parveen; Theunis, Koen; Fernandez Gallardo, Elia; Voet, Thierry; Zernicka-Goetz, Magdalena

    2016-01-01

    Most human pre-implantation embryos are mosaics of euploid and aneuploid cells. To determine the fate of aneuploid cells and the developmental potential of mosaic embryos, here we generate a mouse model of chromosome mosaicism. By treating embryos with a spindle assembly checkpoint inhibitor during the four- to eight-cell division, we efficiently generate aneuploid cells, resulting in embryo death during peri-implantation development. Live-embryo imaging and single-cell tracking in chimeric embryos, containing aneuploid and euploid cells, reveal that the fate of aneuploid cells depends on lineage: aneuploid cells in the fetal lineage are eliminated by apoptosis, whereas those in the placental lineage show severe proliferative defects. Overall, the proportion of aneuploid cells is progressively depleted from the blastocyst stage onwards. Finally, we show that mosaic embryos have full developmental potential, provided they contain sufficient euploid cells, a finding of significance for the assessment of embryo vitality in the clinic. PMID:27021558

  7. Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential

    PubMed Central

    Bolton, Helen; Graham, Sarah J. L.; Van der Aa, Niels; Kumar, Parveen; Theunis, Koen; Fernandez Gallardo, Elia; Voet, Thierry; Zernicka-Goetz, Magdalena

    2016-01-01

    Most human pre-implantation embryos are mosaics of euploid and aneuploid cells. To determine the fate of aneuploid cells and the developmental potential of mosaic embryos, here we generate a mouse model of chromosome mosaicism. By treating embryos with a spindle assembly checkpoint inhibitor during the four- to eight-cell division, we efficiently generate aneuploid cells, resulting in embryo death during peri-implantation development. Live-embryo imaging and single-cell tracking in chimeric embryos, containing aneuploid and euploid cells, reveal that the fate of aneuploid cells depends on lineage: aneuploid cells in the fetal lineage are eliminated by apoptosis, whereas those in the placental lineage show severe proliferative defects. Overall, the proportion of aneuploid cells is progressively depleted from the blastocyst stage onwards. Finally, we show that mosaic embryos have full developmental potential, provided they contain sufficient euploid cells, a finding of significance for the assessment of embryo vitality in the clinic. PMID:27021558

  8. Transmission and Progression to Disease of Mycobacterium tuberculosis Phylogenetic Lineages in The Netherlands

    PubMed Central

    Verhagen, Lilly M.; Borgdorff, Martien W.; van Soolingen, Dick

    2015-01-01

    The aim of this study was to determine if mycobacterial lineages affect infection risk, clustering, and disease progression among Mycobacterium tuberculosis cases in The Netherlands. Multivariate negative binomial regression models adjusted for patient-related factors and stratified by patient ethnicity were used to determine the association between phylogenetic lineages and infectivity (mean number of positive contacts around each patient) and clustering (as defined by number of secondary cases within 2 years after diagnosis of an index case sharing the same fingerprint) indices. An estimate of progression to disease by each risk factor was calculated as a bootstrapped risk ratio of the clustering index by the infectivity index. Compared to the Euro-American reference, Mycobacterium africanum showed significantly lower infectivity and clustering indices in the foreign-born population, while Mycobacterium bovis showed significantly lower infectivity and clustering indices in the native population. Significantly lower infectivity was also observed for the East African Indian lineage in the foreign-born population. Smear positivity was a significant risk factor for increased infectivity and increased clustering. Estimates of progression to disease were significantly associated with age, sputum-smear status, and behavioral risk factors, such as alcohol and intravenous drug abuse, but not with phylogenetic lineages. In conclusion, we found evidence of a bacteriological factor influencing indicators of a strain's transmissibility, namely, a decreased ability to infect and a lower clustering index in ancient phylogenetic lineages compared to their modern counterparts. Confirmation of these findings via follow-up studies using tuberculin skin test conversion data should have important implications on M. tuberculosis control efforts. PMID:26224845

  9. The Earliest Thymic T Cell Progenitors Sustain B Cell and Myeloid Lineage Potentials

    PubMed Central

    Luc, Sidinh; Luis, Tiago C.; Boukarabila, Hanane; Macaulay, Iain C.; Buza-Vidas, Natalija; Bouriez-Jones, Tiphaine; Lutteropp, Michael; Woll, Petter S.; Loughran, Stephen J.; Mead, Adam J.; Hultquist, Anne; Brown, John; Mizukami, Takuo; Matsuoka, Sahoko; Ferry, Helen; Anderson, Kristina; Duarte, Sara; Atkinson, Deborah; Soneji, Shamit; Domanski, Aniela; Farley, Alison; Sanjuan-Pla, Alejandra; Carella, Cintia; Patient, Roger; de Bruijn, Marella; Enver, Tariq; Nerlov, Claus; Blackburn, Clare; Godin, Isabelle; Jacobsen, Sten Eirik W.

    2012-01-01

    The stepwise commitment from hematopoietic stem cells in the bone marrow (BM) to T lymphocyte-restricted progenitors in the thymus represents a paradigm for understanding the requirement for distinct extrinsic cues during different stages of lineage restriction from multipotent to lineage restricted progenitors. However, the commitment stage at which progenitors migrate from the BM to the thymus remains unclear. Here we provide functional and molecular evidence at the single cell level that the earliest progenitors in the neonatal thymus possessed combined granulocyte-monocyte, T and B lymphocyte, but not megakaryocyte-erythroid lineage potential. These potentials were identical to those of thymus-seeding progenitors in the BM, which were closely related at the molecular level. These findings establish the distinct lineage-restriction stage at which the T lineage commitment transits from the BM to the remote thymus. PMID:22344248

  10. Widespread Occurrence of Secondary Lipid Biosynthesis Potential in Microbial Lineages

    PubMed Central

    Shulse, Christine N.; Allen, Eric E.

    2011-01-01

    Bacterial production of long-chain omega-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3), is constrained to a narrow subset of marine γ-proteobacteria. The genes responsible for de novo bacterial PUFA biosynthesis, designated pfaEABCD, encode large, multi-domain protein complexes akin to type I iterative fatty acid and polyketide synthases, herein referred to as “Pfa synthases”. In addition to the archetypal Pfa synthase gene products from marine bacteria, we have identified homologous type I FAS/PKS gene clusters in diverse microbial lineages spanning 45 genera representing 10 phyla, presumed to be involved in long-chain fatty acid biosynthesis. In total, 20 distinct types of gene clusters were identified. Collectively, we propose the designation of “secondary lipids” to describe these biosynthetic pathways and products, a proposition consistent with the “secondary metabolite” vernacular. Phylogenomic analysis reveals a high degree of functional conservation within distinct biosynthetic pathways. Incongruence between secondary lipid synthase functional clades and taxonomic group membership combined with the lack of orthologous gene clusters in closely related strains suggests horizontal gene transfer has contributed to the dissemination of specialized lipid biosynthetic activities across disparate microbial lineages. PMID:21629834

  11. Lineage, fate, and fate potential of NG2-glia.

    PubMed

    Nishiyama, Akiko; Boshans, Linda; Goncalves, Christopher M; Wegrzyn, Jill; Patel, Kiran D

    2016-05-01

    NG2 cells represent a fourth major glial cell population in the mammalian central nervous system (CNS). They arise from discrete germinal zones in mid-gestation embryos and expand to occupy the entire CNS parenchyma. Genetic fate mapping studies have shown that oligodendrocytes and a subpopulation of ventral protoplasmic astrocytes arise from NG2 cells. This review describes recent findings on the fate and fate potential of NG2 cells under physiological and pathological conditions. We discuss age-dependent changes in the fate and fate potential of NG2 cells and possible mechanisms that could be involved in restricting their oligodendrocyte differentiation or fate plasticity. This article is part of a Special Issue entitled SI:NG2-glia(Invited only). PMID:26301825

  12. Loss of tumorigenic potential upon transdifferentiation from keratinocytic into melanocytic lineage.

    PubMed

    Fehrenbach, Sabrina; Novak, Daniel; Bernhardt, Mathias; Larribere, Lionel; Boukamp, Petra; Umansky, Viktor; Utikal, Jochen

    2016-01-01

    Lineage-specific transcription factors determine the cell fate during development. Direct conversion of several cell types into other lineages has been achieved by the overexpression of specific transcription factors. Even cancer cells have been demonstrated to be amenable to transdifferentiation. Here, we identified a distinct set of transcription factors, which are sufficient to transform cells of the keratinocytic lineage to melanocyte-like cells. Melanocyte marker expression was induced and melanosome formation was observed in non-tumorigenic keratinocytes (HaCaT) and tumorigenic squamous cell carcinoma (MET-4) cells. Moreover, reduced proliferation, cell metabolism, invasion and migration were measured in vitro in transdifferentiated MT-MET-4 cells. A loss of tumorigenic potential of squamous cell carcinoma cells could be due to the upregulation of the melanocyte differentiation associated gene IL-24. Our data show that cells from the keratinocytic lineage can be transdifferented into the melanocytic lineage and provide a proof of principle for a potential new therapeutic strategy. PMID:27387763

  13. Loss of tumorigenic potential upon transdifferentiation from keratinocytic into melanocytic lineage

    PubMed Central

    Fehrenbach, Sabrina; Novak, Daniel; Bernhardt, Mathias; Larribere, Lionel; Boukamp, Petra; Umansky, Viktor; Utikal, Jochen

    2016-01-01

    Lineage-specific transcription factors determine the cell fate during development. Direct conversion of several cell types into other lineages has been achieved by the overexpression of specific transcription factors. Even cancer cells have been demonstrated to be amenable to transdifferentiation. Here, we identified a distinct set of transcription factors, which are sufficient to transform cells of the keratinocytic lineage to melanocyte-like cells. Melanocyte marker expression was induced and melanosome formation was observed in non-tumorigenic keratinocytes (HaCaT) and tumorigenic squamous cell carcinoma (MET-4) cells. Moreover, reduced proliferation, cell metabolism, invasion and migration were measured in vitro in transdifferentiated MT-MET-4 cells. A loss of tumorigenic potential of squamous cell carcinoma cells could be due to the upregulation of the melanocyte differentiation associated gene IL-24. Our data show that cells from the keratinocytic lineage can be transdifferented into the melanocytic lineage and provide a proof of principle for a potential new therapeutic strategy. PMID:27387763

  14. Lineage-specific function of Engrailed-2 in the progression of chronic myelogenous leukemia to T-cell blast crisis

    PubMed Central

    Abollo-Jiménez, Fernando; Campos-Sánchez, Elena; Toboso-Navasa, Amparo; Vicente-Dueñas, Carolina; González-Herrero, Inés; Alonso-Escudero, Esther; González, Marcos; Segura, Víctor; Blanco, Óscar; Martínez-Climent, José Ángel; Sánchez-García, Isidro; Cobaleda, César

    2014-01-01

    In hematopoietic malignancies, oncogenic alterations interfere with cellular differentiation and lead to tumoral development. Identification of the proteins regulating differentiation is essential to understand how they are altered in malignancies. Chronic myelogenous leukemia (CML) is a biphasic disease initiated by an alteration taking place in hematopoietic stem cells. CML progresses to a blast crisis (BC) due to a secondary differentiation block in any of the hematopoietic lineages. However, the molecular mechanisms of CML evolution to T-cell BC remain unclear. Here, we have profiled the changes in DNA methylation patterns in human samples from BC-CML, in order to identify genes whose expression is epigenetically silenced during progression to T-cell lineage-specific BC. We have found that the CpG-island of the ENGRAILED-2 (EN2) gene becomes methylated in this progression. Afterwards, we demonstrate that En2 is expressed during T-cell development in mice and humans. Finally, we further show that genetic deletion of En2 in a CML transgenic mouse model induces a T-cell lineage BC that recapitulates human disease. These results identify En2 as a new regulator of T-cell differentiation whose disruption induces a malignant T-cell fate in CML progression, and validate the strategy used to identify new developmental regulators of hematopoiesis. PMID:24675889

  15. T-Cell Lineage Determination

    PubMed Central

    Yang, Qi; Bell, J. Jeremiah; Bhandoola, Avinash

    2010-01-01

    Summary T cells originate from hematopoietic stem cells (HSCs) in the bone marrow but complete their development in the thymus. HSCs give rise to a variety of non-renewing hematopoietic progenitors, among which a rare subset migrates to the thymus via the bloodstream. The earliest T-cell progenitors identified in the thymus are not T-lineage restricted but possess the ability to give rise to cells of many different lineages. Alternative lineage potentials are gradually lost as progenitors progress towards later developmental stages. Here, we review the early developmental events that might be involved in T-cell lineage fate determination, including the properties of possible thymus settling progenitors, their homing into the thymus, and their T-cell lineage specification and commitment. PMID:20969581

  16. Lymphoid lineage differentiation potential of mouse nuclear transfer embryonic stem cells.

    PubMed

    Eslami-Arshaghi, Tarlan; Salehi, Mohammad; Soleimani, Masoud; Gholipourmalekabadi, Mazaher; Mossahebi-Mohammadi, Majid; Ardeshirylajimi, Abdolreza; Rajabi, Hoda

    2015-09-01

    Stem cells therapy is considered as an efficient strategy for the treatment of some diseases. Nevertheless, some obstacles such as probability of rejection by the immune system limit applications of this strategy. Therefore, several efforts have been made to overcome this among which using the induced pluripotent stem cells (iPSCs) and nuclear transfer embryonic stem cell (nt-ESCs) are the most efficient strategies. The objective of this study was to evaluate the differentiation potential of the nt-ESCs to lymphoid lineage in the presence of IL-7, IL-3, FLT3-ligand and TPO growth factors in vitro. To this end, the nt-ESCs cells were prepared and treated with aforementioned growth factors for 7 and 14 days. Then, the cells were examined for expression of lymphoid markers (CD3, CD25, CD127 and CD19) by quantitative PCR (q-PCR) and flow cytometry. An increased expression of CD19 and CD25 markers was observed in the treated cells compared with the negative control samples by day 7. After 14 days, the expression level of all the tested CD markers significantly increased in the treated groups in comparison with the control. The current study reveals the potential of the nt-ESCs in differentiation to lymphoid lineage in the presence of defined growth factors. PMID:26239678

  17. A case of cellular alchemy: lineage reprogramming and its potential in regenerative medicine.

    PubMed

    Asuelime, Grace E; Shi, Yanhong

    2012-08-01

    The field of regenerative medicine is rapidly gaining momentum as an increasing number of reports emerge concerning the induced conversions observed in cellular fate reprogramming. While in recent years, much attention has been focused on the conversion of fate-committed somatic cells to an embryonic-like or pluripotent state, there are still many limitations associated with the applications of induced pluripotent stem cell reprogramming, including relatively low reprogramming efficiency, the times required for the reprogramming event to take place, the epigenetic instability, and the tumorigenicity associated with the pluripotent state. On the other hand, lineage reprogramming involves the conversion from one mature cell type to another without undergoing conversion to an unstable intermediate. It provides an alternative approach in regenerative medicine that has a relatively lower risk of tumorigenesis and increased efficiency within specific cellular contexts. While lineage reprogramming provides exciting potential, there is still much to be assessed before this technology is ready to be applied in a clinical setting. PMID:22371436

  18. In vitro assays misrepresent in vivo lineage potentials of murine lymphoid progenitors.

    PubMed

    Richie Ehrlich, Lauren I; Serwold, Thomas; Weissman, Irving L

    2011-03-01

    The identity of T-cell progenitors that seed the thymus has remained controversial, largely because many studies differ over whether these progenitors retain myeloid potential. Contradictory reports diverge in their use of various in vitro and in vivo assays. To consolidate these discordant findings, we compared the myeloid potential of 2 putative thymus seeding populations, common lymphoid progenitors (CLPs) and multipotent progenitors (MPPs), and the earliest intrathymic progenitor (DN1), using 2 in vitro assays and in vivo readouts. These assays gave contradictory results: CLP and DN1 displayed surprisingly robust myeloid potential on OP9-DL1 in vitro stromal cocultures but displayed little myeloid potential in vivo, as well as in methylcellulose cultures. MPP, on the other hand, displayed robust myeloid potential in all settings. We conclude that stromal cocultures reveal cryptic, but nonphysiologic, myeloid potentials of lymphoid progenitors, providing an explanation for contradictory findings in the field and underscoring the importance of using in vivo assays for the determination of physiologic lineage potentials. PMID:21163922

  19. Septo-temporal distribution and lineage progression of hippocampal neurogenesis in a primate (Callithrix jacchus) in comparison to mice

    PubMed Central

    Amrein, Irmgard; Nosswitz, Michael; Slomianka, Lutz; van Dijk, R. Maarten; Engler, Stefanie; Klaus, Fabienne; Raineteau, Olivier; Azim, Kasum

    2015-01-01

    Adult born neurons in the hippocampus show species-specific differences in their numbers, the pace of their maturation and their spatial distribution. Here, we present quantitative data on adult hippocampal neurogenesis in a New World primate, the common marmoset (Callithrix jacchus) that demonstrate parts of the lineage progression and age-related changes. Proliferation was largely (∼70%) restricted to stem cells or early progenitor cells, whilst the remainder of the cycling pool could be assigned almost exclusively to Tbr2+ intermediate precursor cells in both neonate and adult animals (20–122 months). Proliferating DCX+ neuroblasts were virtually absent in adults, although rare MCM2+/DCX+ co-expression revealed a small, persisting proliferative potential. Co-expression of DCX with calretinin was very limited in marmosets, suggesting that these markers label distinct maturational stages. In adult marmosets, numbers of MCM2+, Ki67+, and significantly Tbr2+, DCX+, and CR+ cells declined with age. The distributions of granule cells, proliferating cells and DCX+ young neurons along the hippocampal longitudinal axis were equal in marmosets and mice. In both species, a gradient along the hippocampal septo-temporal axis was apparent for DCX+ and resident granule cells. Both cell numbers are higher septally than temporally, whilst proliferating cells were evenly distributed along this axis. Relative to resident granule cells, however, the ratio of proliferating cells and DCX+ neurons remained constant in the septal, middle, and temporal hippocampus. In marmosets, the extended phase of the maturation of young neurons that characterizes primate hippocampal neurogenesis was due to the extension in a large CR+/DCX- cell population. This clear dissociation between DCX+ and CR+ young neurons has not been reported for other species and may therefore represent a key primate-specific feature of adult hippocampal neurogenesis. PMID:26175670

  20. Regulation of early T-lineage gene expression and developmental progression by the progenitor cell transcription factor PU.1

    PubMed Central

    Champhekar, Ameya; Damle, Sagar S.; Freedman, George; Carotta, Sebastian; Nutt, Stephen L.

    2015-01-01

    The ETS family transcription factor PU.1 is essential for the development of several blood lineages, including T cells, but its function in intrathymic T-cell precursors has been poorly defined. In the thymus, high PU.1 expression persists through multiple cell divisions in early stages but then falls sharply during T-cell lineage commitment. PU.1 silencing is critical for T-cell commitment, but it has remained unknown how PU.1 activities could contribute positively to T-cell development. Here we employed conditional knockout and modified antagonist PU.1 constructs to perturb PU.1 function stage-specifically in early T cells. We show that PU.1 is needed for full proliferation, restricting access to some non-T fates, and controlling the timing of T-cell developmental progression such that removal or antagonism of endogenous PU.1 allows precocious access to T-cell differentiation. Dominant-negative effects reveal that this repression by PU.1 is mediated indirectly. Genome-wide transcriptome analysis identifies novel targets of PU.1 positive and negative regulation affecting progenitor cell signaling and cell biology and indicating distinct regulatory effects on different subsets of progenitor cell transcription factors. Thus, in addition to supporting early T-cell proliferation, PU.1 regulates the timing of activation of the core T-lineage developmental program. PMID:25846797

  1. Membrane potential and cancer progression

    PubMed Central

    Yang, Ming; Brackenbury, William J.

    2013-01-01

    Membrane potential (Vm), the voltage across the plasma membrane, arises because of the presence of different ion channels/transporters with specific ion selectivity and permeability. Vm is a key biophysical signal in non-excitable cells, modulating important cellular activities, such as proliferation and differentiation. Therefore, the multiplicities of various ion channels/transporters expressed on different cells are finely tuned in order to regulate the Vm. It is well-established that cancer cells possess distinct bioelectrical properties. Notably, electrophysiological analyses in many cancer cell types have revealed a depolarized Vm that favors cell proliferation. Ion channels/transporters control cell volume and migration, and emerging data also suggest that the level of Vm has functional roles in cancer cell migration. In addition, hyperpolarization is necessary for stem cell differentiation. For example, both osteogenesis and adipogenesis are hindered in human mesenchymal stem cells (hMSCs) under depolarizing conditions. Therefore, in the context of cancer, membrane depolarization might be important for the emergence and maintenance of cancer stem cells (CSCs), giving rise to sustained tumor growth. This review aims to provide a broad understanding of the Vm as a bioelectrical signal in cancer cells by examining several key types of ion channels that contribute to its regulation. The mechanisms by which Vm regulates cancer cell proliferation, migration, and differentiation will be discussed. In the long term, Vm might be a valuable clinical marker for tumor detection with prognostic value, and could even be artificially modified in order to inhibit tumor growth and metastasis. PMID:23882223

  2. Potential merger of ancient lineages in a passerine bird discovered based on evidence from host-specific ectoparasites

    PubMed Central

    Block, Nicholas L; Goodman, Steven M; Hackett, Shannon J; Bates, John M; Raherilalao, Marie J

    2015-01-01

    The merger of formerly isolated lineages is hypothesized to occur in vertebrates under certain conditions. However, despite many demonstrated instances of introgression between taxa in secondary contact, examples of lineage mergers are rare. Preliminary mtDNA sequencing of a Malagasy passerine, Xanthomixis zosterops (Passeriformes: Bernieridae), indicated a possible instance of merging lineages. We tested the hypothesis that X. zosterops lineages are merging by comparing mtDNA sequence and microsatellite data, as well as mtDNA sequence data from host-specific feather lice in the genus Myrsidea (Phthiraptera: Menoponidae). Xanthomixis zosterops comprises four deeply divergent, broadly sympatric, cryptic mtDNA clades that likely began diverging approximately 3.6 million years ago. Despite this level of divergence, the microsatellite data indicate that the X. zosterops mtDNA clades are virtually panmictic. Three major phylogroups of Myrsidea were found, supporting previous allopatry of the X. zosterops clades. In combination, the datasets from X. zosterops and its Myrsidea document a potential merger of previously allopatric lineages that likely date to the Pliocene. This represents the first report of sympatric apparent hybridization among more than two terrestrial vertebrate lineages. Further, the mtDNA phylogeographic pattern of X. zosterops, namely the syntopy of more than two deeply divergent cryptic clades, appears to be a novel scenario among vertebrates. We highlight the value of gathering multiple types of data in phylogeographic studies to contribute to the study of vertebrate speciation. PMID:26380702

  3. Strains of the Propionibacterium acnes type III lineage are associated with the skin condition progressive macular hypomelanosis

    PubMed Central

    Barnard, Emma; Liu, Jared; Yankova, Eliza; Cavalcanti, Silvana M.; Magalhães, Marcelo; Li, Huiying; Patrick, Sheila; McDowell, Andrew

    2016-01-01

    Progressive macular hypomelanosis (PMH) is a common skin disorder that causes hypopigmentation in a variety of skin types. Although the underlying aetiology of this condition is unclear, there is circumstantial evidence that links the skin bacterium Propionibacterium acnes to the condition. We now describe the first detailed population genetic analysis of P. acnes isolates recovered from paired lesional and non-lesional skin of PMH patients. Our results demonstrate a strong statistical association between strains from the type III phylogenetic lineage and PMH lesions (P = 0.0019), but not those representing other phylogroups, including those associated with acne (type IA1). We also demonstrate, based on in silico 16S rDNA analysis, that PMH isolates previously recovered from patients in Europe are also consistent with the type III lineage. Using comparative genome analysis, we identified multiple genomic regions that are specific for, or absent from, type III strains compared to other phylogroups. In the former case, these include open reading frames with putative functions in metabolism, transport and transcriptional regulation, as well as predicted proteins of unknown function. Further study of these genomic elements, along with transcriptional and functional analyses, may help to explain why type III strains are associated with PMH. PMID:27555369

  4. Tbr2 is essential for hippocampal lineage progression from neural stem cells to intermediate progenitors and neurons

    PubMed Central

    Hodge, Rebecca D.; Nelson, Branden R.; Kahoud, Robert J.; Yang, Roderick; Mussar, Kristin E.; Reiner, Steven L.; Hevner, Robert F.

    2012-01-01

    Neurogenesis in the dentate gyrus has been implicated in cognitive functions including learning and memory, and may be abnormal in major neuropsychiatric disorders such as depression. Dentate neurogenesis is regulated by interactions between extrinsic factors and intrinsic transcriptional cascades that are currently not well understood. Here we show that Tbr2 (also known as Eomes), a T-box transcription factor expressed by intermediate neuronal progenitors (INPs), is critically required for neurogenesis in the dentate gyrus of developing and adult mice. In the absence of Tbr2, INPs are depleted despite augmented neural stem cell (NSC) proliferation, and neurogenesis is halted as the result of failed neuronal differentiation. Interestingly, we find that Tbr2 likely promotes lineage progression from NSC to neuronal-specified INP in part by repression of Sox2, a key determinant of NSC identity. These findings suggest that Tbr2 expression in INPs is critical for neuronal differentiation in the dentate gyrus, and that INPs are an essential stage in the lineage from NSCs to new granule neurons in the dentate gyrus. PMID:22553033

  5. Strains of the Propionibacterium acnes type III lineage are associated with the skin condition progressive macular hypomelanosis.

    PubMed

    Barnard, Emma; Liu, Jared; Yankova, Eliza; Cavalcanti, Silvana M; Magalhães, Marcelo; Li, Huiying; Patrick, Sheila; McDowell, Andrew

    2016-01-01

    Progressive macular hypomelanosis (PMH) is a common skin disorder that causes hypopigmentation in a variety of skin types. Although the underlying aetiology of this condition is unclear, there is circumstantial evidence that links the skin bacterium Propionibacterium acnes to the condition. We now describe the first detailed population genetic analysis of P. acnes isolates recovered from paired lesional and non-lesional skin of PMH patients. Our results demonstrate a strong statistical association between strains from the type III phylogenetic lineage and PMH lesions (P = 0.0019), but not those representing other phylogroups, including those associated with acne (type IA1). We also demonstrate, based on in silico 16S rDNA analysis, that PMH isolates previously recovered from patients in Europe are also consistent with the type III lineage. Using comparative genome analysis, we identified multiple genomic regions that are specific for, or absent from, type III strains compared to other phylogroups. In the former case, these include open reading frames with putative functions in metabolism, transport and transcriptional regulation, as well as predicted proteins of unknown function. Further study of these genomic elements, along with transcriptional and functional analyses, may help to explain why type III strains are associated with PMH. PMID:27555369

  6. The potential for gene flow in a dependent lineage system of a harvester ant: fair meiosis in the F1 generation.

    PubMed

    Curry, Meghan M; Wheeler, Diana E; Yang, Kimberly; Anderson, Kirk E

    2010-01-01

    We investigated the potential for gene flow in a dependent lineage (DL) system of the harvester ant Pogonomyrmex. Each DL system is composed of 2 reproductively isolated lineages that are locked in an obligate mutualism. The genetic components that produce the worker phenotype are acquired by hybridizing with the partner lineage. In the mating flight, queens of both lineages mate with multiple males from each lineage. During colony growth and reproduction, eggs fertilized by partner-lineage sperm produce F(1) hybrid workers with interlineage genomes, whereas eggs fertilized by same-lineage sperm result in the development of new queens with intralineage genomes. New males are typically produced from unfertilized eggs laid by the pure-lineage queen but in her absence may be produced by interlineage F(1) workers. We investigated the potential for interlineage gene flow in this system using 2 classes of lineage-specific nuclear markers to identify hybrid genome combinations. We confirmed the production of viable interlineage F(1) reproductive females in field colonies, the occurrence of which is associated with the relative frequencies of each lineage in the population: interlineage F(1) queens occurred only in the rare lineage of the population with dramatically skewed lineage frequencies. In laboratory colonies, we detected fair meiosis in interlineage F(1) workers leading to the production of viable and haploid interlineage F(2) males. We conclude that the genomes of each lineage recombine freely, suggesting that extrinsic postzygotic selection maintains the integrity of each lineage genome. We compare our findings with those of the H1/H2 DL system. PMID:20022894

  7. P01.08LINEAGE-SPECIFIC SPLICING OF AN ALTERNATIVE EXON OF ANXA7 PROMOTES EGFR SIGNALING ACTIVATION AND TUMOR PROGRESSION IN GLIOBLASTOMA

    PubMed Central

    Ferrarese, R.; Bug, E.; Maticzka, D.; Reichardt, W.; Masilamani, A.P.; Dai, F.; Weyerbrock, A.; Prinz, M.; Bredel, M.; Carro, M.S.

    2014-01-01

    Tissue-specific alternative splicing is critical to the emergence of tissue identity during development, yet its role in malignant transformation is undefined. Tissue-specific splicing involves evolutionarily-conserved, alternative exons, which represent only a minority of total alternative exons. Many, however, have functional features that influence signaling pathways to profound biological effect. In the brain, Annexin A7 isoform 1 (ANXA7-I1) is exclusively expressed in mature neurons, while isoform 2 (ANXA7-I2) in which exon 6 is skipped, is expressed in glial and progenitor cells. We show that lineage-specific splicing of the cassette exon 6 in the membrane-binding tumor suppressor ANXA7diminishes endosomal targeting and consequent signal termination of the EGFR oncoprotein during brain tumor progression. Splicing of this exon is mediated by Polypyrimidine Tract-Binding Protein 1 (PTBP1), a ribonucleoprotein normally repressed during neuronal development but which we found to be highly expressed also in glioblastomas through loss of a brain-enriched microRNA, miR-124, and gene amplification. Here, we show that the PTBP1-ANXA7 splicing-EGFR signal activation axis promotes in vitro cell migration and invasion, and tumor angiogenesis in vivo. In glioblastoma, ANXA7 splicing is likely inherited from a potential tumor-initiating ancestor but this trait is further exploited through accumulation of mutations that enhance EGFR signaling. Our data illustrate how lineage-specific splicing of a tissue-regulated alternative exon in a constituent of an oncogenic pathway eliminates its tumor suppressor function and promotes glioblastoma progression. This paradigm may offer a general model as to how tissue-specific regulatory mechanisms can contribute to reprogramming normal development to oncogenesis.

  8. Intracellular Inactivation of Thyroid Hormone Is a Survival Mechanism for Muscle Stem Cell Proliferation and Lineage Progression

    PubMed Central

    Dentice, Monica; Ambrosio, Raffaele; Damiano, Valentina; Sibilio, Annarita; Luongo, Cristina; Guardiola, Ombretta; Yennek, Siham; Zordan, Paola; Minchiotti, Gabriella; Colao, Annamaria; Marsili, Alessandro; Brunelli, Silvia; Del Vecchio, Luigi; Larsen, P. Reed; Tajbakhsh, Shahragim; Salvatore, Domenico

    2014-01-01

    Summary Precise control of the thyroid hormone (T3)-dependent transcriptional program is required by multiple cell systems, including muscle stem cells. Deciphering how this is achieved and how the T3 signal is controlled in stem cell niches is essentially unknown. We report that in response to proliferative stimuli such as acute skeletal muscle injury, type 3 deiodinase (D3), the thyroid hormone-inactivating enzyme, is induced in satellite cells where it reduces intracellular thyroid signaling. Satellite cell-specific genetic ablation of dio3 severely impairs skeletal muscle regeneration. This impairment is due to massive satellite cell apoptosis caused by exposure of activated satellite cells to the circulating TH. The execution of this proapoptotic program requires an intact FoxO3/MyoD axis, both genes positively regulated by intracellular TH. Thus, D3 is dynamically exploited in vivo to chronically attenuate TH signaling under basal conditions while also being available to acutely increase gene programs required for satellite cell lineage progression. PMID:25456740

  9. NSE/αNAE positivity in B-lineage acute lymphoblastic leukemia: revisiting a potential cytochemical diagnostic pitfall.

    PubMed

    Sharma, P; Tyagi, S

    2014-01-01

    Cytochemical staining for leukemia typing is declining in hematology laboratories, but the use of flow cytometry may not be possible in some settings. Aberrant cytochemical nonspecific esterase/α-naphthyl acetate esterase (NSE/αNAE) positive B-lymphoblasts can cause confusion with monoblasts, a potentially dangerous pitfall. This unusual cytochemical NSE/αNAE positivity had been associated with relatively poorer outcome of acute lymphoblastic leukemia (ALL) in the era prior to the advent of routine multicolor flow cytometric immunophenotyping. We reviewed morphological, cytochemical and flow-cytometric data from five cases of B-lineage ALL that showed NSE/αNAE positivity and were diagnosed definitively using multi-parametric flow cytometric immunophenotypic analysis. Diffuse or dot-like (localized) strong cytochemical NSE/αNAE activity was detected in all cases and all showed one or more features of high risk disease. The number of NSE/αNAE positive blasts in the marrow varied from 10 to 75%. The morphological differential diagnoses included T-lymphoid lineage ALL and acute monoblastic leukemia (AML-M5). Flow cytometric data revealed B-lineage antigens and the absence of monocytic or other myeloid markers resolved the diagnosis. These cases underscore the importance of immunophenotyping in all cases of suspected ALL regardless of the cytochemical findings. Although the numbers are small, the association with high risk disease observed in all five of our cases may corroborate the previously reported poor prognostic value of such aberrant cytochemical staining. PMID:23957699

  10. The Potential of Menstrual Blood-Derived Stem Cells in Differentiation to Epidermal Lineage: A Preliminary Report

    PubMed Central

    Faramarzi, Hossein; Mehrabani, Davood; Fard, Maryam; Akhavan, Maryam; Zare, Sona; Bakhshalizadeh, Shabnam; Manafi, Amir; Kazemnejad, Somaieh; Shirazi, Reza

    2016-01-01

    BACKGROUND Menstrual blood-derived stem cells (MenSCs) are a novel source of stem cells that can be easily isolated non-invasively from female volunteered donor without ethical consideration. These mesenchymal-like stem cells have high rate of proliferation and possess multi lineage differentiation potency. This study was undertaken to isolate the MenSCs and assess their potential in differentiation into epidermal lineage. METHODS About 5-10 ml of menstrual blood (MB) was collected using sterile Diva cups inserted into vagina during menstruation from volunteered healthy fertile women aged between 22-30 years. MB was transferred into Falcon tubes containing phosphate buffered saline (PBS) without Ca2+ or Mg2+ supplemented with 2.5 µg/ml fungizone, 100 µg/mL streptomycin, 100 U/mL penicillin and 0.5 mM EDTA. Mononuclear cells were separated using Ficoll-Hypaque density gradient centrifugation and washed out in PBS. The cell pellet was suspended in DMEM-F12 medium supplemented with 10% FBS and cultured in tissue culture plates. The isolated cells were co-cultured with keratinocytes derived from the foreskin of healthy newborn male aged 2-10 months who was a candidate for circumcision for differentiation into epidermal lineage. RESULTS The isolated MenSCs were adhered to the plate and exhibited spindle-shaped morphology. Flow cytometric analysis revealed the expression of mesenchymal markers of CD10, CD29, CD73, and CD105 and lack of hematopoietic stem cells markers. An early success in derivation of epidermal lineage from MenSCs was visible. CONCLUSION The MenSCs are a real source to design differentiation to epidermal cells that can be used non-invasively in various dermatological lesions and diseases. PMID:27308237

  11. A GIS Model Predicting Potential Distributions of a Lineage: A Test Case on Hermit Spiders (Nephilidae: Nephilengys)

    PubMed Central

    Năpăruş, Magdalena; Kuntner, Matjaž

    2012-01-01

    Background Although numerous studies model species distributions, these models are almost exclusively on single species, while studies of evolutionary lineages are preferred as they by definition study closely related species with shared history and ecology. Hermit spiders, genus Nephilengys, represent an ecologically important but relatively species-poor lineage with a globally allopatric distribution. Here, we model Nephilengys global habitat suitability based on known localities and four ecological parameters. Methodology/Principal Findings We geo-referenced 751 localities for the four most studied Nephilengys species: N. cruentata (Africa, New World), N. livida (Madagascar), N. malabarensis (S-SE Asia), and N. papuana (Australasia). For each locality we overlaid four ecological parameters: elevation, annual mean temperature, annual mean precipitation, and land cover. We used linear backward regression within ArcGIS to select two best fit parameters per species model, and ModelBuilder to map areas of high, moderate and low habitat suitability for each species within its directional distribution. For Nephilengys cruentata suitable habitats are mid elevation tropics within Africa (natural range), a large part of Brazil and the Guianas (area of synanthropic spread), and even North Africa, Mediterranean, and Arabia. Nephilengys livida is confined to its known range with suitable habitats being mid-elevation natural and cultivated lands. Nephilengys malabarensis, however, ranges across the Equator throughout Asia where the model predicts many areas of high ecological suitability in the wet tropics. Its directional distribution suggests the species may potentially spread eastwards to New Guinea where the suitable areas of N. malabarensis largely surpass those of the native N. papuana, a species that prefers dry forests of Australian (sub)tropics. Conclusions Our model is a customizable GIS tool intended to predict current and future potential distributions of globally

  12. Energy in America: Progress and Potential.

    ERIC Educational Resources Information Center

    American Petroleum Inst., Washington, DC.

    An overview of America's energy situation is presented with emphasis on recent progress, the risk of depending upon foreign oil, and policy choices. Section one reviews the energy problems of the 1970s, issues of the 1980s, concerns for the future, and choices that if made today could alleviate future problems. Section two examines past problems,…

  13. Deficiency of the ribosome biogenesis gene Sbds in hematopoietic stem and progenitor cells causes neutropenia in mice by attenuating lineage progression in myelocytes.

    PubMed

    Zambetti, Noemi A; Bindels, Eric M J; Van Strien, Paulina M H; Valkhof, Marijke G; Adisty, Maria N; Hoogenboezem, Remco M; Sanders, Mathijs A; Rommens, Johanna M; Touw, Ivo P; Raaijmakers, Marc H G P

    2015-10-01

    Shwachman-Diamond syndrome is a congenital bone marrow failure disorder characterized by debilitating neutropenia. The disease is associated with loss-of-function mutations in the SBDS gene, implicated in ribosome biogenesis, but the cellular and molecular events driving cell specific phenotypes in ribosomopathies remain poorly defined. Here, we established what is to our knowledge the first mammalian model of neutropenia in Shwachman-Diamond syndrome through targeted downregulation of Sbds in hematopoietic stem and progenitor cells expressing the myeloid transcription factor CCAAT/enhancer binding protein α (Cebpa). Sbds deficiency in the myeloid lineage specifically affected myelocytes and their downstream progeny while, unexpectedly, it was well tolerated by rapidly cycling hematopoietic progenitor cells. Molecular insights provided by massive parallel sequencing supported cellular observations of impaired cell cycle exit and formation of secondary granules associated with the defect of myeloid lineage progression in myelocytes. Mechanistically, Sbds deficiency activated the p53 tumor suppressor pathway and induced apoptosis in these cells. Collectively, the data reveal a previously unanticipated, selective dependency of myelocytes and downstream progeny, but not rapidly cycling progenitors, on this ubiquitous ribosome biogenesis protein, thus providing a cellular basis for the understanding of myeloid lineage biased defects in Shwachman-Diamond syndrome. PMID:26185170

  14. Deficiency of the ribosome biogenesis gene Sbds in hematopoietic stem and progenitor cells causes neutropenia in mice by attenuating lineage progression in myelocytes

    PubMed Central

    Zambetti, Noemi A.; Bindels, Eric M. J.; Van Strien, Paulina M. H.; Valkhof, Marijke G.; Adisty, Maria N.; Hoogenboezem, Remco M.; Sanders, Mathijs A.; Rommens, Johanna M.; Touw, Ivo P.; Raaijmakers, Marc H. G. P.

    2015-01-01

    Shwachman-Diamond syndrome is a congenital bone marrow failure disorder characterized by debilitating neutropenia. The disease is associated with loss-of-function mutations in the SBDS gene, implicated in ribosome biogenesis, but the cellular and molecular events driving cell specific phenotypes in ribosomopathies remain poorly defined. Here, we established what is to our knowledge the first mammalian model of neutropenia in Shwachman-Diamond syndrome through targeted downregulation of Sbds in hematopoietic stem and progenitor cells expressing the myeloid transcription factor CCAAT/enhancer binding protein α (Cebpa). Sbds deficiency in the myeloid lineage specifically affected myelocytes and their downstream progeny while, unexpectedly, it was well tolerated by rapidly cycling hematopoietic progenitor cells. Molecular insights provided by massive parallel sequencing supported cellular observations of impaired cell cycle exit and formation of secondary granules associated with the defect of myeloid lineage progression in myelocytes. Mechanistically, Sbds deficiency activated the p53 tumor suppressor pathway and induced apoptosis in these cells. Collectively, the data reveal a previously unanticipated, selective dependency of myelocytes and downstream progeny, but not rapidly cycling progenitors, on this ubiquitous ribosome biogenesis protein, thus providing a cellular basis for the understanding of myeloid lineage biased defects in Shwachman-Diamond syndrome. PMID:26185170

  15. Isolation, characterization and the multi-lineage differentiation potential of rabbit bone marrow-derived mesenchymal stem cells

    PubMed Central

    Tan, Sik-Loo; Ahmad, Tunku Sara; Selvaratnam, Lakshmi; Kamarul, Tunku

    2013-01-01

    Mesenchymal stem cells (MSCs) are recognized by their plastic adherent ability, fibroblastic-like appearance, expression of specific surface protein markers, and are defined by their ability to undergo multi-lineage differentiation. Although rabbit bone marrow-derived MSCs (rbMSCs) have been used extensively in previous studies especially in translational research, these cells have neither been defined morphologically and ultrastructurally, nor been compared with their counterparts in humans in their multi-lineage differentiation ability. A study was therefore conducted to define the morphology, surface marker proteins, ultrastructure and multi-lineage differentiation ability of rbMSCs. Herein, the primary rbMSC cultures of three adult New Zealand white rabbits (at least 4 months old) were used for three independent experiments. rbMSCs were isolated using the gradient-centrifugation method, an established technique for human MSCs (hMSCs) isolation. Cells were characterized by phase contrast microscopy observation, transmission electron microscopy analysis, reverse transcriptase-polymerase chain reaction (PCR) analysis, immunocytochemistry staining, flow cytometry, alamarBlue® assay, histological staining and quantitative (q)PCR analysis. The isolated plastic adherent cells were in fibroblastic spindle-shape and possessed eccentric, irregular-shaped nuclei as well as rich inner cytoplasmic zones similar to that of hMSCs. The rbMSCs expressed CD29, CD44, CD73, CD81, CD90 and CD166, but were negative (or dim positive) for CD34, CD45, CD117 and HLD-DR. Despite having similar morphology and phenotypic expression, rbMSCs possessed significantly larger cell size but had a lower proliferation rate as compared with hMSCs. Using established protocols to differentiate hMSCs, rbMSCs underwent osteogenic, adipogenic and chondrogenic differentiation. Interestingly, differentiated rbMSCs demonstrated higher levels of osteogenic (Runx2) and chondrogenic (Sox9) gene expressions

  16. Potentially hypervirulent Clostridium difficile PCR ribotype 078 lineage isolates in pigs and possible implications for humans in Taiwan.

    PubMed

    Wu, Ying-Chen; Lee, Jen-Jie; Tsai, Bo-Yang; Liu, Yi-Fen; Chen, Chih-Ming; Tien, Ni; Tsai, Pei-Jane; Chen, Ter-Hsin

    2016-02-01

    Clostridium difficile is a human and animal pathogen. Recently, the incidence of community-acquired C. difficile infection has increased, and many studies have indicated that C. difficile might be food-borne. The correlation between C. difficile infection in humans and in animals has been a topic of debate. The objective of this study was to determine the genetic relatedness of C. difficile from human and pigs in Taiwan. We investigated the molecular epidemiology of C. difficile in healthy humans and pigs from 2011 to 2015. The isolation rate of C. difficile from pigs in 13 commercial farms was 49% (100/204), and a high proportion of hypervirulent (C. difficile carrying tcdA, tcdB, and cdtA/B genes and a 39-bp deletion in the tcdC gene) ribotype 078 lineage isolates (90%, 90/100; including 078, 126, 127, and 066-like isolates) were identified. In addition, the C. difficile ribotype 127 isolates from pigs typically exhibited moxifloxacin resistance (37/43; 86%). In healthy humans, the isolation rate was 4.3% (3/69), and all healthy human isolates were non-toxigenic. In particular, we compared the porcine isolates with two patient strains (ribotype 127) obtained from two hospitals in central Taiwan. The multilocus variable number tandem repeat analysis revealed a high genetic relatedness between ribotype 127 from patients and pigs. This study indicated that isolates of the ribotype 078 lineage, and especially ribotype 127, were widely distributed in pig farms and showed a high frequency of moxifloxacin resistance. The closely related ribotype 127 from patients and pigs may have had a common origin or low diversity. In conclusion, C. difficile ribotype 127 is a noteworthy pathogen in pigs and poses a potential public health threat. PMID:26915500

  17. Local parasite lineage sharing in temperate grassland birds provides clues about potential origins of Galapagos avian Plasmodium.

    PubMed

    Levin, Iris I; Colborn, Rachel E; Kim, Daniel; Perlut, Noah G; Renfrew, Rosalind B; Parker, Patricia G

    2016-02-01

    Oceanic archipelagos are vulnerable to natural introduction of parasites via migratory birds. Our aim was to characterize the geographic origins of two Plasmodium parasite lineages detected in the Galapagos Islands and in North American breeding bobolinks (Dolichonyx oryzivorus) that regularly stop in Galapagos during migration to their South American overwintering sites. We used samples from a grassland breeding bird assemblage in Nebraska, United States, and parasite DNA sequences from the Galapagos Islands, Ecuador, to compare to global data in a DNA sequence registry. Homologous DNA sequences from parasites detected in bobolinks and more sedentary birds (e.g., brown-headed cowbirds Molothrus ater, and other co-occurring bird species resident on the North American breeding grounds) were compared to those recovered in previous studies from global sites. One parasite lineage that matched between Galapagos birds and the migratory bobolink, Plasmodium lineage B, was the most common lineage detected in the global MalAvi database, matching 49 sequences from unique host/site combinations, 41 of which were of South American origin. We did not detect lineage B in brown-headed cowbirds. The other Galapagos-bobolink match, Plasmodium lineage C, was identical to two other sequences from birds sampled in California. We detected a close variant of lineage C in brown-headed cowbirds. Taken together, this pattern suggests that bobolinks became infected with lineage B on the South American end of their migratory range, and with lineage C on the North American breeding grounds. Overall, we detected more parasite lineages in bobolinks than in cowbirds. Galapagos Plasmodium had similar host breadth compared to the non-Galapagos haemosporidian lineages detected in bobolinks, brown-headed cowbirds, and other grassland species. This study highlights the utility of global haemosporidian data in the context of migratory bird-parasite connectivity. It is possible that migratory bobolinks

  18. Hepatitis B virus lineages in mammalian hosts: Potential for bidirectional cross-species transmission

    PubMed Central

    Bonvicino, Cibele R; Moreira, Miguel A; Soares, Marcelo A

    2014-01-01

    The hepatitis B virus (HBV) is a cosmopolitan infectious agent currently affecting over 350 million people worldwide, presently accounting for more than two billion infections. In addition to man, other hepatitis virus strains infect species of several mammalian families of the Primates, Rodentia and Chiroptera orders, in addition to birds. The mounting evidence of HBV infection in African, Asian and neotropical primates draws attention to the potential cross-species, zoonotic transmission of these viruses to man. Moreover, recent evidence also suggests the humans may also function as a source of viral infection to other mammals, particularly to domestic animals like poultry and swine. In this review, we list all evidence of HBV and HBV-like infection of nonhuman mammals and discuss their potential roles as donors or recipients of these viruses to humans and to other closely-related species. PMID:24976704

  19. Anti-arthritic agents: progress and potential.

    PubMed

    Laev, Sergey S; Salakhutdinov, Nariman F

    2015-07-01

    Osteoarthritis and rheumatoid arthritis are the two most common types of arthritis. Cartilage breakdown is a key feature of both diseases which contributes to the pain and joint deformity experienced by patients. Therefore, anti-arthritis drugs are of great importance. The aim of this review is to present recent progress in studies of various agents against osteoarthritis and rheumatoid arthritis. The structures and activities of anti-arthritic agents, which used in medical practice or are in development, are presented and discussed. The effects and mechanisms of action of opioids, glucocorticoids, non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, natural products derived from plants, nutraceuticals, and a number of new and perspective agents are considered. Various perspective targets for the treatment of osteoarthritis and rheumatoid arthritis are also discussed. Trials of good quality are needed to draw solid conclusions regarding efficacy of many of the studied agents. Unfortunately, to date, there is no pharmacologic agent proven to prevent the progression of both diseases, and there is an urgent need for further development of better anti-arthritic agents. PMID:26014481

  20. Metabolic potential of a single cell belonging to one of the most abundant lineages in freshwater bacterioplankton

    PubMed Central

    Garcia, Sarahi L; McMahon, Katherine D; Martinez-Garcia, Manuel; Srivastava, Abhishek; Sczyrba, Alexander; Stepanauskas, Ramunas; Grossart, Hans-Peter; Woyke, Tanja; Warnecke, Falk

    2013-01-01

    Actinobacteria within the acI lineage are often numerically dominating in freshwater ecosystems, where they can account for >50% of total bacteria in the surface water. However, they remain uncultured to date. We thus set out to use single-cell genomics to gain insights into their genetic make-up, with the aim of learning about their physiology and ecological niche. A representative from the highly abundant acI-B1 group was selected for shotgun genomic sequencing. We obtained a draft genomic sequence in 75 larger contigs (sum=1.16 Mb), with an unusually low genomic G+C mol% (∼42%). Actinobacteria core gene analysis suggests an almost complete genome recovery. We found that the acI-B1 cell had a small genome, with a rather low percentage of genes having no predicted functions (∼15%) as compared with other cultured and genome-sequenced microbial species. Our metabolic reconstruction hints at a facultative aerobe microorganism with many transporters and enzymes for pentoses utilization (for example, xylose). We also found an actinorhodopsin gene that may contribute to energy conservation under unfavorable conditions. This project reveals the metabolic potential of a member of the global abundant freshwater Actinobacteria. PMID:22810059

  1. Targeting cells of the myeloid lineage attenuates pain and disease progression in a prostate model of bone cancer.

    PubMed

    Thompson, Michelle L; Jimenez-Andrade, Juan M; Chartier, Stephane; Tsai, James; Burton, Elizabeth A; Habets, Gaston; Lin, Paul S; West, Brian L; Mantyh, Patrick W

    2015-09-01

    Tumor cells frequently metastasize to bone where they can generate cancer-induced bone pain (CIBP) that can be difficult to fully control using available therapies. Here, we explored whether PLX3397, a high-affinity small molecular antagonist that binds to and inhibits phosphorylation of colony-stimulating factor-1 receptor, the tyrosine-protein kinase c-Kit, and the FMS-like tyrosine kinase 3, can reduce CIBP. These 3 targets all regulate the proliferation and function of a subset of the myeloid cells including macrophages, osteoclasts, and mast cells. Preliminary experiments show that PLX3397 attenuated inflammatory pain after formalin injection into the hind paw of the rat. As there is an inflammatory component in CIBP, involving macrophages and osteoclasts, the effect of PLX3397 was explored in a prostate model of CIBP where skeletal pain, cancer cell proliferation, tumor metastasis, and bone remodeling could be monitored in the same animal. Administration of PLX3397 was initiated on day 14 after prostate cancer cell injection when the tumor was well established, and tumor-induced bone remodeling was first evident. Over the next 6 weeks, sustained administration of PLX3397 attenuated CIBP behaviors by approximately 50% and was equally efficacious in reducing tumor cell growth, formation of new tumor colonies in bone, and pathological tumor-induced bone remodeling. Developing a better understanding of potential effects that analgesic therapies have on the tumor itself may allow the development of therapies that not only better control the pain but also positively impact disease progression and overall survival in patients with bone cancer. PMID:25993548

  2. CDKN2 Gene Deletion as Poor Prognosis Predictor Involved in the Progression of Adult B-Lineage Acute Lymphoblastic Leukemia Patients

    PubMed Central

    Xu, Na; Li, Yu-ling; Zhou, Xuan; Cao, Rui; Li, Huan; Lu, Qi-si; Li, Lin; Lu, Zi-yuan; Huang, Ji-xian; Sun, Jing; Liu, Qi-fa; Du, Qing-feng; Liu, Xiao-li

    2015-01-01

    Deletion of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) is well known in many hematologic malignancies, but only few reports have investigated this deletion effect on clinical prognosis. This study performed analysis of the CDKN2 deletion in 215 adult B- lineage acute lymphoblastic leukemia (B-ALL) patients, and related cytogenetic prognostic factors (BCR/ABL; E2A/PBXl; TEL/AML1; Mixed Lineage Leukemia (MLL) rearrangement; MYC, Immunoglobulin heavy locus (IGH) translocation). The prevalence of CDKN2 deletions in all study populations was 28.4%. There is no difference between patients with CDKN2 deletion and wild-type patients in sex, age, white blood cells (WBC) count, BM blast percentage, extra infiltration and induction complete remission (CR) rate. Analysis in relapse patients revealed that the distribution of CDKN2 deletion is higher in relapse patients (44.6%) than all patients (28.4%, P=0.006). Deletion of CDKN2 was significantly associated with poor outcomes including decreased overall survival (OS) (P<0.001), lower disease free-survival (DFS) (P<0.001), and increased cumulative incidence of relapse (P=0.002); Also, CDKN2 deletion was strongly associated with IGH translocation (P=0.021); and had an adverse effect on patients with BCR-ABL fusion gene or with MLL rearrangement. Patients with CDKN2 gene deletion benefited from allogenic hematopoietic stem cell transplantation (Allo-HSCT). Deletion of CDKN2 gene was commonly observed through leukemia progression and was poor prognostic marker in long-term outcomes. PMID:26516359

  3. Progress towards ultracold gases in arbitrary 2D potentials

    NASA Astrophysics Data System (ADS)

    Corcovilos, Theodore

    2016-05-01

    We describe our progress in building an apparatus for investigating degenerate quantum gases of potassium in arbitrary two-dimensional optical potentials. The optical potentials are created by holographic projection of an image created using a MEMS mirror array. Systems we would like to study with this experiment are quantum simulations of bosons and fermions at crystal heterojunctions and systems with well defined boundaries, including topological edge states. Funding provided by the Charles E Kaufman Foundation, a part of the Pittsburgh Foundation.

  4. Epigenetic Marks Define the Lineage and Differentiation Potential of Two Distinct Neural Crest-Derived Intermediate Odontogenic Progenitor Populations

    PubMed Central

    Gopinathan, Gokul; Kolokythas, Antonia

    2013-01-01

    Epigenetic mechanisms, such as histone modifications, play an active role in the differentiation and lineage commitment of mesenchymal stem cells. In the present study, epigenetic states and differentiation profiles of two odontogenic neural crest-derived intermediate progenitor populations were compared: dental pulp (DP) and dental follicle (DF). ChIP on chip assays revealed substantial H3K27me3-mediated repression of odontoblast lineage genes DSPP and dentin matrix protein 1 (DMP1) in DF cells, but not in DP cells. Mineralization inductive conditions caused steep increases of mineralization and patterning gene expression levels in DP cells when compared to DF cells. In contrast, mineralization induction resulted in a highly dynamic histone modification response in DF cells, while there was only a subdued effect in DP cells. Both DF and DP progenitors featured H3K4me3-active marks on the promoters of early mineralization genes RUNX2, MSX2, and DLX5, while OSX, IBSP, and BGLAP promoters were enriched for H3K9me3 or H3K27me3. Compared to DF cells, DP cells expressed higher levels of three pluripotency-associated genes, OCT4, NANOG, and SOX2. Finally, gene ontology comparison of bivalent marks unique for DP and DF cells highlighted cell–cell attachment genes in DP cells and neurogenesis genes in DF cells. In conclusion, the present study indicates that the DF intermediate odontogenic neural crest lineage is distinguished from its DP counterpart by epigenetic repression of DSPP and DMP1 genes and through dynamic histone enrichment responses to mineralization induction. Findings presented here highlight the crucial role of epigenetic regulatory mechanisms in the terminal differentiation of odontogenic neural crest lineages. PMID:23379639

  5. Lineage relationship of CD8+ T cell subsets is revealed by progressive changes in the epigenetic landscape

    PubMed Central

    Crompton, Joseph G.; Narayanan, Manikandan; Cuddapah, Suresh; Roychoudhuri, Rahul; Ji, Yun; Yang, Wenjing; Patel, Shashank J.; Sukumar, Madhusudhanan; Palmer, Douglas C.; Peng, Weiqun; Wang, Ena; Marincola, Francesco M.; Klebanoff, Christopher A.; Zhao, Keji; Tsang, John S.; Gattinoni, Luca; Restifo, Nicholas P.

    2016-01-01

    To better elucidate epigenetic mechanisms that correlate with the dynamic gene expression program observed upon T-cell differentiation, we investigated the genomic landscape of histone modifications in naive and memory CD8+ T cells. Using a ChIP-Seq approach coupled with global gene expression profiling, we generated genome-wide histone H3 lysine 4 (H3K4me3) and H3 lysine 27 (H3K27me3) trimethylation maps in naive, T memory stem cells, central memory cells, and effector memory cells in order to gain insight into how histone architecture is remodeled during T cell differentiation. We show that H3K4me3 histone modifications are associated with activation of genes, while H3K27me3 is negatively correlated with gene expression at canonical loci and enhancers associated with T-cell metabolism, effector function, and memory. Our results also reveal histone modifications and gene expression signatures that distinguish the recently identified T memory stem cells from other CD8+ T-cell subsets. Taken together, our results suggest that CD8+ lymphocytes undergo chromatin remodeling in a progressive fashion. These findings have major implications for our understanding of peripheral T-cell ontogeny and the formation of immunological memory. PMID:25914936

  6. Lineage relationship of CD8(+) T cell subsets is revealed by progressive changes in the epigenetic landscape.

    PubMed

    Crompton, Joseph G; Narayanan, Manikandan; Cuddapah, Suresh; Roychoudhuri, Rahul; Ji, Yun; Yang, Wenjing; Patel, Shashank J; Sukumar, Madhusudhanan; Palmer, Douglas C; Peng, Weiqun; Wang, Ena; Marincola, Francesco M; Klebanoff, Christopher A; Zhao, Keji; Tsang, John S; Gattinoni, Luca; Restifo, Nicholas P

    2016-07-01

    To better elucidate epigenetic mechanisms that correlate with the dynamic gene expression program observed upon T-cell differentiation, we investigated the genomic landscape of histone modifications in naive and memory CD8(+) T cells. Using a ChIP-Seq approach coupled with global gene expression profiling, we generated genome-wide histone H3 lysine 4 (H3K4me3) and H3 lysine 27 (H3K27me3) trimethylation maps in naive, T memory stem cells, central memory cells, and effector memory cells in order to gain insight into how histone architecture is remodeled during T cell differentiation. We show that H3K4me3 histone modifications are associated with activation of genes, while H3K27me3 is negatively correlated with gene expression at canonical loci and enhancers associated with T-cell metabolism, effector function, and memory. Our results also reveal histone modifications and gene expression signatures that distinguish the recently identified T memory stem cells from other CD8(+) T-cell subsets. Taken together, our results suggest that CD8(+) lymphocytes undergo chromatin remodeling in a progressive fashion. These findings have major implications for our understanding of peripheral T-cell ontogeny and the formation of immunological memory. PMID:25914936

  7. Concise Review: Primary Cilia: Control Centers for Stem Cell Lineage Specification and Potential Targets for Cell-Based Therapies.

    PubMed

    Bodle, Josephine C; Loboa, Elizabeth G

    2016-06-01

    Directing stem cell lineage commitment prevails as the holy grail of translational stem cell research, particularly to those interested in the application of mesenchymal stem cells and adipose-derived stem cells in tissue engineering. However, elucidating the mechanisms underlying their phenotypic specification persists as an active area of research. In recent studies, the primary cilium structure has been intimately associated with defining cell phenotype, maintaining stemness, as well as functioning in a chemo, electro, and mechanosensory capacity in progenitor and committed cell types. Many hypothesize that the primary cilium may indeed be another important player in defining and controlling cell phenotype, concomitant with lineage-dictated cytoskeletal dynamics. Many of the studies on the primary cilium have emerged from disparate areas of biological research, and crosstalk amongst these areas of research is just beginning. To date, there has not been a thorough review of how primary cilia fit into the current paradigm of stem cell differentiation and this review aims to summarize the current cilia work in this context. The goal of this review is to highlight the cilium's function and integrate this knowledge into the working knowledge of stem cell biologists and tissue engineers developing regenerative medicine technologies. Stem Cells 2016;34:1445-1454. PMID:26866419

  8. Refining the phylum Chlorobi by resolving the phylogeny and metabolic potential of the representative of a deeply branching, uncultivated lineage.

    PubMed

    Hiras, Jennifer; Wu, Yu-Wei; Eichorst, Stephanie A; Simmons, Blake A; Singer, Steven W

    2016-04-01

    Recent studies have expanded the phylum Chlorobi, demonstrating that the green sulfur bacteria (GSB), the original cultured representatives of the phylum, are a part of a broader lineage whose members have more diverse metabolic capabilities that overlap with members of the phylum Bacteroidetes. The 16S rRNA gene of an uncultivated clone, OPB56, distantly related to the phyla Chlorobi and Bacteroidetes, was recovered from Obsidian Pool in Yellowstone National Park; however, the detailed phylogeny and function of OPB56 and related clones have remained unknown. Culturing of thermophilic bacterial consortia from compost by adaptation to grow on ionic-liquid pretreated switchgrass provided a consortium in which one of the most abundant members, NICIL-2, clustered with OPB56-related clones. Phylogenetic analysis using the full-length 16S rRNA gene from NICIL-2 demonstrated that it was part of a monophyletic clade, referred to as OPB56, distinct from the Bacteroidetes and Chlorobi. A near complete draft genome (>95% complete) was recovered from metagenomic data from the culture adapted to grow on ionic-liquid pretreated switchgrass using an automated binning algorithm, and this genome was used for marker gene-based phylogenetic analysis and metabolic reconstruction. Six additional genomes related to NICIL-2 were reconstructed from metagenomic data sets obtained from thermal springs at Yellowstone National Park and Nevada Great Boiling Spring. In contrast to the 16S rRNA gene phylogenetic analysis, protein phylogenetic analysis was most consistent with the clustering of the Chlorobea, Ignavibacteria and OPB56 into a single phylum level clade. Metabolic reconstruction of NICIL-2 demonstrated a close linkage with the class Ignavibacteria and the family Rhodothermaceae, a deeply branching Bacteroidetes lineage. The combined phylogenetic and functional analysis of the NICIL-2 genome has refined the membership in the phylum Chlorobi and emphasized the close evolutionary and

  9. Automating the design process - Progress, problems, prospects, potential.

    NASA Technical Reports Server (NTRS)

    Heldenfels, R. R.

    1973-01-01

    The design process for large aerospace vehicles is discussed, with particular emphasis on structural design. Problems with current procedures are identified. Then, the contributions possible from automating the design process (defined as the best combination of men and computers) are considered. Progress toward automated design in the aerospace and other communities is reviewed, including NASA studies of the potential development of Integrated Programs for Aerospace-Vehicle Design (IPAD). The need for and suggested directions of future research on the design process, both technical and social, are discussed. Although much progress has been made to exploit the computer in design, it is concluded that technology is available to begin using the computer to speed communications and management as well as calculations in the design process and thus build man-computer teams that can design better, faster and cheaper.

  10. Ancestral reconstruction of tick lineages.

    PubMed

    Mans, Ben J; de Castro, Minique H; Pienaar, Ronel; de Klerk, Daniel; Gaven, Philasande; Genu, Siyamcela; Latif, Abdalla A

    2016-06-01

    Ancestral reconstruction in its fullest sense aims to describe the complete evolutionary history of a lineage. This depends on accurate phylogenies and an understanding of the key characters of each parental lineage. An attempt is made to delineate our current knowledge with regard to the ancestral reconstruction of the tick (Ixodida) lineage. Tick characters may be assigned to Core of Life, Lineages of Life or Edges of Life phenomena depending on how far back these characters may be assigned in the evolutionary Tree of Life. These include housekeeping genes, sub-cellular systems, heme processing (Core of Life), development, moulting, appendages, nervous and organ systems, homeostasis, respiration (Lineages of Life), specific adaptations to a blood-feeding lifestyle, including the complexities of salivary gland secretions and tick-host interactions (Edges of Life). The phylogenetic relationships of lineages, their origins and importance in ancestral reconstruction are discussed. Uncertainties with respect to systematic relationships, ancestral reconstruction and the challenges faced in comparative transcriptomics (next-generation sequencing approaches) are highlighted. While almost 150 years of information regarding tick biology have been assembled, progress in recent years indicates that we are in the infancy of understanding tick evolution. Even so, broad reconstructions can be made with relation to biological features associated with various lineages. Conservation of characters shared with sister and parent lineages are evident, but appreciable differences are present in the tick lineage indicating modification with descent, as expected for Darwinian evolutionary theory. Many of these differences can be related to the hematophagous lifestyle of ticks. PMID:26868413

  11. Bacillus anthracis Diversity and Geographic Potential across Nigeria, Cameroon and Chad: Further Support of a Novel West African Lineage.

    PubMed

    Blackburn, Jason K; Odugbo, Moses Ode; Van Ert, Matthew; O'Shea, Bob; Mullins, Jocelyn; Perreten, Vincent; Perrenten, Vincent; Maho, Angaya; Hugh-Jones, Martin; Hadfield, Ted

    2015-01-01

    Zoonoses, diseases affecting both humans and animals, can exert tremendous pressures on human and veterinary health systems, particularly in resource limited countries. Anthrax is one such zoonosis of concern and is a disease requiring greater public health attention in Nigeria. Here we describe the genetic diversity of Bacillus anthracis in Nigeria and compare it to Chad, Cameroon and a broader global dataset based on the multiple locus variable number tandem repeat (MLVA-25) genetic typing system. Nigerian B. anthracis isolates had identical MLVA genotypes and could only be resolved by measuring highly mutable single nucleotide repeats (SNRs). The Nigerian MLVA genotype was identical or highly genetically similar to those in the neighboring countries, confirming the strains belong to this unique West African lineage. Interestingly, sequence data from a Nigerian isolate shares the anthrose deficient genotypes previously described for strains in this region, which may be associated with vaccine evasion. Strains in this study were isolated over six decades, indicating a high level of temporal strain stability regionally. Ecological niche models were used to predict the geographic distribution of the pathogen for all three countries. We describe a west-east habitat corridor through northern Nigeria extending into Chad and Cameroon. Ecological niche models and genetic results show B. anthracis to be ecologically established in Nigeria. These findings expand our understanding of the global B. anthracis population structure and can guide regional anthrax surveillance and control planning. PMID:26291625

  12. Bacillus anthracis Diversity and Geographic Potential across Nigeria, Cameroon and Chad: Further Support of a Novel West African Lineage

    PubMed Central

    Blackburn, Jason K.; Odugbo, Moses Ode; Van Ert, Matthew; O’Shea, Bob; Mullins, Jocelyn; Perrenten, Vincent; Maho, Angaya; Hugh-Jones, Martin; Hadfield, Ted

    2015-01-01

    Zoonoses, diseases affecting both humans and animals, can exert tremendous pressures on human and veterinary health systems, particularly in resource limited countries. Anthrax is one such zoonosis of concern and is a disease requiring greater public health attention in Nigeria. Here we describe the genetic diversity of Bacillus anthracis in Nigeria and compare it to Chad, Cameroon and a broader global dataset based on the multiple locus variable number tandem repeat (MLVA-25) genetic typing system. Nigerian B. anthracis isolates had identical MLVA genotypes and could only be resolved by measuring highly mutable single nucleotide repeats (SNRs). The Nigerian MLVA genotype was identical or highly genetically similar to those in the neighboring countries, confirming the strains belong to this unique West African lineage. Interestingly, sequence data from a Nigerian isolate shares the anthrose deficient genotypes previously described for strains in this region, which may be associated with vaccine evasion. Strains in this study were isolated over six decades, indicating a high level of temporal strain stability regionally. Ecological niche models were used to predict the geographic distribution of the pathogen for all three countries. We describe a west-east habitat corridor through northern Nigeria extending into Chad and Cameroon. Ecological niche models and genetic results show B. anthracis to be ecologically established in Nigeria. These findings expand our understanding of the global B. anthracis population structure and can guide regional anthrax surveillance and control planning. PMID:26291625

  13. Chromodomain-helicase-DNA binding protein 5, 7 and pronecrotic mixed lineage kinase domain-like protein serve as potential prognostic biomarkers in patients with resected pancreatic adenocarcinomas

    PubMed Central

    Seldon, Crystal S; Colbert, Lauren E; Hall, William A; Fisher, Sarah B; Yu, David S; Landry, Jerome C

    2016-01-01

    Pancreatic cancer is one of the deadliest cancers with a very poor prognosis. Recently, there has been a significant increase in research directed towards identifying potential biomarkers that can be used to diagnose and provide prognostic information for pancreatic cancer. These markers can be used clinically to optimize and personalize therapy for individual patients. In this review, we focused on 3 biomarkers involved in the DNA damage response pathway and the necroptosis pathway: Chromodomain-helicase-DNA binding protein 5, chromodomain-helicase-DNA binding protein 7, and mixed lineage kinase domain-like protein. The aim of this article is to review present literature provided for these biomarkers and current studies in which their effectiveness as prognostic biomarkers are analyzed in order to determine their future use as biomarkers in clinical medicine. Based on the data presented, these biomarkers warrant further investigation, and should be validated in future studies. PMID:27096031

  14. Temporal profiling of the growth and multi-lineage potentiality of adipose tissue-derived mesenchymal stem cells cell-sheets.

    PubMed

    Neo, Puay Yong; See, Eugene Yong-Shun; Toh, Siew Lok; Goh, James Cho-Hong

    2016-07-01

    Cell-sheet tissue engineering retains the benefits of an intact extracellular matrix (ECM) and can be used to produce scaffold-free constructs. Adipose tissue-derived stem cells (ASCs) are multipotent and more easily obtainable than the commonly used bone marrow-derived stem cells (BMSCs). Although BMSC cell sheets have been previously reported to display multipotentiality, a detailed study of the development and multilineage potential of ASC cell sheets (ASC-CSs) is non-existent in the literature. The aims of this study were to temporally profile: (a) the effect of hyperconfluent culture duration on ASC-CSs development; and (b) the multipotentiality of ASC-CSs by differentiation into the osteogenic, adipogenic and chondrogenic lineages. Rabbit ASCs were first isolated and cultured until confluence (day 0). The confluent cells were then cultured in ascorbic acid-supplemented medium for 3 weeks to study cell metabolic activity, cell sheet thickness and early differentiation gene expressions at weekly time points. ASC-CSs and ASCs were then differentiated into the three lineages, using established protocols, and assessed by RT-PCR and histology at multiple time points. ASC-CSs remained healthy up to 3 weeks of hyperconfluent culture. One week-old cell sheets displayed upregulation of early differentiation gene markers (Runx2 and Sox9); however, subsequent differentiation results indicated that they did not necessarily translate to an improved phenotype. ASCs within the preformed cell sheet groups did not differentiate as efficiently as the non-hyperconfluent ASCs, which were directly differentiated. Although ASCs within the cell sheets retained their differentiation capacity and remained viable under prolonged hyperconfluent conditions, future applications of ASC-CSs in tissue engineering should be considered with care. Copyright © 2016 John Wiley & Sons, Ltd. PMID:23784965

  15. Population genetic structure of Phytophthora cinnamomi associated with avocado in California and the discovery of a potentially recent introduction of a new clonal lineage.

    PubMed

    Pagliaccia, D; Pond, E; McKee, B; Douhan, G W

    2013-01-01

    Phytophthora root rot (PRR) of avocado (Persea americana), caused by Phytophthora cinnamomi, is the most serious disease of avocado worldwide. Previous studies have determined that this pathogen exhibits a primarily clonal reproductive mode but no population level studies have been conducted in the avocado-growing regions of California. Therefore, we used amplified fragment length polymorphism based on 22 polymorphic loci and mating type to investigate pathogen diversity from 138 isolates collected in 2009 to 2010 from 15 groves from the Northern and Southern avocado-growing regions. Additional isolates collected from avocado from 1966 to 2007 as well as isolates from other countries and hosts were also used for comparative purposes. Two distinct clades of A2 mating-type isolates from avocado were found based on neighbor joining analysis; one clade contained both newer and older collections from Northern and Southern California, whereas the other clade only contained isolates collected in 2009 and 2010 from Southern California. A third clade was also found that only contained A1 isolates from various hosts. Within the California population, a total of 16 genotypes were found with only one to four genotypes identified from any one location. The results indicate significant population structure in the California avocado P. cinnamomi population, low genotypic diversity consistent with asexual reproduction, potential evidence for the movement of clonal genotypes between the two growing regions, and a potential introduction of a new clonal lineage into Southern California. PMID:23228146

  16. Syndecans as Modulators and Potential Pharmacological Targets in Cancer Progression

    PubMed Central

    Barbouri, Despoina; Afratis, Nikolaos; Gialeli, Chrisostomi; Vynios, Demitrios H.; Theocharis, Achilleas D.; Karamanos, Nikos K.

    2014-01-01

    Extracellular matrix (ECM) components form a dynamic network of key importance for cell function and properties. Key macromolecules in this interplay are syndecans (SDCs), a family of transmembrane heparan sulfate proteoglycans (HSPGs). Specifically, heparan sulfate (HS) chains with their different sulfation pattern have the ability to interact with growth factors and their receptors in tumor microenvironment, promoting the activation of different signaling cascades that regulate tumor cell behavior. The affinity of HS chains with ligands is altered during malignant conditions because of the modification of chain sequence/sulfation pattern. Furthermore, matrix degradation enzymes derived from the tumor itself or the tumor microenvironment, like heparanase and matrix metalloproteinases, ADAM as well as ADAMTS are involved in the cleavage of SDCs ectodomain at the HS and protein core level, respectively. Such released soluble SDCs “shed SDCs” in the ECM interact in an autocrine or paracrine manner with the tumor or/and stromal cells. Shed SDCs, upon binding to several matrix effectors, such as growth factors, chemokines, and cytokines, have the ability to act as competitive inhibitors for membrane proteoglycans, and modulate the inflammatory microenvironment of cancer cells. It is notable that SDCs and their soluble counterparts may affect either the behavior of cancer cells and/or their microenvironment during cancer progression. The importance of these molecules has been highlighted since HSPGs have been proposed as prognostic markers of solid tumors and hematopoietic malignancies. Going a step further down the line, the multi-actions of SDCs in many levels make them appealing as potential pharmacological targets, either by targeting directly the tumor or indirectly the adjacent stroma. PMID:24551591

  17. REOVIRUS: A TARGETED THERAPEUTIC – PROGRESS AND POTENTIAL

    PubMed Central

    Maitra, Radhashree; Ghalib, Mohammad H.; Goel, Sanjay

    2013-01-01

    Medical therapy of patients with malignancy requires a paradigm shift through development of new drugs with a good safety record and novel mechanisms of activity. While there is no dearth of such molecules, one particular agent, “reovirus” is promising by its ability to target cancer cells with aberrant signaling pathways. This double stranded RNA virus has been therapeutically formulated and has rapidly progressed from pre-clinical validation of anti cancer activity to a phase III registration study in platinum refractory metastatic squamous cell carcinoma of the head and neck. During this process, reovirus has demonstrated safety both as a single agent when administered intratumorally and intravenously, as well as in combination therapy, with multiple chemotherapeutics such as gemcitabine, carboplatin/paclitaxel, and docetaxel; and similarly with radiation. The scientific rationale for its development as an anticancer agent stems from the fact that it preferentially replicates in and induces lyses of cells with an activated Kras pathway. As documented in many previous studies, the initial observation of greater tropism in Kras compromised situation might certainly not be the sole and possibly not even the predominant reason for enhanced virulence. All the same, scientists have emphasized on Kras optimistically due to its high prevalence in various types of cancers. Incidence of Kras mutation has been found to be highest in pancreatic cancer (85–90%) followed by colorectal (35–45%) and lung (25–30%). Reovirus, in fact has the potential not only as a therapy but also as a tool to unravel the aberrant cellular pathway leading to carcinogenicity. PMID:23038811

  18. Rare or rarely detected? Ceraceosorus guamensis sp. nov.: a second described species of Ceraceosorales and the potential for underdetection of rare lineages with common sampling techniques.

    PubMed

    Kijpornyongpan, Teeratas; Catherine Aime, M

    2016-08-01

    Ceraceosorales is a monotypic order in Ustilaginomycotina. Its namesake, Ceraceosorus bombacis, was described as a phytopathogen of Bombax ceiba in India. In this study, we describe Ceraceosorus guamensis sp. nov., collected on the South Pacific island of Guam, which appears to represent the second isolation of any member of this order in over 40 years. Ceraceosorus species are monokaryotic and filamentous in culture, producing conidia on potato dextrose agar. However, both species behave yeast-like when cultured on corn meal agar. The internal transcribed spacer (ITS) region (spanning the ITS1-5.8S-ITS2) in both species of Ceraceosorus is highly heterogeneous containing multiple disparate copies that can vary intragenomically by up to 3.5 %. Moreover, this region could not be amplified using the fungal ITS primers most frequently used for culture-independent methods of assessing fungal biodiversity. This fact, combined with the extremely slow growth rates on commonly employed media, may indicate that members of this lineage are potentially underdetected by current sampling methods. PMID:27236321

  19. The myocardial regenerative potential of three-dimensional engineered cardiac tissues composed of multiple human iPS cell-derived cardiovascular cell lineages.

    PubMed

    Masumoto, Hidetoshi; Nakane, Takeichiro; Tinney, Joseph P; Yuan, Fangping; Ye, Fei; Kowalski, William J; Minakata, Kenji; Sakata, Ryuzo; Yamashita, Jun K; Keller, Bradley B

    2016-01-01

    Human induced pluripotent stem cells (hiPSCs) are a robust source for cardiac regenerative therapy due to their potential to support autologous and allogeneic transplant paradigms. The in vitro generation of three-dimensional myocardial tissue constructs using biomaterials as an implantable hiPSC-derived myocardium provides a path to realize sustainable myocardial regeneration. We generated engineered cardiac tissues (ECTs) from three cellular compositions of cardiomyocytes (CMs), endothelial cells (ECs), and vascular mural cells (MCs) differentiated from hiPSCs. We then determined the impact of cell composition on ECT structural and functional properties. In vitro force measurement showed that CM+EC+MC ECTs possessed preferential electromechanical properties versus ECTs without vascular cells indicating that incorporation of vascular cells augmented tissue maturation and function. The inclusion of MCs facilitated more mature CM sarcomeric structure, preferential alignment, and activated multiple tissue maturation pathways. The CM+EC+MC ECTs implanted onto infarcted, immune tolerant rat hearts engrafted, displayed both host and graft-derived vasculature, and ameliorated myocardial dysfunction. Thus, a composition of CMs and multiple vascular lineages derived from hiPSCs and incorporated into ECTs promotes functional maturation and demonstrates myocardial replacement and perfusion relevant for clinical translation. PMID:27435115

  20. The myocardial regenerative potential of three-dimensional engineered cardiac tissues composed of multiple human iPS cell-derived cardiovascular cell lineages

    PubMed Central

    Masumoto, Hidetoshi; Nakane, Takeichiro; Tinney, Joseph P.; Yuan, Fangping; Ye, Fei; Kowalski, William J.; Minakata, Kenji; Sakata, Ryuzo; Yamashita, Jun K.; Keller, Bradley B.

    2016-01-01

    Human induced pluripotent stem cells (hiPSCs) are a robust source for cardiac regenerative therapy due to their potential to support autologous and allogeneic transplant paradigms. The in vitro generation of three-dimensional myocardial tissue constructs using biomaterials as an implantable hiPSC-derived myocardium provides a path to realize sustainable myocardial regeneration. We generated engineered cardiac tissues (ECTs) from three cellular compositions of cardiomyocytes (CMs), endothelial cells (ECs), and vascular mural cells (MCs) differentiated from hiPSCs. We then determined the impact of cell composition on ECT structural and functional properties. In vitro force measurement showed that CM+EC+MC ECTs possessed preferential electromechanical properties versus ECTs without vascular cells indicating that incorporation of vascular cells augmented tissue maturation and function. The inclusion of MCs facilitated more mature CM sarcomeric structure, preferential alignment, and activated multiple tissue maturation pathways. The CM+EC+MC ECTs implanted onto infarcted, immune tolerant rat hearts engrafted, displayed both host and graft-derived vasculature, and ameliorated myocardial dysfunction. Thus, a composition of CMs and multiple vascular lineages derived from hiPSCs and incorporated into ECTs promotes functional maturation and demonstrates myocardial replacement and perfusion relevant for clinical translation. PMID:27435115

  1. [Non-empirical interatomic potentials for transition metals]. Progress report

    SciTech Connect

    Not Available

    1993-05-01

    The report is divided into the following sections: potential-energy functions for d-band metals, potential-energy functions for aluminides and quasicrystals, electronic structure of complex structures and quasicrystals, potential-energy functions in transition-metal oxides, applications to defect structure and mechanical properties, and basic theory of interatomic potentials.

  2. QCD at nonzero chemical potential: Recent progress on the lattice

    NASA Astrophysics Data System (ADS)

    Aarts, Gert; Attanasio, Felipe; Jäger, Benjamin; Seiler, Erhard; Sexty, Dénes; Stamatescu, Ion-Olimpiu

    2016-01-01

    We summarise recent progress in simulating QCD at nonzero baryon density using complex Langevin dynamics. After a brief outline of the main idea, we discuss gauge cooling as a means to control the evolution. Subsequently we present a status report for heavy dense QCD and its phase structure, full QCD with staggered quarks, and full QCD with Wilson quarks, both directly and using the hopping parameter expansion to all orders.

  3. [Genome plasticity and catabolic potential of pseudomonas cepacia]. Progress report

    SciTech Connect

    1993-12-31

    This progress report describes efforts directed at understanding the genomic structure of Pseudomonas cepacia. Variously reported are descriptions of the replicons in the genome, organization of macrorestriction fragments comprising the genome, use of a Tn-5- 751S to insertionally inactivate and map selected genes, construction of IS407 derivatives containing a trimethoprim resistance marker and SwaI site, and analysis of nucleotide sequences of IS401 and IS408.

  4. MicroRNAs as potential targets for progressive pulmonary fibrosis

    PubMed Central

    Rajasekaran, Subbiah; Rajaguru, P.; Sudhakar Gandhi, P. S.

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and devastating disorder. It is characterized by alveolar epithelial cell injury and activation, infiltration of inflammatory cells, initiation of epithelial mesenchymal transition (EMT), aberrant proliferation and activation of fibroblasts, exaggerated deposition of extracellular matrix (ECM) proteins, and finally leading to the destruction of lung parenchyma. MicroRNAs (miRNAs) are endogenous small non-coding RNA molecules that post-transcriptionally regulate gene expression in diverse biological and pathological processes, including cell proliferation, differentiation, apoptosis and metastasis. As a result, miRNAs have emerged as a major area of biomedical research with relevance to pulmonary fibrosis. In this context, the present review discusses specific patterns of dysregulated miRNAs in patients with IPF. Further, we discuss the current understanding of miRNAs involvement in regulating lung inflammation, TGF-β1-mediated EMT and fibroblast differentiation processes, ECM genes expression, and in the progression of lung fibrosis. The possible future directions that might lead to novel therapeutic strategies for the treatment of pulmonary fibrosis are also reviewed. PMID:26594173

  5. Anti-inflammatory agents from plants: progress and potential.

    PubMed

    Recio, M C; Andujar, I; Rios, J L

    2012-01-01

    The identification of substances that can promote the resolution of inflammation in a way that is homeostatic, modulatory, efficient, and well-tolerated by the body is of fundamental importance. Traditional medicines have long provided front-line pharmacotherapy for many millions of people worldwide. Medicinal extracts are a rich source of therapeutic leads for the pharmaceutical industry. The use of medicinal plant therapies to treat chronic illness, including rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), is thus widespread and on the rise.The aim of this review is to present recent progress in clinical anti-inflammatory studies of plant extracts and compound leads such as green tea polyphenols, curcumin, resveratrol, boswellic acid, and cucurbitacins, among others, against chronic inflammatory diseases, mainly RA and IBD. In this context, the present paper also highlights the most promising experimental data on those plant extracts and pure compounds active in animal models of the aforementioned diseases. PMID:22414101

  6. Identification of potential biomarkers of disease progression in bovine tuberculosis.

    PubMed

    Blanco, Federico Carlos; Bigi, Fabiana; Soria, Marcelo Abel

    2014-08-15

    Bovine tuberculosis (bTB) remains an important animal and zoonotic disease in many countries. The diagnosis of bTB is based on tuberculin skin test and IFN-γ release assays (IGRA). Positive animals are separated from the herd and sacrificed. The cost of this procedure is difficult to afford for developing countries with high prevalence of bTB; therefore, the improvement of diagnostic methods and the identification of animals in different stages of the disease will be helpful to control the infection. To identify biomarkers that can discriminate between tuberculin positive cattle with and without tuberculosis lesions (ML+ and ML-, respectively), we assessed a group of immunological parameters with three different classification methods: lineal discriminant analysis (LDA), quadratic discriminant analysis (QDA) and K nearest neighbors (k-nn). For this purpose, we used data from 30 experimentally infected cattle. All the classifiers (LDA, QDA and k-nn) selected IL-2 and IL-17 as the most discriminatory variables. The best classification method was LDA using IL-17 and IL-2 as predictors. The addition of IL-10 to LDA improves the performance of the classifier to discriminate ML-individuals (93.3% vs. 86.7%). Thus, the expression of IL-17, IL-2 and, in some cases, IL-10 would serve as an additional tool to study disease progression in herds with a history of bTB. PMID:24856732

  7. "Human Potential" and Progressive Pedagogy: A Long Cultural History of the Ambiguity of "Race" and "Intelligence"

    ERIC Educational Resources Information Center

    Oland, Trine

    2012-01-01

    This article examines the cultural constructs of progressive pedagogy in Danish school pedagogy and its emerging focus on the child's human potential from the 1920s to the 1950s. It draws on Foucault's notion of "dispositifs" and the "elements of history," encircling a complex transformation of continuity and discontinuity of progressive pedagogy.…

  8. Adaptive coded aperture imaging: progress and potential future applications

    NASA Astrophysics Data System (ADS)

    Gottesman, Stephen R.; Isser, Abraham; Gigioli, George W., Jr.

    2011-09-01

    Interest in Adaptive Coded Aperture Imaging (ACAI) continues to grow as the optical and systems engineering community becomes increasingly aware of ACAI's potential benefits in the design and performance of both imaging and non-imaging systems , such as good angular resolution (IFOV), wide distortion-free field of view (FOV), excellent image quality, and light weight construct. In this presentation we first review the accomplishments made over the past five years, then expand on previously published work to show how replacement of conventional imaging optics with coded apertures can lead to a reduction in system size and weight. We also present a trade space analysis of key design parameters of coded apertures and review potential applications as replacement for traditional imaging optics. Results will be presented, based on last year's work of our investigation into the trade space of IFOV, resolution, effective focal length, and wavelength of incident radiation for coded aperture architectures. Finally we discuss the potential application of coded apertures for replacing objective lenses of night vision goggles (NVGs).

  9. The treatment of rhinovirus infections: progress and potential.

    PubMed

    Turner, R B

    2001-01-01

    The common cold is an important illness both as a result of the economic impact of this common disease and because of the morbidity associated with the complications of the illness. Recent attempts to develop antiviral treatments for the common cold represent a substantial advance over previous efforts. Formidable barriers remain to be overcome, however, before any of these new products will be proven to be clinically useful. Recent advances in our understanding of the pathogenesis of common cold symptoms have provided insights into potential new targets for the treatment of this illness. PMID:11166856

  10. Progress in the development of high degree potential coefficient models

    NASA Technical Reports Server (NTRS)

    Rapp, Richard H.

    1989-01-01

    A natural extension of the recent satellite derived potential coefficient models is the development of high degree (maximum 180 or 360) expansions. Such expansions are based on the combination of the satellite derived models with terrestrial gravity data and satellite altimeter data. Such models are useful for more precise geoid undulation computations, for simulation studies involving different typed of future missions (e.g., gradiometry), and as reference fields for different types of gravimetric computations. The attention is to the effect of the terrain, ellipsoidal terms, and weighting. The basic methods used for the high degree solutions are reviewed. Various correction terms are described and recent models are discussed and compared.

  11. Bacteria Inside Semiconductors as Potential Sensor Elements: Biochip Progress

    PubMed Central

    Sah, Vasu R.; Baier, Robert E.

    2014-01-01

    It was discovered at the beginning of this Century that living bacteria—and specifically the extremophile Pseudomonas syzgii—could be captured inside growing crystals of pure water-corroding semiconductors—specifically germanium—and thereby initiated pursuit of truly functional “biochip-based” biosensors. This observation was first made at the inside ultraviolet-illuminated walls of ultrapure water-flowing semiconductor fabrication facilities (fabs) and has since been, not as perfectly, replicated in simpler flow cell systems for chip manufacture, described here. Recognizing the potential importance of these adducts as optical switches, for example, or probes of metabolic events, the influences of the fabs and their components on the crystal nucleation and growth phenomena now identified are reviewed and discussed with regard to further research needs. For example, optical beams of current photonic circuits can be more easily modulated by integral embedded cells into electrical signals on semiconductors. Such research responds to a recently published Grand Challenge in ceramic science, designing and synthesizing oxide electronics, surfaces, interfaces and nanoscale structures that can be tuned by biological stimuli, to reveal phenomena not otherwise possible with conventional semiconductor electronics. This short review addresses only the fabrication facilities' features at the time of first production of these potential biochips. PMID:24961215

  12. Residential energy efficiency: Progress since 1973 and future potential

    NASA Astrophysics Data System (ADS)

    Rosenfeld, Arthur H.

    1985-11-01

    Today's 85 million U.S. homes use 100 billion of fuel and electricity (1150/home). If their energy intensity (resource energy/ft2) were still frozen at 1973 levels, they would use 18% more. With well-insulated houses, need for space heat is vanishing. Superinsulated Saskatchewan homes spend annually only 270 for space heat, 150 for water heat, and 400 for appliances, yet they cost only 2000±1000 more than conventional new homes. The concept of Cost of Conserved Energy (CCE) is used to rank conservation technologies for existing and new homes and appliances, and to develop supply curves of conserved energy and a least cost scenario. Calculations are calibrated with the BECA and other data bases. By limiting investments in efficiency to those whose CCE is less than current fuel and electricity prices, the potential residential plus commercial energy use in 2000 AD drops to half of that estimated by DOE, and the number of power plants needed drops by 200. For the whole buildings sector, potential savings by 2000 are 8 Mbod (worth 50B/year), at an average CCE of 10/barrel.

  13. DNA barcoding in animal species: progress, potential and pitfalls.

    PubMed

    Waugh, John

    2007-02-01

    Despite 250 years of work in systematics, the majority of species remains to be identified. Rising extinction rates and the need for increased biological monitoring lend urgency to this task. DNA sequencing, with key sequences serving as a "barcode", has therefore been proposed as a technology that might expedite species identification. In particular, the mitochondrial cytochrome c oxidase subunit 1 gene has been employed as a possible DNA marker for species and a number of studies in a variety of taxa have accordingly been carried out to examine its efficacy. In general, these studies demonstrate that DNA barcoding resolves most species, although some taxa have proved intractable. In some studies, barcoding provided a means of highlighting potential cryptic, synonymous or extinct species as well as matching adults with immature specimens. Higher taxa, however, have not been resolved as accurately as species. Nonetheless, DNA barcoding appears to offer a means of identifying species and may become a standard tool. PMID:17226815

  14. Pharmacogenetics: progress, pitfalls and clinical potential for coronary heart disease.

    PubMed

    Humphries, Steve E; Hingorani, Aroon

    2006-02-01

    Much has been written about the potential of pharmacogenetic testing to inform therapy based on an individual's genetic makeup, and to decide the most effective choice of available drugs, or to avoid dangerous side effects. Currently, there is little hard data for either in the field of cardiovascular disease. The usual approach has been opportunistic use of drug trials in unrelated patients, and to look for differences in response or outcome by "candidate gene" genotype, for example genes coding for drug metabolising enzymes (activators and metabolisers), and enzymes and receptors involved in lipid metabolism, adrenergic response, etc. As with all association studies, initially promising results have often failed the test of replication in larger studies, and the relationship between the CETP Taq-I variant and response to statins has now been disproved. The strongest data to date is the report [Chasman, D.I., Posada, D., Subrahmanyan, L., Cook, N.R., Stanton Jr., V.P., Ridker, P.M., 2004. Pharmacogenetic study of statin therapy and cholesterol reduction. J. Am. Med. Assoc. 291, 2821-2827] of a poorer cholesterol-lowering response to Pravastatin in the 7% of patients carrying a certain haplotype of the HMG CoA reductase gene (14% fall versus 19%), but if this is overcome simply by a higher dose, it is of little clinical relevance. Currently, the best example of avoiding side effects is determining genotype at the CYP2C9 locus with respect of warfarin treatment, since carriers for functional variants (>20% of the population) require lower doses for optimal anticoagulation, and homozygotes, although rare, may well experience serious bleeding if given a usual dose. The full potential of this field will only be realised with much further work. PMID:16359930

  15. Phylogenetic lineages in Entomophthoromycota

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Entomophthoromycota Humber is one of five major phylogenetic lineages among the former phylum Zygomycota. These early terrestrial fungi share evolutionarily ancestral characters such as coenocytic mycelium and gametangiogamy as a sexual process resulting in zygospore formation. Previous molecular st...

  16. Colponemids represent multiple ancient alveolate lineages.

    PubMed

    Janouškovec, Jan; Tikhonenkov, Denis V; Mikhailov, Kirill V; Simdyanov, Timur G; Aleoshin, Vladimir V; Mylnikov, Alexander P; Keeling, Patrick J

    2013-12-16

    The alveolates comprise three well-studied protist lineages of significant environmental, medical, and economical importance: apicomplexans (e.g., Plasmodium), dinoflagellates (e.g., Symbiodinium), and ciliates (e.g., Tetrahymena). These major lineages have evolved distinct and unusual characteristics, the origins of which have proved to be difficult evolutionary puzzles. Mitochondrial genomes are a prime example: all three groups depart from canonical form and content, but in different ways. Reconstructing such ancient transitions is difficult without deep-branching lineages that retain ancestral characteristics. Here we describe two such lineages and how they illuminate the ancestral state of alveolate mitochondrial genomes. We established five clonal cultures of colponemids, predatory alveolates without cultured representatives and molecular data. Colponemids represent at least two independent lineages at the phylum level in multilocus phylogenetic analysis; one sister to apicomplexans and dinoflagellates, and the other at a deeper position. A genome survey from one strain showed that ancestral state of the mitochondrial genomes in the three major alveolate lineages consisted of an unusual linear chromosome with telomeres and a substantially larger gene set than known alveolates. Colponemid sequences also identified several environmental lineages as colponemids, altogether suggesting an untapped potential for understanding the origin and evolution of apicomplexans, dinoflagellates, and ciliates. PMID:24316202

  17. Mixed Lineage Leukemia 5 (MLL5) Protein Regulates Cell Cycle Progression and E2F1-responsive Gene Expression via Association with Host Cell Factor-1 (HCF-1)*

    PubMed Central

    Zhou, Peipei; Wang, Zhilong; Yuan, Xiujie; Zhou, Cuihong; Liu, Lulu; Wan, Xiaoling; Zhang, Feng; Ding, Xiaodan; Wang, Chuangui; Xiong, Sidong; Wang, Zhen; Yuan, Jinduo; Li, Qiang; Zhang, Yan

    2013-01-01

    Trithorax group proteins methylate lysine 4 of histone 3 (H3K4) at active gene promoters. MLL5 protein, a member of the Trithorax protein family, has been implicated in the control of the cell cycle progression; however, the underlying molecular mechanism(s) have not been fully determined. In this study, we found that the MLL5 protein can associate with the cell cycle regulator “host cell factor” (HCF-1). The interaction between MLL5 and HCF-1 is mediated by the “HCF-1 binding motif” (HBM) of the MLL5 protein and the Kelch domain of the HCF-1 protein. Confocal microscopy showed that the MLL5 protein largely colocalized with HCF-1 in the nucleus. Knockdown of MLL5 resulted in reduced cell proliferation and cell cycle arrest in the G1 phase. Moreover, down-regulation of E2F1 target gene expression and decreased H3K4me3 levels at E2F1-responsive promoters were observed in MLL5 knockdown cells. Additionally, the core subunits, including ASH2L, RBBP5, and WDR5, that are necessary for effective H3K4 methyltransferase activities of the Trithorax protein complexes, were absent in the MLL5 complex, suggesting that a distinct mechanism may be used by MLL5 for exerting its H3K4 methyltransferase activity. Together, our findings demonstrate that MLL5 could associate with HCF-1 and then be recruited to E2F1-responsive promoters to stimulate H3K4 trimethylation and transcriptional activation, thereby facilitating the cell cycle G1 to S phase transition. PMID:23629655

  18. The Therapeutic Potential of the Ketogenic Diet in Treating Progressive Multiple Sclerosis

    PubMed Central

    Storoni, Mithu; Plant, Gordon T.

    2015-01-01

    Until recently, multiple sclerosis has been viewed as an entirely inflammatory disease without acknowledgment of the significant neurodegenerative component responsible for disease progression and disability. This perspective is being challenged by observations of a dissociation between inflammation and neurodegeneration where the neurodegenerative component may play a more significant role in disease progression. In this review, we explore the relationship between mitochondrial dysfunction and neurodegeneration in multiple sclerosis. We review evidence that the ketogenic diet can improve mitochondrial function and discuss the potential of the ketogenic diet in treating progressive multiple sclerosis for which no treatment currently exists. PMID:26839705

  19. Lineage determinants in early endocrine development

    PubMed Central

    Rieck, Sebastian; Bankaitis, Eric D.; Wright, Christopher V.E.

    2013-01-01

    Pancreatic endocrine cells are produced from a dynamic epithelium in a process that, as in any developing organ, is driven by interacting programs of spatiotemporally regulated intercellular signals and autonomous gene regulatory networks. These algorithms work to push progenitors and their transitional intermediates through a series of railroad-station-like switching decisions to regulate flux along specific differentiation tracks. Extensive research on pancreas organogenesis over the last 20 years, greatly spurred by the potential to restore functional β-cell mass in diabetic patients by transplantation therapy, is advancing our knowledge of how endocrine lineage bias is established and allocation is promoted. The field is working towards the goal of generating a detailed blueprint of how heterogeneous cell populations interact and respond to each other, and other influences such as the extracellular matrix, to move into progressively refined and mature cell states. Here, we highlight how signaling codes and transcriptional networks might determine endocrine lineage within a complex and dynamic architecture, based largely on studies in the mouse. The process begins with the designation of multipotent progenitor cells (MPC) to pancreatic buds that subsequently move through a newly proposed period involving epithelial plexus formation-remodeling, and ends with formation of clustered endocrine islets connected to the vascular and peripheral nervous systems. Developing this knowledge base, and increasing the emphasis on direct comparisons between mouse and human, will yield a more complete and focused picture of pancreas development, and thereby inform β-cell-directed differentiation from human embryonic stem or induced pluripotent stem cells (hESC, iPSC). Additionally, a deeper understanding may provide surprising therapeutic angles by defining conditions that allow the controllable reprogramming of endodermal or pancreatic cell populations. PMID:22728667

  20. Hematopoietic Lineage Diversification, Simplified.

    PubMed

    Drissen, Roy; Nerlov, Claus

    2016-08-01

    Hematopoiesis is a complex process that requires a high degree of transcriptional diversification during lineage commitment and differentiation. de Graaf et al. (2016) have now generated a comprehensive gene expression dataset that allows cell-type-specific genes as well as associated transcription factor expression patterns to be readily identified. PMID:27494670

  1. Bazooka mediates secondary axon morphology in Drosophila brain lineages

    PubMed Central

    2011-01-01

    In the Drosophila brain, neural lineages project bundled axon tracts into a central neuropile. Each lineage exhibits a stereotypical branching pattern and trajectory, which distinguish it from other lineages. In this study, we used a multilineage approach to explore the neural function of the Par-complex member Par3/Bazooka in vivo. Drosophila bazooka is expressed in post-mitotic neurons of the larval brain and localizes within neurons in a lineage-dependent manner. The fact that multiple GAL4 drivers have been mapped to several lineages of the Drosophila brain enables investigation of the role of Bazooka from larval to adult stages Bazooka loss-of-function (LOF) clones had abnormal morphologies, including aberrant pathway choice of ventral projection neurons in the BAla1 lineage, ectopic branching in the DALv2 and BAmv1 lineages, and excess BLD5 lineage axon projections in the optic medulla. Exogenous expression of Bazooka protein in BAla1 neurons rescued defective guidance, supporting an intrinsic requirement for Bazooka in the post-mitotic neuron. Elimination of the Par-complex member Par6 recapitulated Bazooka phenotypes in some but not all lineages, suggesting that the Par complex functions in a lineage-dependent manner, and that Bazooka may act independently in some lineages. Importantly, this study highlights the potential of using a multilineage approach when studying gene function during neural development in Drosophila. PMID:21524279

  2. Bazooka mediates secondary axon morphology in Drosophila brain lineages.

    PubMed

    Spindler, Shana R; Hartenstein, Volker

    2011-01-01

    In the Drosophila brain, neural lineages project bundled axon tracts into a central neuropile. Each lineage exhibits a stereotypical branching pattern and trajectory, which distinguish it from other lineages. In this study, we used a multilineage approach to explore the neural function of the Par-complex member Par3/Bazooka in vivo. Drosophila bazooka is expressed in post-mitotic neurons of the larval brain and localizes within neurons in a lineage-dependent manner. The fact that multiple GAL4 drivers have been mapped to several lineages of the Drosophila brain enables investigation of the role of Bazooka from larval to adult stages Bazooka loss-of-function (LOF) clones had abnormal morphologies, including aberrant pathway choice of ventral projection neurons in the BAla1 lineage, ectopic branching in the DALv2 and BAmv1 lineages, and excess BLD5 lineage axon projections in the optic medulla. Exogenous expression of Bazooka protein in BAla1 neurons rescued defective guidance, supporting an intrinsic requirement for Bazooka in the post-mitotic neuron. Elimination of the Par-complex member Par6 recapitulated Bazooka phenotypes in some but not all lineages, suggesting that the Par complex functions in a lineage-dependent manner, and that Bazooka may act independently in some lineages. Importantly, this study highlights the potential of using a multilineage approach when studying gene function during neural development in Drosophila. PMID:21524279

  3. Direct somatic lineage conversion.

    PubMed

    Tanabe, Koji; Haag, Daniel; Wernig, Marius

    2015-10-19

    The predominant view of embryonic development and cell differentiation has been that rigid and even irreversible epigenetic marks are laid down along the path of cell specialization ensuring the proper silencing of unrelated lineage programmes. This model made the prediction that specialized cell types are stable and cannot be redirected into other lineages. Accordingly, early attempts to change the identity of somatic cells had little success and was limited to conversions between closely related cell types. Nuclear transplantation experiments demonstrated, however, that specialized cells even from adult mammals can be reprogrammed into a totipotent state. The discovery that a small combination of transcription factors can reprogramme cells to pluripotency without the need of oocytes further supported the view that these epigenetic barriers can be overcome much easier than assumed, but the extent of this flexibility was still unclear. When we showed that a differentiated mesodermal cell can be directly converted to a differentiated ectodermal cell without a pluripotent intermediate, it was suggested that in principle any cell type could be converted into any other cell type. Indeed, the work of several groups in recent years has provided many more examples of direct somatic lineage conversions. Today, the question is not anymore whether a specific cell type can be generated by direct reprogramming but how it can be induced. PMID:26416679

  4. Global progress and potentially effective policy responses to reduce maternal mortality.

    PubMed

    Mbizvo, Michael T; Say, Lale

    2012-10-01

    Reducing maternal mortality within significant margins is a global imperative that reflects attainment of development goals. Progress in reducing maternal mortality, in particular among countries with notably high maternal mortality ratios (MMRs), has been substantially slower than the Millennium Development Goal target of an annual rate of 5.5% decline. The latest UN maternal mortality estimates show a reduction in MMR in a number of countries between 1990 and 2008. Understanding the factors associated with progress in countries that have reduced maternal mortality provides other countries and development partners with opportunities to consider and implement policies and interventions that could help accelerate progress. This paper reviews 6 countries that have demonstrated marked progress. The policies that have been effective include innovative financing measures; investment in human resources both in terms of strengthening pre-service education and emphasizing in-service training for healthcare providers; strengthening obstetric care by enhancing infrastructure and upgrading equipment, as well as improving quality of services; and investing in the broader determinants of maternal mortality, particularly family planning and women's education and socioeconomic empowerment. This range of actions, which includes a combination of facility and community-based approaches, provides a list of potentially effective strategies that could be considered when developing programs in other countries with slower progress. Strong political will and multistakeholder involvement and interventions are key in the development and implementation of these policies and actions. PMID:22883916

  5. Potential markers of tongue tumor progression selected by cDNA microarray.

    PubMed

    Carinci, F; Lo Muzio, L; Piattelli, A; Rubini, C; Chiesa, F; Ionna, F; Palmieri, A; Maiorano, E; Pastore, A; Laino, G; Dolci, M; Pezzetti, F

    2005-01-01

    Squamous cell carcinoma (SCC), the most frequent malignant tumor of the oral cavity, generally exhibits a poor prognosis and metastases are the main cause of death. This tumor often arises from pre-malignant lesions. To date, it is difficult to predict if and which pre-malignant lesions may progress into oral SCC using traditional methods. For these reasons, several studies are trying to identify markers useful in the progression of pre-malignant lesions and tumors. To define the genetic expression profile of tongue tumor progression we compared 9 dysplasias (DS), 8 tumors without metastasis (TWM), 11 metastasizing SCCs (MT) of the tongue, and a baseline of 11 normal tissues by using cDNA microarray containing 19.2 K clones. We initially applied hierarchical agglomerative clustering based on information from all 6026 clones. Results were obtained by performing a two steps analysis: a Significance Analysis of Microarray (SAM) and a Gene Ontology search. One hundred and five clones have statistically significant different expression levels (FDR < 0.01) between DS and TWM, whereas 570 genes have statistically significant difference expression levels between TWM and MT (FDR < 0.01) as detected by SAM. By filtering with FatiGo only 33 genes were differentially expressed in TWN, respect to DS, whereas 155 genes were differentially expressed in MT respect to TWM. We detected some genes which encode for oncogenes, transcription factors and cell cycle regulators as potential markers of DS progression. Examples are BAG4, PAX3 and CCNI, respectively. Among potential markers of metastases are some genes related to cell mobility (TSPAN-2 and SNTA1), intercellular adhesion (integrin alpha 7) or extracellular matrix components (ADAMTS2 and cathepsin O). Additionally, under-expressed genes encoded apoptosis-related proteins (PDCD4 and CASP4). In conclusion, we identified several genes differentially expressed in tumor progression which can potentially help in better classifying

  6. Potential Drugs and Methods for Preventing or Delaying the Progression of Huntington’s Disease

    PubMed Central

    Sari, Youssef

    2012-01-01

    Huntington’s disease (HD) is an autosomal dominant inherited and progressive neurodegenerative disorder with motor dysfunction and cognitive deficits. Although, there are no treatments to delay the appearance and the progression of HD, there are potential drugs currently in preclinical and clinical trials that are focused on HD therapy. The signaling pathways involved in HD are not yet clearly elucidated; however, expression of mutant huntingtin protein is considered a key factor in the induction and/or progression of HD. The demonstration that the onset and progression of HD in models of transgenic mice, in particular, are delayed or improved by the application of neurotrophic factors has emphasized their importance in neuroprotection in HD. In addition, other compounds targeting the HD gene or mutant huntingtin protein are currently in preclinical and clinical testing and may show promising neuroprotective effects. There are current patented drugs that are currently being considered as potential therapeutics for HD. These patented drugs may provide promising therapy for HD. PMID:21585328

  7. Hematopoietic stem/progenitor cell commitment to the megakaryocyte lineage.

    PubMed

    Woolthuis, Carolien M; Park, Christopher Y

    2016-03-10

    The classical model of hematopoiesis has long held that hematopoietic stem cells (HSCs) sit at the apex of a developmental hierarchy in which HSCs undergo long-term self-renewal while giving rise to cells of all the blood lineages. In this model, self-renewing HSCs progressively lose the capacity for self-renewal as they transit into short-term self-renewing and multipotent progenitor states, with the first major lineage commitment occurring in multipotent progenitors, thus giving rise to progenitors that initiate the myeloid and lymphoid branches of hematopoiesis. Subsequently, within the myeloid lineage, bipotent megakaryocyte-erythrocyte and granulocyte-macrophage progenitors give rise to unipotent progenitors that ultimately give rise to all mature progeny. However, over the past several years, this developmental scheme has been challenged, with the origin of megakaryocyte precursors being one of the most debated subjects. Recent studies have suggested that megakaryocytes can be generated from multiple pathways and that some differentiation pathways do not require transit through a requisite multipotent or bipotent megakaryocyte-erythrocyte progenitor stage. Indeed, some investigators have argued that HSCs contain a subset of cells with biased megakaryocyte potential, with megakaryocytes directly arising from HSCs under steady-state and stress conditions. In this review, we discuss the evidence supporting these nonclassical megakaryocytic differentiation pathways and consider their relative strengths and weaknesses as well as the technical limitations and potential pitfalls in interpreting these studies. Ultimately, such pitfalls will need to be overcome to provide a comprehensive and definitive understanding of megakaryopoiesis. PMID:26787736

  8. Potential of APDM mobility lab for the monitoring of the progression of Parkinson's disease.

    PubMed

    Mancini, Martina; Horak, Fay B

    2016-05-01

    APDM's Mobility Lab system provides portable, validated, reliable, objective measures of balance and gait that are sensitive to Parkinson's disease (PD). In this review, we describe the potential of objective measures collected with the Mobility Lab system for tracking longitudinal progression of PD. Balance and gait are among the most important motor impairments influencing quality of life for people with PD. Mobility Lab uses body-worn, Opal sensors on the legs, trunk and arms during prescribed tasks, such as the instrumented Get Up and Go test or quiet stance, to quickly quantify the quality of balance and gait in the clinical environment. The same Opal sensors can be sent home with patients to continuously monitor the quality of their daily activities. Objective measures have the potential to monitor progression of mobility impairments in PD throughout its course to improve patient care and accelerate clinical trials. PMID:26872510

  9. Intermolecular potential functions and high resolution molecular spectroscopy of weakly bound complexes. Final progress report

    SciTech Connect

    Muenter, J.S.

    1997-04-01

    This report describes accomplishments over the past year in research supported by this grant. Two papers published in this period are briefly discussed. The general goal of the work is to consolidate the understanding of experimental results through a theoretical model of intermolecular potential energy surfaces. Progress in the experimental and theoretical phases of the program are presented and immediate goals outlined. The ability to construct analytic intermolecular potential functions that accurately predict the energy of interaction between small molecules will have great impact in many areas of chemistry, biochemistry, and biology.

  10. Modern Lineages of Mycobacterium tuberculosis Exhibit Lineage-Specific Patterns of Growth and Cytokine Induction in Human Monocyte-Derived Macrophages

    PubMed Central

    Sarkar, Rajesh; Lenders, Laura; Wilkinson, Katalin A.; Wilkinson, Robert J.; Nicol, Mark P.

    2012-01-01

    Background Strains of Mycobacterium tuberculosis vary in virulence. Strains that have caused outbreaks in the United States and United Kingdom have been shown to subvert the innate immune response as a potential immune evasion mechanism. There is, however, little information available as to whether these patterns of immune subversion are features of individual strains or characteristic of broad clonal lineages of M. tuberculosis. Methods Strains from two major modern lineages (lineage 2 [East-Asian] and lineage 4 [Euro-American]) circulating in the Western Cape in South Africa as well as a comparator modern lineage (lineage 3 [CAS/Delhi]) were identified. We assessed two virulence associated characteristics: mycobacterial growth (in liquid broth and monocyte derived macrophages) and early pro-inflammatory cytokine induction. Results In liquid culture, Lineage 4 strains grew more rapidly and reached higher plateau levels than other strains (lineage 4 vs. lineage 2 p = 0.0024; lineage 4 vs. lineage 3 p = 0.0005). Lineage 3 strains were characterized by low and early plateau levels, while lineage 2 strains showed an intermediate growth phenotype. In monocyte-derived macrophages, lineage 2 strains grew faster than lineage 3 strains (p<0.01) with lineage 4 strains having an intermediate phenotype. Lineage 2 strains induced the lowest levels of pro-inflammatory TNF and IL-12p40 as compared to other lineages (lineage 2: median TNF 362 pg/ml, IL-12p40 91 pg/ml; lineage 3: median TNF 1818 pg/ml, IL-12p40 123 pg/ml; lineage 4: median TNF 1207 pg/ml, IL-12p40 205 pg/ml;). In contrast, lineage 4 strains induced high levels of IL-12p40 and intermediate level of TNF. Lineage 3 strains induced high levels of TNF and intermediate levels of IL-12p40. Conclusions Strains of M. tuberculosis from the three major modern strain lineages possess distinct patterns of growth and cytokine induction. Rapid growth and immune subversion may be key characteristics to the success of

  11. Potential Clinical Value of Multiparametric PET in the Prediction of Alzheimer’s Disease Progression

    PubMed Central

    Chen, Xueqi; Zhou, Yun; Wang, Rongfu; Cao, Haoyin; Reid, Savina; Gao, Rui; Han, Dong

    2016-01-01

    Objective To evaluate the potential clinical value of quantitative functional FDG PET and pathological amyloid-β PET with cerebrospinal fluid (CSF) biomarkers and clinical assessments in the prediction of Alzheimer’s disease (AD) progression. Methods We studied 82 subjects for up to 96 months (median = 84 months) in a longitudinal Alzheimer’s Disease Neuroimaging Initiative (ADNI) project. All preprocessed PET images were spatially normalized to standard Montreal Neurologic Institute space. Regions of interest (ROI) were defined on MRI template, and standard uptake values ratios (SUVRs) to the cerebellum for FDG and amyloid-β PET were calculated. Predictive values of single and multiparametric PET biomarkers with and without clinical assessments and CSF biomarkers for AD progression were evaluated using receiver operating characteristic (ROC) analysis and logistic regression model. Results The posterior precuneus and cingulate SUVRs were identified for both FDG and amyloid-β PET in predicating progression in normal controls (NCs) and subjects with mild cognitive impairment (MCI). FDG parietal and lateral temporal SUVRs were suggested for monitoring NCs and MCI group progression, respectively. 18F-AV45 global cortex attained (78.6%, 74.5%, 75.4%) (sensitivity, specificity, accuracy) in predicting NC progression, which is comparable to the 11C-PiB global cortex SUVR’s in predicting MCI to AD. A logistic regression model to combine FDG parietal and posterior precuneus SUVR and Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) Total Mod was identified in predicating NC progression with (80.0%, 94.9%, 93.9%) (sensitivity, specificity, accuracy). The selected model including FDG posterior cingulate SUVR, ADAS-Cog Total Mod, and Mini-Mental State Exam (MMSE) scores for predicating MCI to AD attained (96.4%, 81.2%, 83.6%) (sensitivity, specificity, accuracy). 11C-PiB medial temporal SUVR with MMSE significantly increased 11C-PiB PET AUC to 0.915 (p<0

  12. The Potential Use of DNA Methylation Biomarkers to Identify Risk and Progression of Type 2 Diabetes

    PubMed Central

    Gillberg, Linn; Ling, Charlotte

    2015-01-01

    Type 2 diabetes mellitus (T2D) is a slowly progressive disease that can be postponed or even avoided through lifestyle changes. Recent data demonstrate highly significant correlations between DNA methylation and the most important risk factors of T2D, including age and body mass index, in blood and human tissues relevant to insulin resistance and T2D. Also, T2D patients and individuals with increased risk of the disease display differential DNA methylation profiles and plasticity compared to controls. Accordingly, the novel clues to DNA methylation fingerprints in blood and tissues with deteriorated metabolic capacity indicate that blood-borne epigenetic biomarkers of T2D progression might become a reality. This Review will address the most recent associations between DNA methylation and diabetes-related traits in human tissues and blood. The overall focus is on the potential of future epigenome-wide studies, carried out across tissues and populations with correlations to pre-diabetes and T2D risk factors, to build up a library of epigenetic markers of risk and early progression of T2D. These markers may, tentatively in combination with other predictors of T2D development, increase the possibility of individual-based lifestyle prevention of T2D and associated metabolic diseases. PMID:25870586

  13. Pluripotent reprogramming and lineage reprogramming: promises and challenges in cardiovascular regeneration.

    PubMed

    He, Wen-Jun; Hou, Qian; Han, Qing-Wang; Han, Wei-Dong; Fu, Xiao-Bing

    2014-08-01

    Cardiovascular disease is a leading cause of death in industrialized countries. Scientists are trying to generate cardiomyocytes in vitro and in vivo to repair damaged heart tissue. Pluripotent reprogramming brings an alternative source of embryonic-like stem cells, and the possibility of regenerating mammalian tissues by first reverting somatic cells to induced pluripotent stem cells, followed by redifferentiating these cells into cardiomyocytes. More recently, lineage reprogramming of fibroblasts directly into functional cardiomyocytes has been reported. The procedure does not involve reverting cells back to a pluripotent stage, and, thus, would presumably reduce tumorigenic potential. Interestingly, lineage reprogramming could be used for in situ conversion of cell fate. Moreover, zebrafish-like regenerative mechanism in mammalian heart tissue, which was observed in mice within the first week of postpartum, should be further addressed. Here, we review the landmark progresses of the two major reprogramming strategies, compare their pros and cons in cardiovascular regeneration, and forecast the future directions of cardiac repair. PMID:24063625

  14. Identification and characterization of mouse otic sensory lineage genes

    PubMed Central

    Hartman, Byron H.; Durruthy-Durruthy, Robert; Laske, Roman D.; Losorelli, Steven; Heller, Stefan

    2015-01-01

    Vertebrate embryogenesis gives rise to all cell types of an organism through the development of many unique lineages derived from the three primordial germ layers. The otic sensory lineage arises from the otic vesicle, a structure formed through invagination of placodal non-neural ectoderm. This developmental lineage possesses unique differentiation potential, giving rise to otic sensory cell populations including hair cells, supporting cells, and ganglion neurons of the auditory and vestibular organs. Here we present a systematic approach to identify transcriptional features that distinguish the otic sensory lineage (from early otic progenitors to otic sensory populations) from other major lineages of vertebrate development. We used a microarray approach to analyze otic sensory lineage populations including microdissected otic vesicles (embryonic day 10.5) as well as isolated neonatal cochlear hair cells and supporting cells at postnatal day 3. Non-otic tissue samples including periotic tissues and whole embryos with otic regions removed were used as reference populations to evaluate otic specificity. Otic populations shared transcriptome-wide correlations in expression profiles that distinguish members of this lineage from non-otic populations. We further analyzed the microarray data using comparative and dimension reduction methods to identify individual genes that are specifically expressed in the otic sensory lineage. This analysis identified and ranked top otic sensory lineage-specific transcripts including Fbxo2, Col9a2, and Oc90, and additional novel otic lineage markers. To validate these results we performed expression analysis on select genes using immunohistochemistry and in situ hybridization. Fbxo2 showed the most striking pattern of specificity to the otic sensory lineage, including robust expression in the early otic vesicle and sustained expression in prosensory progenitors and auditory and vestibular hair cells and supporting cells. PMID:25852475

  15. Engraftment and Lineage Potential of Adult Hematopoietic Stem and Progenitor Cells Is Compromised Following Short-Term Culture in the Presence of an Aryl Hydrocarbon Receptor Antagonist

    PubMed Central

    Gu, Angel; Torres-Coronado, Monica; Tran, Chy-Anh; Vu, Hieu; Epps, Elizabeth W.; Chung, Janet; Gonzalez, Nancy; Blanchard, Suzette

    2014-01-01

    Abstract Hematopoietic stem cell gene therapy for HIV/AIDS is a promising alternative to lifelong antiretroviral therapy. One of the limitations of this approach is the number and quality of stem cells available for transplant following in vitro manipulations associated with stem cell isolation and genetic modification. The development of methods to increase the number of autologous, gene-modified stem cells available for transplantation would overcome this barrier. Hematopoietic stem and progenitor cells (HSPC) from adult growth factor-mobilized peripheral blood were cultured in the presence of an aryl hydrocarbon receptor antagonist (AhRA) previously shown to expand HSPC from umbilical cord blood. Qualitative and quantitative assessment of the hematopoietic potential of minimally cultured (MC-HSPC) or expanded HSPC (Exp-HSPC) was performed using an immunodeficient mouse model of transplantation. Our results demonstrate robust, multilineage engraftment of both MC-HSPC and Exp-HSPC although estimates of expansion based on stem cell phenotype were not supported by a corresponding increase in in vivo engrafting units. Bone marrow of animals transplanted with either MC-HSPC or Exp-HSPC contained secondary engrafting cells verifying the presence of primitive stem cells in both populations. However, the frequency of in vivo engrafting units among the more primitive CD34+/CD90+ HSPC population was significantly lower in Exp-HSPC compared with MC-HSPC. Exp-HSPC also produced fewer lymphoid progeny and more myeloid progeny than MC-HSPC. These results reveal that in vitro culture of adult HSPC in AhRA maintains but does not increase the number of in vivo engrafting cells and that HSPC expanded in vitro contain defects in lymphopoiesis as assessed in this model system. Further investigation is required before implementation of this approach in the clinical setting. PMID:25003230

  16. Progress toward determining the potential of ODS alloys for gas turbine applications

    NASA Technical Reports Server (NTRS)

    Dreshfield, R. L.; Hoppin, G., III; Sheffler, K.

    1983-01-01

    The Materials for Advanced Turbine Engine (MATE) Program managed by the NASA Lewis Research Center is supporting two projects to evaluate the potential of oxide dispersion strengthened (ODS) alloys for aircraft gas turbine applications. One project involves the evaluation of Incoloy (TM) MA-956 for application as a combustor liner material. An assessment of advanced engine potential will be conducted by means of a test in a P&WA 2037 turbofan engine. The other project involves the evaluation of Inconel (TM) MA 6000 for application as a high pressure turbine blade material and includes a test in a Garrett TFE 731 turbofan engine. Both projects are progressing toward these engine tests in 1984.

  17. Exploring potential mechanisms of action of natalizumab in secondary progressive multiple sclerosis.

    PubMed

    Sellebjerg, Finn; Cadavid, Diego; Steiner, Deborah; Villar, Luisa Maria; Reynolds, Richard; Mikol, Daniel

    2016-01-01

    Multiple sclerosis (MS) is a common and chronic central nervous system (CNS) demyelinating disease and a leading cause of permanent disability. Patients most often present with a relapsing-remitting disease course, typically progressing over time to a phase of relentless advancement in secondary progressive MS (SPMS), for which approved disease-modifying therapies are limited. In this review, we summarize the pathophysiological mechanisms involved in the development of SPMS and the rationale and clinical potential for natalizumab, which is currently approved for the treatment of relapsing forms of MS, to exert beneficial effects in reducing disease progression unrelated to relapses in SPMS. In both forms of MS, active brain-tissue injury is associated with inflammation; but in SPMS, the inflammatory response occurs at least partly behind the blood-brain barrier and is followed by a cascade of events, including persistent microglial activation that may lead to chronic demyelination and neurodegeneration associated with irreversible disability. In patients with relapsing forms of MS, natalizumab therapy is known to significantly reduce intrathecal inflammatory responses which results in reductions in brain lesions and brain atrophy as well as beneficial effects on clinical measures, such as reduced frequency and severity of relapse and reduced accumulation of disability. Natalizumab treatment also reduces levels of cerebrospinal fluid chemokines and other biomarkers of intrathecal inflammation, axonal damage and demyelination, and has demonstrated the ability to reduce innate immune activation and intrathecal immunoglobulin synthesis in patients with MS. The efficacy of natalizumab therapy in SPMS is currently being investigated in a randomized, double-blind, placebo-controlled trial. PMID:26788129

  18. Exploring potential mechanisms of action of natalizumab in secondary progressive multiple sclerosis

    PubMed Central

    Sellebjerg, Finn; Cadavid, Diego; Steiner, Deborah; Villar, Luisa Maria; Reynolds, Richard; Mikol, Daniel

    2016-01-01

    Multiple sclerosis (MS) is a common and chronic central nervous system (CNS) demyelinating disease and a leading cause of permanent disability. Patients most often present with a relapsing–remitting disease course, typically progressing over time to a phase of relentless advancement in secondary progressive MS (SPMS), for which approved disease-modifying therapies are limited. In this review, we summarize the pathophysiological mechanisms involved in the development of SPMS and the rationale and clinical potential for natalizumab, which is currently approved for the treatment of relapsing forms of MS, to exert beneficial effects in reducing disease progression unrelated to relapses in SPMS. In both forms of MS, active brain-tissue injury is associated with inflammation; but in SPMS, the inflammatory response occurs at least partly behind the blood–brain barrier and is followed by a cascade of events, including persistent microglial activation that may lead to chronic demyelination and neurodegeneration associated with irreversible disability. In patients with relapsing forms of MS, natalizumab therapy is known to significantly reduce intrathecal inflammatory responses which results in reductions in brain lesions and brain atrophy as well as beneficial effects on clinical measures, such as reduced frequency and severity of relapse and reduced accumulation of disability. Natalizumab treatment also reduces levels of cerebrospinal fluid chemokines and other biomarkers of intrathecal inflammation, axonal damage and demyelination, and has demonstrated the ability to reduce innate immune activation and intrathecal immunoglobulin synthesis in patients with MS. The efficacy of natalizumab therapy in SPMS is currently being investigated in a randomized, double-blind, placebo-controlled trial. PMID:26788129

  19. Role and therapeutic potential of G-protein coupled receptors in breast cancer progression and metastases.

    PubMed

    Singh, Anukriti; Nunes, Jessica J; Ateeq, Bushra

    2015-09-15

    G-protein-coupled receptors (GPCRs) comprise a large family of cell-surface receptors, which have recently emerged as key players in tumorigenesis, angiogenesis and metastasis. In this review, we discussed our current understanding of the many roles played by GPCRs in general, and particularly Angiotensin II type I receptor (AGTR1), a member of the seven-transmembrane-spanning G-protein coupled receptor superfamily, and its significance in breast cancer progression and metastasis. We have also discussed different strategies for targeting AGTR1, and its ligand Angiotension II (Ang II), which might unravel unique opportunities for breast cancer prevention and treatment. For example, AGTR1 blockers (ARBs) which are already in clinical use for treating hypertension, merit further investigation as a therapeutic strategy for AGTR1-positive cancer patients and may have the potential to prevent Ang II-AGTR1 signalling mediated cancer pathogenesis and metastases. PMID:25981295

  20. Role and therapeutic potential of G-protein coupled receptors in breast cancer progression and metastases

    PubMed Central

    Singh, Anukriti; Nunes, Jessica J.; Ateeq, Bushra

    2015-01-01

    G-protein-coupled receptors (GPCRs) comprise a large family of cell-surface receptors, which have recently emerged as key players in tumorigenesis, angiogenesis and metastasis. In this review, we discussed our current understanding of the many roles played by GPCRs in general, and particularly Angiotensin II type I receptor (AGTR1), a member of the seven-transmembrane-spanning G-protein coupled receptor superfamily, and its significance in breast cancer progression and metastasis. We have also discussed different strategies for targeting AGTR1, and its ligand Angiotension II (Ang II), which might unravel unique opportunities for breast cancer prevention and treatment. For example, AGTR1 blockers (ARBs) which are already in clinical use for treating hypertension, merit further investigation as a therapeutic strategy for AGTR1-positive cancer patients and may have the potential to prevent Ang II-AGTR1 signalling mediated cancer pathogenesis and metastases. PMID:25981295

  1. A strategy to reveal potential glycan markers from serum glycoproteins associated with breast cancer progression.

    PubMed

    Abd Hamid, Umi M; Royle, Louise; Saldova, Radka; Radcliffe, Catherine M; Harvey, David J; Storr, Sarah J; Pardo, Maria; Antrobus, Robin; Chapman, Caroline J; Zitzmann, Nicole; Robertson, John F; Dwek, Raymond A; Rudd, Pauline M

    2008-12-01

    Aberrant glycosylation on glycoproteins that are either presented on the surface or secreted by cancer cells is a potential source of disease biomarkers and provides insights into disease pathogenesis. N-Glycans of the total serum glycoproteins from advanced breast cancer patients and healthy individuals were sequenced by HPLC with fluorescence detection coupled with exoglycosidase digestions and mass spectrometry. We observed a significant increase in a trisialylated triantennary glycan containing alpha1,3-linked fucose which forms part of the sialyl Lewis x epitope. Following digestion of the total glycan pool with a combination of sialidase and beta-galactosidase, we segregated and quantified a digestion product, a monogalactosylated triantennary structure containing alpha1,3-linked fucose. We compared breast cancer patients and controls and detected a 2-fold increase in this glycan marker in patients. In 10 patients monitored longitudinally, we showed a positive correlation between this glycan marker and disease progression and also demonstrated its potential as a better indicator of metastasis compared to the currently used biomarkers, CA 15-3 and carcinoembryonic antigen (CEA). A pilot glycoproteomic study of advanced breast cancer serum highlighted acute-phase proteins alpha1-acid glycoprotein, alpha1-antichymotrypsin, and haptoglobin beta-chain as contributors to the increase in the glycan marker which, when quantified from each of these proteins, marked the onset of metastasis in advance of the CA 15-3 marker. These preliminary findings suggest that specific glycans and glycoforms of proteins may be candidates for improved markers in the monitoring of breast cancer progression. PMID:18818422

  2. Lineage and clonal development of gastric glands.

    PubMed

    Nomura, S; Esumi, H; Job, C; Tan, S S

    1998-12-01

    Individual gastric glands of the stomach are composed of cells of different phenotypes. These are derived from multipotent progenitor stem cells located at the isthmus region of the gland. Previous cell lineage analyses suggest that gastric glands, as in the colon and small intestine, are invariably monoclonal by adult stages. However, little is known about the ontogenetic progression of glandular clonality in the stomach. To examine this issue, we employed an in situ cell lineage marker in female mice heterozygous for an X-linked transgene. We found that stomach glands commence development as polyclonal units, but by adulthood (6 weeks), the majority progressed to monoclonal units. Our analysis suggests that at least three progenitor cells are required to initiate the development of individual gastric glands if they are analyzed just after birth. Hence, unlike the colon and small intestine, stomachs showed a significant fraction (10-25%) of polyclonal glands at adult stages. We suggest that these glands persist from polyclonal glands present in the embryonic stomach and hypothesize that they represent a subpopulation of glands with larger numbers of self-renewing stem cells. PMID:9851847

  3. Current progress in stem cell research and its potential for islet cell transplantation.

    PubMed

    Leung, P S; Ng, K Y

    2013-01-01

    Diabetes is characterized by insulin deficiency concomitant with hyperglycemia due to reduced islet cell mass and/or dysfunction. Currently, insulin replacement is the first-line treatment option for patients with type 1 and a severe form of type 2 diabetes. Treatment by insulin injection is generally effective but nonphysiological, and has the potential of producing chronic complications. On the other hand, islet transplantation can maintain normoglycemia without hypoglycemic side effects, potentially freeing diabetic patients of insulin dependence. In practice, islet transplantation remains hindered by the lack of organ donors and transplant rejection concerns. Recent advances in stem cell research and regenerative medicine, however, offer promise for the clinical application of islet cell transplantation. This review article offers a critical appraisal of current molecular induction approaches, such as directed differentiation, microenvironment induction, and genetic modification, which mimic islet cell development by inducing a variety of stem cells; they include embryonic stem cells, induced pluripotent stem cells, and various tissue-derived stem cells to become functional and transplantable insulin-producing islet cells. Despite good progress, several obstacles remain to be overcome before islet transplantation can be translated into a therapy for human patients, including, but are not limited to, immunogenicity and risk of tumorogenesis. PMID:22834839

  4. Identification of human erythroid lineage-committed progenitors.

    PubMed

    Mori, Yasuo; Akashi, Koichi; Weissman, Irving L

    2016-05-01

    Elucidating the developmental pathway leading to erythrocytes and being able to isolate their progenitors is crucial to understanding and treating disorders of red cell imbalance such as anemia, myelodysplastic syndrome, and polycythemia vera. Endoglin (CD105) is a key marker for purifying mouse erythroid lineage-committed progenitors (EPs) from bone marrow. Herein, we show that human EPs can also be isolated from adult bone marrow. We identified three subfractions that possessed different expression patterns of CD105 and CD71 within the previously defined human megakaryocyte/erythrocyte progenitor (hMEP; Lineage-CD34(+)CD38(+)IL-3Rα(-)CD45RA(-)) population. Both CD71(-)CD105(-) and CD71(+)CD105(-) MEPs, at least in vitro, retained bipotency for the megakaryocyte (MegK) and erythrocyte (E) lineages, although the latter sub-population had a differentiation potential skewed toward the E-lineage. Notably, the differentiation output of the CD71(+)CD105(+) subset of cells within the MEP population was completely restricted to the E-lineage with the loss of MegK potential; thus, we termed CD71(+)CD105(-) MEPs and CD71(+)CD105(+) cells as E-biased MEPs (E-MEPs) and EPs, respectively. These previously unclassified populations may facilitate understanding of the molecular mechanisms governing human erythroid development and serve as potential therapeutic targets in disorders of the erythroid lineage. PMID:27263782

  5. Cavin-2 in oral cancer: A potential predictor for tumor progression.

    PubMed

    Unozawa, Motoharu; Kasamatsu, Atsushi; Higo, Morihiro; Fukumoto, Chonji; Koyama, Tomoyoshi; Sakazume, Tomomi; Nakashima, Dai; Ogawara, Katsunori; Yokoe, Hidetaka; Shiiba, Masashi; Tanzawa, Hideki; Uzawa, Katsuhiro

    2016-06-01

    Cavin-2 (CVN2) affects formation of large caveolae, which are membrane-rich cholesterol domains associated with several functions in signal transduction. Accumulating evidence suggests that CVN2 is present in many cellular types; however, the molecular mechanisms of CVN2 in cancers and its clinical relevance are unknown. We proposed a mechanism by which CVN2 regulates caveolin-1 expression leading to slow cellular proliferation by inactivation of the extracellular regulated kinase (ERK) pathway. Quantitative reverse transcriptase-polymerase chain reaction and immunoblot analyses were used to assess the CVN2 regulation mechanism in oral squamous cell carcinoma (OSCC). Immunohistochemistry (IHC) was performed to analyze the correlation between CVN2 expression and clinical behavior in 115 patients with OSCC. A CVN2 overexpressed model of OSCC cells (oeCVN2 cells) was used for functional experiments. CVN2 expression was down-regulated significantly (P < 0.05) in OSCCs compared with normal counterparts in vitro and in vivo. In addition to the findings that a serum deprivation culture induced up-regulation of CVN2 and slowed cellular proliferation, oeCVN2 cell growth decreased because of cell-cycle arrest at the G1 phase resulting from up-regulated cyclin-dependent kinase inhibitors (p21(Cip1) and p27(Kip1) ) and down-regulated cyclins (cyclin D1, cyclin E) and cyclin-dependent kinases (CDK2, CDK4, and CDK6). Interestingly, CVN2 overexpression facilitated caveolin-1 recruitment and colocalization with each other. We also found decreased ERK phosphorylation levels, an upstream event in cell-cycle arrest. Clinically, IHC data from primary OSCCs showed high tumoral progression in CVN2-negative patients with OSCC. CVN2 may be a possible key regulator of OSCC progression via the CVN2/caveolin-1/ERK pathway and a potential therapeutic target for developing new treatments for OSCCs. © 2015 Wiley Periodicals, Inc. PMID:26086332

  6. The Status, Potential and Research Progress of CO2 Storage Worldwide

    NASA Astrophysics Data System (ADS)

    Basava-Reddi, L.; Camps, A.

    2012-04-01

    Energy demand continues to grow and is expected to have increased by 35% by 2035, and CO2 emissions continue to increase with a current pathway to 650ppm by 2050. Carbon dioxide capture and storage (CCS) is considered to be an important carbon dioxide mitigation technology. The IEA CCS Technology Roadmap 2009 based on the 'blue map' scenario predicts that to reach CO2 reduction targets 100 commercial CCS projects is desired by 20201, compared to the G8 target of 20 CCS projects by 2020. A recent analysis of current storage projects and future projections shows the G8 target is possible if adequate resourcing is provided and if CO2-EOR projects are included; however the IEA Roadmap CCS target may be unattainable2. With sufficient funding, 50 projects are achievable by 2025 and 100 projects by 2028 inclusive of CO2-EOR projects, the latter requiring 6 billion Euros of total investment. Project lead times are long, which could be up to 15 years for deep saline formation storage projects, and without sufficient funding the gap between targets and the current number of projects will widen. However, there has been progress. 74 CCS projects have been identified by the Global CCS Institute with 14 large scale integrated projects in the operate and execute phase expressing a total storage capacity of 33 Mtpa: 3 more projects in the execute phase since 2009, and 10 more have announced they will be ready for a final investment decision in the next 12 months hence ready to move to the execute phase3. Explanations of project suspension or cancellation have been predominated by non-technical issues; however there are technical challenges remaining; including injectivity and uncertainty in capacity, particularly for deep saline formations; all of which are being considered by the CCS research community. Other considerations that are currently being assessed are subsurface resource interaction, which includes potential interactions of CO2 storage with hydrocarbon production

  7. Satellite Remote Sensing of Particulate Matter Air Quality: Progress, Potential and Pitfalls (Invited)

    NASA Astrophysics Data System (ADS)

    Christopher, S. A.

    2009-12-01

    Satellite Remote Sensing of Particulate Matter Air Quality: Progress, Potential and Pitfalls Abstract. Fine or respirable particles with particle aerodynamic diameters less than 2.5 µm (PM2.5) affect visibility, change cloud properties, reflect and absorb incoming solar radiation, affect human health and are ubiquitous in the atmosphere. These particles are injected into the atmosphere either as primary emissions or form into the atmosphere by gas to particle conversion. There are various sources of PM2.5 including emissions from automobiles, industrial exhaust, and agricultural fires. In 2006, the United States Environmental Protection Agency (EPA) made the standards stringent by changing the 24-hr averaged PM2.5 mass values from 65µgm-3 to 35µgm-3. This was primarily based on epidemiological studies that showed the long term health benefits of making the PM2.5 standards stringent. Typically PM2.5 mass concentration is measured from surface monitors and in the United States there are nearly 1000 such filter based daily and 600 contiguous stations managed by federal, state, local, and tribal agencies. Worldwide, there are few PM2.5 ground monitors since they are expensive to purchase, maintain and operate. Satellite remote sensing therefore provides a viable method for monitoring PM2.5 from space. Although, there are several hundred satellites currently in orbit and not all of them are suited for PM2.5 air quality assessments. Typically multi-spectral reflected solar radiation measurements from space-borne sensors are converted to aerosol optical depth (AOD) which is a measure of the column (surface to top of atmosphere) integrated extinction (absorption plus scattering). This column AOD (usually at 550 nm) is often converted to PM2.5 mass near the ground using various techniques. In this presentation we discuss the progress over the last decade on assessing PM2.5 from satellites; outline the potential and discuss the various pitfalls that one encounters. We

  8. Differentiation of murine embryonic stem and induced pluripotent stem cells to renal lineage in vitro

    SciTech Connect

    Morizane, Ryuji; Monkawa, Toshiaki; Itoh, Hiroshi

    2009-12-25

    Embryonic stem (ES) cells which have the unlimited proliferative capacity and extensive differentiation potency can be an attractive source for kidney regeneration therapies. Recent breakthroughs in the generation of induced pluripotent stem (iPS) cells have provided with another potential source for the artificially-generated kidney. The purpose of this study is to know how to differentiate mouse ES and iPS cells into renal lineage. We used iPS cells from mouse fibroblasts by transfection of four transcription factors, namely Oct4, Sox2, c-Myc and Klf4. Real-time PCR showed that renal lineage markers were expressed in both ES and iPS cells after the induction of differentiation. It also showed that a tubular specific marker, KSP progressively increased to day 18, although the differentiation of iPS cells was slower than ES cells. The results indicated that renal lineage cells can be differentiated from both murine ES and iPS cells. Several inducing factors were tested whether they influenced on cell differentiation. In ES cells, both of GDNF and BMP7 enhanced the differentiation to metanephric mesenchyme, and Activin enhanced the differentiation of ES cells to tubular cells. Activin also enhanced the differentiation of iPS cells to tubular cells, although the enhancement was lower than in ES cells. ES and iPS cells have a potential to differentiate to renal lineage cells, and they will be an attractive resource of kidney regeneration therapy. This differentiation is enhanced by Activin in both ES and iPS cells.

  9. Orphan nuclear receptor nurr1 as a potential novel marker for progression in human prostate cancer.

    PubMed

    Wang, Jian; Yang, Jing; Zou, Ying; Huang, Guo-Liang; He, Zhi-Wei

    2013-01-01

    A number of studies have indicated that Nurr1, which belongs to a novel class of orphan nuclear receptors (the NR4A family), is important for carcinogenesis. Here we investigated expression of Nurr1 protein in benign and malignant human prostate tissues and association with clinicopathologic features using immunohistochemical techniques. Moreover, we also investigated the ability of Nurr1 to influence proliferation, migration, invasion and apoptosis of human prostate cancer cells using small interfering RNA silencing. Immunohistochemical analysis revealed that the expression of Nurr1 protein was higher in prostate cancer tissues than in benign prostate tissue (P < 0.001), levels being positively correlated with tumor T classification (P = 0.003), N classification (P = 0.017), M classification (P = 0.011) and the Gleason score (P = 0.020) of prostate cancer patients. In vitro, silencing of endogenous Nurr1 attenuated cell proliferation, migration and invasion, and induced apoptosis of prostate cancer cells. These results suggest that Nurr1 may be used as an indicator for prostate cancer progression and be useful for novel potential therapeutic strategies. PMID:23679312

  10. Proteomics profiling of cholangiocarcinoma exosomes: A potential role of oncogenic protein transferring in cancer progression.

    PubMed

    Dutta, Suman; Reamtong, Onrapak; Panvongsa, Wittaya; Kitdumrongthum, Sarunya; Janpipatkul, Keatdamrong; Sangvanich, Polkit; Piyachaturawat, Pawinee; Chairoungdua, Arthit

    2015-09-01

    Cholangiocarcinoma (CCA), a common primary malignant tumor of bile duct epithelia, is highly prevalent in Asian countries and unresponsive to chemotherapeutic drugs. Thus, a newly recognized biological entity for early diagnosis and treatment is highly needed. Exosomes are small membrane bound vesicles found in body fluids and released by most cell types including cancer cells. The vesicles contain specific subset of proteins and nucleic acids corresponding to cell types and play essential roles in pathophysiological processes. The present study aimed to assess the protein profiles of CCA-derived exosomes and their potential roles. We have isolated exosomes from CCA cells namely KKU-M213 and KKU-100 derived from Thai patients and their roles were investigated by incubation with normal human cholangiocyte (H69) cells. Exosomes were internalized into H69 cells and had no effects on viability or proliferation of the host cells. Interestingly, the exosomes from KKU-M213 cells only induced migration and invasion of H69 cells. Proteomic analysis of the exosomes from KKU-M213 cells disclosed multiple cancer related proteins that are not present in H69 exosomes. Consistent with the protein profile, treatment with KKU-M213 exosomes induced β-catenin and reduced E-cadherin expressions in H69 cells. Collectively, our results suggest that a direct cell-to-cell transfer of oncogenic proteins via exosomal pathway may be a novel mechanism for CCA progression and metastasis. PMID:26148937

  11. Evolutionary history of the reprimo tumor suppressor gene family in vertebrates with a description of a new reprimo gene lineage.

    PubMed

    Wichmann, Ignacio A; Zavala, Kattina; Hoffmann, Federico G; Vandewege, Michael W; Corvalán, Alejandro H; Amigo, Julio D; Owen, Gareth I; Opazo, Juan C

    2016-10-10

    Genes related to human diseases should be natural targets for evolutionary studies, since they could provide clues regarding the genetic bases of pathologies and potential treatments. Here we studied the evolution of the reprimo gene family, a group of tumor-suppressor genes that are implicated in p53-mediated cell cycle arrest. These genes, especially the reprimo duplicate located on human chromosome 2, have been associated with epigenetic modifications correlated with transcriptional silencing and cancer progression. We demonstrate the presence of a third reprimo lineage that, together with the reprimo and reprimo-like genes, appears to have been differentially retained during the evolutionary history of vertebrates. We present evidence that these reprimo lineages originated early in vertebrate evolution and expanded as a result of the two rounds of whole genome duplications that occurred in the last common ancestor of vertebrates. The reprimo gene has been lost in birds, and the third reprimo gene lineage has been retained in only a few distantly related species, such as coelacanth and gar. Expression analyses revealed that the reprimo paralogs are mainly expressed in the nervous system. Different vertebrate lineages have retained different reprimo paralogs, and even in species that have retained multiple copies, only one of them is heavily expressed. PMID:27432065

  12. Quantitative lineage tracing strategies to resolve multipotency in tissue-specific stem cells.

    PubMed

    Wuidart, Aline; Ousset, Marielle; Rulands, Steffen; Simons, Benjamin D; Van Keymeulen, Alexandra; Blanpain, Cédric

    2016-06-01

    Lineage tracing has become the method of choice to study the fate and dynamics of stem cells (SCs) during development, homeostasis, and regeneration. However, transgenic and knock-in Cre drivers used to perform lineage tracing experiments are often dynamically, temporally, and heterogeneously expressed, leading to the initial labeling of different cell types and thereby complicating their interpretation. Here, we developed two methods: the first one based on statistical analysis of multicolor lineage tracing, allowing the definition of multipotency potential to be achieved with high confidence, and the second one based on lineage tracing at saturation to assess the fate of all SCs within a given lineage and the "flux" of cells between different lineages. Our analysis clearly shows that, whereas the prostate develops from multipotent SCs, only unipotent SCs mediate mammary gland (MG) development and adult tissue remodeling. These methods offer a rigorous framework to assess the lineage relationship and SC fate in different organs and tissues. PMID:27284162

  13. Quantitative lineage tracing strategies to resolve multipotency in tissue-specific stem cells

    PubMed Central

    Wuidart, Aline; Ousset, Marielle; Rulands, Steffen; Simons, Benjamin D.; Van Keymeulen, Alexandra; Blanpain, Cédric

    2016-01-01

    Lineage tracing has become the method of choice to study the fate and dynamics of stem cells (SCs) during development, homeostasis, and regeneration. However, transgenic and knock-in Cre drivers used to perform lineage tracing experiments are often dynamically, temporally, and heterogeneously expressed, leading to the initial labeling of different cell types and thereby complicating their interpretation. Here, we developed two methods: the first one based on statistical analysis of multicolor lineage tracing, allowing the definition of multipotency potential to be achieved with high confidence, and the second one based on lineage tracing at saturation to assess the fate of all SCs within a given lineage and the “flux” of cells between different lineages. Our analysis clearly shows that, whereas the prostate develops from multipotent SCs, only unipotent SCs mediate mammary gland (MG) development and adult tissue remodeling. These methods offer a rigorous framework to assess the lineage relationship and SC fate in different organs and tissues. PMID:27284162

  14. Web-based interventions for behavior change and self-management: potential, pitfalls, and progress.

    PubMed

    Murray, Elizabeth

    2012-01-01

    The potential advantages of using the Internet to deliver self-care and behavior-change programs are well recognized. An aging population combined with the increasing prevalence of long-term conditions and more effective medical interventions place financial strain on all health care systems. Web-based interventions have the potential to combine the tailored approach of face-to-face interventions with the scalability of public health interventions that have low marginal costs per additional user. From a patient perspective, Web-based interventions can be highly attractive because they are convenient, easily accessible, and can maintain anonymity/privacy. Recognition of this potential has led to research in developing and evaluating Web-based interventions for self-management of long-term conditions and behavior change. Numerous systematic reviews have confirmed the effectiveness of some Web-based interventions, but a number of unanswered questions still remain. This paper reviews the progress made in developing and evaluating Web-based interventions and considers three challenging areas: equity, effectiveness, and implementation. The impact of Web-based interventions on health inequalities remains unclear. Although some have argued that such interventions can increase access to underserved communities, there is evidence to suggest that reliance on Web-based interventions may exacerbate health inequalities by excluding those on the "wrong" side of the digital divide. Although most systematic reviews have found a positive effect on outcomes of interest, effect sizes tend to be small and not all interventions are successful. Further work is needed to determine why some interventions work and others do not. This includes considering the "active ingredients" or mechanism of action of these complex interventions and the context in which they are used. Are there certain demographic, psychological, or clinical factors that promote or inhibit success? Are some behaviors or

  15. Challenges in Making Progress to Improve Cow Efficiency and Potential Tools

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Progress toward improving cow efficiency has been slow. Numerous factors have contributed toward the lack of progress. The first is having a common definition of cow efficiency. Efficiency can be measured at different levels of aggregation in the production system. We can measure the economic ef...

  16. Direct lineage reprogramming to neural cells

    PubMed Central

    Kim, Janghwan; Ambasudhan, Rajesh; Ding, Sheng

    2016-01-01

    Recently we have witnessed an array of studies on direct reprogramming that describe induced inter conversion of mature cell types from higher organisms including human. While these studies reveal an unexpected level of plasticity of differentiated somatic cells, they also provide unprecedented opportunities to develop regenerative therapies for many debilitating disorders and model these ‘diseases-in-a-dish’ for studying their pathophysiology. Here we review the current state of the art in direct lineage reprogramming to neural cells, and discuss the challenges that need to be addressed toward achieving the full potential of this exciting new technology. PMID:22652035

  17. Mitochondrial oncobioenergetic index: A potential biomarker to predict progression from indolent to aggressive prostate cancer

    PubMed Central

    Vayalil, Praveen K.; Landar, Aimee

    2015-01-01

    Mitochondrial function is influenced by alterations in oncogenes and tumor suppressor genes and changes in the microenvironment occurring during tumorigenesis. Therefore, we hypothesized that mitochondrial function will be stably and dynamically altered at each stage of the prostate tumor development. We tested this hypothesis in RWPE-1 cells and its tumorigenic clones with progressive malignant characteristics (RWPE-1 < WPE-NA22 < WPE-NB14 < WPE-NB11 < WPE-NB26) using high-throughput respirometry. Our studies demonstrate that mitochondrial content do not change with increasing malignancy. In premalignant cells (WPE-NA22 and WPE-NB14), OXPHOS is elevated in presence of glucose or glutamine alone or in combination compared to RWPE-1 cells and decreases with increasing malignancy. Glutamine maintained higher OXPHOS than glucose and suggests that it may be an important substrate for the growth and proliferation of prostate epithelial cells. Glycolysis significantly increases with malignancy and follow a classical Warburg phenomenon. Fatty acid oxidation (FAO) is significantly lower in tumorigenic clones and invasive WPE-NB26 does not utilize FAO at all. In this paper, we introduce for the first time the mitochondrial oncobioenergetic index (MOBI), a mathematical representation of oncobioenergetic profile of a cancer cell, which increases significantly upon transformation into localized premalignant form and rapidly falls below the normal as they become aggressive in prostate tumorigenesis. We have validated this in five prostate cancer cell lines and MOBI appears to be not related to androgen dependence or mitochondrial content, but rather dependent on the stage of the cancer. Altogether, we propose that MOBI could be a potential biomarker to distinguish aggressive cancer from that of indolent disease. PMID:26515588

  18. Breast cancer associated a2 isoform vacuolar ATPase immunomodulates neutrophils: potential role in tumor progression.

    PubMed

    Ibrahim, Safaa A; Katara, Gajendra K; Kulshrestha, Arpita; Jaiswal, Mukesh K; Amin, Magdy A; Beaman, Kenneth D

    2015-10-20

    In invasive breast cancer, tumor associated neutrophils (TAN) represent a significant portion of the tumor mass and are associated with increased angiogenesis and metastasis. Identifying the regulatory factors that control TAN behavior will help in developing ideal immunotherapies. Vacuolar ATPases (V-ATPases), multi-subunit proton pumps, are highly expressed in metastatic breast cancer cells. A cleaved peptide from a2 isoform V-ATPase (a2NTD) has immunomodulatory role in tumor microenvironment. Here, we report for the first time the role of V-ATPase in neutrophils modulation. In invasive breast cancer cells, a2NTD was detected and a2V was highly expressed on the surface. Immunohistochemical analysis of invasive breast cancer tissues revealed that increased neutrophil recruitment and blood vessel density correlated with increased a2NTD levels. In order to determine the direct regulatory role of a2NTD on neutrophils, recombinant a2NTD was used for the treatment of neutrophils isolated from the peripheral blood of healthy volunteers. Neutrophils treated with a2NTD (a2Neuɸ) showed increased secretion of IL-1RA, IL-10, CCL-2 and IL-6 that are important mediators in cancer related inflammation. Moreover, a2Neuɸ exhibited an increased production of protumorigenic factors including IL-8, matrix metaloprotinase-9 and vascular endothelial growth factor. Further, functional characterization of a2Neuɸ revealed that a2Neuɸ derived products induce in vitro angiogenesis as well as increase the invasiveness of breast cancer cells. This study establishes the modulatory effect of breast cancer associated a2V on neutrophils, by the action of a2NTD, which has a positive impact on tumor progression, supporting that a2V can be a potential selective target for breast cancer therapy. PMID:26460736

  19. Efficacy of potential chemopreventive agents on rat colon aberrant crypt formation and progression.

    PubMed

    Wargovich, M J; Jimenez, A; McKee, K; Steele, V E; Velasco, M; Woods, J; Price, R; Gray, K; Kelloff, G J

    2000-06-01

    We assessed the effects of 78 potential chemopreventive agents in the F344 rat using two assays in which the inhibition of carcinogen-induced aberrant crypt foci (ACF) in the colon was the measure of efficacy. In both assays ACF were induced by the carcinogen azoxymethane (AOM) in F344 rats by two sequential weekly injections at a dose of 15 mg/kg. Two weeks after the last AOM injection, animals were evaluated for the number of aberrant crypts detected in methylene blue stained whole mounts of rat colon. In the initiation phase protocol agents were given during the period of AOM administration, whereas in the post-initiation assay the chemopreventive agent was introduced during the last 4 weeks of an 8 week assay, a time when ACF had progressed to multiple crypt clusters. The agents were derived from a priority listing based on reports of chemopreventive activity in the literature and/or efficacy data from in vitro models of carcinogenesis. During the initiation phase carboxyl amidoimidazole, p-chlorphenylacetate, chlorpheniramine maleate, D609, diclofenac, etoperidone, eicosatetraynoic acid, farnesol, ferulic acid, lycopene, meclizine, methionine, phenylhexylisothiocyanate, phenylbutyrate, piroxicam, 9-cis-retinoic acid, S-allylcysteine, taurine, tetracycline and verapamil were strong inhibitors of ACF. During the post-initiation phase aspirin, calcium glucarate, ketoprofen, piroxicam, 9-cis-retinoic acid, retinol and rutin inhibited the outgrowth of ACF into multiple crypt clusters. Based on these data, certain phytochemicals, antihistamines, non-steroidal anti-inflammatory drugs and retinoids show unique preclinical promise for chemoprevention of colon cancer, with the latter two drug classes particularly effective in the post-initiation phase of carcinogenesis. PMID:10837003

  20. Breast cancer associated a2 isoform vacuolar ATPase immunomodulates neutrophils: potential role in tumor progression

    PubMed Central

    Ibrahim, Safaa A.; Katara, Gajendra K.; Kulshrestha, Arpita; Jaiswal, Mukesh K.; Amin, Magdy A.; Beaman, Kenneth D.

    2015-01-01

    In invasive breast cancer, tumor associated neutrophils (TAN) represent a significant portion of the tumor mass and are associated with increased angiogenesis and metastasis. Identifying the regulatory factors that control TAN behavior will help in developing ideal immunotherapies. Vacuolar ATPases (V-ATPases), multi-subunit proton pumps, are highly expressed in metastatic breast cancer cells. A cleaved peptide from a2 isoform V-ATPase (a2NTD) has immunomodulatory role in tumor microenvironment. Here, we report for the first time the role of V-ATPase in neutrophils modulation. In invasive breast cancer cells, a2NTD was detected and a2V was highly expressed on the surface. Immunohistochemical analysis of invasive breast cancer tissues revealed that increased neutrophil recruitment and blood vessel density correlated with increased a2NTD levels. In order to determine the direct regulatory role of a2NTD on neutrophils, recombinant a2NTD was used for the treatment of neutrophils isolated from the peripheral blood of healthy volunteers. Neutrophils treated with a2NTD (a2Neuɸ) showed increased secretion of IL-1RA, IL-10, CCL-2 and IL-6 that are important mediators in cancer related inflammation. Moreover, a2Neuɸ exhibited an increased production of protumorigenic factors including IL-8, matrix metaloprotinase-9 and vascular endothelial growth factor. Further, functional characterization of a2Neuɸ revealed that a2Neuɸ derived products induce in vitro angiogenesis as well as increase the invasiveness of breast cancer cells. This study establishes the modulatory effect of breast cancer associated a2V on neutrophils, by the action of a2NTD, which has a positive impact on tumor progression, supporting that a2V can be a potential selective target for breast cancer therapy. PMID:26460736

  1. The developmental origins and lineage contributions of endocardial endothelium.

    PubMed

    Nakano, Atsushi; Nakano, Haruko; Smith, Kelly A; Palpant, Nathan J

    2016-07-01

    Endocardial development involves a complex orchestration of cell fate decisions that coordinate with endoderm formation and other mesodermal cell lineages. Historically, investigations into the contribution of endocardium in the developing embryo was constrained to the heart where these cells give rise to the inner lining of the myocardium and are a major contributor to valve formation. In recent years, studies have continued to elucidate the complexities of endocardial fate commitment revealing a much broader scope of lineage potential from developing endocardium. These studies cover a wide range of species and model systems and show direct contribution or fate potential of endocardium giving rise to cardiac vasculature, blood, fibroblast, and cardiomyocyte lineages. This review focuses on the marked expansion of knowledge in the area of endocardial fate potential. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. PMID:26828773

  2. Early and multiple origins of metastatic lineages within primary tumors.

    PubMed

    Zhao, Zi-Ming; Zhao, Bixiao; Bai, Yalai; Iamarino, Atila; Gaffney, Stephen G; Schlessinger, Joseph; Lifton, Richard P; Rimm, David L; Townsend, Jeffrey P

    2016-02-23

    Many aspects of the evolutionary process of tumorigenesis that are fundamental to cancer biology and targeted treatment have been challenging to reveal, such as the divergence times and genetic clonality of metastatic lineages. To address these challenges, we performed tumor phylogenetics using molecular evolutionary models, reconstructed ancestral states of somatic mutations, and inferred cancer chronograms to yield three conclusions. First, in contrast to a linear model of cancer progression, metastases can originate from divergent lineages within primary tumors. Evolved genetic changes in cancer lineages likely affect only the proclivity toward metastasis. Single genetic changes are unlikely to be necessary or sufficient for metastasis. Second, metastatic lineages can arise early in tumor development, sometimes long before diagnosis. The early genetic divergence of some metastatic lineages directs attention toward research on driver genes that are mutated early in cancer evolution. Last, the temporal order of occurrence of driver mutations can be inferred from phylogenetic analysis of cancer chronograms, guiding development of targeted therapeutics effective against primary tumors and metastases. PMID:26858460

  3. Feedback, Lineages and Self-Organizing Morphogenesis

    PubMed Central

    Calof, Anne L.; Lowengrub, John S.; Lander, Arthur D.

    2016-01-01

    Feedback regulation of cell lineage progression plays an important role in tissue size homeostasis, but whether such feedback also plays an important role in tissue morphogenesis has yet to be explored. Here we use mathematical modeling to show that a particular feedback architecture in which both positive and negative diffusible signals act on stem and/or progenitor cells leads to the appearance of bistable or bi-modal growth behaviors, ultrasensitivity to external growth cues, local growth-driven budding, self-sustaining elongation, and the triggering of self-organization in the form of lamellar fingers. Such behaviors arise not through regulation of cell cycle speeds, but through the control of stem or progenitor self-renewal. Even though the spatial patterns that arise in this setting are the result of interactions between diffusible factors with antagonistic effects, morphogenesis is not the consequence of Turing-type instabilities. PMID:26989903

  4. The potential influence of radiation-induced microenvironments in neoplastic progression

    NASA Technical Reports Server (NTRS)

    Barcellos-Hoff, M. H.; Chatterjee, A. (Principal Investigator)

    1998-01-01

    Ionizing radiation is a complete carcinogen, able both to initiate and promote neoplastic progression and is a known carcinogen of human and murine mammary gland. Tissue response to radiation is a composite of genetic damage, cell death and induction of new gene expression patterns. Although DNA damage is believed to initiate carcinogenesis, the contribution of these other aspects of radiation response are beginning to be explored. Our studies demonstrate that radiation elicits rapid and persistent global alterations in the mammary gland microenvironment. We postulate that radiation-induced microenvironments may affect epithelial cells neoplastic transformation by altering their number or susceptibility. Alternatively, radiation induced microenvironments may exert a selective force on initiated cells and/or be conducive to progression. A key impetus for these studies is the possibility that blocking these events could be a strategy to interrupt neoplastic progression.

  5. Wasted Potential: Training and Career Progression for Part-Time and Temporary Workers.

    ERIC Educational Resources Information Center

    McGivney, Veronica

    A study examined ways in which employers in the United Kingdom are meeting the challenge of training and career progression for part-time and temporary employees. First, the literature was reviewed to gather information on the following topics: the growth of "atypical" work, training and adult workers, differential access to training, factors…

  6. Progressive Muscle Relaxation and Cognitive Restructuring: Potential Problems and Proposed Solutions.

    ERIC Educational Resources Information Center

    Kiselica, Mark S.; Baker, Stanley B.

    1992-01-01

    Reviews common problems experienced by clients during progressive muscle relaxation training (PMRT) and summarizes pertinent solutions to those problems. Discusses difficulties and solutions related to cognitive restructuring training. Notes that cognitive restructuring is often used to enhance effectiveness of PMRT. Concludes with suggestions for…

  7. Potential for progress in carbon cycle modeling: models as tools and representations of reality (Invited)

    NASA Astrophysics Data System (ADS)

    Caldeira, K.

    2013-12-01

    attribution) Potential for progress in carbon-cycle modeling rests in being clear about the problems we seek to solve, and then developing tools to solve those problems. A global carbon cycle model that represents underlying complexity in all its detail may ultimately prove useless: 'We actually made a map of the country, on the scale of a mile to the mile!' 'Have you used it much?' I enquired. 'It has never been spread out, yet,' said Mein Herr: 'the farmers objected: they said it would cover the whole country, and shut out the sunlight! So we now use the country itself, as its own map, and I assure you it does nearly as well.' - Lewis Carroll

  8. Conditional Lineage Ablation to Model Human Diseases

    NASA Astrophysics Data System (ADS)

    Lee, Paul; Morley, Gregory; Huang, Qian; Fischer, Avi; Seiler, Stephanie; Horner, James W.; Factor, Stephen; Vaidya, Dhananjay; Jalife, Jose; Fishman, Glenn I.

    1998-09-01

    Cell loss contributes to the pathogenesis of many inherited and acquired human diseases. We have developed a system to conditionally ablate cells of any lineage and developmental stage in the mouse by regulated expression of the diphtheria toxin A (DTA) gene by using tetracycline-responsive promoters. As an example of this approach, we targeted expression of DTA to the hearts of adult mice to model structural abnormalities commonly observed in human cardiomyopathies. Induction of DTA expression resulted in cell loss, fibrosis, and chamber dilatation. As in many human cardiomyopathies, transgenic mice developed spontaneous arrhythmias in vivo, and programmed electrical stimulation of isolated-perfused transgenic hearts demonstrated a strikingly high incidence of spontaneous and inducible ventricular tachycardia. Affected mice showed marked perturbations of cardiac gap junction channel expression and localization, including a subset with disorganized epicardial activation patterns as revealed by optical action potential mapping. These studies provide important insights into mechanisms of arrhythmogenesis and suggest that conditional lineage ablation may have wide applicability for studies of disease pathogenesis.

  9. DLGP: A database for lineage-conserved and lineage-specific gene pairs in animal and plant genomes.

    PubMed

    Wang, Dapeng

    2016-01-15

    The conservation of gene organization in the genome with lineage-specificity is an invaluable resource to decipher their potential functionality with diverse selective constraints, especially in higher animals and plants. Gene pairs appear to be the minimal structure for such kind of gene clusters that tend to reside in their preferred locations, representing the distinctive genomic characteristics in single species or a given lineage. Despite gene families having been investigated in a widespread manner, the definition of gene pair families in various taxa still lacks adequate attention. To address this issue, we report DLGP (http://lcgbase.big.ac.cn/DLGP/) that stores the pre-calculated lineage-based gene pairs in currently available 134 animal and plant genomes and inspect them under the same analytical framework, bringing out a set of innovational features. First, the taxonomy or lineage has been classified into four levels such as Kingdom, Phylum, Class and Order. It adopts all-to-all comparison strategy to identify the possible conserved gene pairs in all species for each gene pair in certain species and reckon those that are conserved in over a significant proportion of species in a given lineage (e.g. Primates, Diptera or Poales) as the lineage-conserved gene pairs. Furthermore, it predicts the lineage-specific gene pairs by retaining the above-mentioned lineage-conserved gene pairs that are not conserved in any other lineages. Second, it carries out pairwise comparison for the gene pairs between two compared species and creates the table including all the conserved gene pairs and the image elucidating the conservation degree of gene pairs in chromosomal level. Third, it supplies gene order browser to extend gene pairs to gene clusters, allowing users to view the evolution dynamics in the gene context in an intuitive manner. This database will be able to facilitate the particular comparison between animals and plants, between vertebrates and arthropods, and

  10. Metabolic mechanisms of plant growth at low water potentials. Progress report

    SciTech Connect

    Boyer, J.S.

    1986-01-01

    Experiments were conducted to identify primary and secondary factors that cause cell enlargement to be inhibited in the stems of soybean seedlings exposed to low water potentials. The factors that were analyzed are wall extensibility, yield threshold of the walls, hydraulic conductance of the tissue, turgor, osmotic potential, and growth-induced water potentials.

  11. Prospects for T. cruzi lineage-specific serological surveillance of wild mammals.

    PubMed

    Bhattacharyya, Tapan; Mills, Emily A; Jansen, Ana Maria; Miles, Michael A

    2015-11-01

    Sequence diversity in the Trypanosoma cruzi small surface molecule TSSA has yielded antigens for serology to investigate the T. cruzi lineage-specific infection history of patients with Chagas disease. Synthetic peptides can be used as the lineage-specific antigens. Here we consider the rationale, feasibility and potential of applying peptide-based lineage-specific serology to naturally infected wild mammals. The commercial availability of appropriate secondary antibodies encourages this further development, for discovery of new reservoir host species and to reveal the wider ecological distribution of T. cruzi lineages, currently hindered by the need to recover live isolates or to attempt genotyping of DNA extracted from blood samples. PMID:26116784

  12. A Potential Role for Mechanical Forces in the Detachment of Podocytes and the Progression of CKD

    PubMed Central

    Lemley, Kevin V.

    2015-01-01

    Loss of podocytes underlies progression of CKD. Detachment of podocytes from the glomerular basement membrane (GBM) rather than apoptosis or necrosis seems to be the major mechanism of podocyte loss. Such detachment of viable podocytes may be caused by increased mechanical distending and shear forces and/or impaired adhesion to the GBM. This review considers the mechanical challenges that may lead to podocyte loss by detachment from the GBM under physiologic and pathophysiologic conditions, including glomerular hypertension, hyperfiltration, hypertrophy, and outflow of filtrate from subpodocyte spaces. Furthermore, we detail the cellular mechanisms by which podocytes respond to these challenges, discuss the protective effects of angiotensin blockade, and note the questions that must be addressed to better understand the relationship between podocyte detachment and progression of CKD. PMID:25060060

  13. Effects and potential mechanisms of exercise training on cancer progression: a translational perspective.

    PubMed

    Betof, Allison S; Dewhirst, Mark W; Jones, Lee W

    2013-03-01

    Over the past decade there has been increasing research and clinical interest in the role of exercise therapy/rehabilitation as an adjunct therapy to improve symptom control and management following a cancer diagnosis. More recently, the field of 'exercise - oncology' has broadened in scope to investigate whether the benefits extend beyond symptom control to modulate cancer-specific outcomes (i.e., cancer progression and metastasis). Here we review the extant epidemiological evidence examining the association between exercise behavior, functional capacity/exercise capacity, and cancer-specific recurrence and mortality as well as all-cause mortality individuals following a cancer diagnosis. We also evaluate evidence from clinical studies investigating the effects of structured exercise on blood-based biomarkers associated with cancer progression/metastasis as well findings from preclinical investigations examining the effects and molecular mechanisms of exercise in mouse models of cancer. Current gaps in knowledge are also discussed. PMID:22610066

  14. The New Deal: A Potential Role for Secreted Vesicles in Innate Immunity and Tumor Progression

    PubMed Central

    Benito-Martin, Alberto; Di Giannatale, Angela; Ceder, Sophia; Peinado, Héctor

    2015-01-01

    Tumors must evade the immune system to survive and metastasize, although the mechanisms that lead to tumor immunoediting and their evasion of immune surveillance are far from clear. The first line of defense against metastatic invasion is the innate immune system that provides immediate defense through humoral immunity and cell-mediated components, mast cells, neutrophils, macrophages, and other myeloid-derived cells that protect the organism against foreign invaders. Therefore, tumors must employ different strategies to evade such immune responses or to modulate their environment, and they must do so prior metastasizing. Exosomes and other secreted vesicles can be used for cell–cell communication during tumor progression by promoting the horizontal transfer of information. In this review, we will analyze the role of such extracellular vesicles during tumor progression, summarizing the role of secreted vesicles in the crosstalk between the tumor and the innate immune system. PMID:25759690

  15. CK2 phosphorylation of eukaryotic translation initiation factor 5 potentiates cell cycle progression

    PubMed Central

    Homma, Miwako Kato; Wada, Ikuo; Suzuki, Toshiyuki; Yamaki, Junko; Krebs, Edwin G.; Homma, Yoshimi

    2005-01-01

    Casein kinase 2 (CK2) is a ubiquitous eukaryotic Ser/Thr protein kinase that plays an important role in cell cycle progression. Although its function in this process remains unclear, it is known to be required for the G1 and G2/M phase transitions in yeast. Here, we show that CK2 activity changes notably during cell cycle progression and is increased within 3 h of serum stimulation of quiescent cells. During the time period in which it exhibits high enzymatic activity, CK2 associates with and phosphorylates a key molecule for translation initiation, eukaryotic translation initiation factor (eIF) 5. Using MS, we show that Ser-389 and -390 of eIF5 are major sites of phosphorylation by CK2. This is confirmed using eIF5 mutants that lack CK2 sites; the phosphorylation levels of mutant eIF5 proteins are significantly reduced, relative to WT eIF5, both in vitro and in vivo. Expression of these mutants reveals that they have a dominant-negative effect on phosphorylation of endogenous eIF5, and that they perturb synchronous progression of cells through S to M phase, resulting in a significant reduction in growth rate. Furthermore, the formation of mature eIF5/eIF2/eIF3 complex is reduced in these cells, and, in fact, restricted diffusional motion of WT eIF5 was almost abolished in a GFP-tagged eIF5 mutant lacking CK2 phosphorylation sites, as measured by fluorescence correlation spectroscopy. These results suggest that CK2 may be involved in the regulation of cell cycle progression by associating with and phosphorylating a key molecule for translation initiation. PMID:16227438

  16. Phylogenetic lineages in the Botryosphaeriaceae

    PubMed Central

    Crous, Pedro W.; Slippers, Bernard; Wingfield, Michael J.; Rheeder, John; Marasas, Walter F.O.; Philips, Alan J.L.; Alves, Artur; Burgess, Treena; Barber, Paul; Groenewald, Johannes Z.

    2006-01-01

    Botryosphaeria is a species-rich genus with a cosmopolitan distribution, commonly associated with dieback and cankers of woody plants. As many as 18 anamorph genera have been associated with Botryosphaeria, most of which have been reduced to synonymy under Diplodia (conidia mostly ovoid, pigmented, thick-walled), or Fusicoccum (conidia mostly fusoid, hyaline, thin-walled). However, there are numerous conidial anamorphs having morphological characteristics intermediate between Diplodia and Fusicoccum, and there are several records of species outside the Botryosphaeriaceae that have anamorphs apparently typical of Botryosphaeria s.str. Recent studies have also linked Botryosphaeria to species with pigmented, septate ascospores, and Dothiorella anamorphs, or Fusicoccum anamorphs with Dichomera synanamorphs. The aim of this study was to employ DNA sequence data of the 28S rDNA to resolve apparent lineages within the Botryosphaeriaceae. From these data, 12 clades are recognised. Two of these lineages clustered outside the Botryosphaeriaceae, namely Diplodia-like anamorphs occurring on maize, which are best accommodated in Stenocarpella (Diaporthales), as well as an unresolved clade including species of Camarosporium/Microdiplodia. We recognise 10 lineages within the Botryosphaeriaceae, including an unresolved clade (Diplodia/Lasiodiplodia/Tiarosporella), Botryosphaeria s.str. (Fusicoccum anamorphs), Macrophomina, Neoscytalidium gen. nov., Dothidotthia (Dothiorella anamorphs), Neofusicoccum gen. nov. (Botryosphaeria-like teleomorphs, Dichomera-like synanamorphs), Pseudofusicoccum gen. nov., Saccharata (Fusicoccum- and Diplodia-like synanamorphs), “Botryosphaeria” quercuum (Diplodia-like anamorph), and Guignardia (Phyllosticta anamorphs). Separate teleomorph and anamorph names are not provided for newly introduced genera, even where both morphs are known. The taxonomy of some clades and isolates (e.g. B. mamane) remains unresolved due to the absence of ex

  17. Lineage of origin in rhabdomyosarcoma informs pharmacological response

    PubMed Central

    Abraham, Jinu; Nuñez-Álvarez, Yaiza; Hettmer, Simone; Carrió, Elvira; Chen, Hung-I Harry; Nishijo, Koichi; Huang, Elaine T.; Prajapati, Suresh I.; Walker, Robert L.; Davis, Sean; Rebeles, Jennifer; Wiebush, Hunter; McCleish, Amanda T.; Hampton, Sheila T.; Bjornson, Christopher R.R.; Brack, Andrew S.; Wagers, Amy J.; Rando, Thomas A.; Capecchi, Mario R.; Marini, Frank C.; Ehler, Benjamin R.; Zarzabal, Lee Ann; Goros, Martin W.; Michalek, Joel E.; Meltzer, Paul S.; Langenau, David M.; LeGallo, Robin D.; Mansoor, Atiya; Chen, Yidong; Suelves, Mònica; Rubin, Brian P.; Keller, Charles

    2014-01-01

    Lineage or cell of origin of cancers is often unknown and thus is not a consideration in therapeutic approaches. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood cancer for which the cell of origin remains debated. We used conditional genetic mouse models of aRMS to activate the pathognomonic Pax3:Foxo1 fusion oncogene and inactivate p53 in several stages of prenatal and postnatal muscle development. We reveal that lineage of origin significantly influences tumor histomorphology and sensitivity to targeted therapeutics. Furthermore, we uncovered differential transcriptional regulation of the Pax3:Foxo1 locus by tumor lineage of origin, which led us to identify the histone deacetylase inhibitor entinostat as a pharmacological agent for the potential conversion of Pax3:Foxo1-positive aRMS to a state akin to fusion-negative RMS through direct transcriptional suppression of Pax3:Foxo1. PMID:25030697

  18. FLT3 and NPM1 mutations in myelodysplastic syndromes: Frequency and potential value for predicting progression to acute myeloid leukemia.

    PubMed

    Bains, Ashish; Luthra, Rajyalakshmi; Medeiros, L Jeffrey; Zuo, Zhuang

    2011-01-01

    We reviewed FLT3 and NPM1 mutation data in a large cohort of patients with myelodysplastic syndrome (MDS). The frequencies of FLT3 and NPM1 mutation were 2.0% and 4.4%, respectively, and mutations were restricted to cases of intermediate- and high-risk MDS. Cytogenetic abnormalities were identified in 46.9% of cases. FLT3 mutations were associated with a complex karyotype (P = .009), whereas NPM1 mutations were associated with a diploid karyotype (P < .001). FLT3 mutation (P < .001) was associated with progression to acute myeloid leukemia (AML), as were a higher bone marrow (BM) blast count (P < .001) and complex cytogenetics (P = .039). No patient with an NPM1 mutation alone had disease that progressed to AML. Cox proportional regression multivariate analysis indicated that FLT3 mutation, NPM1 mutation, complex cytogenetics, BM blast count, pancytopenia, and age were independent factors that correlated with progression-free survival. We conclude that FLT3 and NPM1 mutations are rare in MDS, but assessment of mutation status is potentially useful for predicting progression to AML. PMID:21173125

  19. The role of N-glycans in colorectal cancer progression: potential biomarkers and therapeutic applications

    PubMed Central

    de Freitas Junior, Julio Cesar Madureira; Morgado-Díaz, José Andrés

    2016-01-01

    Changes in glycosylation, which is one of the most common protein post-translational modifications, are considered to be a hallmark of cancer. N-glycans can modulate cell migration, cell-cell adhesion, cell signaling, growth and metastasis. The colorectal cancer (CRC) is a leading cause of cancer-related mortality and the correlation between CRC progression and changes in the pattern of expression of N-glycans is being considered in the search for new biomarkers. Here, we review the role of N-glycans in CRC cell biology. The perspectives on emerging N-glycan-related anticancer therapies, along with new insights and challenges, are also discussed. PMID:26539643

  20. Potential role of tumor microenvironment in the progression of oral cancer.

    PubMed

    Patil, Shankargouda; Rao, Roopa; Raj, Thirumal

    2015-03-01

    The stromal cells adjacent to the tumor including the fibroblasts, infammatory cells, lymphatic and vascular endothelial cells constitute the 'tumor microenvironment' (TM).(1) Recent in vivo and invitro studies have emphasized the role of stromal components on the growth, differentiation and invasiveness of the tumor cells. In addition, vascular, lymphatic or perineural invasion have proven to have independent prognostic value.(2) Despite the compelling evidence correlating the TM with the initiation and progression of cancer, our knowledge on the role of the genes mediating the various cellular interactions in the tumour stroma is limited.(2,3). PMID:26057928

  1. The Potential Role of Nitric Oxide in Halting Cancer Progression Through Chemoprevention.

    PubMed

    Vahora, Huzefa; Khan, Munawwar Ali; Alalami, Usama; Hussain, Arif

    2016-03-01

    Nitric oxide (NO) in general plays a beneficial physiological role as a vasorelaxant and the role of NO is decided by its concentration present in physiological environments. NO either facilitates cancer-promoting characters or act as an anti-cancer agent. The dilemma in this regard still remains unanswered. This review summarizes the recent information on NO and its role in carcinogenesis and tumor progression, as well as dietary chemopreventive agents which have NO-modulating properties with safe cytotoxic profile. Understanding the molecular mechanisms and cross-talk modulating NO effect by these chemopreventive agents can allow us to develop better therapeutic strategies for cancer treatment. PMID:27051643

  2. The Potential Role of Nitric Oxide in Halting Cancer Progression Through Chemoprevention

    PubMed Central

    Vahora, Huzefa; Khan, Munawwar Ali; Alalami, Usama; Hussain, Arif

    2016-01-01

    Nitric oxide (NO) in general plays a beneficial physiological role as a vasorelaxant and the role of NO is decided by its concentration present in physiological environments. NO either facilitates cancer-promoting characters or act as an anti-cancer agent. The dilemma in this regard still remains unanswered. This review summarizes the recent information on NO and its role in carcinogenesis and tumor progression, as well as dietary chemopreventive agents which have NO-modulating properties with safe cytotoxic profile. Understanding the molecular mechanisms and cross-talk modulating NO effect by these chemopreventive agents can allow us to develop better therapeutic strategies for cancer treatment. PMID:27051643

  3. Appearance traits in fish farming: progress from classical genetics to genomics, providing insight into current and potential genetic improvement

    PubMed Central

    Colihueque, Nelson; Araneda, Cristian

    2014-01-01

    Appearance traits in fish, those external body characteristics that influence consumer acceptance at point of sale, have come to the forefront of commercial fish farming, as culture profitability is closely linked to management of these traits. Appearance traits comprise mainly body shape and skin pigmentation. Analysis of the genetic basis of these traits in different fish reveals significant genetic variation within populations, indicating potential for their genetic improvement. Work into ascertaining the minor or major genes underlying appearance traits for commercial fish is emerging, with substantial progress in model fish in terms of identifying genes that control body shape and skin colors. In this review, we describe research progress to date, especially with regard to commercial fish, and discuss genomic findings in model fish in order to better address the genetic basis of the traits. Given that appearance traits are important in commercial fish, the genomic information related to this issue promises to accelerate the selection process in coming years. PMID:25140172

  4. Appearance traits in fish farming: progress from classical genetics to genomics, providing insight into current and potential genetic improvement.

    PubMed

    Colihueque, Nelson; Araneda, Cristian

    2014-01-01

    Appearance traits in fish, those external body characteristics that influence consumer acceptance at point of sale, have come to the forefront of commercial fish farming, as culture profitability is closely linked to management of these traits. Appearance traits comprise mainly body shape and skin pigmentation. Analysis of the genetic basis of these traits in different fish reveals significant genetic variation within populations, indicating potential for their genetic improvement. Work into ascertaining the minor or major genes underlying appearance traits for commercial fish is emerging, with substantial progress in model fish in terms of identifying genes that control body shape and skin colors. In this review, we describe research progress to date, especially with regard to commercial fish, and discuss genomic findings in model fish in order to better address the genetic basis of the traits. Given that appearance traits are important in commercial fish, the genomic information related to this issue promises to accelerate the selection process in coming years. PMID:25140172

  5. Chemokines in Cancer Development and Progression and Their Potential as Targeting Molecules for Cancer Treatment

    PubMed Central

    Mukaida, Naofumi; Sasaki, So-ichiro; Baba, Tomohisa

    2014-01-01

    Chemokines were initially identified as bioactive substances, which control the trafficking of inflammatory cells including granulocytes and monocytes/macrophages. Moreover, chemokines have profound impacts on other types of cells associated with inflammatory responses, such as endothelial cells and fibroblasts. These observations would implicate chemokines as master regulators in various inflammatory responses. Subsequent studies have further revealed that chemokines can regulate the movement of a wide variety of immune cells including lymphocytes, natural killer cells, and dendritic cells in both physiological and pathological conditions. These features endow chemokines with crucial roles in immune responses. Furthermore, increasing evidence points to the vital effects of several chemokines on the proliferative and invasive properties of cancer cells. It is widely acknowledged that cancer develops and progresses to invade and metastasize in continuous interaction with noncancerous cells present in cancer tissues, such as macrophages, lymphocytes, fibroblasts, and endothelial cells. The capacity of chemokines to regulate both cancerous and noncancerous cells highlights their crucial roles in cancer development and progression. Here, we will discuss the roles of chemokines in carcinogenesis and the possibility of chemokine targeting therapy for the treatment of cancer. PMID:24966464

  6. Mapping the route from naive pluripotency to lineage specification.

    PubMed

    Kalkan, Tüzer; Smith, Austin

    2014-12-01

    In the mouse blastocyst, epiblast cells are newly formed shortly before implantation. They possess a unique developmental plasticity, termed naive pluripotency. For development to proceed, this naive state must be subsumed by multi-lineage differentiation within 72 h following implantation. In vitro differentiation of naive embryonic stem cells (ESCs) cultured in controlled conditions provides a tractable system to dissect and understand the process of exit from naive pluripotency and entry into lineage specification. Exploitation of this system in recent large-scale RNAi and mutagenesis screens has uncovered multiple new factors and modules that drive or facilitate progression out of the naive state. Notably, these studies show that the transcription factor network that governs the naive state is rapidly dismantled prior to upregulation of lineage specification markers, creating an intermediate state that we term formative pluripotency. Here, we summarize these findings and propose a road map for state transitions in ESC differentiation that reflects the orderly dynamics of epiblast progression in the embryo. PMID:25349449

  7. Two distinct, geographically overlapping lineages of the corallimorpharian Ricordea florida (Cnidaria: Hexacorallia: Ricordeidae)

    NASA Astrophysics Data System (ADS)

    Torres-Pratts, H.; Lado-Insua, T.; Rhyne, A. L.; Rodríguez-Matos, L.; Schizas, N. V.

    2011-06-01

    We examined the genetic variation of the corallimorpharian Ricordea florida; it is distributed throughout the Caribbean region and is heavily harvested for the marine aquarium trade. Eighty-four distinct individuals of R. florida were sequenced from four geographically distant Caribbean locations (Curaçao, Florida, Guadeloupe, and Puerto Rico). Analysis of the ribosomal nuclear region (ITS1, 5.8S, ITS2) uncovered two geographically partially overlapping genetic lineages in R. florida, probably representing two cryptic species. Lineage 1 was found in Florida and Puerto Rico, and Lineage 2 was found in Florida, Puerto Rico, Guadeloupe, and Curaçao. Because of the multi-allelic nature of the ITS region, four individuals from Lineage 1 and six from Lineage 2 were cloned to evaluate the levels of hidden intra-individual variability. Pairwise genetic comparisons indicated that the levels of intra-individual and intra-lineage variability (<1%) were approximately an order of magnitude lower than the divergence (~9%) observed between the two lineages. The fishery regulations of the aquarium trade regard R. florida as one species. More refined regulations should take into account the presence of two genetic lineages, and they should be managed separately in order to preserve the long-term evolutionary potential of this corallimorpharian. The discovery of two distinct lineages in R. florida illustrates the importance of evaluating genetic variability in harvested species prior to the implementation of management policies.

  8. Mapping differentiation pathways from hematopoietic stem cells using Flk2/Flt3 lineage tracing

    PubMed Central

    Boyer, Scott W.; Beaudin, Anna E.; Forsberg, E. Camilla

    2012-01-01

    Genetic fate-mapping approaches provide a unique opportunity to assess differentiation pathways under physiological conditions. We have recently employed a lineage tracing approach to define hematopoietic differentiation pathways in relation to expression of the tyrosine kinase receptor Flk2.1 Based on our examination of reporter activity across all stem, progenitor and mature populations in our Flk2-Cre lineage model, we concluded that all mature blood lineages are derived through a Flk2+ intermediate, both at steady-state and under stress conditions. Here, we re-examine in depth our initial conclusions and perform additional experiments to test alternative options of lineage specification. Our data unequivocally support the conclusion that onset of Flk2 expression results in loss of self-renewal but preservation of multilineage differentiation potential. We discuss the implications of these data for defining stem cell identity and lineage potential among hematopoietic populations. PMID:22895180

  9. [KIM-1 and NGAL as potential biomarkers for the diagnosis and cancer progression].

    PubMed

    Marchewka, Zofia; Tacik, Aneta; Piwowar, Agnieszka

    2016-01-01

    On the basis of scientific literature, there is growing evidence that KIM-1 and NGAL are interesting and promising biomarkers not only in acute and chronic inflammatory processes but also in oncogenesis. There are a number of studies which investigate their possible use in diagnosis, treatment and monitoring of therapy effectiveness. The results of recent research suggests that they may play an important role in standard oncology practice. Simultaneous measurement of KIM-1 and NGAL in urine can play a crucial role in carcinogenesis assessment and cancer progression. In the future, they can become rapid diagnostic indicators, which allow one to determine cancer subtype leading to biopsy replacement and therapy improvement. In the present work, beside biochemical characteristics of KIM-1 and NGAL, we will also discuss their role in the diagnosis and assessment of development of cancer. PMID:27117109

  10. Gluten Sensitivity – A Potentially Reversible Cause of Progressive Cerebellar Ataxia and Myoclonus - A Case Report

    PubMed Central

    Bohra, Vikram; Duggal, Ashish; Ghuge, Vijay V; Chaudhary, Neera

    2015-01-01

    Gluten sensitivity is an umbrella term used for diverse clinical manifestations occurring as a result of abnormal immunological reactivity to dietary gluten in genetically susceptible individuals. Celiac disease is the most well-known but not the only manifestation of gluten sensitivity. Myoclonus with Ataxia is a rare manifestation of gluten sensitivity and should be considered in the differential diagnosis of all patients with idiopathic sporadic ataxia. The presence of gluten-related immune markers in normal population however complicates the reliable diagnosis of gluten related neurological disorders and clinical improvement on gluten free diet can serve as a diagnostic tool for this disease. We report a case of sporadic progressive cerebellar ataxia with myoclonus with positive antigliadin antibodies, which improved with a trial of gluten free diet. This case highlights an important diagnostic and therapeutic principle in management of late onset idiopathic ataxia. PMID:26673942

  11. Comparative analysis of CRISPR loci in different Listeria monocytogenes lineages.

    PubMed

    Di, Huiling; Ye, Lei; Yan, He; Meng, Hecheng; Yamasak, Shinji; Shi, Lei

    2014-11-21

    Listeria monocytogenes, an important food-borne pathogen, causes high mortality rate of listeriosis. Pan-genomic comparisons revealed the species genome of L. monocytogenes is highly stable but not completely clonal. The population structure of this species displays at least four evolutionary lineages (I-IV). Isolates of different lineages displayed distinct genetic, phenotypic and ecologic characteristics, which appear to affect their ability to be transmitted through foods and to cause human disease, as well as their ability to thrive in markedly phage-rich environments. CRISPR (clustered regularly interspaced short palindrome repeats), a recently described adaptive immunity system, not only confers defense against invading elements derived from bacteriophages or plasmids in many bacteria and archaeal, but also displays strains-level variations in almost any given endowed species. This work was aimed to investigate CRISPR diversity in L. monocytogenes strains of different lineages and estimated the potential practicability of the CRISPR-based approach to resolve this species' biodiversity. Only a third of strains contained all three CRISPR loci (here defined as LMa, LMb and LMc) at same time. Combined the strain-level variations in presence/absence of each CRISPR locus and its relative size and spacer arrangements, a total of 29 CRISPR genotypes and 11 groups were defined within a collection of 128 strains covering all serotypes. The CRISPR-based approach showed powerful ability to subtype the more commonly food-borne isolates of serotype 1/2a (lineage II) and serotypes 1/2b (lineage I), but limited by the absence of typical CRISPR structure in many lineage I isolates. Strikingly, we found a long associated cas1 gene as well as two self-targeting LMb spacers accidently homologous with endogenous genes in a fraction of serotype 1/2a isolations, demonstrated that CRISPR I B system might involve in bacterial physiology besides antiviral immunity. PMID:25445602

  12. Theory and Practice of Lineage Tracing.

    PubMed

    Hsu, Ya-Chieh

    2015-11-01

    Lineage tracing is a method that delineates all progeny produced by a single cell or a group of cells. The possibility of performing lineage tracing initiated the field of Developmental Biology and continues to revolutionize Stem Cell Biology. Here, I introduce the principles behind a successful lineage-tracing experiment. In addition, I summarize and compare different methods for conducting lineage tracing and provide examples of how these strategies can be implemented to answer fundamental questions in development and regeneration. The advantages and limitations of each method are also discussed. PMID:26284340

  13. A Potential Role for Alterations of Zinc and Zinc Transport Proteins in the Progression of Alzheimer’s Disease

    PubMed Central

    Lovell, M.A.

    2010-01-01

    Although multiple studies have suggested a role for alterations of zinc (Zn) and zinc transport (ZnT) proteins in the pathogenesis of Alzheimer’s disease (AD), the exact role of this essential trace element in the progression of AD remains unclear. The following review discusses the normal role of Zn and ZnT proteins in brain and the potential effects of their alteration in the pathogenesis of AD particularly in the processing of the amyloid precursor protein and amyloid beta peptide generation and aggregation. PMID:19276540

  14. Gaining Momentum, Losing Ground. Tapping America's Potential (TAP) Progress Report, 2008. Executive Summary

    ERIC Educational Resources Information Center

    Tapping America's Potential, 2008

    2008-01-01

    In July 2005, Business Roundtable and fifteen of America's most prominent business organizations--Tapping America's Potential, the TAP coalition--issued a report stating that "one of the pillars of American economic prosperity--U.S. scientific and technological superiority--is beginning to atrophy even as other nations are developing their own…

  15. Pedagogical Content Knowledge in Science Education: Perspectives and Potential for Progress

    ERIC Educational Resources Information Center

    Kind, Vanessa

    2009-01-01

    Pedagogical content knowledge (PCK), since its inception as teacher-specific professional knowledge, has been researched extensively. Drawing on a wide range of literature, this paper seeks to clarify how the potential offered by PCK could be utilised to further develop science teacher education. An analysis of PCK models proposed by various…

  16. Progression-free survival as a potential surrogate for overall survival in metastatic breast cancer

    PubMed Central

    Beauchemin, Catherine; Cooper, Dan; Lapierre, Marie-Ève; Yelle, Louise; Lachaine, Jean

    2014-01-01

    Background Progression-free survival (PFS) and time to progression (TTP) are frequently used to establish the clinical efficacy of anti-cancer drugs. However, the surrogacy of PFS/TTP for overall survival (OS) remains a matter of uncertainty in metastatic breast cancer (mBC). This study assessed the relationship between PFS/TTP and OS in mBC using a trial-based approach. Methods We conducted a systematic literature review according to the PICO method: ‘Population’ consisted of women with mBC; ‘Interventions’ and ‘Comparators’ were standard treatments for mBC or best supportive care; ‘Outcomes’ of interest were median PFS/TTP and OS. We first performed a correlation analysis between median PFS/TTP and OS, and then conducted subgroup analyses to explore possible reasons for heterogeneity. Then, we assessed the relationship between the treatment effect on PFS/TTP and OS. The treatment effect on PFS/TTP and OS was quantified by the absolute difference of median values. We also conducted linear regression analysis to predict the effects of a new anti-cancer drug on OS on the basis of its effects on PFS/TTP. Results A total of 5,041 studies were identified, and 144 fulfilled the eligibility criteria. There was a statistically significant relationship between median PFS/TTP and OS across included trials (r=0.428; P<0.01). Correlation coefficient for the treatment effect on PFS/TTP and OS was estimated at 0.427 (P<0.01). The obtained linear regression equation was ΔOS =−0.088 (95% confidence interval [CI] −1.347–1.172) + 1.753 (95% CI 1.307–2.198) × ΔPFS (R2=0.86). Conclusion Results of this study indicate a significant association between PFS/TTP and OS in mBC, which may justify the use of PFS/TTP in the approval for commercialization and reimbursement of new anti-cancer drugs in this cancer setting. PMID:24971020

  17. Kinesin Family member 4A: A Potential Predictor for Progression of Human Oral Cancer

    PubMed Central

    Minakawa, Yasuyuki; Kasamatsu, Atsushi; Koike, Hirofumi; Higo, Morihiro; Nakashima, Dai; Kouzu, Yukinao; Sakamoto, Yosuke; Ogawara, Katsunori; Shiiba, Masashi; Tanzawa, Hideki; Uzawa, Katsuhiro

    2013-01-01

    Background Kinesin family member 4A (KIF4A), a microtubule-based motor protein, was implicated in regulation of chromosomal structure and kinetochore microtubule dynamics. Considering the functions of KIF4A, we assumed that KIF4A is involved in progression of oral squamous cell carcinomas (OSCCs) via activation of the spindle assembly checkpoint (SAC). However, little is known about the relevance of KIF4A in the behavior of OSCC. We investigated the KIF4A expression status and its functional mechanisms in OSCC. Methods The KIF4A expression levels in seven OSCC-derived cells were analyzed by quantitative reverse transcriptase-polymerase chain reaction and immunoblotting analyses. Using a KIF4A knockdown model, we assessed the expression of (SAC)-related molecules (BUB1, MAD2, CDC20, and cyclin B1), cell-cycle, and cellular proliferation. In addition to in vitro data, the clinical correlation between the KIF4A expression levels in primary OSCCs (n = 106 patients) and the clinicopathologic status by immunohistochemistry (IHC) also were evaluated. Results KIF4A mRNA and protein were up-regulated significantly (P < 0.05) in seven OSCC-derived cells compared with human normal oral keratinocytes. In the KIF4A knockdown cells, SAC activation was observed via increased BUB1 expression on the kinetochores, appropriate kinetochore localization of MAD2, down-regulation of CDC20, up-regulation of cyclin B1, and cell-cycle arrested at G2/M phase. The results showed that cellular proliferation of KIF4A knockdown cells decreased significantly (P < 0.05) compared with control cells. IHC showed that KIF4A expression in primary OSCCs was significantly (P < 0.05) greater than in the normal oral counterparts and that KIF4A-positive OSCCs were correlated closely (P < 0.05) with tumoral size. Conclusions Our results proposed for the first time that KIF4A controls cellular proliferation via SAC activation. Therefore, KIF4A might be a key regulator for tumoral progression in OSCCs. PMID

  18. Microarray based comparison of two Escherichia coli O157:H7 lineages

    PubMed Central

    Dowd, Scot E; Ishizaki, Hiroshi

    2006-01-01

    Background Previous research has identified the potential for the existence of two separate lineages of Escherichia coli O157:H7. Clinical isolates tended to cluster primarily within one of these two lineages. To determine if there are virulence related genes differentially expressed between the two lineages we chose to utilize microarray technology to perform an initial screening. Results Using a 610 gene microarray, designed against the E. coli O157 EDL 933 transcriptome, targeting primarily virulence systems, we chose 3 representative Lineage I isolates (LI groups mostly clinical isolates) and 3 representative Lineage II isolates (LII groups mostly bovine isolates). Using standard dye swap experimental designs, statistically different expression (P < 0.05) of 73 genes between the two lineages was revealed. Result highlights indicate that under in vitro anaerobic growth conditions, there is up-regulation of stx2b, ureD, curli (csgAFEG), and stress related genes (hslJ, cspG, ibpB, ibpA) in Lineage I, which may contribute to enhanced virulence or transmission potential. Lineage II exhibits significant up-regulation of type III secretion apparatus, LPS, and flagella related transcripts. Conclusion These results give insight into comparative regulation of virulence genes as well as providing directions for future research. Ultimately, evaluating the expression of key virulence factors among different E. coli O157 isolates has inherent value and the interpretation of such expression data will continue to evolve as our understanding of virulence, pathogenesis and transmission improves. PMID:16539702

  19. G-coupled protein receptors and breast cancer progression: potential drug targets.

    PubMed

    Taborga, Marcelo; Corcoran, Kelly E; Fernandes, Neil; Ramkissoon, Shakti H; Rameshwar, Pranela

    2007-03-01

    Breast cancer remains a leading cause of death despite early screening and advances in medicine. Bone marrow metastasis often complicates the clinical picture by requiring more aggressive treatment and worsening long-term prognoses. Recent therapeutic targeting of hormonal receptors such as human epidermal growth factor receptor 2 and estrogen receptor has shown limited success in treating localized disease for those patients whose cancer cells are responsive. Although traditional approaches such as chemotherapy have demonstrated many successes, these agents fail to target quiescent cancer stem cells, which might have entered the bone marrow where they might be responsible for the quiescence population. Following years of clinical remission, these dormant cells could lead to secondary cancer resurgence. To date, little progress has been made in the development of targeted treatments for receptor negative and metastatic disease. In this review, we discuss the role of G-protein coupled receptors, including neurokinin-1, neurokinin-2 and chemokine receptor 4, as novel targets in the treatment of breast cancer. PMID:17346217

  20. Alchemy in the underworld - recent progress and future potential of organic geochemistry applied to speleothems.

    NASA Astrophysics Data System (ADS)

    Blyth, Alison

    2016-04-01

    Speleothems are well used archives for chemical records of terrestrial environmental change, and the integration of records from a range of isotopic, inorganic, and organic geochemical techniques offers significant power in reconstructing both changes in past climates and identifying the resultant response in the overlying terrestrial ecosystems. The use of organic geochemistry in this field offers the opportunity to recover new records of vegetation change (via biomarkers and compound specific isotopes), temperature change (via analysis of glycerol dialkyl glycerol tetraethers, a compound group derived from microbes and varying in structure in response to temperature and pH), and changes in soil microbial behaviour (via combined carbon isotope analysis). However, to date the use of organic geochemical techniques has been relatively limited, due to issues relating to sample size, concerns about contamination, and unanswered questions about the origins of the preserved organic matter and rates of transport. Here I will briefly review recent progress in the field, and present a framework for the future research needed to establish organic geochemical analysis in speleothems as a robust palaeo-proxy approach.

  1. Wood biomass: The potential of willow. Progress report, November 1987--December 1990

    SciTech Connect

    White, E.H.; Abrahamson, L.P.

    1991-10-01

    Experiments were established in central New York State in spring, 1987, to evaluate the potential of Salix for wood biomass production using ultrashort-rotation intensive-culture techniques. Five selected willow clones and one hybrid poplar clone planted at 1 {times} 1 foot spacing were tested for biomass production with annual coppicing. This report presents results of this research as of December 31, 1990. (VC)

  2. Monitoring genetic and metabolic potential for in situ bioremediation: Mass spectrometry. 1997 annual progress report

    SciTech Connect

    Buchanan, M.V.; Hurst, G.B.; Britt, P.F.; McLuckey, S.A.; Doktycz, M.J.

    1997-09-01

    'A number of US Department of Energy (DOE) sites are contaminated with mixtures of dense non-aqueous phase liquids (DNAPLs) such as carbon tetrachloride, chloroform,. perchloroethylene, and trichloroethylene. At many of these sites, in situ microbial bioremediation is an attractive strategy for cleanup because it has the potential to degrade DNAPLs in situ without producing toxic byproducts. A rapid screening method to determine the broad range metabolic and genetic potential for contaminant degradation would greatly reduce the cost and time involved in assessment for in situ bioremediation as well as for monitoring ongoing bioremediation treatment. In this project, the ORNL Organic Mass Spectrometry (OMS) group is developing mass-spectrometry-based methods to screen for the genetic and metabolic potential for assessment and monitoring of in situ bioremediation of DNAPLs. In close collaboration, Professor Mary Lidstrom''s group at the University of Washington is identifying short DNA sequences related to microbial processes involved in the biodegradation of pollutants. This work will lay the foundation for development of a field-portable mass-spectrometry-based technique for rapid assessment and monitoring of bioremediation processes on site.'

  3. Up-Regulation of S100A11 in Lung Adenocarcinoma – Its Potential Relationship with Cancer Progression

    PubMed Central

    Woo, Tetsukan; Okudela, Koji; Mitsui, Hideaki; Tajiri, Michihiko; Rino, Yasushi; Ohashi, Kenichi; Masuda, Munetaka

    2015-01-01

    We previously reported that patients with lung adenocarcinomas with KRAS gene mutations and strong proliferating activity had poorer outcomes, even in the early stage of the disease. The aim of the present study was to elucidate the potential molecular basis of these highly malignant lung tumors by focusing on S100 proteins (S100A2, S100A7, and S100A11), which are downstream targets of oncogenic KRAS and promoters of tumor progression. The immunohistochemical expression of S100 proteins was examined in 179 primary lung adenocarcinomas, and the potential relationships between their levels and clinicopathologic factors were analyzed. Among the three subtypes, S100A11 levels were significantly higher in adenocarcinomas with KRAS mutations and strong proliferating activity. They were also higher in adenocarcinomas with poorly differentiated tumors. Furthermore, higher levels of S100A11 were associated with shorter disease-free survival. These results suggest that the up-regulation of S100A11 plays a role in tumor progression, particularly in KRAS-mutated lung adenocarcinomas. PMID:26544866

  4. Pluripotency Factors on Their Lineage Move

    PubMed Central

    Weidgang, Clair E.; Seufferlein, Thomas; Kleger, Alexander; Mueller, Martin

    2016-01-01

    Pluripotent stem cells are characterised by continuous self-renewal while maintaining the potential to differentiate into cells of all three germ layers. Regulatory networks of maintaining pluripotency have been described in great detail and, similarly, there is great knowledge on key players that regulate their differentiation. Interestingly, pluripotency has various shades with distinct developmental potential, an observation that coined the term of a ground state of pluripotency. A precise interplay of signalling axes regulates ground state conditions and acts in concert with a combination of key transcription factors. The balance between these transcription factors greatly influences the integrity of the pluripotency network and latest research suggests that minute changes in their expression can strengthen but also collapse the network. Moreover, recent studies reveal different facets of these core factors in balancing a controlled and directed exit from pluripotency. Thereby, subsets of pluripotency-maintaining factors have been shown to adopt new roles during lineage specification and have been globally defined towards neuroectodermal and mesendodermal sets of embryonic stem cell genes. However, detailed underlying insights into how these transcription factors orchestrate cell fate decisions remain largely elusive. Our group and others unravelled complex interactions in the regulation of this controlled exit. Herein, we summarise recent findings and discuss the potential mechanisms involved. PMID:26770212

  5. [Progress on neuropsychology and event-related potentials in patients with brain trauma].

    PubMed

    Dong, Ri-xia; Cai, Wei-xiong; Tang, Tao; Huang, Fu-yin

    2010-02-01

    With the development of information technology, as one of the research frontiers in neurophysiology, event-related potentials (ERP) is concerned increasingly by international scholars, which provides a feasible and objective method for exploring cognitive function. There are many advances in neuropsychology due to new assessment tool for the last years. The basic theories in the field of ERP and neuropsychology were reviewed in this article. The research and development in evaluating cognitive function of patients with syndrome after brain trauma were focused in this review, and the perspectives for the future research of ERP was also explored. PMID:20232746

  6. Recent Progress in Lab-on-a-Chip Technology and Its Potential Application to Clinical Diagnoses

    PubMed Central

    2013-01-01

    We present the construction of the lab-on-a-chip (LOC) system, a state-of-the-art technology that uses polymer materials (i.e., poly[dimethylsiloxane]) for the miniaturization of conventional laboratory apparatuses, and show the potential use of these microfluidic devices in clinical applications. In particular, we introduce the independent unit components of the LOC system and demonstrate how each component can be functionally integrated into one monolithic system for the realization of a LOC system. In specific, we demonstrate microscale polymerase chain reaction with the use of a single heater, a microscale sample injection device with a disposable plastic syringe and a strategy for device assembly under environmentally mild conditions assisted by surface modification techniques. In this way, we endeavor to construct a totally integrated, disposable microfluidic system operated by a single mode, the pressure, which can be applied on-site with enhanced device portability and disposability and with simple and rapid operation for medical and clinical diagnoses, potentially extending its application to urodynamic studies in molecular level. PMID:23610705

  7. Distinguishing between storm and tsunami in the geological record; progress, perturbations and potential

    NASA Astrophysics Data System (ADS)

    Switzer, A. D.

    2010-12-01

    Palaeoestorm and palaeotsunami research now incorporates not only geologists and geomorphologists but computer and mathematical modellers, geophysicists, chronology experts, palaeontologists, hydrologists, coastal planners and ecologists. Recent studies on modern events such as the 2004 Indian Ocean tsunami and several large cyclone events (eg Hurricane Katrina) have provided new insights and now present the research community with a good opportunity to reflect on the progress made in the field, evaluate some recent criticisms and highlight knowledge gaps for future study. There is no globally applicable sedimentological criteria for differentiating between tsunami and storms in washover sandsheets. What can be compiled for the many deposits attributed to palaeo-washover is a suite of sedimentary features or commonalities, often called signatures. These signatures must be considered in terms of the local setting as they are very much site dependant. Palaeo-washover deposits can only be attributed to an event type through careful analysis of spatial features such as the elevation, lateral extent and run-up of the deposit along with sedimentary features such as grading, the presence of intraclasts, and particle size distribution of the sediments. These analyses when combined may lead to a suite of evidence that can point to storm or tsunami as the likely depositional agent. Unfortunately when considered alone many of the characteristics are equivocal. In fact most of the signatures presented in the literature for tsunami deposition, including the presence of marine diatoms or increases in particular elemental concentrations only indicate the marine origin of the sediments and inundation by ocean water. Hence storm surges, sea level change or regional subsidence may show similar sedimentological characteristics. Recent work has recognized the equivocal nature of many so called 'tsunami signatures' found in sandsheets. This stated, there remain many cases in the

  8. Concise Review: Chemical Approaches for Modulating Lineage-Specific Stem Cells and Progenitors

    PubMed Central

    Xu, Tao; Zhang, Mingliang; Laurent, Timothy; Xie, Min

    2013-01-01

    Generation and manipulation of lineage-restricted stem and progenitor cells in vitro and/or in vivo are critical for the development of stem cell-based clinical therapeutics. Lineage-restricted stem and progenitor cells have many advantageous qualities, including being able to efficiently engraft and differentiate into desirable cell types in vivo after transplantation, and they are much less tumorigenic than pluripotent cells. Generation of lineage-restricted stem and progenitor cells can be achieved by directed differentiation from pluripotent stem cells or lineage conversion from easily obtained somatic cells. Small molecules can be very helpful in these processes since they offer several important benefits. For example, the risk of tumorigenesis is greatly reduced when small molecules are used to replace integrated transcription factors, which are widely used in cell fate conversion. Furthermore, small molecules are relatively easy to apply, optimize, and manufacture, and they can more readily be developed into conventional pharmaceuticals. Alternatively, small molecules can be used to expand or selectively control the differentiation of lineage-restricted stem and progenitor cells for desirable therapeutics purposes in vitro or in vivo. Here we summarize recent progress in the use of small molecules for the expansion and generation of desirable lineage-restricted stem and progenitor cells in vitro and for selectively controlling cell fate of lineage-restricted stem and progenitor cells in vivo, thereby facilitating stem cell-based clinical applications. PMID:23580542

  9. microRNAs as Potential Biomarkers in Adrenocortical Cancer: Progress and Challenges

    PubMed Central

    Cherradi, Nadia

    2016-01-01

    Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis and limited therapeutic options. Over the last decade, pan-genomic analyses of genetic and epigenetic alterations and genome-wide expression profile studies allowed major advances in the understanding of the molecular genetics of ACC. Besides the well-known dysfunctional molecular pathways in adrenocortical tumors, such as the IGF2 pathway, the Wnt pathway, and TP53, high-throughput technologies enabled a more comprehensive genomic characterization of adrenocortical cancer. Integration of expression profile data with exome sequencing, SNP array analysis, methylation, and microRNA (miRNA) profiling led to the identification of subgroups of malignant tumors with distinct molecular alterations and clinical outcomes. miRNAs post-transcriptionally silence their target gene expression either by degrading mRNA or by inhibiting translation. Although our knowledge of the contribution of deregulated miRNAs to the pathogenesis of ACC is still in its infancy, recent studies support their relevance in gene expression alterations in these tumors. Some miRNAs have been shown to carry potential diagnostic and prognostic values, while others may be good candidates for therapeutic interventions. With the emergence of disease-specific blood-borne miRNAs signatures, analyses of small cohorts of patients with ACC suggest that circulating miRNAs represent promising non-invasive biomarkers of malignancy or recurrence. However, some technical challenges still remain, and most of the miRNAs reported in the literature have not yet been validated in sufficiently powered and longitudinal studies. In this review, we discuss the current knowledge regarding the deregulation of tumor-associated and circulating miRNAs in ACC patients, while emphasizing their potential significance in pathogenic pathways in light of recent insights into the role of miRNAs in shaping the tumor microenvironment. PMID:26834703

  10. Recent Progress Toward Hydrogen Medicine: Potential of Molecular Hydrogen for Preventive and Therapeutic Applications

    PubMed Central

    Ohta, Shigeo

    2011-01-01

    Persistent oxidative stress is one of the major causes of most lifestyle-related diseases, cancer and the aging process. Acute oxidative stress directly causes serious damage to tissues. Despite the clinical importance of oxidative damage, antioxidants have been of limited therapeutic success. We have proposed that molecular hydrogen (H2) has potential as a “novel” antioxidant in preventive and therapeutic applications [Ohsawa et al., Nat Med. 2007: 13; 688-94]. H2 has a number of advantages as a potential antioxidant: H2 rapidly diffuses into tissues and cells, and it is mild enough neither to disturb metabolic redox reactions nor to affect reactive oxygen species (ROS) that function in cell signaling, thereby, there should be little adverse effects of consuming H2. There are several methods to ingest or consume H2, including inhaling hydrogen gas, drinking H2-dissolved water (hydrogen water), taking a hydrogen bath, injecting H2-dissolved saline (hydrogen saline), dropping hydrogen saline onto the eye, and increasing the production of intestinal H2 by bacteria. Since the publication of the first H2 paper in Nature Medicine in 2007, the biological effects of H2 have been confirmed by the publication of more than 38 diseases, physiological states and clinical tests in leading biological/medical journals, and several groups have started clinical examinations. Moreover, H2 shows not only effects against oxidative stress, but also various anti-inflammatory and anti-allergic effects. H2 regulates various gene expressions and protein-phosphorylations, though the molecular mechanisms underlying the marked effects of very small amounts of H2 remain elusive. PMID:21736547

  11. Recent progress toward hydrogen medicine: potential of molecular hydrogen for preventive and therapeutic applications.

    PubMed

    Ohta, Shigeo

    2011-01-01

    Persistent oxidative stress is one of the major causes of most lifestyle-related diseases, cancer and the aging process. Acute oxidative stress directly causes serious damage to tissues. Despite the clinical importance of oxidative damage, antioxidants have been of limited therapeutic success. We have proposed that molecular hydrogen (H(2)) has potential as a "novel" antioxidant in preventive and therapeutic applications [Ohsawa et al., Nat Med. 2007: 13; 688-94]. H(2) has a number of advantages as a potential antioxidant: H(2) rapidly diffuses into tissues and cells, and it is mild enough neither to disturb metabolic redox reactions nor to affect reactive oxygen species (ROS) that function in cell signaling, thereby, there should be little adverse effects of consuming H(2). There are several methods to ingest or consume H(2), including inhaling hydrogen gas, drinking H(2)-dissolved water (hydrogen water), taking a hydrogen bath, injecting H(2)- dissolved saline (hydrogen saline), dropping hydrogen saline onto the eye, and increasing the production of intestinal H(2) by bacteria. Since the publication of the first H(2) paper in Nature Medicine in 2007, the biological effects of H(2) have been confirmed by the publication of more than 38 diseases, physiological states and clinical tests in leading biological/medical journals, and several groups have started clinical examinations. Moreover, H(2) shows not only effects against oxidative stress, but also various anti-inflammatory and antiallergic effects. H(2) regulates various gene expressions and protein-phosphorylations, though the molecular mechanisms underlying the marked effects of very small amounts of H(2) remain elusive. PMID:21736547

  12. Effect of Temperature on Growth and Sporulation of US-22, US-23, and US-24 Clonal Lineages of Phytophthora infestans and Implications for Late Blight Epidemiology.

    PubMed

    Seidl Johnson, Anna C; Frost, Kenneth E; Rouse, Douglas I; Gevens, Amanda J

    2015-04-01

    Epidemics of late blight, caused by Phytophthora infestans (Mont.) de Bary, have been studied by plant pathologists and regarded with great concern by potato and tomato growers since the Irish potato famine in the 1840s. P. infestans populations have continued to evolve, with unique clonal lineages arising which differ in pathogen fitness and pathogenicity, potentially impacting epidemiology. In 2012 and 2013, the US-23 clonal lineage predominated late blight epidemics in most U.S. potato and tomato production regions, including Wisconsin. This lineage was unknown prior to 2009. For isolates of three recently identified clonal lineages of P. infestans (US-22, US-23, and US-24), sporulation rates were experimentally determined on potato and tomato foliage and the effect of temperature on lesion growth rate on tomato was investigated. The US-22 and US-23 isolates had greater lesion growth rates on tomato than US-24 isolates. Sporulation rates for all isolates were greater on potato than tomato, and the US-23 isolates had greater sporulation rates on both tomato and potato than the US-22 and US-24 isolates. Experimentally determined correlates of fitness were input to the LATEBLIGHT model and epidemics were simulated using archived Wisconsin weather data from four growing seasons (2009 to 2012) to investigate the effect of isolates of these new lineages on late blight epidemiology. The fast lesion growth rates of US-22 and US-23 isolates resulted in severe epidemics in all years tested, particularly in 2011. The greater sporulation rates of P. infestans on potato resulted in simulated epidemics that progressed faster than epidemics simulated for tomato; the high sporulation rates of US-23 isolates resulted in simulated epidemics more severe than simulated epidemics of isolates of the US-22 and US-24 isolates and EC-1 clonal lineages on potato and tomato. Additionally, US-23 isolates consistently caused severe simulated epidemics when lesion growth rate and sporulation

  13. Single-Cell RNA-Seq Reveals Lineage and X Chromosome Dynamics in Human Preimplantation Embryos.

    PubMed

    Petropoulos, Sophie; Edsgärd, Daniel; Reinius, Björn; Deng, Qiaolin; Panula, Sarita Pauliina; Codeluppi, Simone; Plaza Reyes, Alvaro; Linnarsson, Sten; Sandberg, Rickard; Lanner, Fredrik

    2016-05-01

    Mouse studies have been instrumental in forming our current understanding of early cell-lineage decisions; however, similar insights into the early human development are severely limited. Here, we present a comprehensive transcriptional map of human embryo development, including the sequenced transcriptomes of 1,529 individual cells from 88 human preimplantation embryos. These data show that cells undergo an intermediate state of co-expression of lineage-specific genes, followed by a concurrent establishment of the trophectoderm, epiblast, and primitive endoderm lineages, which coincide with blastocyst formation. Female cells of all three lineages achieve dosage compensation of X chromosome RNA levels prior to implantation. However, in contrast to the mouse, XIST is transcribed from both alleles throughout the progression of this expression dampening, and X chromosome genes maintain biallelic expression while dosage compensation proceeds. We envision broad utility of this transcriptional atlas in future studies on human development as well as in stem cell research. PMID:27062923

  14. Single-Cell RNA-Seq Reveals Lineage and X Chromosome Dynamics in Human Preimplantation Embryos

    PubMed Central

    Petropoulos, Sophie; Edsgärd, Daniel; Reinius, Björn; Deng, Qiaolin; Panula, Sarita Pauliina; Codeluppi, Simone; Plaza Reyes, Alvaro; Linnarsson, Sten; Sandberg, Rickard; Lanner, Fredrik

    2016-01-01

    Summary Mouse studies have been instrumental in forming our current understanding of early cell-lineage decisions; however, similar insights into the early human development are severely limited. Here, we present a comprehensive transcriptional map of human embryo development, including the sequenced transcriptomes of 1,529 individual cells from 88 human preimplantation embryos. These data show that cells undergo an intermediate state of co-expression of lineage-specific genes, followed by a concurrent establishment of the trophectoderm, epiblast, and primitive endoderm lineages, which coincide with blastocyst formation. Female cells of all three lineages achieve dosage compensation of X chromosome RNA levels prior to implantation. However, in contrast to the mouse, XIST is transcribed from both alleles throughout the progression of this expression dampening, and X chromosome genes maintain biallelic expression while dosage compensation proceeds. We envision broad utility of this transcriptional atlas in future studies on human development as well as in stem cell research. PMID:27062923

  15. The Characterization of Psychrophilic Microorganisms and their potentially useful Cold-Active Glycosidases Final Progress Report

    SciTech Connect

    Brenchly, Jean E.

    2008-06-30

    Our studies of novel, cold-loving microorganisms have focused on two distinct extreme environments. The first is an ice core sample from a 120,000 year old Greenland glacier. The results of this study are particularly exciting and have been highlighted with press releases and additional coverage. The first press release in 2004 was based on our presentation at the General Meeting of the American Society for Microbiology and was augmented by coverage of our publication (Appl. Environ. Microbiol. 2005. Vol. 71:7806) in the Current Topics section of the ASM news journal, “Microbe.” Of special interest for this report was the isolation of numerous, phylogenetically distinct and potentially novel ultrasmall microorganisms. The detection and isolation of members of the ultrasmall population is significant because these cells pass through 0.2 micron pore filters that are generally used to trap microorganisms from environmental samples. Thus, analyses by other investigators that examined only cells captured on the filters would have missed a significant portion of this population. Only a few ultrasmall isolates had been obtained prior to our examination of the ice core samples. Our development of a filtration enrichment and subsequent cultivation of these organisms has added extensively to the collection of, and knowledge about, this important population in the microbial world.

  16. Progress toward therapeutic potential for AFQ056 in Fragile X syndrome

    PubMed Central

    Sourial, Mary; Cheng, Connie; Doering, Laurie C

    2013-01-01

    Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and the leading single-gene cause of autism. It is caused by the lack of production of the Fragile X mental retardation protein (FMRP), resulting in cognitive deficits, hyperactivity, and autistic behaviors. Breakthrough advances in potential therapy for FXS followed the discovery that aberrant group 1 metabotropic glutamate receptor (mGluR) signaling is an important constituent of the pathophysiology of the syndrome. Research has indicated that upon neuronal stimulation, FMRP acts downstream of group 1 mGluRs (mGluRs1/5) to inhibit protein synthesis, long-term depression, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor internalization. To offset the deficits caused by the lack of FMRP, many pharmaceutical companies have designed medicinal drugs to target the unrestrained stimulation of mGluR5 signaling in FXS. Indeed, promising results from animal and clinical studies suggest that mGluR5 antagonists such as AFQ056 can successfully correct many of the deficits in FXS. In this review, we cover the animal studies performed to date that test the role of AFQ056 as a selective mGluR5 antagonist to alleviate the phenotypes of FXS.

  17. Transcriptomic gene-network analysis of exposure to silver nanoparticle reveals potentially neurodegenerative progression in mouse brain neural cells.

    PubMed

    Lin, Ho-Chen; Huang, Chin-Lin; Huang, Yuh-Jeen; Hsiao, I-Lun; Yang, Chung-Wei; Chuang, Chun-Yu

    2016-08-01

    Silver nanoparticles (AgNPs) are commonly used in daily living products. AgNPs can induce inflammatory response in neuronal cells, and potentially develop neurological disorders. The gene networks in response to AgNPs-induced neurodegenerative progression have not been clarified in various brain neural cells. This study found that 3-5nm AgNPs were detectable to enter the nuclei of mouse neuronal cells after 24-h of exposure. The differentially expressed genes in mouse brain neural cells exposure to AgNPs were further identified using Phalanx Mouse OneArray® chip, and permitted to explore the gene network pathway regulating in neurodegenerative progression according to Cytoscape analysis. In focal adhesion pathway of ALT astrocytes, AgNPs induced the gene expression of RasGRF1 and reduced its downstream BCL2 gene for apoptosis. In cytosolic DNA sensing pathway of microglial BV2 cells, AgNPs reduced the gene expression of TREX1 and decreased IRF7 to release pro-inflammatory cytokines for inflammation and cellular activation. In MAPK pathway of neuronal N2a cells, AgNPs elevated GADD45α gene expression, and attenuated its downstream PTPRR gene to interfere with neuron growth and differentiation. Moreover, AgNPs induced beta amyloid deposition in N2a cells, and decreased PSEN1 and PSEN2, which may disrupt calcium homeostasis and presynaptic dysfunction for Alzheimer's disease development. These findings suggested that AgNPs exposure reveals the potency to induce the progression of neurodegenerative disorder. PMID:27131904

  18. From regenerative dentistry to regenerative medicine: progress, challenges, and potential applications of oral stem cells

    PubMed Central

    Xiao, Li; Nasu, Masanori

    2014-01-01

    Adult mesenchymal stem cells (MSCs) and epithelial stem cells play essential roles in tissue repair and self-healing. Oral MSCs and epithelial stem cells can be isolated from adult human oral tissues, for example, teeth, periodontal ligament, and gingiva. Cocultivated adult oral epithelial stem cells and MSCs could represent some developmental events, such as epithelial invagination and tubular structure formation, signifying their potentials for tissue regeneration. Oral epithelial stem cells have been used in regenerative medicine over 1 decade. They are able to form a stratified cell sheet under three-dimensional culture conditions. Both experimental and clinical data indicate that the cell sheets can not only safely and effectively reconstruct the damaged cornea in humans, but also repair esophageal ulcer in animal models. Oral MSCs include dental pulp stem cells (DPSCs), stem cells from exfoliated deciduous teeth (SHED), stem cells from apical papilla (SCAP), periodontal ligament stem cells (PDLSCs), and mesenchymal stem cells from gingiva (GMSCs). They are widely applied in both regenerative dentistry and medicine. DPSCs, SHED, and SCAP are able to form dentin–pulp complex when being transplanted into immunodeficient animals. They have been experimentally used for the regeneration of dental pulp, neuron, bone muscle and blood vessels in animal models and have shown promising results. PDLSCs and GMSCs are demonstrated to be ideal cell sources for repairing the damaged tissues of periodontal, muscle, and tendon. Despite the abovementioned applications of oral stem cells, only a few human clinical trials are now underway to use them for the treatment of certain diseases. Since clinical use is the end goal, their true regenerative power and safety need to be further examined. PMID:25506228

  19. Functional and Biological Role of Endothelial Precursor Cells in Tumour Progression: A New Potential Therapeutic Target in Haematological Malignancies.

    PubMed

    Reale, Antonia; Melaccio, Assunta; Lamanuzzi, Aurelia; Saltarella, Ilaria; Dammacco, Franco; Vacca, Angelo; Ria, Roberto

    2016-01-01

    It was believed that vasculogenesis occurred only during embryo life and that postnatal formation of vessels arose from angiogenesis. Recent findings demonstrate the existence of Endothelial Precursor Cells (EPCs), which take partin postnatal vasculogenesis. EPCs are recruited from the bone marrow under the stimulation of growth factors and cytokines and reach the sites of neovascularization in both physiological and pathological conditions such as malignancies where they contribute to the "angiogenic switch" and tumor progression. An implementation of circulating EPCs in the bloodstream of patients with haematological malignancies has been demonstrated. This increase is strictly related to the bone marrow microvessel density and correlated with a poor prognosis. The EPCs characterization is a very complex process and still under investigation. This literature review aims to provide an overview of the functional and biological role of EPCs in haematological malignancies and to investigate their potential as a new cancer therapeutic target. PMID:26788072

  20. Nucleolin identified by comparative mass‑spectra analysis is a potential marker for invasive progression of hepatocellular carcinoma.

    PubMed

    Qian, Bin; Yao, Yusheng; Liu, Yihong; Yan, Maolin; Huang, Ying; Chen, Yanqing

    2014-09-01

    At present, the diagnosis and prognosis of hepatocellular carcinoma (HCC) metastasis remains poor. Recently, a number of proteins associated with the metastasis and invasion of HCC were identified; however, the effective markers require further elucidation. In the current study, a nucleolin expression was observed in MHCC97L and HCCLM9 HCC cell lines, with low and high metastatic potentials respectively, using comparative proteomics. The data indicated that nucleolin expression in the nucleus was significantly higher in HCCLM9 cells, and it primarily influenced the migration of HCC cells in vitro. Thus, to the best of our knowledge this is the first study to hypothesize that nucleolin may be a novel marker for HCC invasive progression. PMID:24927373

  1. PROGRESSIVE VENTILATION OF THE OCEANS - POTENTIAL FOR RETURN TO ANOXIC CONDITIONS IN THE POST-PALEOZOIC

    SciTech Connect

    Wilde, Pat; Berry, William B.N.

    1980-09-01

    After the ventilation of the residual anoxic layer in the late Paleozoic (Berry and Wilde, 1978) a return to ephemeral anoxic conditions in the ocean is suggested by anoxic sediments found in the Mesozoic cores of the deep-sea drilling program (Schlanger and Jenkyns 1977, and Theide and Van Andel 1977). A preliminary physical oceanographic model is presented to explain the development of oxygen depleted layers in mid-waters below the surface wind-mixed layer during non-glacial climates. The model shows the range of temperature, salinity and density values for hypothetical water masses for two climatically related oceanographic situations: Case A where bottom waters are formed at mid-latitudes at the surface salinity maxima, and Case B where bottom waters are produced at high latitudes but not by sea-ice formation as in the modern ocean. The hypothetical water masses are characterized by examples from the modern ocean and extrapolation to non-glacial times is made by eliminating water masses produced by or influenced by sea-ice formation in modern glacial times. The state of oxidation is made by plotting the model water masses on an oxygen saturation diagram and comparing the relative oxygen capacity with modern conditions of zonal organic productivity. The model indicates for Case A (high latitude temperatures above 5°C) two oxygen, depleted layers in the equatorial regions (1) from about 200m to the depth of completed oxidation of surface material separated by an oxygenated zone to (2) a deep depleted zone along the base of the pycnocline at 2900 M. The deep depleted zone extends along the Case A pycnocline polarward toward the high latitude productivity maximum. For case B with a pycnocline at about 1500m the deep anoxic layer is not sustained. Considerations of density only, suggest that neutral stratification and the potential for overturn is enhanced for climates transitional between Case A and Case B where the density contrast between major water masses

  2. SWI/SNF complex prevents lineage reversion and induces temporal patterning in neural stem cells.

    PubMed

    Eroglu, Elif; Burkard, Thomas R; Jiang, Yanrui; Saini, Nidhi; Homem, Catarina C F; Reichert, Heinrich; Knoblich, Juergen A

    2014-03-13

    Members of the SWI/SNF chromatin-remodeling complex are among the most frequently mutated genes in human cancer, but how they suppress tumorigenesis is currently unclear. Here, we use Drosophila neuroblasts to demonstrate that the SWI/SNF component Osa (ARID1) prevents tumorigenesis by ensuring correct lineage progression in stem cell lineages. We show that Osa induces a transcriptional program in the transit-amplifying population that initiates temporal patterning, limits self-renewal, and prevents dedifferentiation. We identify the Prdm protein Hamlet as a key component of this program. Hamlet is directly induced by Osa and regulates the progression of progenitors through distinct transcriptional states to limit the number of transit-amplifying divisions. Our data provide a mechanistic explanation for the widespread tumor suppressor activity of SWI/SNF. Because the Hamlet homologs Evi1 and Prdm16 are frequently mutated in cancer, this mechanism could well be conserved in human stem cell lineages. PAPERCLIP: PMID:24630726

  3. Differential age susceptibility to influenza B/Victoria lineage viruses in the 2015 Australian influenza season.

    PubMed

    Barr, Ian G; Vijaykrishna, Dhanasekaran; Sullivan, Sheena G

    2016-01-01

    Influenza B viruses make up an important part of the burden from seasonal influenza globally. The 2015 season in Australia saw an unusual predominance of influenza B with a distinctive switch during the season from B/Yamagata/16/88 lineage viruses to B/Victoria/2/87 lineage viruses. We also noted significant differences in the age groups infected by the different B lineages, with B/Victoria infecting a younger population than B/Yamagata, that could not be explained by potential prior exposure. PMID:26848118

  4. Lineage management for on-demand data

    NASA Astrophysics Data System (ADS)

    Collins, J. A.; Brodzik, M.; Billingsley, B. W.

    2009-12-01

    Most data consumers would agree that data should be easily available, and welcome the ability to subset, reformat, and reproject archived data before they retrieve the data for local use. Although these features in a data delivery system potentially enhance the interdisciplinary or collaborative use of the data, they also raise concerns for the archive providing those data. The Searchlight project at the National Snow and Ice Data Center (NSIDC) has successfully dealt with many of the technical issues surrounding the dynamic delivery of user-defined data subsets. These data manipulation accomplishments only solve part of the dynamic data delivery problem: We now need to associate accurate provenance and processing information with the customized data product. The user needs the provenance and history in order to make accurate judgements regarding the appropriate use of the data. Our User Support team may need that provenance and history in order to provide a level of service similar to that available for our documented, archived data sets. This presentation will examine the Searchlight team's response to the emerging issue of handling lineage information associated with dynamically generated data products.

  5. Telomerase reverse transcriptase potentially promotes the progression of oral squamous cell carcinoma through induction of epithelial-mesenchymal transition.

    PubMed

    Zhao, Tengda; Hu, Fengchun; Qiao, Bin; Chen, Zhifeng; Tao, Qian

    2015-05-01

    In recent years, researchers have found the critical role of telomerase in cellular transformation, proliferation, stemness and cell survival. High levels of telomerase reverse transcriptase (TERT) expression and telomerase activation have been reported in most cancer cells. Moreover, overexpression of human TERT (hTERT) is reported to be correlated with advanced invasive stage of the tumor progression and poor prognosis. Epithelial-mesenchymal transition (EMT), characterized by the loss of the cell-cell contact of epithelial cells and the acquisition of migratory and motile properties, is known to be a central mechanism responsible for invasiveness and metastasis of various cancers. Thus, we investigated whether hTERT plays a potential role in the development of EMT. As we expected, our clinical results showed that hTERT is overexpressed in oral epithelial dysplasia (OED) and OSCC tissues and correlates with clinical aggressiveness of oral squamous cell carcinoma (OSCC) patients. We then overexpressed hTERT in primary human oral epithelial cells (HOECS) and found that hTERT has the potential to prolong the lifespan, a process confering the characteristics of EMT by activating the Wnt/β-catenin pathway. Our findings provided an explanation for the aggressive nature of human tumors overexpressing hTERT and the possibly mechanism that links hTERT to EMT property, which represents a possible therapeutic target in highly metastatic cancers. PMID:25775973

  6. Ocean-Atmosphere Heat Exchange: Limitations of Currently Available Datasets and Potential for Future Progress (Solicited Talk)

    NASA Astrophysics Data System (ADS)

    Josey, Simon

    2016-04-01

    The flux of heat between the ocean and the atmosphere is a key element of the global climate system, central to variations in the ocean heat budget and variations in surface temperature. Factors determining the heat exchange will be discussed using models and observations with an emphasis on the period 1990-2015. This period include changes associated with the potential warming hiatus and more recently the major El Nino event that developed in 2015. The ability of leading datasets to reliably estimate surface flux changes is limited by a number of factors and these will be discussed in the context of variations in other components of the climate system. Progress towards obtaining more reliable climatological estimates of the heat exchange will also be considered with reference to recent developments using residual techniques and ocean reanalyses in addition to atmospheric reanalysis, remote sensing and ship based datasets. In addition, use of surface meteorological fields to generate ocean model forcing will be examined together with recent developments using high resolution coupled ocean-atmosphere models. Finally, the potential for significant advances in regions of major uncertainty using the growing network of surface flux buoys will be discussed with a focus on two moorings now in place in the Southern Ocean.

  7. Characterization of the Variability of Epstein-Barr Virus Genes in Nasopharyngeal Biopsies: Potential Predictors for Carcinoma Progression

    PubMed Central

    Banko, Ana V.; Lazarevic, Ivana B.; Folic, Miljan M.; Djukic, Vojko B.; Cirkovic, Andja M.; Karalic, Danijela Z.; Cupic, Maja D.; Jovanovic, Tanja P.

    2016-01-01

    Epstein-Barr virus (EBV) infection is a significant factor in the pathogenesis of nasopharyngeal carcinoma, especially in the undifferentiated carcinoma of nasopharyngeal type (UCNT, World Health Organization type III), which is the dominant histopathological type in high-risk areas. The major EBV oncogene is latent membrane protein 1 (LMP1). LMP1 gene shows variability with different tumorigenic and immunogenic potentials. EBV nuclear antigen 1 (EBNA1) regulates progression of EBV-related tumors; however, the influence of EBNA1 sequence variability on tumor pathogenesis is controversial. The aims of this study were to characterize polymorphisms of EBV genes in non-endemic nasopharyngeal carcinoma biopsies and to investigate potential sequence patterns that correlate with the clinical presentation of nasopharyngeal carcinoma. In total, 116 tumor biopsies of undifferentiated carcinoma of nasopharyngeal type (UCNT), collected from 2008 to 2014, were evaluated in this study. The genes EBNA2, LMP1, and EBNA1 were amplified using nested-PCR. EBNA2 genotyping was performed by visualization of PCR products using gel electrophoresis. Investigation of LMP1 and EBNA1 included sequence, phylogenetic, and statistical analyses. The presence of EBV DNA was significantly distributed between TNM stages. LMP1 variability showed six variants, with the detection of the first China1 and North Carolina variants in European nasopharyngeal carcinoma biopsies. Newly discovered variants Srb1 and Srb2 were UCNT-specific LMP1 polymorphisms. The B95-8 and North Carolina variants are possible predictors for favorable TNM stages. In contrast, deletions in LMP1 are possible risk factors for the most disfavorable TNM stage, independent of EBNA2 or EBNA1 variability. A newly discovered EBNA1 subvariant, P-thr-sv-5, could be a potential diagnostic marker, as it represented a UCNT-specific EBNA1 subvariant. A particular combination of EBNA2, LMP1, and EBNA1 polymorphisms, type 1/Med/P-thr was

  8. Lineage Selection and the Maintenance of Sex

    PubMed Central

    de Vienne, Damien M.; Giraud, Tatiana; Gouyon, Pierre-Henri

    2013-01-01

    Sex predominates in eukaryotes, despite its short-term disadvantage when compared to asexuality. Myriad models have suggested that short-term advantages of sex may be sufficient to counterbalance its twofold costs. However, despite decades of experimental work seeking such evidence, no evolutionary mechanism has yet achieved broad recognition as explanation for the maintenance of sex. We explore here, through lineage-selection models, the conditions favouring the maintenance of sex. In the first model, we allowed the rate of transition to asexuality to evolve, to determine whether lineage selection favoured species with the strongest constraints preventing the loss of sex. In the second model, we simulated more explicitly the mechanisms underlying the higher extinction rates of asexual lineages than of their sexual counterparts. We linked extinction rates to the ecological and/or genetic features of lineages, thereby providing a formalisation of the only figure included in Darwin's “The origin of species”. Our results reinforce the view that the long-term advantages of sex and lineage selection may provide the most satisfactory explanations for the maintenance of sex in eukaryotes, which is still poorly recognized, and provide figures and a simulation website for training and educational purposes. Short-term benefits may play a role, but it is also essential to take into account the selection of lineages for a thorough understanding of the maintenance of sex. PMID:23825582

  9. Context-dependent regulation of hematopoietic lineage choice by HEBAlt.

    PubMed

    Wang, Duncheng; Claus, Carol L; Rajkumar, Paula; Braunstein, Marsela; Moore, Amanda J; Sigvardsson, Mikael; Anderson, Michele K

    2010-10-01

    Hematopoietic development is controlled by combinatorial interactions between E-protein transcription factors and other lineage regulators that operate in the context of gene-regulatory networks. The E-proteins HEB and E2A are critical for T cell and B cell development, but the mechanisms by which their activities are directed to different genes in each lineage are unclear. We found that a short form of HEB, HEBAlt, acts downstream of Delta-like (DL)-Notch signaling to promote T cell development. In this paper, we show that forced expression of HEBAlt in mouse hematopoietic progenitors inhibited B cell development, but it allowed them to adopt a myeloid fate. HEBAlt interfered with the activity of E2A homodimers and with the expression of the transcription factor Pax5, both of which are critical for B cell development. However, when combined with DL-Notch signaling, HEBAlt enhanced the generation of T cell progenitors at the expense of myeloid cells. The longer form of HEB, HEBCan, also inhibited E47 activity and Pax5 expression, but it did not collaborate with DL-Notch signaling to suppress myeloid potential. Therefore, HEBAlt can suppress B cell or myeloid potential in a context-specific manner, which suggests a role for this factor in maintaining T lineage priming prior to commitment. PMID:20826759

  10. Creativity: Potential and Progress.

    ERIC Educational Resources Information Center

    Sisk, Dorothy A.

    This paper explores definitions of creativity, theories and models of creativity, and the classic stages of creativity. Creativity is best defined in terms of an interactive process. The creative process in adults often results in creative and useful products, and such creativity is judged in terms of their quantity and quality of patents,…

  11. Influenza B vaccine lineage selection—An optimized trivalent vaccine

    PubMed Central

    Mosterín Höpping, Ana; Fonville, Judith M.; Russell, Colin A.; James, Sarah; Smith, Derek J.

    2016-01-01

    Epidemics of seasonal influenza viruses cause considerable morbidity and mortality each year. Various types and subtypes of influenza circulate in humans and evolve continuously such that individuals at risk of serious complications need to be vaccinated annually to keep protection up to date with circulating viruses. The influenza vaccine in most parts of the world is a trivalent vaccine, including an antigenically representative virus of recently circulating influenza A/H3N2, A/H1N1, and influenza B viruses. However, since the 1970s influenza B has split into two antigenically distinct lineages, only one of which is represented in the annual trivalent vaccine at any time. We describe a lineage selection strategy that optimizes protection against influenza B using the standard trivalent vaccine as a potentially cost effective alternative to quadrivalent vaccines. PMID:26896685

  12. Lineage associated expression of virulence traits in bovine-adapted Staphylococcus aureus.

    PubMed

    Budd, Kathleen E; Mitchell, Jennifer; Keane, Orla M

    2016-06-30

    Bovine mastitis is the most costly disease to the dairy industry worldwide with Staphylococcus aureus commonly associated with intramammary infections that are persistent and refractory to treatment. The strains of S. aureus that cause mastitis predominantly belong to a number of well-described bovine-adapted lineages. The objective of this study was to determine if a variety of potential virulence traits were associated with lineage. Bovine-adapted S. aureus isolates (n=120), belonging to lineages CC97, CC151 and ST136, were tested for their ability to adhere to and internalise within cultured bovine mammary epithelial cells (bMEC), to bind bovine fibronectin, to form a biofilm in TSB, TSB+1% glucose and TSB+4% NaCl, and to induce an immune response from bMEC. There were no significant differences between the lineages in ability to adhere to or internalise within bMEC although there were significant differences between individual isolates. For lineages CC97 and ST136, mammalian cell adherence was correlated with the ability to bind bovine fibronectin, however isolates from CC151 could not bind bovine fibronectin in vitro, but adhered to bMEC in a fibronectin-independent manner. There were significant differences between the lineages in ability to form a biofilm in all three growth media with ST136 forming the strongest biofilm while CC151 formed the weakest biofilm. Lineages also differed in their ability to elicit an immune response from bMEC with CC97 eliciting a stronger immune response than CC151 and ST136. These data indicate the potential for both lineage and strain-specific virulence and a strain-specific response to infection in vivo and caution against extrapolating an effect from a single strain of S. aureus to draw conclusions regarding virulence or the host response to infection in unrelated lineages. PMID:27259823

  13. Postembryonic lineages of the Drosophila brain: I. Development of the lineage-associated fiber tracts

    PubMed Central

    Lovick, Jennifer K.; Ngo, Kathy T.; Omoto, Jaison J.; Wong, Darren C.; Nguyen, Joseph D.; Hartenstein, Volker

    2013-01-01

    Neurons of the Drosophila central brain fall into approximately 100 paired groups, termed lineages. Each lineage is derived from a single asymmetrically-dividing neuroblast. Embryonic neuroblasts produce 1,500 primary neurons (per hemisphere) that make up the larval CNS followed by a second mitotic period in the larva that generates approximately 10,000 secondary, adult-specific neurons. Clonal analyses based on previous works using lineage-specific Gal4 drivers have established that such lineages form highly invariant morphological units. All neurons of a lineage project as one or a few axon tracts (secondary axon tracts, SATs) with characteristic trajectories, thereby representing unique hallmarks. In the neuropil, SATs assemble into larger fiber bundles (fascicles) which interconnect different neuropil compartments. We have analyzed the SATs and fascicles formed by lineages during larval, pupal, and adult stages using antibodies against membrane molecules (Neurotactin/Neuroglian) and synaptic proteins (Bruchpilot/N-Cadherin). The use of these markers allows one to identify fiber bundles of the adult brain and associate them with SATs and fascicles of the larval brain. This work lays the foundation for assigning the lineage identity of GFP-labeled MARCM clones on the basis of their close association with specific SATs and neuropil fascicles, as described in the accompanying paper (Wong et al., 2013. Postembryonic lineages of the Drosophila brain: II. Identification of lineage projection patterns based on MARCM clones. Submitted.). PMID:23880429

  14. Postembryonic lineages of the Drosophila brain: I. Development of the lineage-associated fiber tracts.

    PubMed

    Lovick, Jennifer K; Ngo, Kathy T; Omoto, Jaison J; Wong, Darren C; Nguyen, Joseph D; Hartenstein, Volker

    2013-12-15

    Neurons of the Drosophila central brain fall into approximately 100 paired groups, termed lineages. Each lineage is derived from a single asymmetrically-dividing neuroblast. Embryonic neuroblasts produce 1,500 primary neurons (per hemisphere) that make up the larval CNS followed by a second mitotic period in the larva that generates approximately 10,000 secondary, adult-specific neurons. Clonal analyses based on previous works using lineage-specific Gal4 drivers have established that such lineages form highly invariant morphological units. All neurons of a lineage project as one or a few axon tracts (secondary axon tracts, SATs) with characteristic trajectories, thereby representing unique hallmarks. In the neuropil, SATs assemble into larger fiber bundles (fascicles) which interconnect different neuropil compartments. We have analyzed the SATs and fascicles formed by lineages during larval, pupal, and adult stages using antibodies against membrane molecules (Neurotactin/Neuroglian) and synaptic proteins (Bruchpilot/N-Cadherin). The use of these markers allows one to identify fiber bundles of the adult brain and associate them with SATs and fascicles of the larval brain. This work lays the foundation for assigning the lineage identity of GFP-labeled MARCM clones on the basis of their close association with specific SATs and neuropil fascicles, as described in the accompanying paper (Wong et al., 2013. Postembryonic lineages of the Drosophila brain: II. Identification of lineage projection patterns based on MARCM clones. Submitted.). PMID:23880429

  15. Stat3 inhibition in neural lineage cells.

    PubMed

    Chiba, Tomohiro; Mack, Laura; Delis, Natalia; Brill, Boris; Groner, Bernd

    2012-06-01

    Abstract Deregulation of signal transducer and activator of transcription 3 (Stat3) is attracting attentions in neurological disorders of elderly populations, e.g., Stat3 is inactivated in hippocampal neurons of Alzheimer's disease (AD) brains, whereas it is often constitutively activated in glioblastoma multiforme (GBM), correlating with poor prognosis. Stat3-inhibiting drugs have been intensively developed for chemotherapy based on the fact that GBM, in many cases, are "addicted" to Stat3 activation. Stat3 inhibitors, however, potentially have unfavorable side effects on postmitotic neurons, normal permanent residents in the central nervous system. It is, therefore, of great importance to address detailed cellular responses of neural lineage cells including normal neurons, astrocytes, and neuronal/glial cancer cell lines to several classes of Stat3 inhibitors focusing on their effective concentrations. Here, we picked up five human and mouse cancer cell lines (Neuro-2a and SH-SY5Y neuroblastoma cell lines and Tu-9648, U-87MG, and U-373MG glioblastoma cell lines) and treated with various Stat3 inhibitors. Among them, Stattic, FLLL31, and resveratrol potently suppressed P-Stat3 and cell viability in all the tested cell lines. Stat3 knockdown or expression of dominant-negative Stat3 further sensitized cells to the inhibitors. Expression of familial AD-related mutant amyloid precursor protein sensitized neuronal cells, not glial cells, to Stat3 inhibitors by reducing P-Stat3 levels. Primary neurons and astrocytes also responded to Stat3 inhibitors with similar sensitivities to those observed in cancer cell lines. Thus, Stat3 inhibitors should be carefully targeted to GBM cells to avoid potential neurotoxicity leading to AD-like neuropsychiatric dysfunctions. PMID:25436682

  16. The Three Lineages of the Diploid Hybrid Verticillium longisporum Differ in Virulence and Pathogenicity.

    PubMed

    Novakazi, Fluturë; Inderbitzin, Patrik; Sandoya, German; Hayes, Ryan J; von Tiedemann, Andreas; Subbarao, Krishna V

    2015-05-01

    Verticillium longisporum is an economically important vascular pathogen of Brassicaceae crops in different parts of the world. V. longisporum is a diploid hybrid that consists of three different lineages, each of which originated from a separate hybridization event between two different sets of parental species. We used 20 isolates representing the three V. longisporum lineages and the relative V. dahliae, and performed pathogenicity tests on 11 different hosts, including artichoke, cabbage, cauliflower, cotton, eggplant, horseradish, lettuce, linseed, oilseed rape (canola), tomato, and watermelon. V. longisporum was overall more virulent on the Brassicaceae crops than V. dahliae, which was more virulent than V. longisporum across the non-Brassicaceae crops. There were differences in virulence between the three V. longisporum lineages. V. longisporum lineage A1/D1 was the most virulent lineage on oilseed rape, and V. longisporum lineage A1/D2 was the most virulent lineage on cabbage and horseradish. We also found that on the non-Brassicaceae hosts eggplant, tomato, lettuce, and watermelon, V. longisporum was more or equally virulent than V. dahliae. This suggests that V. longisporum may have a wider potential host range than currently appreciated. PMID:25585057

  17. Evidence of two distinct phylogenetic lineages of dog rabies virus circulating in Cambodia.

    PubMed

    Mey, Channa; Metlin, Artem; Duong, Veasna; Ong, Sivuth; In, Sotheary; Horwood, Paul F; Reynes, Jean-Marc; Bourhy, Hervé; Tarantola, Arnaud; Buchy, Philippe

    2016-03-01

    This first extensive retrospective study of the molecular epidemiology of dog rabies in Cambodia included 149 rabies virus (RABV) entire nucleoprotein sequences obtained from 1998-2011. The sequences were analyzed in conjunction with RABVs from other Asian countries. Phylogenetic reconstruction confirmed the South-East Asian phylogenetic clade comprising viruses from Cambodia, Vietnam, Thailand, Laos and Myanmar. The present study represents the first attempt to classify the phylogenetic lineages inside this clade, resulting in the confirmation that all the Cambodian viruses belonged to the South-East Asian (SEA) clade. Three distinct phylogenetic lineages in the region were established with the majority of viruses from Cambodia closely related to viruses from Thailand, Laos and Vietnam, forming the geographically widespread phylogenetic lineage SEA1. A South-East Asian lineage SEA2 comprised two viruses from Cambodia was identified, which shared a common ancestor with RABVs originating from Laos. Viruses from Myanmar formed separate phylogenetic lineages within the major SEA clade. Bayesian molecular clock analysis suggested that the time to most recent common ancestor (TMRCA) of all Cambodian RABVs dated to around 1950. The TMRCA of the Cambodian SEA1 lineage was around 1964 and that of the SEA2 lineage was around 1953. The results identified three phylogenetically distinct and geographically separated lineages inside the earlier identified major SEA clade, covering at least five countries in the region. A greater understanding of the molecular epidemiology of rabies in South-East Asia is an important step to monitor progress on the efforts to control canine rabies in the region. PMID:26705238

  18. Physiological ecology and functional traits of North American native and Eurasian introduced Phragmites australis lineages

    PubMed Central

    Mozdzer, Thomas J.; Brisson, Jacques; Hazelton, Eric L. G.

    2013-01-01

    Physiological ecology and plant functional traits are often used to explain plant invasion. To gain a better understanding of how traits influence invasion, studies usually compare the invasive plant to a native congener, but there are few conspecific examples in the literature. In North America, the presence of native and introduced genetic lineages of the common reed, Phragmites australis, presents a unique example to evaluate how traits influence plant invasion. We reviewed the literature on functional traits of P. australis lineages in North America, specifically contrasting lineages present on the Atlantic Coast. We focused on differences in physiology between the lineage introduced from Eurasia and the lineage native to North America, specifically seeking to identify the causes underlying the recent expansion of the introduced lineage. Our goals were to better understand which traits may confer invasiveness, provide predictions of how these lineages may respond to interspecific competition or imminent global change, and provide guidance for future research. We reviewed published studies and articles in press, and conducted personal communications with appropriate researchers and managers to develop a comparative dataset. We compared the native and introduced lineages and focused on plant physiological ecology and functional traits. Under both stressful and favourable conditions, our review showed that introduced P. australis consistently exhibited greater ramet density, height and biomass, higher and more plastic relative growth rate, nitrogen productivity and specific leaf area, higher mass specific nitrogen uptake rates, as well as greater phenotypic plasticity compared with the native lineage. We suggest that ecophysiological and other plant functional traits elucidate potential mechanisms for the introduced lineage's invasiveness under current and predicted global change conditions. However, our review identified a disconnect between field surveys

  19. Regional assessments of the hydrocarbon generation potential of selected North American proterozoic rock sequences. Progress report, September 1989--April 1990

    SciTech Connect

    Engel, M.H.; Elmore, R.D.

    1990-04-01

    Our primary research objectives for the first year of this grant are nearing completion. This includes comprehensive sedimentologic/organic geochemical studies of two depositionally distinct, unmetamorphosed units, the Nonesuch Formation ({approximately}1.1 Ga lacustrine rift deposit) and the Dripping Spring Quartzite ({approximately}1.3 Ga marine shelf deposit). As discussed in this progress report, an attempt has been made to (1) identify source rocks by quantification and characterization of constituent organic matter, (2) recognize depositional/diagenetic/catagenetic factors that may have influenced source rock quality and (3) evaluate the possibility of previous or current hydrocarbon generation and migration. Organic petrology and geochemical analyses suggest important differences between kerogens in the Michigan (MI) and Wisconsin (WI) Nonesuch Formation study areas. When considered within a geographic/stratigraphic framework, the Nonesuch Formation in the MI study area exhibits superior source rock potential. It is suggested that sedimentary organic matter in the WI area was subject to more extensive microbial alteration during early diagenesis. It is also possible that thermal maturity levels were slightly to moderately higher in WI than MI. Petrologic evidence for migrated bitumens and the stable isotope composition of late vein carbonates suggest, furthermore, that oil generation and migration may have actually been more extensive in the WI study area.

  20. Microvesicles as a potential biomarker of neoplastic diseases and their role in development and progression of neoplasm

    PubMed Central

    Kajdos, Magdalena; Janas, Łukasz; Kolasa-Zwierzchowska, Dorota; Wilczyński, Jacek R.

    2015-01-01

    Neoplastic diseases together with cardiovascular diseases are the most frequent causes of death in the Polish population. Cancers of reproductive organs with breast cancer are responsible for the highest morbidity and mortality in women suffering from neoplasm diseases. Asymptomatic dynamics of the development of a neoplasm and no deviations from the normal level of laboratory results contribute to the fact that malignant diseases are diagnosed too late. The aim of modern medicine is to diagnose cancer at the earliest stage, however, there is no sufficiently sensitive and specific biomarker which can be used for diagnostic, prognostic and therapeutic purposes. Cellular interactions play the main role in the development, angiogenesis and invasiveness of a tumor. Recent research suggests the possibility of microvesicles (MVs) involvement in communication between cells. The MVs ability to fuse with various cells is used in cell-to-cell contact. Microvesicles cargo may include growth factors, their receptors, protease, adhesion molecules, signaling molecules and the sequence of DNA, mRNA, and micro-RNA. Larger quantities of MVs released from neoplastic cells affect both the local environment and systematic range causing metastases and progression. The research on molecular mechanisms of MVs’ release and the presence of characteristic oncogenes in blood of patients with neoplasms is being carried out. Confirmation of MVs presence in patients’ serum can potentially serve as useful information for therapeutic purposes and as the biomarker of a neoplastic disease. PMID:26848301

  1. microRNAs with different functions and roles in disease development and as potential biomarkers of diabetes: progress and challenges.

    PubMed

    Seyhan, Attila A

    2015-05-01

    Biomarkers provide information on early detection of diseases, in determining individuals at risk of developing complications or subtyping individuals for disease phenotypes. In addition, biomarkers may lead to better treatment strategies, personalized therapy, and improved outcome. A major gap in the field of biomarker development is that we have not identified appropriate (minimally invasive, life-style independent and informative) biomarkers for the underlying disease process(es) that can be measured in readily accessible samples (e.g. serum, plasma, blood, urine). miRNAs function as regulators in wide ranging cellular and physiological functions and also participate in many physiopathological processes and thus have been linked to many diseases including diabetes, metabolic and cardiovascular diseases, cancer, neurodegenerative diseases, and autoimmunity. Many miRNAs have been shown to have predictive value as potential biomarkers in a variety of diseases including diabetes, which are detectable in some instances many years before the manifestation of disease. Although some technical challenges still remain, due to their availability in the circulation, relative stability, and ease of detection; miRNAs have emerged as a promising new class of biomarkers to provide information on early detection of disease, monitoring disease progression, in determining individual's risk of developing complications or subtyping individuals for disease phenotypes, and to monitor response to therapeutic interventions. As a final note, most of the miRNAs reported in the literature have not yet been validated in sufficiently powered and longitudinal studies for specificity for that particular disease. PMID:25765998

  2. [Research Progress in Technology of Using Soil Micro-organisms to Generate Electricity and Its Potential Applications].

    PubMed

    Deng, Huan; Xue, Hong-jing; Jiang, Yun-bin; Zhong, Wen-hui

    2015-10-01

    Microbial fuel cells ( microbial fuel cells, MFCs) are devices in which micro-organisms convert chemical energy into electrical power. Soil has electrogenic bacteria and organic substrates, thus can generate electrical current in MFCs. Soil MFCs can be operated and applied to real-time and continuously monitor soil pollution, remove soil pollutants and to reduce methane emitted from flooded rice paddy, without energy consumption and the application of chemical reagents to the soil. Instead, the operation of soil MFCs generates small amount of electrical power. Therefore, soil MFCs are useful in the development of environment-friendly technology for monitoring and remediating soil pollution, which have potential value for applications in the domain of environmental science and engineering. However, much of advanced technology hasn't been applied into soil MFCs since the studies on soil MFCs was not started until recently. This paper summarized the research progress in related to soil MFCs combining with the frontier of MFCs technology, and brought forward the possible direction in studies on soil MFCs. PMID:26841633

  3. Inferring Gene Family Histories in Yeast Identifies Lineage Specific Expansions

    PubMed Central

    Ames, Ryan M.; Money, Daniel; Lovell, Simon C.

    2014-01-01

    The complement of genes found in the genome is a balance between gene gain and gene loss. Knowledge of the specific genes that are gained and lost over evolutionary time allows an understanding of the evolution of biological functions. Here we use new evolutionary models to infer gene family histories across complete yeast genomes; these models allow us to estimate the relative genome-wide rates of gene birth, death, innovation and extinction (loss of an entire family) for the first time. We show that the rates of gene family evolution vary both between gene families and between species. We are also able to identify those families that have experienced rapid lineage specific expansion/contraction and show that these families are enriched for specific functions. Moreover, we find that families with specific functions are repeatedly expanded in multiple species, suggesting the presence of common adaptations and that these family expansions/contractions are not random. Additionally, we identify potential specialisations, unique to specific species, in the functions of lineage specific expanded families. These results suggest that an important mechanism in the evolution of genome content is the presence of lineage-specific gene family changes. PMID:24921666

  4. Cartilage on the Move: Cartilage Lineage Tracing During Tadpole Metamorphosis

    PubMed Central

    Kerney, Ryan R.; Brittain, Alison L.; Hall, Brian K.; Buchholz, Daniel R.

    2012-01-01

    The reorganization of cranial cartilages during tadpole metamorphosis is a set of complex processes. The fates of larval cartilage-forming cells (chondrocytes) and sources of adult chondrocytes are largely unknown. Individual larval cranial cartilages may either degenerate or remodel, while many adult cartilages appear to form de novo during metamorphosis. Determining the extent to which adult chondrocytes/cartilages are derived from larval chondrocytes during metamorphosis requires new techniques in chondrocyte lineage tracing. We have developed two transgenic systems to label cartilage cells throughout the body with fluorescent proteins. One system strongly labels early tadpole cartilages only. The other system inducibly labels forming cartilages at any developmental stage. We examined cartilages of the skull (viscero- and neurocranium), and identified larval cartilages that either resorb or remodel into adult cartilages. Our data show that the adult otic capsules, tecti anterius and posterius, hyale, and portions of Meckel’s cartilage are derived from larval chondrocytes. Our data also suggest that most adult cartilages form de novo, though we cannot rule out the potential for extreme larval chondrocyte proliferation or de- and re-differentiation, which could dilute our fluorescent protein signal. The transgenic lineage tracing strategies developed here are the first examples of inducible, skeleton-specific, lineage tracing in Xenopus. PMID:23036161

  5. Mitochondrial DNA polymorphism in a maternal lineage of Holstein cows.

    PubMed Central

    Hauswirth, W W; Laipis, P J

    1982-01-01

    Two mitochondrial genotypes are shown to exist within one Holstein cow maternal lineage. They were detected by the appearance of an extra Hae III recognition site in one genotype. The nucleotide sequence of this region has been determined and the genotypes are distinguished by an adenine/guanine base transition which creates the new Hae III site. This point mutation occurs within an open reading frame at the third position of a glycine codon and therefore does not alter the amino acid sequence. The present pattern of genotypes within the lineage demands that multiple shifts between genotypes must have occurred within the past 20 years with the most rapid shift taking place in no more than 4 years and indicates that mitochondrial DNA polymorphism can occur between maternally related mammals. The process that gave rise to different genotypes in one lineage is clearly of fundamental importance in understanding intraspecific mitochondrial polymorphism and evolution in mammals. Several potential mechanisms for rapid mitochondrial DNA variation are discussed in light of these results. Images PMID:6289312

  6. Quantifying Selective Pressures Driving Bacterial Evolution Using Lineage Analysis

    NASA Astrophysics Data System (ADS)

    Lambert, Guillaume; Kussell, Edo

    2015-01-01

    Organisms use a variety of strategies to adapt to their environments and maximize long-term growth potential, but quantitative characterization of the benefits conferred by the use of such strategies, as well as their impact on the whole population's rate of growth, remains challenging. Here, we use a path-integral framework that describes how selection acts on lineages—i.e., the life histories of individuals and their ancestors—to demonstrate that lineage-based measurements can be used to quantify the selective pressures acting on a population. We apply this analysis to Escherichia coli bacteria exposed to cyclical treatments of carbenicillin, an antibiotic that interferes with cell-wall synthesis and affects cells in an age-dependent manner. While the extensive characterization of the life history of thousands of cells is necessary to accurately extract the age-dependent selective pressures caused by carbenicillin, the same measurement can be recapitulated using lineage-based statistics of a single surviving cell. Population-wide evolutionary pressures can be extracted from the properties of the surviving lineages within a population, providing an alternative and efficient procedure to quantify the evolutionary forces acting on a population. Importantly, this approach is not limited to age-dependent selection, and the framework can be generalized to detect signatures of other trait-specific selection using lineage-based measurements. Our results establish a powerful way to study the evolutionary dynamics of life under selection and may be broadly useful in elucidating selective pressures driving the emergence of antibiotic resistance and the evolution of survival strategies in biological systems.

  7. Adaptable individuals and innovative lineages.

    PubMed

    Sterelny, Kim

    2016-03-19

    This paper suggests (i) that while work on animal innovation has made good progress in understanding some of the proximate mechanisms and selective regimes through which innovation emerges, it has somewhat neglected the role of the social environment of innovation; a neglect manifest in the fact that innovation counts are almost always counts of resource-acquisition innovations; the invention of social tools is rarely considered. The same is true of many experimental projects, as these typically impose food acquisition tasks on their experimental subjects. (ii) That neglect is important, because innovations often pose collective action problems; the hominin species were technically innovative because they were also socially adaptable. (iii) In part for this reason, there remains a disconnect between research on hominin innovation and research on animal innovation. (iv) Finally, the paper suggests that there is something of a disconnect between the theoretical work on innovation in hominin evolution (based on theories of cultural evolution) and the experimental tradition on human innovation. That disconnect is largely due to the theoretical work retreating from strong claims about the proximate mechanisms of human cultural accumulation. PMID:26926286

  8. Phylogenetic and molecular analyses of human parainfluenza type 3 virus in Buenos Aires, Argentina, between 2009 and 2013: The emergence of new genetic lineages.

    PubMed

    Goya, Stephanie; Mistchenko, Alicia Susana; Viegas, Mariana

    2016-04-01

    Despite that human parainfluenza type 3 viruses (HPIV3) are one of the leading causes of acute lower respiratory tract infections in children under five, there is no licensed vaccine and there is limited current information on the molecular characteristics of regional and global circulating strains. The aim of this study was to describe the molecular characterization of HPIV3 circulating in Buenos Aires. We performed a genetic and phylogenetic analysis of the HN glycoprotein gene. Between 2009 and 2013, 124 HPIV3-positive samples taken from hospitalized pediatric patients were analyzed. Four new genetic lineages were described. Among them, C1c and C3d lineages showed local circulation patterns, whereas C3e and C3f comprised sequences from very distant countries. Despite the diversity of the described genotypes, C3a and C3d predominated over the others, the latter was present during the first years of the study and it was progressively replaced by C3a. Molecular analyses showed 28 non-synonymous substitutions; of these, 13 were located in potentially predicted B-cell epitopes. Taken together, the emergence of genetic lineages and the information of the molecular characteristics of HN protein may contribute to the general knowledge of HPIV3 molecular epidemiology for future vaccine development and antiviral therapies. PMID:26780643

  9. Differentiation and transdifferentiation potentials of cancer stem cells

    PubMed Central

    Liu, Allan Yi; Ouyang, Gaoliang

    2015-01-01

    Tumor cells actively contribute to constructing their own microenvironment during tumorigenesis and tumor progression. The tumor microenvironment contains multiple types of stromal cells that work together with the extracellular matrix and local and systemic factors to coordinately contribute to tumor initiation and progression. Tumor cells and their stromal compartments acquire many genetic and/or epigenetic alternations to facilitate tumor growth and metastasis. The cancer stem cell (CSC) concept has been widely applied to interpreting tumor initiation, growth, metastasis, dormancy and relapse. CSCs have differentiation abilities to generate the original lineage cells that are similar to their normal stem cell counterparts. Interestingly, recent evidence demonstrates that CSCs also have the potential to transdifferentiate into vascular endothelial cells and pericytes, indicating that CSCs can transdifferentiate into other lineage cells for promoting tumor growth and metastasis in some tissue contexts instead of only recruiting stromal cells from local or distant tissues. Although the transdifferentiation of CSCs into tumor stromal cells provides a new dimension that explains tumor heterogeneity, many aspects of CSC transdifferentiation remain elusive. In this review, we summarize the multi-lineage differentiation and transdifferentiation potentials of CSCs as well as discuss their potential contributions to tumor heterogeneity and tumor microenvironment in tumor progression. PMID:26474460

  10. Postembryonic lineages of the Drosophila brain: II. Identification of lineage projection patterns based on MARCM clones

    PubMed Central

    Wong, Darren C.; Lovick, Jennifer K.; Ngo, Kathy T.; Borisuthirattana, Wichanee; Omoto, Jaison J.; Hartenstein, Volker

    2014-01-01

    The Drosophila central brain is largely composed of lineages, units of sibling neurons derived from a single progenitor cell or neuroblast. During the early embryonic period neuroblast generate the primary neurons that constitute the larval brain. Neuroblasts reactivate in the larva, adding to their lineages a large number of secondary neurons which, according to previous studies in which selected lineages were labeled by stably expressed markers, differentiate during metamorphosis, sending terminal axonal and dendritic branches into defined volumes of the brain neuropil. We call the overall projection pattern of neurons forming a given lineage the “projection envelope” of that lineage. By inducing MARCM clones at the early larval stage, we labeled the secondary progeny of each neuroblast. For the supraesophageal ganglion excluding mushroom body (the part of the brain investigated in the present work) we obtained 81 different types of clones, Based on the trajectory of their secondary axon tracts (described in the accompanying paper), we assigned these clones to specific lineages defined in the larva. Since a labeled clone reveals all aspects (cell bodies, axon tracts, terminal arborization) of a lineage, we were able to describe projection envelopes for all secondary lineages of the supraesophageal ganglion. This work provides a framework by which the secondary neurons (forming the vast majority of adult brain neurons) can be assigned to genetically and developmentally defined groups. It also represents a step towards the goal to establish, for each lineage, the link between its mature anatomical and functional phenotype, and the genetic make-up of the neuroblast it descends from. PMID:23872236

  11. Postembryonic lineages of the Drosophila brain: II. Identification of lineage projection patterns based on MARCM clones.

    PubMed

    Wong, Darren C; Lovick, Jennifer K; Ngo, Kathy T; Borisuthirattana, Wichanee; Omoto, Jaison J; Hartenstein, Volker

    2013-12-15

    The Drosophila central brain is largely composed of lineages, units of sibling neurons derived from a single progenitor cell or neuroblast. During the early embryonic period, neuroblasts generate the primary neurons that constitute the larval brain. Neuroblasts reactivate in the larva, adding to their lineages a large number of secondary neurons which, according to previous studies in which selected lineages were labeled by stably expressed markers, differentiate during metamorphosis, sending terminal axonal and dendritic branches into defined volumes of the brain neuropil. We call the overall projection pattern of neurons forming a given lineage the "projection envelope" of that lineage. By inducing MARCM clones at the early larval stage, we labeled the secondary progeny of each neuroblast. For the supraesophageal ganglion excluding mushroom body (the part of the brain investigated in the present work) we obtained 81 different types of clones. Based on the trajectory of their secondary axon tracts (described in the accompanying paper, Lovick et al., 2013), we assigned these clones to specific lineages defined in the larva. Since a labeled clone reveals all aspects (cell bodies, axon tracts, terminal arborization) of a lineage, we were able to describe projection envelopes for all secondary lineages of the supraesophageal ganglion. This work provides a framework by which the secondary neurons (forming the vast majority of adult brain neurons) can be assigned to genetically and developmentally defined groups. It also represents a step towards the goal to establish, for each lineage, the link between its mature anatomical and functional phenotype, and the genetic make-up of the neuroblast it descends from. PMID:23872236

  12. Diversity rankings among bacterial lineages in soil.

    PubMed

    Youssef, Noha H; Elshahed, Mostafa S

    2009-03-01

    We used rarefaction curve analysis and diversity ordering-based approaches to rank the 11 most frequently encountered bacterial lineages in soil according to diversity in 5 previously reported 16S rRNA gene clone libraries derived from agricultural, undisturbed tall grass prairie and forest soils (n=26,140, 28 328, 31 818, 13 001 and 53 533). The Planctomycetes, Firmicutes and the delta-Proteobacteria were consistently ranked among the most diverse lineages in all data sets, whereas the Verrucomicrobia, Gemmatimonadetes and beta-Proteobacteria were consistently ranked among the least diverse. On the other hand, the rankings of alpha-Proteobacteria, Acidobacteria, Actinobacteria, Bacteroidetes and Chloroflexi varied widely in different soil clone libraries. In general, lineages exhibiting largest differences in diversity rankings also exhibited the largest difference in relative abundance in the data sets examined. Within these lineages, a positive correlation between relative abundance and diversity was observed within the Acidobacteria, Actinobacteria and Chloroflexi, and a negative diversity-abundance correlation was observed within the Bacteroidetes. The ecological and evolutionary implications of these results are discussed. PMID:18987677

  13. Towards One Generic Name for Monophyletic Lineages

    Technology Transfer Automated Retrieval System (TEKTRAN)

    With the integration of asexually reproducing fungi into meaningful phylogenies, the need to use the same generic name for a monophyletic lineage has become urgent. At present Article 59 of the International Code of Botanical Nomenclature (ICBN) requires the use of a sexual state name for sexually r...

  14. A microfluidic platform enabling single-cell RNA-seq of multigenerational lineages

    PubMed Central

    Kimmerling, Robert J.; Lee Szeto, Gregory; Li, Jennifer W.; Genshaft, Alex S.; Kazer, Samuel W.; Payer, Kristofor R.; de Riba Borrajo, Jacob; Blainey, Paul C.; Irvine, Darrell J.; Shalek, Alex K.; Manalis, Scott R.

    2016-01-01

    We introduce a microfluidic platform that enables off-chip single-cell RNA-seq after multi-generational lineage tracking under controlled culture conditions. We use this platform to generate whole-transcriptome profiles of primary, activated murine CD8+ T-cell and lymphocytic leukemia cell line lineages. Here we report that both cell types have greater intra- than inter-lineage transcriptional similarity. For CD8+ T-cells, genes with functional annotation relating to lymphocyte differentiation and function—including Granzyme B—are enriched among the genes that demonstrate greater intra-lineage expression level similarity. Analysis of gene expression covariance with matched measurements of time since division reveals cell type-specific transcriptional signatures that correspond with cell cycle progression. We believe that the ability to directly measure the effects of lineage and cell cycle-dependent transcriptional profiles of single cells will be broadly useful to fields where heterogeneous populations of cells display distinct clonal trajectories, including immunology, cancer, and developmental biology. PMID:26732280

  15. SWI/SNF-Mediated Lineage Determination in Mesenchymal Stem Cells Confers Resistance to Osteoporosis.

    PubMed

    Nguyen, Kevin Hong; Xu, Fuhua; Flowers, Stephen; Williams, Edek A J; Fritton, J Christopher; Moran, Elizabeth

    2015-10-01

    Redirecting the adipogenic potential of bone marrow-derived mesenchymal stem cells to other lineages, particularly osteoblasts, is a key goal in regenerative medicine. Controlling lineage selection through chromatin remodeling complexes such as SWI/SNF, which act coordinately to establish new patterns of gene expression, would be a desirable intervention point, but the requirement for the complex in essentially every lineage pathway has generally precluded selectivity. However, a novel approach now appears possible by targeting the subset of SWI/SNF powered by the alternative ATPase, mammalian brahma (BRM). BRM is not required for development, which has hindered understanding of its contributions, but knockdown genetics here, designed to explore the hypothesis that BRM-SWI/SNF has different regulatory roles in different mesenchymal stem cell lineages, shows that depleting BRM from mesenchymal stem cells has a dramatic effect on the balance of lineage selection between osteoblasts and adipocytes. BRM depletion enhances the proportion of cells expressing markers of osteoblast precursors at the expense of cells able to differentiate along the adipocyte lineage. This effect is evident in primary bone marrow stromal cells as well as in established cell culture models. The altered precursor balance has major physiological significance, which becomes apparent as protection against age-related osteoporosis and as reduced bone marrow adiposity in adult BRM-null mice. PMID:26059320

  16. Testing for intraspecific postzygotic isolation between cryptic lineages of Pseudacris crucifer

    PubMed Central

    Stewart, Kathryn A; Lougheed, Stephen C

    2013-01-01

    Phenotypically cryptic lineages appear common in nature, yet little is known about the mechanisms that initiate and/or maintain barriers to gene flow, or how secondary contact between them might influence evolutionary trajectories. The consequences of such contact between diverging lineages depend on hybrid fitness, highlighting the potential for postzygotic isolating barriers to play a role in the origins of biological species. Previous research shows that two cryptic, deeply diverged intraspecific mitochondrial lineages of a North American chorus frog, the spring peeper (Pseudacris crucifer), meet in secondary contact in Southwestern Ontario, Canada. Our study quantified hatching success, tadpole survival, size at metamorphosis, and development time for experimentally generated pure lineage and hybrid tadpoles. Results suggest that lineages differ in tadpole survival and that F1 hybrids may have equal fitness and higher than average mass at metamorphosis compared with pure parental crosses. These findings imply hybrid early life viability may not be the pivotal reproductive isolation barrier helping to maintain lineage boundaries. However, we observed instances of tadpole gigantism, failure to metamorphose, and bent tails in some tadpoles from hybrid families. We also speculate and provide some evidence that apparent advantages or similarities of hybrids compared with pure lineage tadpoles may disappear when tadpoles are raised with competitors of different genetic makeup. This pilot study implies that ecological context and consideration of extrinsic factors may be a key to revealing mechanisms causing negative hybrid fitness during early life stages, a provocative avenue for future investigations on barriers to gene flow among these intraspecific lineages. PMID:24363891

  17. Cardiac acceleration at the onset of exercise: a potential parameter for monitoring progress during physical training in sports and rehabilitation.

    PubMed

    Hettinga, Florentina J; Monden, Paul G; van Meeteren, Nico L U; Daanen, Hein A M

    2014-05-01

    There is a need for easy-to-use methods to assess training progress in sports and rehabilitation research. The present review investigated whether cardiac acceleration at the onset of physical exercise (HRonset) can be used as a monitoring variable. The digital databases of Scopus and PubMed were searched to retrieve studies investigating HRonset. In total 652 studies were retrieved. These articles were then classified as having emphasis on HRonset in a sports or rehabilitation setting, which resulted in 8 of 112 studies with a sports application and 6 of 68 studies with a rehabilitation application that met inclusion criteria. Two co-existing mechanisms underlie HRonset: feedforward (central command) and feedback (mechanoreflex, metaboreflex, baroreflex) control. A number of studies investigated HRonset during the first few seconds of exercise (HRonsetshort), in which central command and the mechanoreflex determine vagal withdrawal, the major mechanism by which heart rate (HR) increases. In subsequent sports and rehabilitation studies, interest focused on HRonset during dynamic exercise over a longer period of time (HRonsetlong). Central command, mechanoreflexes, baroreflexes, and possibly metaboreflexes contribute to HRonset during the first seconds and minutes of exercise, which in turn leads to further vagal withdrawal and an increase in sympathetic activity. HRonset has been described as the increase in HR compared with resting state (delta HR) or by exponential modeling, with measurement intervals ranging from 0-4 s up to 2 min. Delta HR was used to evaluate HRonsetshort over the first 4 s of exercise, as well as for analyzing HRonsetlong. In exponential modeling, the HR response to dynamic exercise is biphasic, consisting of fast (parasympathetic, 0-10 s) and slow (sympathetic, 1-4 min) components. Although available studies differed largely in measurement protocols, cross-sectional and longitudinal training studies showed that studies analyzing HRonset

  18. CRX Is a Diagnostic Marker of Retinal and Pineal Lineage Tumors

    PubMed Central

    Santagata, Sandro; Maire, Cecile L.; Idbaih, Ahmed; Geffers, Lars; Correll, Mick; Holton, Kristina; Quackenbush, John; Ligon, Keith L.

    2009-01-01

    Background CRX is a homeobox transcription factor whose expression and function is critical to maintain retinal and pineal lineage cells and their progenitors. To determine the biologic and diagnostic potential of CRX in human tumors of the retina and pineal, we examined its expression in multiple settings. Methodology/Principal Findings Using situ hybridization and immunohistochemistry we show that Crx RNA and protein expression are exquisitely lineage restricted to retinal and pineal cells during normal mouse and human development. Gene expression profiling analysis of a wide range of human cancers and cancer cell lines also supports that CRX RNA is highly lineage restricted in cancer. Immunohistochemical analysis of 22 retinoblastomas and 13 pineal parenchymal tumors demonstrated strong expression of CRX in over 95% of these tumors. Importantly, CRX was not detected in the majority of tumors considered in the differential diagnosis of pineal region tumors (n = 78). The notable exception was medulloblastoma, 40% of which exhibited CRX expression in a heterogeneous pattern readily distinguished from that seen in retino-pineal tumors. Conclusions/Significance These findings describe new potential roles for CRX in human cancers and highlight the general utility of lineage restricted transcription factors in cancer biology. They also identify CRX as a sensitive and specific clinical marker and a potential lineage dependent therapeutic target in retinoblastoma and pineoblastoma. PMID:19936203

  19. Acute Versus Progressive Onset of Diabetes in NOD Mice: Potential Implications for Therapeutic Interventions in Type 1 Diabetes.

    PubMed

    Mathews, Clayton E; Xue, Song; Posgai, Amanda; Lightfoot, Yaima L; Li, Xia; Lin, Andrea; Wasserfall, Clive; Haller, Michael J; Schatz, Desmond; Atkinson, Mark A

    2015-11-01

    Most natural history models for type 1 diabetes (T1D) propose that overt hyperglycemia results after a progressive loss of insulin-secreting β-cell mass and/or function. To experimentally address this concept, we prospectively determined morning blood glucose measurements every other day in multiple cohorts (total n = 660) of female NOD/ShiLtJ mice starting at 8 weeks of age until diabetes onset or 26 weeks of age. Consistent with this notion, a majority of mice that developed diabetes (354 of 489 [72%]) displayed a progressive increase in blood glucose with transient excursions >200 mg/dL, followed by acute and persistent hyperglycemia at diabetes onset. However, 135 of the 489 (28%) diabetic animals demonstrated normal glucose values followed by acute (i.e., sudden) hyperglycemia. Interestingly, diabetes onset occurred earlier in mice with acute versus progressive disease onset (15.37 ± 0.3207 vs. 17.44 ± 0.2073 weeks of age, P < 0.0001). Moreover, the pattern of onset (i.e., progressive vs. acute) dramatically influenced the ability to achieve reversal of T1D by immunotherapeutic intervention, with increased effectiveness observed in situations of a progressive deterioration in euglycemia. These studies highlight a novel natural history aspect in this animal model, one that may provide important guidance for the selection of subjects participating in human trials seeking disease reversal. PMID:26216853

  20. Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice.

    PubMed

    Adam, Rene C; Yang, Hanseul; Rockowitz, Shira; Larsen, Samantha B; Nikolova, Maria; Oristian, Daniel S; Polak, Lisa; Kadaja, Meelis; Asare, Amma; Zheng, Deyou; Fuchs, Elaine

    2015-05-21

    Adult stem cells occur in niches that balance self-renewal with lineage selection and progression during tissue homeostasis. Following injury, culture or transplantation, stem cells outside their niche often display fate flexibility. Here we show that super-enhancers underlie the identity, lineage commitment and plasticity of adult stem cells in vivo. Using hair follicle as a model, we map the global chromatin domains of hair follicle stem cells and their committed progenitors in their native microenvironments. We show that super-enhancers and their dense clusters ('epicentres') of transcription factor binding sites undergo remodelling upon lineage progression. New fate is acquired by decommissioning old and establishing new super-enhancers and/or epicentres, an auto-regulatory process that abates one master regulator subset while enhancing another. We further show that when outside their niche, either in vitro or in wound-repair, hair follicle stem cells dynamically remodel super-enhancers in response to changes in their microenvironment. Intriguingly, some key super-enhancers shift epicentres, enabling their genes to remain active and maintain a transitional state in an ever-changing transcriptional landscape. Finally, we identify SOX9 as a crucial chromatin rheostat of hair follicle stem cell super-enhancers, and provide functional evidence that super-enhancers are dynamic, dense transcription-factor-binding platforms which are acutely sensitive to pioneer master regulators whose levels define not only spatial and temporal features of lineage-status but also stemness, plasticity in transitional states and differentiation. PMID:25799994

  1. Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice

    PubMed Central

    Adam, Rene C.; Yang, Hanseul; Rockowitz, Shira; Larsen, Samantha B.; Nikolova, Maria; Oristian, Daniel S.; Polak, Lisa; Kadaja, Meelis; Asare, Amma; Zheng, Deyou; Fuchs, Elaine

    2015-01-01

    Adult stem cells (SCs) reside in niches which balance self-renewal with lineage selection and progression during tissue homeostasis. Following injury, culture or transplantation, SCs outside their niche often display fate flexibility1-4. Here we show that super-enhancers5 underlie the identity, lineage commitment and plasticity of adult SCs in vivo. Using hair follicle (HF) as model, we map the global chromatin domains of HFSCs and their committed progenitors in their native microenvironments. We show that super-enhancers and their dense clusters (‘epicenters’) of transcription factor (TF) binding sites change upon lineage progression. New fate is acquired by decommissioning old and establishing new super-enhancers and/or epicenters, an auto-regulatory process that abates one master regulator subset while enhancing another. We further show that when outside their niche, either in vitro or in wound-repair, HFSCs dynamically remodel super-enhancers in response to changes in their microenvironment. Intriguingly, some key super-enhancers shift epicenters, enabling them to remain active and maintain a transitional state in an ever-changing transcriptional landscape. Finally, we identify SOX9 as a crucial chromatin rheostat of HFSC super-enhancers, and provide functional evidence that super-enhancers are dynamic, dense TF-binding platforms which are acutely sensitive to pioneer master regulators whose levels define not only spatial and temporal features of lineage-status, but also stemness, plasticity in transitional states and differentiation. PMID:25799994

  2. Potential involvement of miR-375 in the premalignant progression of oral squamous cell carcinoma mediated via transcription factor KLF5

    PubMed Central

    Li, Siyuan; Shan, Xiaofeng; Liu, Xiaosong; Hua, Hong; Zhao, Chuanke; Feng, Zhendong; Cai, Zhigang; Zhang, Lihe; Zhou, Demin

    2015-01-01

    To elucidate the genetic effect involved in the premalignant progression of chronic inflammation to cancer, we performed microRNA and mRNA profiling in oral lichen planus (OLP), oral squamous cell carcinoma (OSCC), and normal tissue from the same patients. We demonstrate the involvement of a suppressive microRNA, miR-375, in the regulation of this premalignant progression via KLF5, a transcription factor that modulates the expression of genes contributing to proliferation and apoptosis. We found that miR-375 abundance decreased in tissues with progression from the normal state to OLP and subsequently to OSCC. Restoration of miR-375 by transduction of a synthetic mimic into OSCC cells repressed cellular proliferation and promoted apoptosis, with concomitant down-regulation of KLF5, and vice versa. The direct binding of miR-375 to the 3′-untranslated region of KLF5 was further confirmed. Additionally, Survivin (BIRC5), a target of KLF5, was also regulated by miR-375, explaining the susceptibility of miR-375-mimic transfected cells to apoptosis. Further analysis of clinical specimens suggested that expression of KLF5 and BIRC5 is up-regulated during the progression from inflammation to cancer. Our findings provide novel insights into the involvement of microRNAs in progression of inflammation to carcinoma and suggest a potential early-stage biomarker or therapy target for oral carcinoma. PMID:26474386

  3. Hypermethylation of the spleen tyrosine kinase promoter in T-lineage acute lymphoblastic leukemia.

    PubMed

    Goodman, Patricia A; Burkhardt, Nicole; Juran, Brian; Tibbles, Heather E; Uckun, Faith M

    2003-04-24

    Sequence analysis of the noncoding first exon (exon 1) of the Syk gene demonstrated the presence of a previously cloned CpG island (GenBank #Z 65706). Transient transfection analysis in Daudi cells demonstrated promoter activity (18-fold increase over parental luciferase plasmid) for a 348 bp BstXI-BsrBI fragment containing this island. This region exhibits a high GC content (approximately 75%), contains several SP1 binding sites and a potential initiator sequence, but lacks a strong TATA consensus. Bisulfite sequencing and methylation-specific PCR (MSP) of this region demonstrated that the Syk promoter CpG island was largely unmethylated in B-lineage leukemia cell lines, control peripheral blood cells, human thymocytes and CD3(+) T lymphocytes. However, dense methylation was seen in four T-lineage leukemia cell lines, Jurkat, H9, Molt 3 and HUT 78. MSP screening of leukemia cells from six T-lineage acute lymphoblastic leukemia (ALL) patients demonstrated methylation of the Syk promoter CpG island in one T-lineage ALL patient. Promoter methylation was correlated with reduced to absent expression of Syk mRNA and SYK protein in the T-lineage leukemia cell lines. Treatment of the leukemia lines Ha and Molt 3, with the methylation inhibitor, 5-aza-2'-deoxycytidine (5-aza-CdR) resulted in increased Syk mRNA expression. The presence of a methylated promoter sequence in these T-lineage leukemia cell lines and in one T-lineage patient suggests a potential role for SYK as a tumor suppressor in T-ALL. PMID:12717427

  4. Ancestral relationships of the major eukaryotic lineages.

    PubMed

    Sogin, M L; Morrison, H G; Hinkle, G; Silberman, J D

    1996-03-01

    Molecular systematics has revolutionized our understanding of microbial evolution. Phylogenetic frameworks relating all organisms in this biosphere can be inferred from comparisons of slowly evolving molecules such as the small and large subunit ribosomal RNAs. Unlike today's text book standard, the "Five Kingdoms" (plants, animals, fungi, protists and bacteria), molecular studies define three primary lines of descent (Eukaryotes, Eubacteria, and Archaebacteria). Within the Eukaryotes, the "higher" kingdoms (Fungi, Plantae, and Animalia) are joined by at least two novel complex evolutionary assemblages, the "Alveolates" (ciliates, dinoflagellates and apicomplexans) and the "Stramenopiles" (diatoms, oomycetes, labyrinthulids, brown algae and chrysophytes). The separation of these eukaryotic groups (described as the eukaryotic "crown") occurred approximately 10(9) years ago and was preceded by a succession of earlier diverging protist lineages, some as ancient as the separation of the prokaryotic domains. The molecular phylogenies suggest that multiple endosymbiotic events introduced plastids into discrete eukaryotic lineages. PMID:9019131

  5. Launching the T-Lineage Developmental Programme

    PubMed Central

    Rothenberg, Ellen V.; Moore, Jonathan E.; Yui, Mary A.

    2011-01-01

    Preface Multipotent blood progenitor cells enter the thymus and begin a protracted differentiation process in which they gradually acquire T-cell characteristics while shedding their legacy of developmental plasticity. Notch signalling and basic helix-loop-helix E-protein transcription factors collaborate repeatedly to trigger and sustain this process throughout the period leading up to T-cell lineage commitment. Nevertheless, the process is discontinuous with separately regulated steps that demand roles for additional collaborating factors. This review discusses new evidence on the coordination of specification and commitment in the early T-cell pathway; effects of microenvironmental signals; the inheritance of stem-cell regulatory factors; and the ensemble of transcription factors that modulate the effects of Notch and E proteins, to distinguish individual stages and to polarize T-lineage fate determination. PMID:18097446

  6. Lineages of varicella-zoster virus.

    PubMed

    McGeoch, Duncan J

    2009-04-01

    Relationships among varicella-zoster virus (VZV; Human herpesvirus 3) genome sequences were examined to evaluate descent of strains, structures of lineages and incidence of recombination events. Eighteen complete, published genome sequences were aligned and 494 single nucleotide polymorphisms (SNPs) extracted, each as two alleles. At 281 SNPs, a single sequence differed from all the others. Distributions of the remaining 213 SNPs indicated that the sequences fell into five groups, which coincided with previously recognized phylogenetic groupings, termed E1, E2, J, M1 and M2. The 213-SNP set was divisible into 104 SNPs that were specific to a single group, and 109 cross-group SNPs that defined relationships among groups. This last set was evaluated by criteria of continuities in relationships between groups and breaks in such patterns, to identify crossover points and ascribe them to lineages. For the 99 cross-group SNPs in the genome's long unique region, it was seen that the E2 and M2 groups were almost completely distinct in their SNP alleles, and the E1 group was derived from a recombinant of E2 and M2. A valid phylogenetic tree could thus be constructed for the four E2 and two M2 strains. There was no substantive evidence for recombination within the E2 group or the E1 group (ten strains). The J and M1 groups each contained only one strain, and both were interpreted as having substantial distinct histories plus possible recombinant elements from the E2 and M2 lineages. The view of VZV recombination and phylogeny reached represents a major clarification of deep relationships among VZV lineages. PMID:19264671

  7. Ecological opportunity and the adaptive diversification of lineages.

    PubMed

    Wellborn, Gary A; Langerhans, R Brian

    2015-01-01

    The tenet that ecological opportunity drives adaptive diversification has been central to theories of speciation since Darwin, yet no widely accepted definition or mechanistic framework for the concept currently exists. We propose a definition for ecological opportunity that provides an explicit mechanism for its action. In our formulation, ecological opportunity refers to environmental conditions that both permit the persistence of a lineage within a community, as well as generate divergent natural selection within that lineage. Thus, ecological opportunity arises from two fundamental elements: (1) niche availability, the ability of a population with a phenotype previously absent from a community to persist within that community and (2) niche discordance, the diversifying selection generated by the adaptive mismatch between a population's niche-related traits and the newly encountered ecological conditions. Evolutionary response to ecological opportunity is primarily governed by (1) spatiotemporal structure of ecological opportunity, which influences dynamics of selection and development of reproductive isolation and (2) diversification potential, the biological properties of a lineage that determine its capacity to diversify. Diversification under ecological opportunity proceeds as an increase in niche breadth, development of intraspecific ecotypes, speciation, and additional cycles of diversification that may themselves be triggered by speciation. Extensive ecological opportunity may exist in depauperate communities, but it is unclear whether ecological opportunity abates in species-rich communities. Because ecological opportunity should generally increase during times of rapid and multifarious environmental change, human activities may currently be generating elevated ecological opportunity - but so far little work has directly addressed this topic. Our framework highlights the need for greater synthesis of community ecology and evolutionary biology, unifying

  8. Ecological opportunity and the adaptive diversification of lineages

    PubMed Central

    Wellborn, Gary A; Langerhans, R Brian

    2015-01-01

    The tenet that ecological opportunity drives adaptive diversification has been central to theories of speciation since Darwin, yet no widely accepted definition or mechanistic framework for the concept currently exists. We propose a definition for ecological opportunity that provides an explicit mechanism for its action. In our formulation, ecological opportunity refers to environmental conditions that both permit the persistence of a lineage within a community, as well as generate divergent natural selection within that lineage. Thus, ecological opportunity arises from two fundamental elements: (1) niche availability, the ability of a population with a phenotype previously absent from a community to persist within that community and (2) niche discordance, the diversifying selection generated by the adaptive mismatch between a population's niche-related traits and the newly encountered ecological conditions. Evolutionary response to ecological opportunity is primarily governed by (1) spatiotemporal structure of ecological opportunity, which influences dynamics of selection and development of reproductive isolation and (2) diversification potential, the biological properties of a lineage that determine its capacity to diversify. Diversification under ecological opportunity proceeds as an increase in niche breadth, development of intraspecific ecotypes, speciation, and additional cycles of diversification that may themselves be triggered by speciation. Extensive ecological opportunity may exist in depauperate communities, but it is unclear whether ecological opportunity abates in species-rich communities. Because ecological opportunity should generally increase during times of rapid and multifarious environmental change, human activities may currently be generating elevated ecological opportunity – but so far little work has directly addressed this topic. Our framework highlights the need for greater synthesis of community ecology and evolutionary biology, unifying

  9. Genome sequesnce of lineage III Listeria monocytogenes strain HCC23

    Technology Transfer Automated Retrieval System (TEKTRAN)

    More than 98% of reported human listeriosis cases are caused by Listeria monocytogenes serotypes within lineages I and II. Serotypes within lineage III (4a and 4c) are commonly isolated from environmental and food specimens. We report the first complete genome sequence of a lineage III isolate, HCC2...

  10. Phylogenomics of the Zygomycete lineages: Exploring phylogeny and genome evolution

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The Zygomycete lineages mark the major transition from zoosporic life histories of the common ancestors of Fungi and the earliest diverging chytrid lineages (Chytridiomycota and Blastocladiomycota). Genome comparisons from these lineages may reveal gene content changes that reflect the transition to...

  11. Genetic Mosaics and the Germ Line Lineage

    PubMed Central

    Samuels, Mark E.; Friedman, Jan M.

    2015-01-01

    Genetic mosaics provide information about cellular lineages that is otherwise difficult to obtain, especially in humans. De novo mutations act as cell markers, allowing the tracing of developmental trajectories of all descendants of the cell in which the new mutation arises. De novo mutations may arise at any time during development but are relatively rare. They have usually been observed through medical ascertainment, when the mutation causes unusual clinical signs or symptoms. Mutational events can include aneuploidies, large chromosomal rearrangements, copy number variants, or point mutations. In this review we focus primarily on the analysis of point mutations and their utility in addressing questions of germ line versus somatic lineages. Genetic mosaics demonstrate that the germ line and soma diverge early in development, since there are many examples of combined somatic and germ line mosaicism for de novo mutations. The occurrence of simultaneous mosaicism in both the germ line and soma also shows that the germ line is not strictly clonal but arises from at least two, and possibly multiple, cells in the embryo with different ancestries. Whole genome or exome DNA sequencing technologies promise to expand the range of studies of genetic mosaics, as de novo mutations can now be identified through sequencing alone in the absence of a medical ascertainment. These technologies have been used to study mutation patterns in nuclear families and in monozygotic twins, and in animal model developmental studies, but not yet for extensive cell lineage studies in humans. PMID:25898403

  12. Environmental biology of the marine Roseobacter lineage.

    PubMed

    Wagner-Döbler, Irene; Biebl, Hanno

    2006-01-01

    The Roseobacter lineage is a phylogenetically coherent, physiologically heterogeneous group of alpha-Proteobacteria comprising up to 25% of marine microbial communities, especially in coastal and polar oceans, and it is the only lineage in which cultivated bacteria are closely related to environmental clones. Currently 41 subclusters are described, covering all major marine ecological niches (seawater, algal blooms, microbial mats, sediments, sea ice, marine invertebrates). Members of the Roseobacter lineage play an important role for the global carbon and sulfur cycle and the climate, since they have the trait of aerobic anoxygenic photosynthesis, oxidize the greenhouse gas carbon monoxide, and produce the climate-relevant gas dimethylsulfide through the degradation of algal osmolytes. Production of bioactive metabolites and quorum-sensing-regulated control of gene expression mediate their success in complex communities. Studies of representative isolates in culture, whole-genome sequencing, e.g., of Silicibacter pomeroyi, and the analysis of marine metagenome libraries have started to reveal the environmental biology of this important marine group. PMID:16719716

  13. Lymphatic endothelial lineage assemblage during corneal lymphangiogenesis.

    PubMed

    Connor, Alicia L; Kelley, Philip M; Tempero, Richard M

    2016-03-01

    Postnatal inflammatory lymphangiogenesis presumably requires precise regulatory processes to properly assemble proliferating lymphatic endothelial cells (LECs). The specific mechanisms that regulate the assembly of LECs during new lymphatic vessel synthesis are unclear. Dynamic endothelial shuffling and rearrangement has been proposed as a mechanism of blood vessel growth. We developed genetic lineage-tracing strategies using an inductive transgenic technology to track the fate of entire tandem dimer tomato-positive (tdT) lymphatic vessels or small, in some cases clonal, populations of LECs. We coupled this platform with a suture-induced mouse model of corneal lymphangiogenesis and used different analytic microscopy techniques including serial live imaging to study the spatial properties of proliferating tdT(+) LEC progenies. LEC precursors and their progeny expanded from the corneal limbal lymphatic vessel and were assembled contiguously to comprise a subunit within a new lymphatic vessel. VE-cadherin blockade induced morphologic abnormalities in newly synthesized lymphatic vessels, but did not disrupt the tdT(+) lymphatic endothelial lineage assembly. Analysis of this static and dynamic data based largely on direct in vivo observations supports a model of lymphatic endothelial lineage assemblage during corneal inflammatory lymphangiogenesis. PMID:26658452

  14. Matrix elasticity directs stem cell lineage specification

    NASA Astrophysics Data System (ADS)

    Discher, Dennis

    2010-03-01

    Adhesion of stem cells - like most cells - is not just a membrane phenomenon. Most tissue cells need to adhere to a ``solid'' for viability, and over the last decade it has become increasingly clear that the physical ``elasticity'' of that solid is literally ``felt'' by cells. Here we show that Mesenchymal Stem Cells (MSCs) specify lineage and commit to phenotypes with extreme sensitivity to the elasticity typical of tissues [1]. In serum only media, soft matrices that mimic brain appear neurogenic, stiffer matrices that mimic muscle are myogenic, and comparatively rigid matrices that mimic collagenous bone prove osteogenic. Inhibition of nonmuscle myosin II activity blocks all elasticity directed lineage specification, which indicates that the cytoskeleton pulls on matrix through adhesive attachments. Results have significant implications for `therapeutic' stem cells and have motivated development of a proteomic-scale method to identify mechano-responsive protein structures [2] as well as deeper physical studies of matrix physics [3] and growth factor pathways [4]. [4pt] [1] A. Engler, et al. Matrix elasticity directs stem cell lineage specification. Cell (2006).[0pt] [2] C.P. Johnson, et al. Forced unfolding of proteins within cells. Science (2007).[0pt] [3] A.E.X. Brown, et al. Multiscale mechanics of fibrin polymer: Gel stretching with protein unfolding and loss of water. Science (2009).[0pt] [4] D.E. Discher, et al. Growth factors, matrices, and forces combine and control stem cells. Science (2009).

  15. Lymphatic endothelial lineage assemblage during corneal lymphangiogenesis

    PubMed Central

    Connor, Alicia L.; Kelley, Philip M.; Tempero, Richard M.

    2015-01-01

    Post natal inflammatory lymphangiogenesis presumably requires precise regulatory processes to properly assemble proliferating lymphatic endothelial cells (LECs). The specific mechanisms that regulate the assembly of LECs during new lymphatic vessel synthesis are unclear. Dynamic endothelial shuffling and rearrangement has been proposed as a mechanism of blood vessel growth. We developed genetic lineage tracing strategies using an inductive transgenic technology to track the fate of entire tandem dimer tomato positive (tdT) lymphatic vessels or small, in some cases clonal, populations of LECs. We coupled this platform with a suture induced mouse model of corneal lymphangiogenesis and used different analytic microscopy techniques including serial live imaging to study the spatial properties of proliferating tdT+ LEC progenies. LEC precursors and their progeny expanded from the corneal limbal lymphatic vessel and were assembled contiguously to comprise a subunit within a new lymphatic vessel. VE-cadherin blockade induced morphologic abnormalities in newly synthesized lymphatic vessels, but did not disrupt the tdT+ lymphatic endothelial lineage assembly. Analysis of this static and dynamic data based largely on direct in vivo observations supports a model of lymphatic endothelial lineage assemblage during corneal inflammatory lymphangiogenesis. PMID:26658452

  16. Ecological and genetic divergence between two lineages of Middle American túngara frogs Physalaemus (= Engystomops) pustulosus

    PubMed Central

    2010-01-01

    distribution gap. Niche conservatism possibly contributes to preventing movements across the gap and gene flow between both groups. Genetic and ecological data indicate that there is the potential for ecological divergence in allopatry between lineages. In this context we discuss whether the Northern and Southern lineages should be recognized as separate species, and we conclude that further studies of pre- and post-zygotic isolation are needed for a final assessment. Identified population clusters should motivate future behavioral and ecological research regarding within-species biodiversity and speciation mechanisms. PMID:20482771

  17. Water relations traits of C4 grasses depend on phylogenetic lineage, photosynthetic pathway, and habitat water availability

    PubMed Central

    Liu, Hui; Osborne, Colin P.

    2015-01-01

    The repeated evolution of C4 photosynthesis in independent lineages has resulted in distinct biogeographical distributions in different phylogenetic lineages and the variants of C4 photosynthesis. However, most previous studies have only considered C3/C4 differences without considering phylogeny, C4 subtype, or habitat characteristics. We hypothesized that independent lineages of C4 grasses have structural and physiological traits that adapt them to environments with differing water availability. We measured 40 traits of 33 species from two major C4 grass lineages in a common glasshouse environment. Chloridoideae species were shorter, with narrower and longer leaves, smaller but denser stomata, and faster curling leaves than Panicoideae species, but overall differences in leaf hydraulic and gas exchange traits between the two lineages were weak. Chloridoideae species had two different ways to reach higher drought resistance potential than Panicoideae; NAD-ME species used water saving, whereas PCK species used osmotic adjustment. These patterns could be explained by the interactions of lineage×C4 subtype and lineage×habitat water availability in affected traits. Specifically, phylogeny tended to have a stronger influence on structural traits, and C4 subtype had more important effects on physiological traits. Although hydraulic traits did not differ consistently between lineages, they showed strong covariation and relationships with leaf structure. Thus, phylogenetic lineage, photosynthetic pathway, and adaptation to habitat water availability act together to influence the leaf water relations traits of C4 grasses. This work expands our understanding of ecophysiology in major C4 grass lineages, with implications for explaining their regional and global distributions in relation to climate. PMID:25504656

  18. Water relations traits of C4 grasses depend on phylogenetic lineage, photosynthetic pathway, and habitat water availability.

    PubMed

    Liu, Hui; Osborne, Colin P

    2015-02-01

    The repeated evolution of C4 photosynthesis in independent lineages has resulted in distinct biogeographical distributions in different phylogenetic lineages and the variants of C4 photosynthesis. However, most previous studies have only considered C3/C4 differences without considering phylogeny, C4 subtype, or habitat characteristics. We hypothesized that independent lineages of C4 grasses have structural and physiological traits that adapt them to environments with differing water availability. We measured 40 traits of 33 species from two major C4 grass lineages in a common glasshouse environment. Chloridoideae species were shorter, with narrower and longer leaves, smaller but denser stomata, and faster curling leaves than Panicoideae species, but overall differences in leaf hydraulic and gas exchange traits between the two lineages were weak. Chloridoideae species had two different ways to reach higher drought resistance potential than Panicoideae; NAD-ME species used water saving, whereas PCK species used osmotic adjustment. These patterns could be explained by the interactions of lineage×C4 subtype and lineage×habitat water availability in affected traits. Specifically, phylogeny tended to have a stronger influence on structural traits, and C4 subtype had more important effects on physiological traits. Although hydraulic traits did not differ consistently between lineages, they showed strong covariation and relationships with leaf structure. Thus, phylogenetic lineage, photosynthetic pathway, and adaptation to habitat water availability act together to influence the leaf water relations traits of C4 grasses. This work expands our understanding of ecophysiology in major C4 grass lineages, with implications for explaining their regional and global distributions in relation to climate. PMID:25504656

  19. The effect of dimethyl fumarate (Tecfidera™) on lymphocyte counts: A potential contributor to progressive multifocal leukoencephalopathy risk.

    PubMed

    Khatri, Bhupendra O; Garland, Jeffery; Berger, Joseph; Kramer, John; Sershon, Lisa; Olapo, Tayo; Sesing, Jean; Dukic, Mary; Rehn, Eileen

    2015-07-01

    Dimethyl fumarate (Tecfidera™) is an effective therapy for relapsing forms of multiple sclerosis (MS). Our study suggests that this drug may have immunosuppressive properties evidenced by significant sustained reduction in CD8 lymphocyte counts and, to a lesser extent, CD4 lymphocyte counts. This observation is relevant in light of the recent case of progressive multifocal leukoencephalopathy in a patient receiving this drug. PMID:26195059

  20. Reconstructing lineage hierarchies of the distal lung epithelium using single-cell RNA-seq.

    PubMed

    Treutlein, Barbara; Brownfield, Doug G; Wu, Angela R; Neff, Norma F; Mantalas, Gary L; Espinoza, F Hernan; Desai, Tushar J; Krasnow, Mark A; Quake, Stephen R

    2014-05-15

    The mammalian lung is a highly branched network in which the distal regions of the bronchial tree transform during development into a densely packed honeycomb of alveolar air sacs that mediate gas exchange. Although this transformation has been studied by marker expression analysis and fate-mapping, the mechanisms that control the progression of lung progenitors along distinct lineages into mature alveolar cell types are still incompletely known, in part because of the limited number of lineage markers and the effects of ensemble averaging in conventional transcriptome analysis experiments on cell populations. Here we show that single-cell transcriptome analysis circumvents these problems and enables direct measurement of the various cell types and hierarchies in the developing lung. We used microfluidic single-cell RNA sequencing (RNA-seq) on 198 individual cells at four different stages encompassing alveolar differentiation to measure the transcriptional states which define the developmental and cellular hierarchy of the distal mouse lung epithelium. We empirically classified cells into distinct groups by using an unbiased genome-wide approach that did not require a priori knowledge of the underlying cell types or the previous purification of cell populations. The results confirmed the basic outlines of the classical model of epithelial cell-type diversity in the distal lung and led to the discovery of many previously unknown cell-type markers, including transcriptional regulators that discriminate between the different populations. We reconstructed the molecular steps during maturation of bipotential progenitors along both alveolar lineages and elucidated the full life cycle of the alveolar type 2 cell lineage. This single-cell genomics approach is applicable to any developing or mature tissue to robustly delineate molecularly distinct cell types, define progenitors and lineage hierarchies, and identify lineage-specific regulatory factors. PMID:24739965

  1. Potential Serum Markers for Monitoring the Progression of Hepatitis B Virus-Associated Chronic Hepatic Lesions to Liver Cirrhosis

    PubMed Central

    Wu, Cheng; Liu, Lijie; Zhao, Peng; Tang, Dan; Yao, Dingkang; Zhu, Liang; Wang, Zhiqiang

    2015-01-01

    Background/Aims To screen for serum protein/peptide biomarkers of hepatitis B virus (HBV)-associated chronic hepatic lesions in an attempt to profile the progression of HBV-associated chronic hepatic lesions using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) techniques. Methods Using SELDI-TOF MS, serum protein/peptide profiles on the CM10 ProteinChip arrays were obtained from a training group including 26 HBV-associated hepatocellular carcinoma patients with liver cirrhosis (LC), 30 HBV-associated LC patients, 85 patients at different stages of liver fibrosis, and 30 asymptomatic HBV carriers. The most valuable SELDI peak for predicting the progression to LC in HBV-infected patients was identified. Results A SELDI peak of M/Z 5805 with value for predicting LC in HBV-infected patients was found and was identified as a peptide of the C-terminal fraction of the fibrinogen α-chain precursor, isoform 1. Conclusions The peptide of the C-terminal fraction of the fibrinogen α-chain precursor, isoform 1 with M/Z 5805, may be a serological biomarker for progression to LC in HBV-infected patients. PMID:25963079

  2. Recovering mitochondrial DNA lineages of extinct Amerindian nations in extant homopatric Brazilian populations

    PubMed Central

    2010-01-01

    Background Brazilian Amerindians have experienced a drastic population decrease in the past 500 years. Indeed, many native groups from eastern Brazil have vanished. However, their mitochondrial mtDNA haplotypes, still persist in Brazilians, at least 50 million of whom carry Amerindian mitochondrial lineages. Our objective was to test whether, by analyzing extant rural populations from regions anciently occupied by specific Amerindian groups, we could identify potentially authentic mitochondrial lineages, a strategy we have named 'homopatric targeting'. Results We studied 173 individuals from Queixadinha, a small village located in a territory previously occupied by the now extinct Botocudo Amerindian nation. Pedigree analysis revealed 74 unrelated matrilineages, which were screened for Amerindian mtDNA lineages by restriction fragment length polymorphism. A cosmopolitan control group was composed of 100 individuals from surrounding cities. All Amerindian lineages identified had their hypervariable segment HVSI sequenced, yielding 13 Amerindian haplotypes in Queixadinha, nine of which were not present in available databanks or in the literature. Among these haplotypes, there was a significant excess of haplogroup C (70%) and absence of haplogroup A lineages, which were the most common in the control group. The novelty of the haplotypes and the excess of the C haplogroup suggested that we might indeed have identified Botocudo lineages. To validate our strategy, we studied teeth extracted from 14 ancient skulls of Botocudo Amerindians from the collection of the National Museum of Rio de Janeiro. We recovered mtDNA sequences from all the teeth, identifying only six different haplotypes (a low haplotypic diversity of 0.8352 ± 0.0617), one of which was present among the lineages observed in the extant individuals studied. Conclusions These findings validate the technique of homopatric targeting as a useful new strategy to study the peopling and colonization of the New

  3. Recent Reticulate Evolution in the Ecologically Dominant Lineage of Coccolithophores.

    PubMed

    Bendif, El Mahdi; Probert, Ian; Díaz-Rosas, Francisco; Thomas, Daniela; van den Engh, Ger; Young, Jeremy R; von Dassow, Peter

    2016-01-01

    The coccolithophore family Noëlaerhabdaceae contains a number of taxa that are very abundant in modern oceans, including the cosmopolitan bloom-forming Emiliania huxleyi. Introgressive hybridization has been suggested to account for incongruences between nuclear, mitochondrial and plastidial phylogenies of morphospecies within this lineage, but the number of species cultured to date remains rather limited. Here, we present the characterization of 5 new Noëlaerhabdaceae culture strains isolated from samples collected in the south-east Pacific Ocean. These were analyzed morphologically using scanning electron microscopy and phylogenetically by sequencing 5 marker genes (nuclear 18S and 28S rDNA, plastidial tufA, and mitochondrial cox1 and cox3 genes). Morphologically, one of these strains corresponded to Gephyrocapsa ericsonii and the four others to Reticulofenestra parvula. Ribosomal gene sequences were near identical between these new strains, but divergent from G. oceanica, G. muellerae, and E. huxleyi. In contrast to the clear distinction in ribosomal phylogenies, sequences from other genomic compartments clustered with those of E. huxleyi strains with which they share an ecological range (i.e., warm temperate to tropical waters). These data provide strong support for the hypothesis of past (and potentially ongoing) introgressive hybridization within this ecologically important lineage and for the transfer of R. parvula to Gephyrocapsa. These results have important implications for understanding the role of hybridization in speciation in vast ocean meta-populations of phytoplankton. PMID:27252694

  4. Expression of oligodendrocyte lineage genes in oligodendroglial and astrocytic gliomas.

    PubMed

    Riemenschneider, Markus J; Koy, Timmo H; Reifenberger, Guido

    2004-03-01

    The oligodendrocyte lineage genes OLIG1 and OLIG2 have been reported as potential diagnostic markers for oligodendrogliomas [Lu et al. (2001) Proc Natl Acad Sci USA 98:10851-10856; Marie et al. (2001) Lancet 358:298-300]. We investigated the mRNA expression of OLIG1 and OLIG2, as well as four other genes involved in oligodendrocyte development ( E2A, HEB, NKX2.2, and PDGFRA) in a panel of 70 gliomas, including 9 oligodendrogliomas, 11 anaplastic oligodendrogliomas, 5 oligoastrocytomas, 10 anaplastic oligoastrocytomas, 10 diffuse astrocytomas, 10 anaplastic astrocytomas, and 15 glioblastomas. Most tumors demonstrated higher transcript levels of these genes as compared to non-neoplastic adult brain tissue. Four glioblastomas showed markedly increased PDGFRA mRNA expression due to PDGFRA gene amplification. Statistical analyses revealed no significant expression differences between oligodendroglial and astrocytic tumors. In oligodendroglial tumors, expression of the six genes was not significantly correlated to loss of heterozygosity on chromosome arms 1p and 19q. Thus, expression of the investigated oligodendrocyte lineage genes is up-regulated relative to non-neoplastic brain tissue in the majority of oligodendroglial and astrocytic tumors, suggesting that glioma cells are arrested in or recapitulate molecular phenotypes corresponding to early stages of glial development. However, the determination of mRNA expression of these genes by means of reverse transcription-PCR does not appear to be diagnostically useful as a marker for oligodendrogliomas. PMID:14730454

  5. Canonical Wnt signaling in the oligodendroglial lineage--puzzles remain.

    PubMed

    Guo, Fuzheng; Lang, Jordan; Sohn, Jiho; Hammond, Elizabeth; Chang, Marcello; Pleasure, David

    2015-10-01

    The straightforward concept that accentuated Wnt signaling via the Wnt-receptor-β-catenin-TCF/LEF cascade (also termed canonical Wnt signaling or Wnt/β-catenin signaling) delays or blocks oligodendrocyte differentiation is very appealing. According to this concept, canonical Wnt signaling is responsible for remyelination failure in multiple sclerosis and for persistent hypomyelination in periventricular leukomalacia. This has given rise to the hope that pharmacologically inhibiting this signaling will be of therapeutic potential in these disabling neurological disorders. But current studies suggest that Wnt/β-catenin signaling plays distinct roles in oligodendrogenesis, oligodendrocyte differentiation, and myelination in a context-dependent manner (central nervous system regions, developmental stages), and that Wnt/β-catenin signaling interplays with, and is subjected to regulation by, other central nervous system factors and signaling pathways. On this basis, we propose the more nuanced concept that endogenous Wnt/β-catenin activity is delicately and temporally regulated to ensure the seamless development of oligodendroglial lineage cells in different contexts. In this review, we discuss the role Wnt/β-catenin signaling in oligodendrocyte development, focusing on the interpretation of disparate results, and highlighting areas where important questions remain to be answered about oligodendroglial lineage Wnt/β-catenin signaling. PMID:25782433

  6. Recent Reticulate Evolution in the Ecologically Dominant Lineage of Coccolithophores

    PubMed Central

    Bendif, El Mahdi; Probert, Ian; Díaz-Rosas, Francisco; Thomas, Daniela; van den Engh, Ger; Young, Jeremy R.; von Dassow, Peter

    2016-01-01

    The coccolithophore family Noëlaerhabdaceae contains a number of taxa that are very abundant in modern oceans, including the cosmopolitan bloom-forming Emiliania huxleyi. Introgressive hybridization has been suggested to account for incongruences between nuclear, mitochondrial and plastidial phylogenies of morphospecies within this lineage, but the number of species cultured to date remains rather limited. Here, we present the characterization of 5 new Noëlaerhabdaceae culture strains isolated from samples collected in the south-east Pacific Ocean. These were analyzed morphologically using scanning electron microscopy and phylogenetically by sequencing 5 marker genes (nuclear 18S and 28S rDNA, plastidial tufA, and mitochondrial cox1 and cox3 genes). Morphologically, one of these strains corresponded to Gephyrocapsa ericsonii and the four others to Reticulofenestra parvula. Ribosomal gene sequences were near identical between these new strains, but divergent from G. oceanica, G. muellerae, and E. huxleyi. In contrast to the clear distinction in ribosomal phylogenies, sequences from other genomic compartments clustered with those of E. huxleyi strains with which they share an ecological range (i.e., warm temperate to tropical waters). These data provide strong support for the hypothesis of past (and potentially ongoing) introgressive hybridization within this ecologically important lineage and for the transfer of R. parvula to Gephyrocapsa. These results have important implications for understanding the role of hybridization in speciation in vast ocean meta-populations of phytoplankton. PMID:27252694

  7. Noncoding RNA Expression Aberration Is Associated with Cancer Progression and Is a Potential Biomarker in Esophageal Squamous Cell Carcinoma

    PubMed Central

    Sugihara, Hidetaka; Ishimoto, Takatsugu; Miyake, Keisuke; Izumi, Daisuke; Baba, Yoshifumi; Yoshida, Naoya; Watanabe, Masayuki; Baba, Hideo

    2015-01-01

    Esophageal cancer is one of the most common cancers worldwide. Esophageal squamous cell carcinoma (ESCC) is the major histological type of esophageal cancer in Eastern Asian countries. Several types of noncoding RNAs (ncRNAs) function as key epigenetic regulators of gene expression and are implicated in various physiological processes. Unambiguous evidence indicates that dysregulation of ncRNAs is deeply implicated in carcinogenesis, cancer progression and metastases of various cancers, including ESCC. The current review summarizes recent findings on the ncRNA-mediated mechanisms underlying the characteristic behaviors of ESCC that will help support the development of biomarkers and the design of novel therapeutic strategies. PMID:26610479

  8. Lineage-instructive function of C/EBPα in multipotent hematopoietic cells and early thymic progenitors.

    PubMed

    Wölfler, Albert; Danen-van Oorschot, Astrid A; Haanstra, Jurgen R; Valkhof, Marijke; Bodner, Claudia; Vroegindeweij, Eric; van Strien, Paulette; Novak, Alexandra; Cupedo, Tom; Touw, Ivo P

    2010-11-18

    Hematopoiesis is tightly controlled by transcription regulatory networks, but how and when specific transcription factors control lineage commitment are still largely unknown. Within the hematopoietic stem cell (Lin(-)Sca-1(+)c-Kit(+)) compartment these lineage-specific transcription factors are expressed at low levels but are up-regulated with the process of lineage specification. CCAAT/enhancer binding protein α (C/EBPα) represents one of these factors and is involved in myeloid development and indispensable for formation of granulocytes. To track the cellular fate of stem and progenitor cells, which express C/EBPα, we developed a mouse model expressing Cre recombinase from the Cebpa promoter and a conditional EYFP allele. We show that Cebpa/EYFP(+) cells represent a significant subset of multipotent hematopoietic progenitors, which predominantly give rise to myeloid cells in steady-state hematopoiesis. C/EBPα induced a strong myeloid gene expression signature and down-regulated E2A-induced regulators of early lymphoid development. In addition, Cebpa/EYFP(+) cells compose a fraction of early thymic progenitors with robust myeloid potential. However, Cebpa/EYFP(+) multipotent hematopoietic progenitors and early thymic progenitors retained the ability to develop into erythroid and T-lymphoid lineages, respectively. These findings support an instructive but argue against a lineage-restrictive role of C/EBPα in multipotent hematopoietic and thymic progenitors. PMID:20807890

  9. Two myogenic lineages within the developing somite.

    PubMed

    Ordahl, C P; Le Douarin, N M

    1992-02-01

    It is well known that the muscles of the vertebrate body are derived from the somite. Precursor cells within the somite proper form the back or axial muscles while other precursor cells migrate away from the somite to populate the muscle of the limbs and ventral body wall. Although both types of muscle are generally thought of as arising from a common progenitor population, the myotome, recent evidence points to developmental differences in these two groups of muscles which may reflect different developmental lineages. To test the lineage hypothesis, we used microsurgery and the chick-quail nucleolar marker system to follow the developmental fate of the lateral and medial halves of somites at the wing level. The results showed that the structures of the mature somite (myotome and sclerotome) are derived virtually exclusively from cells residing in the medial half of the newly formed somite. On the other hand, virtually all of the cells residing in the lateral half of the newly formed somite are destined to leave the somite proper and populate the limb muscle and, probably, other somite-derived mesenchymal structures in the limb and ventral body wall. Switch-graft experiments show that the two halves of newly formed somites are largely interchangeable demonstrating that their ultimate developmental fate is position-dependent and that it becomes fixed as a result of extrinsic influences which act during later stages of somitogenesis. We conclude that at least two distinct myogenic lineages exist in the somite; one giving rise to the muscles of the back and the other giving rise to the limb musculature. PMID:1591996

  10. Cardiac Cell Lineages that Form the Heart

    PubMed Central

    Meilhac, Sigolène M.; Lescroart, Fabienne; Blanpain, Cédric; Buckingham, Margaret E.

    2014-01-01

    Myocardial cells ensure the contractility of the heart, which also depends on other mesodermal cell types for its function. Embryological experiments had identified the sources of cardiac precursor cells. With the advent of genetic engineering, novel tools have been used to reconstruct the lineage tree of cardiac cells that contribute to different parts of the heart, map the development of cardiac regions, and characterize their genetic signature. Such knowledge is of fundamental importance for our understanding of cardiogenesis and also for the diagnosis and treatment of heart malformations. PMID:25183852