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Sample records for multiple cell populations

  1. Related B cell clones populate the meninges and parenchyma of patients with multiple sclerosis.

    Lovato, Laura; Willis, Simon N; Rodig, Scott J; Caron, Tyler; Almendinger, Stefany E; Howell, Owain W; Reynolds, Richard; O'Connor, Kevin C; Hafler, David A

    2011-02-01

    In the central nervous system of patients with multiple sclerosis, B cell aggregates populate the meninges, raising the central question as to whether these structures relate to the B cell infiltrates found in parenchymal lesions or instead, represent a separate central nervous system immune compartment. We characterized the repertoires derived from meningeal B cell aggregates and the corresponding parenchymal infiltrates from brain tissue derived primarily from patients with progressive multiple sclerosis. The majority of expanded antigen-experienced B cell clones derived from meningeal aggregates were also present in the parenchyma. We extended this investigation to include 20 grey matter specimens containing meninges, 26 inflammatory plaques, 19 areas of normal appearing white matter and cerebral spinal fluid. Analysis of 1833 B cell receptor heavy chain variable region sequences demonstrated that antigen-experienced clones were consistently shared among these distinct compartments. This study establishes a relationship between extraparenchymal lymphoid tissue and parenchymal infiltrates and defines the arrangement of B cell clones that populate the central nervous system of patients with multiple sclerosis.

  2. Multiple dendritic cell populations activate CD4+ T cells after viral stimulation.

    Adele M Mount

    2008-02-01

    Full Text Available Dendritic cells (DC are a heterogeneous cell population that bridge the innate and adaptive immune systems. CD8alpha DC play a prominent, and sometimes exclusive, role in driving amplification of CD8(+ T cells during a viral infection. Whether this reliance on a single subset of DC also applies for CD4(+ T cell activation is unknown. We used a direct ex vivo antigen presentation assay to probe the capacity of flow cytometrically purified DC populations to drive amplification of CD4(+ and CD8(+ T cells following infection with influenza virus by different routes. This study examined the contributions of non-CD8alpha DC populations in the amplification of CD8(+ and CD4(+ T cells in cutaneous and systemic influenza viral infections. We confirmed that in vivo, effective immune responses for CD8(+ T cells are dominated by presentation of antigen by CD8alpha DC but can involve non-CD8alpha DC. In contrast, CD4(+ T cell responses relied more heavily on the contributions of dermal DC migrating from peripheral lymphoid tissues following cutaneous infection, and CD4 DC in the spleen after systemic infection. CD4(+ T cell priming by DC subsets that is dependent upon the route of administration raises the possibility that vaccination approaches could be tailored to prime helper T cell immunity.

  3. Changes in the Cell Population in Brain White Matter in Multiple System Atrophy

    Nykjaer, Charlotte Havelund; Brudek, Tomasz; Salvesen, Lisette

    2017-01-01

    . OBJECTIVES AND METHODS: To establish the extent of involvement of the white matter in the disease, we have used stereology to quantify the total number of neurons and glial cells (oligodendrocytes, astrocytes, and microglia) in the brains from 10 MSA patients and 11 controls. RESULTS: The mean total number...... of white matter interstitial neurons in the patient brains was 0.5 × 10(9) (coefficient of variation = standard deviation/mean = 0.37), which was significantly lower than the 1.1 × 10(9) (0.41) in the control brains (P = .001) and equal to a reduction by ∼50%. The patient brains had a significantly higher...... number of white matter microglia, 1.5 × 10(9) (0.47) versus 0.7 × 10(9) (0.39) microglia in the control subjects (P = .003) and equal to an increase by ∼ 100%. There was no significant difference in mean total numbers of white matter oligodendrocytes and astrocytes between the groups. CONCLUSIONS: We...

  4. Concomitant targeting of multiple key transcription factors effectively disrupts cancer stem cells enriched in side population of human pancreatic cancer cells.

    Xiyan Wang

    Full Text Available A major challenge in the treatment of pancreatic ductal adenocarcinoma is the failure of chemotherapy, which is likely due to the presence of the cancer stem cells (CSCs.To identify side population (SP cells and characterize s-like properties in human pancreatic cancer cell lines (h-PCCLs and to exploit the efficacy of concomitant targeting of multiple key transcription factors governing the stemness of pancreatic CSCs in suppressing CSC-like phenotypes.Flow cytometry and Hoechst 33342 DNA-binding dye efflux assay were used to sort SP and non-SP (NSP cells from three h-PCCLs: PANC-1, SW1990, and BxPc-3. The self-renewal ability, invasiveness, migration and drug resistance of SP cells were evaluated. Expression of CSC marker genes was analyzed. Tumorigenicity was assessed using a xenograft model in nude mice. Effects of a complex decoy oligonucleotide (cdODN-SCO designed to simultaneously targeting Sox2, Oct4 and c-Myc were assessed.CSCs were enriched in the side proportion (SP cells contained in the h-PCCLs and they possessed aggressive growth, invasion, migration and drug-resistance properties, compared with NSP cells. SP cells overexpressed stem cell markers CD133 and ALDH1, pluripotency maintaining factors Nanog, Sox2 and Oct4, oncogenic transcription factor c-Myc, signaling molecule Notch1, and drug resistant gene ABCG2. Moreover, SP cells consistently demonstrated significantly greater tumorigenicity than NSP cells in xenograft model of nude mice. CdODN-SOC efficiently suppressed all CSC properties and phenotypes, and minimized the tumorigenic capability of the SP cells and the resistance to chemotherapy. By comparison, the negative control failed to do so.The findings indicate that targeting the key genes conferring the stemness of CSCs can efficiently eliminate CSC-like phenotypes, and thus may be considered a new approach for cancer therapy. Specifically, the present study establishes the combination of Sox2/Oct4/c-Myc targeting as a

  5. Identification of markers that functionally define a quiescent multiple myeloma cell sub-population surviving bortezomib treatment

    Adomako, Alfred; Calvo, Veronica; Biran, Noa; Osman, Keren; Chari, Ajai; Paton, James C; Paton, Adrienne W; Moore, Kateri; Schewe, Denis M; Aguirre-Ghiso, Julio A

    2015-01-01

    The mechanisms allowing residual multiple myeloma (MM) cells to persist after bortezomib (Bz) treatment remain unclear. We hypothesized that studying the biology of bortezomib-surviving cells may reveal markers to identify these cells and survival signals to target and kill residual MM cells. We used H2B-GFP label retention, biochemical tools and in vitro and in vivo experiments to characterize growth arrest and the unfolded protein responses in quiescent Bz-surviving cells. We also tested the effect of a demethylating agent, 5-Azacytidine, on Bz-induced quiescence and whether inhibiting the chaperone GRP78/BiP (henceforth GRP78) with a specific toxin induced apoptosis in Bz-surviving cells. Finally, we used MM patient samples to test whether GRP78 levels might associate with disease progression. Statistical analysis employed t-test and Mann-Whitney tests at a 95% confidence. We report that Bz-surviving MM cells in vitro and in vivo enter quiescence characterized by p21 CIP1 upregulation. Bz-surviving MM cells also downregulated CDK6, Ki67 and P-Rb. H2B-GFP label retention showed that Bz-surviving MM cells are either slow-cycling or deeply quiescent. The Bz-induced quiescence was stabilized by low dose (500nM) of 5-azacytidine (Aza) pre-treatment, which also potentiated the initial Bz-induced apoptosis. We also found that expression of GRP78, an unfolded protein response (UPR) survival factor, persisted in MM quiescent cells. Importantly, GRP78 downregulation using a specific SubAB bacterial toxin killed Bz-surviving MM cells. Finally, quantification of Grp78 high /CD138+ MM cells from patients suggested that high levels correlated with progressive disease. We conclude that Bz-surviving MM cells display a GRP78 HIGH /p21 HIGH /CDK6 LOW /P-Rb LOW profile, and these markers may identify quiescent MM cells capable of fueling recurrences. We further conclude that Aza + Bz treatment of MM may represent a novel strategy to delay recurrences by enhancing Bz

  6. Multiple passage cells theory

    Riva, R.

    1983-01-01

    A review of the main concepts envolved in non astigmatic multiple passes cells is presented. It is shown that these concepts can be extended to ring cavities in which the analysis of the ray propagation (in the paraxial approaching) in two separated plans is accomplished. The concepts developed are applyed to a simple ring cavity (one curve mirror and two plane ones) showing that the acquired pattern of the rays on the mirrors is the one of a Lissajours figure which allows a better use of the mirror's area and consequently a larger number of passes. The cavity has applications in optical delay lines, measurements of mirrors reflectivities and possibly in passive optical gyroscopes. (Author) [pt

  7. Taking multiple infections of cells and recombination into account leads to small within-host effective-population-size estimates of HIV-1.

    Rajesh Balagam

    2011-01-01

    Full Text Available Whether HIV-1 evolution in infected individuals is dominated by deterministic or stochastic effects remains unclear because current estimates of the effective population size of HIV-1 in vivo, N(e, are widely varying. Models assuming HIV-1 evolution to be neutral estimate N(e~10²-10⁴, smaller than the inverse mutation rate of HIV-1 (~10⁵, implying the predominance of stochastic forces. In contrast, a model that includes selection estimates N(e>10⁵, suggesting that deterministic forces would hold sway. The consequent uncertainty in the nature of HIV-1 evolution compromises our ability to describe disease progression and outcomes of therapy. We perform detailed bit-string simulations of viral evolution that consider large genome lengths and incorporate the key evolutionary processes underlying the genomic diversification of HIV-1 in infected individuals, namely, mutation, multiple infections of cells, recombination, selection, and epistatic interactions between multiple loci. Our simulations describe quantitatively the evolution of HIV-1 diversity and divergence in patients. From comparisons of our simulations with patient data, we estimate N(e~10³-10⁴, implying predominantly stochastic evolution. Interestingly, we find that N(e and the viral generation time are correlated with the disease progression time, presenting a route to a priori prediction of disease progression in patients. Further, we show that the previous estimate of N(e>10⁵ reduces as the frequencies of multiple infections of cells and recombination assumed increase. Our simulations with N(e~10³-10⁴ may be employed to estimate markers of disease progression and outcomes of therapy that depend on the evolution of viral diversity and divergence.

  8. Fractional populations in multiple gene inheritance.

    Chung, Myung-Hoon; Kim, Chul Koo; Nahm, Kyun

    2003-01-22

    With complete knowledge of the human genome sequence, one of the most interesting tasks remaining is to understand the functions of individual genes and how they communicate. Using the information about genes (locus, allele, mutation rate, fitness, etc.), we attempt to explain population demographic data. This population evolution study could complement and enhance biologists' understanding about genes. We present a general approach to study population genetics in complex situations. In the present approach, multiple allele inheritance, multiple loci inheritance, natural selection and mutations are allowed simultaneously in order to consider a more realistic situation. A simulation program is presented so that readers can readily carry out studies with their own parameters. It is shown that the multiplicity of the loci greatly affects the demographic results of fractional population ratios. Furthermore, the study indicates that some high infant mortality rates due to congenital anomalies can be attributed to multiple loci inheritance. The simulation program can be downloaded from http://won.hongik.ac.kr/~mhchung/index_files/yapop.htm. In order to run this program, one needs Visual Studio.NET platform, which can be downloaded from http://msdn.microsoft.com/netframework/downloads/default.asp.

  9. Multiple Stellar Populations in Star Clusters

    Piotto, G.

    2013-09-01

    For half a century it had been astronomical dogma that a globular cluster (GC) consists of stars born at the same time out of the same material, and this doctrine has borne rich fruits. In recent years, high resolution spectroscopy and high precision photometry (from space and ground-based observations) have shattered this paradigm, and the study of GC populations has acquired a new life that is now moving it in new directions. Evidence of multiple stellar populations have been identified in the color-magnitude diagrams of several Galactic and Magellanic Cloud GCs where they had never been imagined before.

  10. Chapter 22. Cell population kinetics

    Tubiana, M.

    1975-01-01

    The main contribution of radioisotopes to the development of a new discipline, cell population kinetics, was shown. The aim of this science is to establish, for each tissue of the organism, the life span of its component cells and the mechanisms governing its growth, its differentiation and its homeostasis with respect to outside attacks. Labelling techniques have been used to follow the cells during these various processes. The case of non-dividing cells was considered first, taking as example, the red blood cells of which the lifetime was studied, after which the case of proliferating cells was examined using 14 C- or tritium-labelled thymidine. The methods used to measure the cell cycle parameters were described: labelled-mitosis curve method, double-labelling and continuous labelling methods, proliferation coefficient measurement. Cell kinetics were shown to allow an interpretation of radiobiological data. Finally the practical value of cell kinetics research was shown [fr

  11. Population dynamics in vasopressin cells.

    Leng, Gareth; Brown, Colin; Sabatier, Nancy; Scott, Victoria

    2008-01-01

    Most neurons sense and code change, and when presented with a constant stimulus they adapt, so as to be able to detect a fresh change. However, for some things it is important to know their absolute level; to encode such information, neurons must sustain their response to an unchanging stimulus while remaining able to respond to a change in that stimulus. One system that encodes the absolute level of a stimulus is the vasopressin system, which generates a hormonal signal that is proportional to plasma osmolality. Vasopressin cells sense plasma osmolality and secrete appropriate levels of vasopressin from the neurohypophysis as needed to control water excretion; this requires sustained secretion under basal conditions and the ability to increase (or decrease) secretion should plasma osmolality change. Here we explore the mechanisms that enable vasopressin cells to fulfill this function, and consider how coordination between the cells might distribute the secretory load across the population of vasopressin cells. 2008 S. Karger AG, Basel.

  12. Stationary Size Distributions of Growing Cells with Binary and Multiple Cell Division

    Rading, M. M.; Engel, T. A.; Lipowsky, R.; Valleriani, A.

    2011-10-01

    Populations of unicellular organisms that grow under constant environmental conditions are considered theoretically. The size distribution of these cells is calculated analytically, both for the usual process of binary division, in which one mother cell produces always two daughter cells, and for the more complex process of multiple division, in which one mother cell can produce 2 n daughter cells with n=1,2,3,… . The latter mode of division is inspired by the unicellular algae Chlamydomonas reinhardtii. The uniform response of the whole population to different environmental conditions is encoded in the individual rates of growth and division of the cells. The analytical treatment of the problem is based on size-dependent rules for cell growth and stochastic transition processes for cell division. The comparison between binary and multiple division shows that these different division processes lead to qualitatively different results for the size distribution and the population growth rates.

  13. Trichoepithelioma And Multiple Basal Cell Epithelioma

    Dey S.K

    1996-01-01

    Full Text Available A combination of multiple trichoepithelioma and basal cell epithelioma is reported. Although malignant degeneration of trichoepithelioma is debated, clinical and histopathological studies, in our case, hint at that. The case is reported for its rarity.

  14. Viability in holder of irradiated cells: distinguish between repair and cell multiplication

    Araujo, A.C. de.

    1980-01-01

    In experiments in which liquid holding recovery (LHR) was measured, the majority of cellular population is formed by non-viable cells and cell multiplication may be important for LHR expression. In order to distinguish between recuperation of viability (true LHR) and cell multiplication, it was necessary to employ improved plating techniques and a fluctuation test based on Poisson distribution. Our results are an indication that this fluctuation test, used together with the traditional method, is a good tool to distinguish repair from cell multiplication. (author)

  15. PRKCA and multiple sclerosis: association in two independent populations.

    Janna Saarela

    2006-03-01

    Full Text Available Multiple sclerosis (MS is a chronic disease of the central nervous system responsible for a large portion of neurological disabilities in young adults. Similar to what occurs in numerous complex diseases, both unknown environmental factors and genetic predisposition are required to generate MS. We ascertained a set of 63 Finnish MS families, originating from a high-risk region of the country, to identify a susceptibility gene within the previously established 3.4-Mb region on 17q24. Initial single nucleotide polymorphism (SNP-based association implicated PRKCA (protein kinase C alpha gene, and this association was replicated in an independent set of 148 Finnish MS families (p = 0.0004; remaining significant after correction for multiple testing. Further, a dense set of 211 SNPs evenly covering the PRKCA gene and the flanking regions was selected from the dbSNP database and analyzed in two large, independent MS cohorts: in 211 Finnish and 554 Canadian MS families. A multipoint SNP analysis indicated linkage to PRKCA and its telomeric flanking region in both populations, and SNP haplotype and genotype combination analyses revealed an allelic variant of PRKCA, which covers the region between introns 3 and 8, to be over-represented in Finnish MS cases (odds ratio = 1.34, 95% confidence interval 1.07-1.68. A second allelic variant, covering the same region of the PRKCA gene, showed somewhat stronger evidence for association in the Canadian families (odds ratio = 1.64, 95% confidence interval 1.39-1.94. Initial functional relevance for disease predisposition was suggested by the expression analysis: The transcript levels of PRKCA showed correlation with the copy number of the Finnish and Canadian "risk" haplotypes in CD4-negative mononuclear cells of five Finnish multiplex families and in lymphoblast cell lines of 11 Centre d'Etude du Polymorphisme Humain (CEPH individuals of European origin.

  16. Improved survival of multiple myeloma patients with late relapse after high-dose treatment and stem cell support, a population-based study of 348 patients in Denmark in 1994-2004

    Vangsted, Annette Juul; Klausen, Tobias W; Andersen, Niels F

    2010-01-01

    To analyse if patients with early relapse after high-dose chemotherapy with stem cell support (HDT) benefit from new treatment strategies in a population-based setting.......To analyse if patients with early relapse after high-dose chemotherapy with stem cell support (HDT) benefit from new treatment strategies in a population-based setting....

  17. Identifying Multiple Populations in M71 using CN

    Gerber, Jeffrey M.; Friel, Eileen D.; Vesperini, Enrico

    2018-01-01

    It is now well established that globular clusters (GCs) host multiple stellar populations characterized by differences in several light elements. While these populations have been found in nearly all GCs, we still lack an entirely successful model to explain their formation. A key constraint to these models is the detailed pattern of light element abundances seen among the populations; different techniques for identifying these populations probe different elements and do not always yield the same results. We study a large sample of stars in the GC M71 for light elements C and N, using the CN and CH band strength to identify multiple populations. Our measurements come from low-resolution spectroscopy obtained with the WIYN-3.5m telescope for ~150 stars from the tip of the red-giant branch down to the main-sequence turn-off. The large number of stars and broad spatial coverage of our sample (out to ~3.5 half-light radii) allows us to carry out a comprehensive characterization of the multiple populations in M71. We use a combination of the various spectroscopic and photometric indicators to draw a more complete picture of the properties of the populations and to investigate the consistency of classifications using different techniques.

  18. Multiple cell CPV nickel-hydrogen battery

    Jones, Ken R.; Zagrodnik, Jeffrey P.

    1991-01-01

    Johnson Controls, Inc. has developed a multiple cell CPV nickel hydrogen battery that offers significant weight, volume, and cost advantages for aerospace applications. The baseline design was successfully demonstrated through the testing of a 26-cell prototype, which completed over 7000 44 percent depth-of-discharge low earth orbit cycles. Prototype designs using both nominal 5 and 10 inch diameter vessels are currently being developed for a variety of customers and applications.

  19. Hematopoietic stem cell transplantation in multiple sclerosis

    Rogojan, C; Frederiksen, J L

    2009-01-01

    Intensive immunosuppresion followed by hematopoietic stem cell transplantation (HSCT) has been suggested as potential treatment in severe forms of multiple sclerosis (MS). Since 1995 ca. 400 patients have been treated with HSCT. Stabilization or improvement occurred in almost 70% of cases at least...

  20. A General Method for QTL Mapping in Multiple Related Populations Derived from Multiple Parents

    Yan AO

    2009-03-01

    Full Text Available It's well known that incorporating some existing populations derived from multiple parents may improve QTL mapping and QTL-based breeding programs. However, no general maximum likelihood method has been available for this strategy. Based on the QTL mapping in multiple related populations derived from two parents, a maximum likelihood estimation method was proposed, which can incorporate several populations derived from three or more parents and also can be used to handle different mating designs. Taking a circle design as an example, we conducted simulation studies to study the effect of QTL heritability and sample size upon the proposed method. The results showed that under the same heritability, enhanced power of QTL detection and more precise and accurate estimation of parameters could be obtained when three F2 populations were jointly analyzed, compared with the joint analysis of any two F2 populations. Higher heritability, especially with larger sample sizes, would increase the ability of QTL detection and improve the estimation of parameters. Potential advantages of the method are as follows: firstly, the existing results of QTL mapping in single population can be compared and integrated with each other with the proposed method, therefore the ability of QTL detection and precision of QTL mapping can be improved. Secondly, owing to multiple alleles in multiple parents, the method can exploit gene resource more adequately, which will lay an important genetic groundwork for plant improvement.

  1. B Cells and Autoantibodies in Multiple Sclerosis

    Anne-Katrin Pröbstel

    2015-07-01

    Full Text Available While over the past decades T cells have been considered key players in the pathogenesis of multiple sclerosis (MS, it has only recently become evident that B cells have a major contributing role. Our understanding of the role of B cells has evolved substantially following the clinical success of B cell-targeting therapies and increasing experimental evidence for significant B cell involvement. Rather than mere antibody-producing cells, it is becoming clear that they are team players with the capacity to prime and regulate T cells, and function both as pro- and anti-inflammatory mediators. However, despite tremendous efforts, the target antigen(s of B cells in MS have yet to be identified. The first part of this review summarizes the clinical evidence and results from animal studies pointing to the relevance of B cells in the pathogenesis of MS. The second part gives an overview of the currently known potential autoantigen targets. The third part recapitulates and critically appraises the currently available B cell-directed therapies.

  2. Competitive Stem Cell Recruitment by Multiple Cytotactic Cues

    Mendelson, Avital; Cheung, Yukkee; Paluch, Kamila; Chen, Mo; Kong, Kimi; Tan, Jiali; Dong, Ziming; Sia, Samuel K.; Mao, Jeremy J.

    2014-01-01

    A multitude of cytotactic cues direct cell migration in development, cancer metastasis and wound healing. However, our understanding of cell motility remains fragmented partially because current migration devices only allow the study of independent factors. We developed a cell motility assay that allows competitive recruitment of a given cell population simultaneously by gradients of multiple cytotactic cues, observable under real-time imaging. Well-defined uniform gradients of cytotactic cues can be independently generated and sustained in each channel. As a case study, bone marrow mesenchymal stem/stromal cells (MSCs) were exposed to 15 cytokines that are commonly present in arthritis. Cytokines that induced robust recruitment of MSCs in multiple groups were selected to ‘compete’ in a final round to yield the most chemotactic factor(s) based on cell migration numbers, distances, migration indices and motility over time. The potency of a given cytokine in competition frequently differed from its individual action, substantiating the need to test multiple cytokines concurrently due to synergistic or antagonistic effects. This new device has the rare capacity to screen molecules that induce cell migration in cancer therapy, drug development and tissue regeneration. PMID:23364311

  3. 2-Aminopurine overrides multiple cell cycle checkpoints in BHK cells.

    Andreassen, P R; Margolis, R L

    1992-01-01

    BHK cells blocked at any of several points in the cell cycle override their drug-induced arrest and proceed in the cycle when exposed concurrently to the protein kinase inhibitor 2-aminopurine (2-AP). For cells arrested at various points in interphase, 2-AP-induced cell cycle progression is made evident by arrival of the drug-treated cell population in mitosis. Cells that have escaped from mimosine G1 arrest, from hydroxyurea or aphidicolin S-phase arrest, or from VM-26-induced G2 arrest subs...

  4. New type of cells with multiple chromosome rearrangements

    Aseeva, E.A.; Domracheva, E.V.; Neverova, A.L; Bogomazova, A.N.; Snigiryova, G.P.; Novitskaya, N.N.; Khazins, E.D.

    2008-01-01

    Full text: A comparative analysis of the distribution and the frequency of multiaberrant cells (MAC) among lymphocytes in different categories of low dose (up to 0.5 Gy) irradiated people was carried out. MAC were found in most of the examined groups and they were absent in the control population. A highest MAC frequency was observed in people exposed to alpha radiation (Pu, Ra). This fact allows MAC to be considered as an indicator of a high-energy local exposure. A new type of cells with multiple chromosome rearrangements was discovered in the course of analysis of stable aberrations by the FISH method. The biological consequences of MAC formation and possibility of revealing the whole diversity of cells with multiple aberrations by means of modern molecular-cytogenetic methods is discussed

  5. Dopamine, T cells and multiple sclerosis (MS).

    Levite, Mia; Marino, Franca; Cosentino, Marco

    2017-05-01

    Dopamine is a key neurotransmitter that induces critical effects in the nervous system and in many peripheral organs, via 5 dopamine receptors (DRs): D1R-D5R. Dopamine also induces many direct and very potent effects on many DR-expressing immune cells, primarily T cells and dendritic cells. In this review, we focus only on dopamine receptors, effects and production in T cells. Dopamine by itself (at an optimal concentration of~0.1 nM) induces multiple function of resting normal human T cells, among them: T cell adhesion, chemotactic migration, homing, cytokine secretion and others. Interestingly, dopamine activates resting effector T cells (Teffs), but suppresses regulatory T cells (Tregs), and both effects lead eventually to Teff activation. Dopamine-induced effects on T cells are dynamic, context-sensitive and determined by the: T cell activation state, T cell type, DR type, and dopamine concentration. Dopamine itself, and also few dopaminergic molecules/ drugs that are in clinical use for cardiac, neurological and other non-immune indications, have direct effects on human T cells (summarized in this review). These dopaminergic drugs include: dopamine = intropin, L-DOPA, bromocriptine, pramipexole, pergolide, haloperidol, pimozide, and amantadine. Other dopaminergic drugs were not yet tested for their direct effects on T cells. Extensive evidence in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) show dopaminergic dysregulations in T cells in these diseases: D1-like DRs are decreased in Teffs of MS patients, and dopamine does not affect these cells. In contrast, D1-like DRs are increased in Tregs of MS patients, possibly causing functional Treg impairment in MS. Treatment of MS patients with interferon β (IFN-β) increases D1-like DRs and decreases D2-like DRs in Teffs, decreases D1-like DRs in Tregs, and most important: restores responsiveness of patient's Teffs to dopamine. DR agonists and antagonists confer some benefits in

  6. Correlation of proliferative and clonogenic tumor cells in multiple myeloma

    Karp, J.E.; Burke, P.J.; Saylor, P.L.; Humphrey, R.L.

    1984-01-01

    To expand on the findings from previous clinical trials that the growth of residual tumor is increased at a predictable time following initial drug administration, malignant plasma cells from bone marrows of patients with multiple myeloma (MM) were examined for changes in proliferation and clonogenicity induced in vivo by cyclophosphamide and in vitro by drug-induced humoral stimulatory activity. Peak plasma cell [ 3 H]thymidine labeling index (LI) occurred predictably following drug and paralleled changes in agar colony formation by marrow cells obtained during therapy. Colony-forming capacity of pretreatment MM marrow populations was enhanced when those cells were cultured with humoral stimulatory activity, similar to the increased colony formation detected in Day 9 postcyclophosphamide marrows at the time of peak plasma cell LI. To further define a relationship between proliferative plasma cells and colony-forming tumor cells, MM marrows were fractionated by sedimentation on an isokinetic gradient. Enrichment of a proliferative tumor cell cohort was achieved, evidenced by [ 3 H]thymidine LI. Colony-forming cells were also enriched by isokinetic gradient sedimentation, and agar colony formation by MM marrow cell fractions correlated with the kinetic characteristics of the isolated subpopulations. These studies of whole and fractionated human MM marrow cell populations suggest that the kinetically active cells which are induced to proliferate in vivo and in vitro are closely related to the clonogenic tumor cells which produce colonies in agar and which, like those cells measured by [ 3 H]thymidine LI, respond to growth stimulation by drug-induced humoral stimulatory activity

  7. Lower Urinary Tract Symptoms in Elderly Population With Multiple Sclerosis

    Camille Chesnel

    2018-03-01

    Full Text Available Purpose The aim of this study is to compare the clinical and urodynamic characteristics of urinary disorders in multiple sclerosis (MS patients in a geriatric population with a nongeriatric population. Methods This study was conducted retrospectively between 2010 and 2016. Each patient with MS aged 65 and older was matched with 2 patients with MS aged less than 65 in sex, form of MS, and Expended Disability Status Scale (EDSS. Demographic data, urinary symptoms, treatment, quality of life, repercussion of lower urinary tract symptoms on daily life activities and psychological state and urodynamic parameters were collected. Differences between the 2 populations were evaluated using Student test, chi-square, or Fischer tests. Results Twenty-four patients with MS aged 65 and older (mean age, 69.8 years were matched with 48 patients aged less than 65 years (mean age, 49.4 years. Maximum urethral closure pressure was lower in the elderly population than in the nongeriatric population (mean±standard deviation [SD]: 35.6±18.5 cm H2O vs. 78.2±52.3 cm H2O, P<0.001. In the male population, there was no statistical difference in any other clinical or urodynamic endpoints. In the female population, voiding symptoms was more described in the nongeriatric population (Urinary Symptom Profile low stream: 3.4±3.5 vs. 1.7±2.4, P=0.04, geriatric population had less urinary treatment (P=0.05. LUTS had less impact on quality of life (Qualiveen: 1.4±1.0 vs. 2.1±0.9, P=0.02 on the geriatric population than in the nongeriatric of female MS patients. Conclusions Geriatric population of MS has few differences of urinary disorders compared to a nongeriatric population with EDSS, sex, and MS form equal. However, the psychological impact of these urinary disorders is less important in female geriatric population.

  8. Song convergence in multiple urban populations of silvereyes (Zosterops lateralis).

    Potvin, Dominique A; Parris, Kirsten M

    2012-08-01

    Recent studies have revealed differences between urban and rural vocalizations of numerous bird species. These differences include frequency shifts, amplitude shifts, altered song speed, and selective meme use. If particular memes sung by urban populations are adapted to the urban soundscape, "urban-typical" calls, memes, or repertoires should be consistently used in multiple urban populations of the same species, regardless of geographic location. We tested whether songs or contact calls of silvereyes (Zosterops lateralis) might be subject to such convergent cultural evolution by comparing syllable repertoires of geographically dispersed urban and rural population pairs throughout southeastern Australia. Despite frequency and tempo differences between urban and rural calls, call repertoires were similar between habitat types. However, certain song syllables were used more frequently by birds from urban than rural populations. Partial redundancy analysis revealed that both geographic location and habitat characteristics were important predictors of syllable repertoire composition. These findings suggest convergent cultural evolution: urban populations modify both song and call syllables from their local repertoire in response to noise.

  9. Identify multiple myeloma stem cells: Utopia?

    Saltarella, Ilaria; Lamanuzzi, Aurelia; Reale, Antonia; Vacca, Angelo; Ria, Roberto

    2015-01-26

    Multiple myeloma (MM) is a hematologic malignancy of monoclonal plasma cells which remains incurable despite recent advances in therapies. The presence of cancer stem cells (CSCs) has been demonstrated in many solid and hematologic tumors, so the idea of CSCs has been proposed for MM, even if MM CSCs have not been define yet. The existence of myeloma CSCs with clonotypic B and clonotypic non B cells was postulated by many groups. This review aims to focus on these distinct clonotypic subpopulations and on their ability to develop and sustain MM. The bone marrow microenvironment provides to MM CSCs self-renewal, survival and drug resistance thanks to the presence of normal and cancer stem cell niches. The niches and CSCs interact each other through adhesion molecules and the interplay between ligands and receptors activates stemness signaling (Hedgehog, Wnt and Notch pathways). MM CSCs are also supposed to be responsible for drug resistance that happens in three steps from the initial cancer cell homing microenvironment-mediated to development of microenvironment-independent drug resistance. In this review, we will underline all these aspects of MM CSCs.

  10. Involvement of multiple cell lineages in atherogenesis | Ogeng'o ...

    Involvement of multiple cell lineages in atherogenesis. ... mast cells, dendritic cells, macrophages and immigrant cells usually found in blood, namely ... which influence inflammation, migration, proliferation and secretory activity of each other in ...

  11. Deconstructing stem cell population heterogeneity: Single-cell analysis and modeling approaches

    Wu, Jincheng; Tzanakakis, Emmanuel S.

    2014-01-01

    Isogenic stem cell populations display cell-to-cell variations in a multitude of attributes including gene or protein expression, epigenetic state, morphology, proliferation and proclivity for differentiation. The origins of the observed heterogeneity and its roles in the maintenance of pluripotency and the lineage specification of stem cells remain unclear. Addressing pertinent questions will require the employment of single-cell analysis methods as traditional cell biochemical and biomolecular assays yield mostly population-average data. In addition to time-lapse microscopy and flow cytometry, recent advances in single-cell genomic, transcriptomic and proteomic profiling are reviewed. The application of multiple displacement amplification, next generation sequencing, mass cytometry and spectrometry to stem cell systems is expected to provide a wealth of information affording unprecedented levels of multiparametric characterization of cell ensembles under defined conditions promoting pluripotency or commitment. Establishing connections between single-cell analysis information and the observed phenotypes will also require suitable mathematical models. Stem cell self-renewal and differentiation are orchestrated by the coordinated regulation of subcellular, intercellular and niche-wide processes spanning multiple time scales. Here, we discuss different modeling approaches and challenges arising from their application to stem cell populations. Integrating single-cell analysis with computational methods will fill gaps in our knowledge about the functions of heterogeneity in stem cell physiology. This combination will also aid the rational design of efficient differentiation and reprogramming strategies as well as bioprocesses for the production of clinically valuable stem cell derivatives. PMID:24035899

  12. Negative binomial models for abundance estimation of multiple closed populations

    Boyce, Mark S.; MacKenzie, Darry I.; Manly, Bryan F.J.; Haroldson, Mark A.; Moody, David W.

    2001-01-01

    Counts of uniquely identified individuals in a population offer opportunities to estimate abundance. However, for various reasons such counts may be burdened by heterogeneity in the probability of being detected. Theoretical arguments and empirical evidence demonstrate that the negative binomial distribution (NBD) is a useful characterization for counts from biological populations with heterogeneity. We propose a method that focuses on estimating multiple populations by simultaneously using a suite of models derived from the NBD. We used this approach to estimate the number of female grizzly bears (Ursus arctos) with cubs-of-the-year in the Yellowstone ecosystem, for each year, 1986-1998. Akaike's Information Criteria (AIC) indicated that a negative binomial model with a constant level of heterogeneity across all years was best for characterizing the sighting frequencies of female grizzly bears. A lack-of-fit test indicated the model adequately described the collected data. Bootstrap techniques were used to estimate standard errors and 95% confidence intervals. We provide a Monte Carlo technique, which confirms that the Yellowstone ecosystem grizzly bear population increased during the period 1986-1998.

  13. Effect of Population III Multiplicity on Dark Star Formation

    Stacy, Athena; Pawlik, Andreas H.; Bromm, Volker; Loeb, Abraham

    2012-01-01

    We numerically study the mutual interaction between dark matter (DM) and Population III (Pop III) stellar systems in order to explore the possibility of Pop III dark stars within this physical scenario. We perform a cosmological simulation, initialized at z approx. 100, which follows the evolution of gas and DM. We analyze the formation of the first mini halo at z approx. 20 and the subsequent collapse of the gas to densities of 10(exp 12)/cu cm. We then use this simulation to initialize a set of smaller-scale 'cut-out' simulations in which we further refine the DM to have spatial resolution similar to that of the gas. We test multiple DM density profiles, and we employ the sink particle method to represent the accreting star-forming region. We find that, for a range of DM configurations, the motion of the Pop III star-disk system serves to separate the positions of the protostars with respect to the DM density peak, such that there is insufficient DM to influence the formation and evolution of the protostars for more than approx. 5000 years. In addition, the star-disk system causes gravitational scattering of the central DM to lower densities, further decreasing the influence of DM over time. Any DM-powered phase of Pop III stars will thus be very short-lived for the typical multiple system, and DM will not serve to significantly prolong the life of Pop III stars.

  14. Plasma Cell Neoplasms (Including Multiple Myeloma)—Patient Version

    Plasma cell neoplasms occur when abnormal plasma cells form cancerous tumors. When there is only one tumor, the disease is called a plasmacytoma. When there are multiple tumors, it is called multiple myeloma. Start here to find information on plasma cell neoplasms treatment, research, and statistics.

  15. Amelioration of NK cell function driven by Vα24+ invariant NKT cell activation in multiple myeloma.

    Iyoda, Tomonori; Yamasaki, Satoru; Hidaka, Michihiro; Kawano, Fumio; Abe, Yu; Suzuki, Kenshi; Kadowaki, Norimitsu; Shimizu, Kanako; Fujii, Shin-Ichiro

    2018-02-01

    NK cells represent a first line of immune defense, but are progressively dysregulated in multiple myeloma (MM) patients. To restore and facilitate their antitumor effect, NK cells are required in sufficient quantities and must be stimulated. We initially assessed the proportions of NKT and NK cells in 34 MM patients. The frequencies of both in PBMC populations correlated with those in BMMNCs irrespective of low BMMNC numbers. We then assessed the adjunctive effect of stimulating NKT cells with CD1d and α-GalCer complexes on the NK cells. The expression of NKG2D on CD56 dim CD16 + NK cells and DNAM-1 on CD56 bright CD16 - NK cells increased after NKT cell activation. Apparently, NK cell-mediated anti-tumor effects were dependent on NKG2D and DNAM-1 ligands on myeloma cells. Thus, NK cell function in patients could be ameliorated, beyond the effect of immunosuppression, by NKT cell activation. This NKT-driven NK cell therapy could represent a potential new treatment modality. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Phenotype heterogeneity in cancer cell populations

    Almeida, Luis; Chisholm, Rebecca; Clairambault, Jean; Escargueil, Alexandre; Lorenzi, Tommaso; Lorz, Alexander; Trélat, Emmanuel

    2016-01-01

    Phenotype heterogeneity in cancer cell populations, be it of genetic, epigenetic or stochastic origin, has been identified as a main source of resistance to drug treatments and a major source of therapeutic failures in cancers. The molecular mechanisms of drug resistance are partly understood at the single cell level (e.g., overexpression of ABC transporters or of detoxication enzymes), but poorly predictable in tumours, where they are hypothesised to rely on heterogeneity at the cell population scale, which is thus the right level to describe cancer growth and optimise its control by therapeutic strategies in the clinic. We review a few results from the biological literature on the subject, and from mathematical models that have been published to predict and control evolution towards drug resistance in cancer cell populations. We propose, based on the latter, optimisation strategies of combined treatments to limit emergence of drug resistance to cytotoxic drugs in cancer cell populations, in the monoclonal situation, which limited as it is still retains consistent features of cell population heterogeneity. The polyclonal situation, that may be understood as “bet hedging” of the tumour, thus protecting itself from different sources of drug insults, may lie beyond such strategies and will need further developments. In the monoclonal situation, we have designed an optimised therapeutic strategy relying on a scheduled combination of cytotoxic and cytostatic treatments that can be adapted to different situations of cancer treatments. Finally, we review arguments for biological theoretical frameworks proposed at different time and development scales, the so-called atavistic model (diachronic view relying on Darwinian genotype selection in the coursof billions of years) and the Waddington-like epigenetic landscape endowed with evolutionary quasi-potential (synchronic view relying on Lamarckian phenotype instruction of a given genome by reversible mechanisms), to

  17. Phenotype heterogeneity in cancer cell populations

    Almeida, Luis [CNRS UMR 7598, LJLL, & INRIA MAMBA team, Sorbonne Universités, UPMC Univ Paris 06, Boîte courrier 187, 4 Pl. Jussieu, 75252 Paris cedex 05, France, luis@ann.jussieu.fr (France); Chisholm, Rebecca [School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia, rebecca.chisholm@gmail.com (Australia); Clairambault, Jean [INRIA MAMBA team & LJLL, UMR 7598, Sorbonne Universités, UPMC Univ Paris 06, Boîte courrier 187, 4 Pl. Jussieu, 75252 Paris cedex 05, France, jean.clairambault@inria.fr, Corresponding author (France); Escargueil, Alexandre [INSERM “Cancer Biology and Therapeutics”, Sorbonne Universités, UPMC Univ Paris 06, UMR-S 938, CDR St Antoine, Hôpital St Antoine, 184 Fbg. St Antoine, 75571 Paris cedex 12, France, alexandre.escargueil@upmc.fr (France); Lorenzi, Tommaso [CMLA, ENS Cachan, 61, Av. du Président Wilson, 94230 Cachan cedex & INRIA MAMBA team, & LJLL, UMR 7598, UPMC Univ Paris 06, Boîte courrier 187, 4 Pl. Jussieu, 75252 Paris cedex 05, France, tommaso.lorenzi@gmail.com (France); Lorz, Alexander [Sorbonne Universités, UPMC Univ Paris 06, LJLL, UMR 7598 & INRIA Boîte courrier 187, 4 Pl. Jussieu, 75252 Paris cedex 05, France, alex.lorz@ann.jussieu.fr (France); Trélat, Emmanuel [Institut Universitaire de France, Sorbonne Universités, UPMC Univ Paris 06, LJLL, UMR 7598, Boîte courrier 187, UPMC Univ Paris 06, 4 Pl. Jussieu, 75252 Paris cedex 05, France, emmanuel.trelat@upmc.fr (France)

    2016-06-08

    Phenotype heterogeneity in cancer cell populations, be it of genetic, epigenetic or stochastic origin, has been identified as a main source of resistance to drug treatments and a major source of therapeutic failures in cancers. The molecular mechanisms of drug resistance are partly understood at the single cell level (e.g., overexpression of ABC transporters or of detoxication enzymes), but poorly predictable in tumours, where they are hypothesised to rely on heterogeneity at the cell population scale, which is thus the right level to describe cancer growth and optimise its control by therapeutic strategies in the clinic. We review a few results from the biological literature on the subject, and from mathematical models that have been published to predict and control evolution towards drug resistance in cancer cell populations. We propose, based on the latter, optimisation strategies of combined treatments to limit emergence of drug resistance to cytotoxic drugs in cancer cell populations, in the monoclonal situation, which limited as it is still retains consistent features of cell population heterogeneity. The polyclonal situation, that may be understood as “bet hedging” of the tumour, thus protecting itself from different sources of drug insults, may lie beyond such strategies and will need further developments. In the monoclonal situation, we have designed an optimised therapeutic strategy relying on a scheduled combination of cytotoxic and cytostatic treatments that can be adapted to different situations of cancer treatments. Finally, we review arguments for biological theoretical frameworks proposed at different time and development scales, the so-called atavistic model (diachronic view relying on Darwinian genotype selection in the coursof billions of years) and the Waddington-like epigenetic landscape endowed with evolutionary quasi-potential (synchronic view relying on Lamarckian phenotype instruction of a given genome by reversible mechanisms), to

  18. Phenotype heterogeneity in cancer cell populations

    Almeida, Luis; Chisholm, Rebecca; Clairambault, Jean; Escargueil, Alexandre; Lorenzi, Tommaso; Lorz, Alexander; Trélat, Emmanuel

    2016-06-01

    Phenotype heterogeneity in cancer cell populations, be it of genetic, epigenetic or stochastic origin, has been identified as a main source of resistance to drug treatments and a major source of therapeutic failures in cancers. The molecular mechanisms of drug resistance are partly understood at the single cell level (e.g., overexpression of ABC transporters or of detoxication enzymes), but poorly predictable in tumours, where they are hypothesised to rely on heterogeneity at the cell population scale, which is thus the right level to describe cancer growth and optimise its control by therapeutic strategies in the clinic. We review a few results from the biological literature on the subject, and from mathematical models that have been published to predict and control evolution towards drug resistance in cancer cell populations. We propose, based on the latter, optimisation strategies of combined treatments to limit emergence of drug resistance to cytotoxic drugs in cancer cell populations, in the monoclonal situation, which limited as it is still retains consistent features of cell population heterogeneity. The polyclonal situation, that may be understood as "bet hedging" of the tumour, thus protecting itself from different sources of drug insults, may lie beyond such strategies and will need further developments. In the monoclonal situation, we have designed an optimised therapeutic strategy relying on a scheduled combination of cytotoxic and cytostatic treatments that can be adapted to different situations of cancer treatments. Finally, we review arguments for biological theoretical frameworks proposed at different time and development scales, the so-called atavistic model (diachronic view relying on Darwinian genotype selection in the coursof billions of years) and the Waddington-like epigenetic landscape endowed with evolutionary quasi-potential (synchronic view relying on Lamarckian phenotype instruction of a given genome by reversible mechanisms), to

  19. Interval scanning photomicrography of microbial cell populations.

    Casida, L. E., Jr.

    1972-01-01

    A single reproducible area of the preparation in a fixed focal plane is photographically scanned at intervals during incubation. The procedure can be used for evaluating the aerobic or anaerobic growth of many microbial cells simultaneously within a population. In addition, the microscope is not restricted to the viewing of any one microculture preparation, since the slide cultures are incubated separately from the microscope.

  20. Detection and Characterization of Circulating Tumour Cells in Multiple Myeloma

    Liangxuan Zhang

    2016-01-01

    Full Text Available Multiple myeloma (MM remains an incurable disease despite recent therapeutic improvements. The ability to detect and characterize MM circulating tumour cells (CTCs in peripheral blood provides an alternative to replace or augment invasive bone marrow (BM biopsies with a simple blood draw, providing real-time, clinically relevant information leading to improved disease management and therapy selection. Here we have developed and qualified an enrichment-free, cell-based immunofluorescence MM CTC assay that utilizes an automated digital pathology algorithm to distinguish MM CTCs from white blood cells (WBCs on the basis of CD138 and CD45 expression levels, as well as a number of morphological parameters. These MM CTCs were further characterized for expression of phospho-ribosomal protein S6 (pS6 as a readout for PI3K/AKT pathway activation. Clinical feasibility of the assay was established by testing blood samples from a small cohort of patients, where we detected populations of both CD138 pos and CD138 neg MM CTCs. In this study, we developed an immunofluorescent cell-based assay to detect and characterize CTCs in MM.

  1. Multiple modes of proepicardial cell migration require heartbeat.

    Plavicki, Jessica S; Hofsteen, Peter; Yue, Monica S; Lanham, Kevin A; Peterson, Richard E; Heideman, Warren

    2014-05-15

    The outermost layer of the vertebrate heart, the epicardium, forms from a cluster of progenitor cells termed the proepicardium (PE). PE cells migrate onto the myocardium to give rise to the epicardium. Impaired epicardial development has been associated with defects in valve development, cardiomyocyte proliferation and alignment, cardiac conduction system maturation and adult heart regeneration. Zebrafish are an excellent model for studying cardiac development and regeneration; however, little is known about how the zebrafish epicardium forms. We report that PE migration occurs through multiple mechanisms and that the zebrafish epicardium is composed of a heterogeneous population of cells. Heterogeneity is first observed within the PE and persists through epicardium formation. Using in vivo imaging, histology and confocal microscopy, we show that PE cells migrate through a cellular bridge that forms between the pericardial mesothelium and the heart. We also observed the formation of PE aggregates on the pericardial surface, which were released into the pericardial cavity. It was previously reported that heartbeat-induced pericardiac fluid advections are necessary for PE cluster formation and subsequent epicardium development. We manipulated heartbeat genetically and pharmacologically and found that PE clusters clearly form in the absence of heartbeat. However, when heartbeat was inhibited the PE failed to migrate to the myocardium and the epicardium did not form. We isolated and cultured hearts with only a few epicardial progenitor cells and found a complete epicardial layer formed. However, pharmacologically inhibiting contraction in culture prevented epicardium formation. Furthermore, we isolated control and silent heart (sih) morpholino (MO) injected hearts prior to epicardium formation (60 hpf) and co-cultured these hearts with "donor" hearts that had an epicardium forming (108 hpf). Epicardial cells from donor hearts migrated on to control but not sih MO

  2. Population Pharmacokinetics of Cladribine in Patients with Multiple Sclerosis.

    Savic, Radojka M; Novakovic, Ana M; Ekblom, Marianne; Munafo, Alain; Karlsson, Mats O

    2017-10-01

    The aims of this study were to characterize the concentration-time course of cladribine (CdA) and its main metabolite 2-chloroadenine (CAde), estimate interindividual variability in pharmacokinetics (PK), and identify covariates explaining variability in the PK of CdA. This population PK analysis was based on the combined dataset from four clinical studies in patients with multiple sclerosis (MS): three phase I studies, including one food and one drug-drug interaction study, and one phase III clinical study. Plasma and urine concentration data of CdA and CAde were modeled simultaneously. The analysis comprised a total of 2619 CdA and CAde plasma and urine concentration observations from 173 patients with MS who received an intravenous infusion or oral tablet doses of CdA as a single agent or in combination with interferon (IFN) β-1a. CdA PK data were best described by a three-compartment model, while a one-compartment model best described the PK of CAde. CdA renal clearance (CL R ) was correlated with creatinine clearance (CL CR ), predicting a decrease in the total clearance of 19%, 30% and 40% for patients with mild (CL CR  = 65 ml/min), moderate (CL CR  = 40 ml/min) and severe (CL CR  = 20 ml/min) renal impairment, respectively. Food decreased the extent of CdA absorption by 11.2% and caused an absorption delay. Coadministration with IFNβ-1a was found to increase non-CL R (CL NR ) by 21%, resulting in an increase of 11% in total clearance. Both CdA and CAde displayed linear PK after intravenous and oral administration of CdA, with CdA renal function depending on CL CR . Trial registration number for study 25643: NCT00213135.

  3. Targeting population heterogeneity for optimal cell factories

    Heins, Anna-Lena; Carlqvist, Magnus; Helmark, S.

    the heterogeneity level of the population. To further investigate these phenomena and gain a deeper understanding of population heterogeneity, Saccharomyces cerevisiae growth reporter strains based on the expression of green fluorescent protein (GFP) were constructed which enabled us to perform single cell level...... analysis, and thereby created the possibility to map population heterogeneity. A factorial design with pH, glucose concentration and oxygen level was performed in batch cultivations using the growth reporter strains to evaluate the effect of those environmental factors on heterogeneity level and amount......To achieve an efficient production process, it is essential to optimize both the strain and the cultivation conditions. Traditionally, a microbial population has been considered homogeneous in optimization studies of fermentation processes. However, research has shown that a typical microbial...

  4. Response of secondary production and its components to multiple stressors in nematode field populations.

    Doroszuk, A.; Brake, te E.; Crespo-Gonzalez, D.; Kammenga, J.E.

    2007-01-01

    Realistic measures of the impact of individual or multiple stressors are important for ecological risk assessment. Although multiple anthropogenic stressors are common in human-dominated environments, knowledge of their influence on functional population parameters such as secondary production (P)

  5. Multiple gastrointestinal metastases of Merkel cell carcinoma.

    Poškus, Eligijus; Platkevičius, Gediminas; Simanskaitė, Vilma; Rimkevičiūtė, Ernesta; Petrulionis, Marius; Strupas, Kestutis

    2016-01-01

    Merkel cell carcinoma is an aggressive skin malignancy. Primary Merkel cell carcinomas are treated by wide radical excision with or without adjuvant radiotherapy, while benefits of adjuvant chemotherapy remain doubtful. There are only several cases of gastrointestinal metastases of Merkel cell carcinoma reported so far. We report a case of recurrent Merkel cell carcinoma with metastases to the stomach and the small intestines after wide excision of primary Merkel cell carcinoma. Copyright © 2016 The Lithuanian University of Health Sciences. Production and hosting by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  6. Population genetic diversity and fitness in multiple environments

    McGreevy Thomas J

    2010-07-01

    Full Text Available Abstract Background When a large number of alleles are lost from a population, increases in individual homozygosity may reduce individual fitness through inbreeding depression. Modest losses of allelic diversity may also negatively impact long-term population viability by reducing the capacity of populations to adapt to altered environments. However, it is not clear how much genetic diversity within populations may be lost before populations are put at significant risk. Development of tools to evaluate this relationship would be a valuable contribution to conservation biology. To address these issues, we have created an experimental system that uses laboratory populations of an estuarine crustacean, Americamysis bahia with experimentally manipulated levels of genetic diversity. We created replicate cultures with five distinct levels of genetic diversity and monitored them for 16 weeks in both permissive (ambient seawater and stressful conditions (diluted seawater. The relationship between molecular genetic diversity at presumptive neutral loci and population vulnerability was assessed by AFLP analysis. Results Populations with very low genetic diversity demonstrated reduced fitness relative to high diversity populations even under permissive conditions. Population performance decreased in the stressful environment for all levels of genetic diversity relative to performance in the permissive environment. Twenty percent of the lowest diversity populations went extinct before the end of the study in permissive conditions, whereas 73% of the low diversity lines went extinct in the stressful environment. All high genetic diversity populations persisted for the duration of the study, although population sizes and reproduction were reduced under stressful environmental conditions. Levels of fitness varied more among replicate low diversity populations than among replicate populations with high genetic diversity. There was a significant correlation

  7. Optical cell sorting with multiple imaging modalities

    Banas, Andrew; Carrissemoux, Caro; Palima, Darwin

    2017-01-01

    healthy cells. With the richness of visual information, a lot of microscopy techniques have been developed and have been crucial in biological studies. To utilize their complementary advantages we adopt both fluorescence and brightfield imaging in our optical cell sorter. Brightfield imaging has...... the advantage of being non-invasive, thus maintaining cell viability. Fluorescence imaging, on the other hand, takes advantages of the chemical specificity of fluorescence markers and can validate machine vision results from brightfield images. Visually identified cells are sorted using optical manipulation...

  8. Cell-based therapeutic strategies for multiple sclerosis

    Scolding, Neil J; Pasquini, Marcelo; Reingold, Stephen C

    2017-01-01

    and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities......, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved...

  9. Primary progressive multiple sclerosis in the Polish population

    Waldemar Brola

    2017-03-01

    Full Text Available Objectives: The aim of the study was the epidemiological analysis and evaluation of selected clinical and sociodemographic factors in Polish patients with primary progressive multiple sclerosis. Methods: The study included patients from 7 provinces in central and eastern Poland registered in the Registry of Patients with Multiple Sclerosis on 31 December 2016. The incidence of various forms of the disease was compared, and clinical, demographic and social disparities between relapsing-remitting and primary progressive multiple sclerosis were analysed. Results: Of 3,199 registered patients, 2,188 persons (66.2% had the relapsing-remitting form of multiple sclerosis, 774 (24.2% had the secondary progressive type and 307 (9.6% suffered from primary progressive disease. The first symptoms of primary progressive multiple sclerosis appeared almost 10 years later than in patients with the relapsing-remitting type (39.2 ± 11.4 vs. 29.8 ± 9.8. The period from the first symptoms to diagnosis was more than twice as long in patients with primary progressive multiple sclerosis (5.8 ± 3.4 as in those with relapsing-remitting disease (2.4 ± 1.6. The average degree of disability in the Expanded Disability Status Scale was similar and amounted to 3.2 ± 2.1 for relapsing-remitting and 3.6 ± 2.4 for primary progressive multiple sclerosis. The relapsing-remitting form was observed more often in women (2.4:1, and the primary progressive form appeared with equal frequency in both sexes (1:1. Disease-modifying treatment was received by 34% of patients with relapsing-remitting and in only 1.9% of patients with primary progressive multiple sclerosis. Conclusions: The primary progressive form affects approximately 10% of Polish patients with multiple sclerosis. The first symptoms appear at about 40 years of age with equal frequency in both sexes, and its diagnosis takes more than twice as much time as in the case of relapsing-remitting multiple

  10. Modeling population dynamics of mitochondria in mammalian cells

    Kornick, Kellianne; Das, Moumita

    Mitochondria are organelles located inside eukaryotic cells and are essential for several key cellular processes such as energy (ATP) production, cell signaling, differentiation, and apoptosis. All organisms are believed to have low levels of variation in mitochondrial DNA (mtDNA), and alterations in mtDNA are connected to a range of human health conditions, including epilepsy, heart failure, Parkinsons disease, diabetes, and multiple sclerosis. Therefore, understanding how changes in mtDNA accumulate over time and are correlated to changes in mitochondrial function and cell properties can have a profound impact on our understanding of cell physiology and the origins of some diseases. Motivated by this, we develop and study a mathematical model to determine which cellular parameters have the largest impact on mtDNA population dynamics. The model consists of coupled ODEs to describe subpopulations of healthy and dysfunctional mitochondria subject to mitochondrial fission, fusion, autophagy, and mutation. We study the time evolution and stability of each sub-population under specific selection biases and pressures by tuning specific terms in our model. Our results may provide insights into how sub-populations of mitochondria survive and evolve under different selection pressures. This work was supported by a Grant from the Moore Foundation.

  11. Multiple giant cell lesions in a patient with Noonan syndrome with multiple lentigines

    van den Berg, Henk; Schreuder, Willem Hans; Jongmans, Marjolijn; van Bommel-Slee, Danielle; Witsenburg, Bart; de Lange, Jan

    2016-01-01

    A patient with Noonan syndrome with multiple lentigines (NSML) and multiple giant cell lesions (MGCL) in mandibles and maxillae is described. A mutation p.Thr468Met in the PTPN11-gene was found. This is the second reported NSML patient with MGCL. Our case adds to the assumption that, despite a

  12. Natural killer cell lines preferentially kill clonogenic multiple myeloma cells and decrease myeloma engraftment in a bioluminescent xenograft mouse model.

    Swift, Brenna E; Williams, Brent A; Kosaka, Yoko; Wang, Xing-Hua; Medin, Jeffrey A; Viswanathan, Sowmya; Martinez-Lopez, Joaquin; Keating, Armand

    2012-07-01

    Novel therapies capable of targeting drug resistant clonogenic MM cells are required for more effective treatment of multiple myeloma. This study investigates the cytotoxicity of natural killer cell lines against bulk and clonogenic multiple myeloma and evaluates the tumor burden after NK cell therapy in a bioluminescent xenograft mouse model. The cytotoxicity of natural killer cell lines was evaluated against bulk multiple myeloma cell lines using chromium release and flow cytometry cytotoxicity assays. Selected activating receptors on natural killer cells were blocked to determine their role in multiple myeloma recognition. Growth inhibition of clonogenic multiple myeloma cells was assessed in a methylcellulose clonogenic assay in combination with secondary replating to evaluate the self-renewal of residual progenitors after natural killer cell treatment. A bioluminescent mouse model was developed using the human U266 cell line transduced to express green fluorescent protein and luciferase (U266eGFPluc) to monitor disease progression in vivo and assess bone marrow engraftment after intravenous NK-92 cell therapy. Three multiple myeloma cell lines were sensitive to NK-92 and KHYG-1 cytotoxicity mediated by NKp30, NKp46, NKG2D and DNAM-1 activating receptors. NK-92 and KHYG-1 demonstrated 2- to 3-fold greater inhibition of clonogenic multiple myeloma growth, compared with killing of the bulk tumor population. In addition, the residual colonies after treatment formed significantly fewer colonies compared to the control in a secondary replating for a cumulative clonogenic inhibition of 89-99% at the 20:1 effector to target ratio. Multiple myeloma tumor burden was reduced by NK-92 in a xenograft mouse model as measured by bioluminescence imaging and reduction in bone marrow engraftment of U266eGFPluc cells by flow cytometry. This study demonstrates that NK-92 and KHYG-1 are capable of killing clonogenic and bulk multiple myeloma cells. In addition, multiple myeloma

  13. involvement of multiple cell lineages in atherogenesis

    2017-07-12

    Jul 12, 2017 ... Elucidation of all ... molecular mechanisms which underly this .... intima. Monocyte chemoattractant protein-1 ... cell interaction, release of microparticles, pro – ..... Monocytes and macrophages dynamics during atherogenesis.

  14. Individual motile CD4+ T cells can participate in efficient multi-killing through conjugation to multiple tumor cells

    Liadi, Ivan; Singh, Harjeet; Romain, Gabrielle; Rey-Villamizar, Nicolas; Merouane, Amine; Adolacion, Jay R T.; Kebriaei, Partow; Huls, Helen; Qiu, Peng; Roysam, Badrinath; Cooper, Laurence J.N.; Varadarajan, Navin

    2015-01-01

    T cells genetically modified to express a CD19-specific chimeric antigen receptor (CAR) for the investigational treatment of B-cell malignancies comprise a heterogeneous population, and their ability to persist and participate in serial killing of tumor cells is a predictor of therapeutic success. We implemented Timelapse Imaging Microscopy In Nanowell Grids (TIMING) to provide direct evidence that CD4+CAR+ T cells (CAR4 cells) can engage in multi-killing via simultaneous conjugation to multiple tumor cells. Comparisons of the CAR4 cells and CD8+CAR+ T cells (CAR8 cells) demonstrate that while CAR4 cells can participate in killing and multi-killing, they do so at slower rates, likely due to the lower Granzyme B content. Significantly, in both sets of T cells, a minor sub-population of individual T cells identified by their high motility, demonstrated efficient killing of single tumor cells. By comparing both the multi-killer and single killer CAR+ T cells it appears that the propensity and kinetics of T-cell apoptosis was modulated by the number of functional conjugations. T cells underwent rapid apoptosis, and at higher frequencies, when conjugated to single tumor cells in isolation and this effect was more pronounced on CAR8 cells. Our results suggest that the ability of CAR+ T cells to participate in multi-killing should be evaluated in the context of their ability to resist activation induced cell death (AICD). We anticipate that TIMING may be utilized to rapidly determine the potency of T-cell populations and may facilitate the design and manufacture of next-generation CAR+ T cells with improved efficacy. PMID:25711538

  15. Generation of multiple cell types in Bacillus subtilis.

    Lopez, Daniel; Vlamakis, Hera; Kolter, Roberto

    2009-01-01

    Bacillus subtilis is a Gram-positive bacterium that is well known for its ability to differentiate into metabolically inactive spores that are highly resistant to environmental stresses. In fact, populations of genetically identical B. subtilis comprise numerous distinct cell types. In addition to spores, cells can become genetically competent, motile, produce extracellular matrix or degradative enzymes, or secrete toxins that allow them to cannibalize their neighbors. Many of the cell fates listed above appear to be mutually exclusive. In this review, we discuss how individual cells within a population control their gene expression to ensure that proper regulation of differentiation occurs. These different cell fates are regulated by an intricate network that relies primarily on the activity of three major transcriptional regulators: Spo0A, DegU, and ComK. While individual cells must choose distinct cell fates, the population as a whole exhibits a spectrum of phenotypes whose diversity may increase fitness.

  16. Multiple bifurcations and periodic 'bubbling' in a delay population model

    Peng Mingshu

    2005-01-01

    In this paper, the flip bifurcation and periodic doubling bifurcations of a discrete population model without delay influence is firstly studied and the phenomenon of Feigenbaum's cascade of periodic doublings is also observed. Secondly, we explored the Neimark-Sacker bifurcation in the delay population model (two-dimension discrete dynamical systems) and the unique stable closed invariant curve which bifurcates from the nontrivial fixed point. Finally, a computer-assisted study for the delay population model is also delved into. Our computer simulation shows that the introduction of delay effect in a nonlinear difference equation derived from the logistic map leads to much richer dynamic behavior, such as stable node → stable focus → an lower-dimensional closed invariant curve (quasi-periodic solution, limit cycle) or/and stable periodic solutions → chaotic attractor by cascading bubbles (the combination of potential period doubling and reverse period-doubling) and the sudden change between two different attractors, etc

  17. Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia

    Miotto, Olivo; Almagro-Garcia, Jacob; Manske, Magnus; MacInnis, Bronwyn; Campino, Susana; Rockett, Kirk A; Amaratunga, Chanaki; Lim, Pharath; Suon, Seila; Sreng, Sokunthea; Anderson, Jennifer M; Duong, Socheat; Nguon, Chea; Chuor, Char Meng; Saunders, David; Se, Youry; Lon, Chantap; Fukuda, Mark M; Amenga-Etego, Lucas; Hodgson, Abraham VO; Asoala, Victor; Imwong, Mallika; Takala-Harrison, Shannon; Nosten, Francois; Su, Xin-zhuan; Ringwald, Pascal; Ariey, Frédéric; Dolecek, Christiane; Hien, Tran Tinh; Boni, Maciej F; Thai, Cao Quang; Amambua-Ngwa, Alfred; Conway, David J; Djimdé, Abdoulaye A; Doumbo, Ogobara K; Zongo, Issaka; Ouedraogo, Jean-Bosco; Alcock, Daniel; Drury, Eleanor; Auburn, Sarah; Koch, Oliver; Sanders, Mandy; Hubbart, Christina; Maslen, Gareth; Ruano-Rubio, Valentin; Jyothi, Dushyanth; Miles, Alistair; O’Brien, John; Gamble, Chris; Oyola, Samuel O; Rayner, Julian C; Newbold, Chris I; Berriman, Matthew; Spencer, Chris CA; McVean, Gilean; Day, Nicholas P; White, Nicholas J; Bethell, Delia; Dondorp, Arjen M; Plowe, Christopher V; Fairhurst, Rick M; Kwiatkowski, Dominic P

    2013-01-01

    We describe an analysis of genome variation in 825 Plasmodium falciparum samples from Asia and Africa that reveals an unusual pattern of parasite population structure at the epicentre of artemisinin resistance in western Cambodia. Within this relatively small geographical area we have discovered several distinct but apparently sympatric parasite subpopulations with extremely high levels of genetic differentiation. Of particular interest are three subpopulations, all associated with clinical resistance to artemisinin, which have skewed allele frequency spectra and remarkably high levels of haplotype homozygosity, indicative of founder effects and recent population expansion. We provide a catalogue of SNPs that show high levels of differentiation in the artemisinin-resistant subpopulations, including codon variants in various transporter proteins and DNA mismatch repair proteins. These data provide a population genetic framework for investigating the biological origins of artemisinin resistance and for defining molecular markers to assist its elimination. PMID:23624527

  18. Multiple sclerosis in women having children by multiple partners. A population-based study in Denmark

    Basso, Olga; Campi, Rita; Frydenberg, Morten

    2004-01-01

    We investigated whether having children with multiple men is a risk factor for being diagnosed with multiple sclerosis (MS). We studied a cohort of 151,328 women, of whom 64,704 had different men fathering their children and 86,624 the same partner for all births. Women were included if they had ...

  19. Dose-optimal vaccine allocation over multiple populations

    L.E. Duijzer (Evelot); W.L. van Jaarsveld (Willem); J. Wallinga (Jacco); R. Dekker (Rommert)

    2015-01-01

    textabstractFor a large number of infectious diseases, vaccination is the most effective way to prevent an epidemic. However, the vaccine stockpile is hardly ever sufficient to treat the entire population, which brings about the challenge of vaccine allocation. To aid decision makers facing this

  20. Forest management under uncertainty for multiple bird population objectives

    Moore, C.T.; Plummer, W.T.; Conroy, M.J.; Ralph, C. John; Rich, Terrell D.

    2005-01-01

    We advocate adaptive programs of decision making and monitoring for the management of forest birds when responses by populations to management, and particularly management trade-offs among populations, are uncertain. Models are necessary components of adaptive management. Under this approach, uncertainty about the behavior of a managed system is explicitly captured in a set of alternative models. The models generate testable predictions about the response of populations to management, and monitoring data provide the basis for assessing these predictions and informing future management decisions. To illustrate these principles, we examine forest management at the Piedmont National Wildlife Refuge, where management attention is focused on the recovery of the Red-cockaded Woodpecker (Picoides borealis) population. However, managers are also sensitive to the habitat needs of many non-target organisms, including Wood Thrushes (Hylocichla mustelina) and other forest interior Neotropical migratory birds. By simulating several management policies on a set of-alternative forest and bird models, we found a decision policy that maximized a composite response by woodpeckers and Wood Thrushes despite our complete uncertainty regarding system behavior. Furthermore, we used monitoring data to update our measure of belief in each alternative model following one cycle of forest management. This reduction of uncertainty translates into a reallocation of model influence on the choice of optimal decision action at the next decision opportunity.

  1. The search for multiple populations in Magellanic Cloud Clusters IV: Coeval multiple stellar populations in the young star cluster NGC 1978

    Martocchia, S.; Niederhofer, F.; Dalessandro, E.; Bastian, N.; Kacharov, N.; Usher, C.; Cabrera-Ziri, I.; Lardo, C.; Cassisi, S.; Geisler, D.; Hilker, M.; Hollyhead, K.; Kozhurina-Platais, V.; Larsen, S.; Mackey, D.; Mucciarelli, A.; Platais, I.; Salaris, M.

    2018-04-01

    We have recently shown that the ˜2 Gyr old Large Magellanic Cloud star cluster NGC 1978 hosts multiple populations in terms of star-to-star abundance variations in [N/Fe]. These can be seen as a splitting or spread in the sub-giant and red giant branches (SGB and RGB) when certain photometric filter combinations are used. Due to its relative youth, NGC 1978 can be used to place stringent limits on whether multiple bursts of star-formation have taken place within the cluster, as predicted by some models for the origin of multiple populations. We carry out two distinct analyses to test whether multiple star-formation epochs have occurred within NGC 1978. First, we use UV CMDs to select stars from the first and second population along the SGB, and then compare their positions in optical CMDs, where the morphology is dominantly controlled by age as opposed to multiple population effects. We find that the two populations are indistinguishable, with age differences of 1 ± 20 Myr between them. This is in tension with predictions from the AGB scenario for the origin of multiple populations. Second, we estimate the broadness of the main sequence turnoff (MSTO) of NGC 1978 and we report that it is consistent with the observational errors. We find an upper limit of ˜65 Myr on the age spread in the MSTO of NGC 1978. This finding is in conflict with the age spread scenario as origin of the extendend MSTO in intermediate age clusters, while it fully supports predictions from the stellar rotation model.

  2. T helper 17.1 cells associate with multiple sclerosis disease activity: perspectives for early intervention.

    van Langelaar, Jamie; van der Vuurst de Vries, Roos M; Janssen, Malou; Wierenga-Wolf, Annet F; Spilt, Isis M; Siepman, Theodora A; Dankers, Wendy; Verjans, Georges M G M; de Vries, Helga E; Lubberts, Erik; Hintzen, Rogier Q; van Luijn, Marvin M

    2018-05-01

    Interleukin-17-expressing CD4+ T helper 17 (Th17) cells are considered as critical regulators of multiple sclerosis disease activity. However, depending on the species and pro-inflammatory milieu, Th17 cells are functionally heterogeneous, consisting of subpopulations that differentially produce interleukin-17, interferon-gamma and granulocyte macrophage colony-stimulating factor. In the current study, we studied distinct effector phenotypes of human Th17 cells and their correlation with disease activity in multiple sclerosis patients. T helper memory populations single- and double-positive for C-C chemokine receptor 6 (CCR6) and CXC chemokine receptor 3 (CXCR3) were functionally assessed in blood and/or cerebrospinal fluid from a total of 59 patients with clinically isolated syndrome, 35 untreated patients and 24 natalizumab-treated patients with relapsing-remitting multiple sclerosis, and nine patients with end-stage multiple sclerosis. Within the clinically isolated syndrome group, 23 patients had a second attack within 1 year and 26 patients did not experience subsequent attacks during a follow-up of >5 years. Low frequencies of T helper 1 (Th1)-like Th17 (CCR6+CXCR3+), and not Th17 (CCR6+CXCR3-) effector memory populations in blood strongly associated with a rapid diagnosis of clinically definite multiple sclerosis. In cerebrospinal fluid of clinically isolated syndrome and relapsing-remitting multiple sclerosis patients, Th1-like Th17 effector memory cells were abundant and showed increased production of interferon-gamma and granulocyte macrophage colony-stimulating factor compared to paired CCR6+ and CCR6-CD8+ T cell populations and their blood equivalents after short-term culturing. Their local enrichment was confirmed ex vivo using cerebrospinal fluid and brain single-cell suspensions. Across all pro-inflammatory T helper cells analysed in relapsing-remitting multiple sclerosis blood, Th1-like Th17 subpopulation T helper 17.1 (Th17.1; CCR6+CXCR3+CCR4

  3. Multiple populations of pantropical spotted dolphins in Hawaiian waters.

    Courbis, Sarah; Baird, Robin W; Cipriano, Frank; Duffield, Deborah

    2014-01-01

    Understanding gene flow and dispersal patterns is important for predicting effects of natural events and anthropogenic activities on animal populations. In Hawaii, most species of odontocetes are managed as single populations. Recent exceptions include false killer whales, spinner dolphins, and common bottlenose dolphins, for which studies have shown fidelity to individual islands or groups of islands. Our study focused on pantropical spotted dolphins. We analyzed mitochondrial control region and 11 microsatellite loci from 101 individuals from 4 areas: Hawaii, Maui/Lanai, Oahu, and Kauai/Niihau. We examined F ST, F' ST, R ST, Jost's D, and ΦST and used TESS to estimate number of populations and assignment probabilities. Our results support genetic differentiation among Hawaii, Maui/Lanai, and Oahu and suggest that pantropical spotted dolphins near Kauai/Niihau are likely transient and in low numbers. Between island regions, F ST for microsatellites ranged from 0.016 to 0.045 and for mtDNA, from 0.011 to 0.282. F ' ST, ranged from 0.098 to 0.262 for microsatellites and 0.019 to 0.415 for mtDNA. R ST and ΦST showed similar results to F ST for microsatellites and mtDNA respectively, and Jost's D fell between F ST and F ' ST. TESS supported 3 populations, and greatest mean assignment probability by island region ranged from 0.50 to 0.72. The private alleles method indicated migration rates among regions from 1.49 to 3.45, and effective population size of the island of Hawaii was estimated to be 220. There was no strong evidence to support sex-biased dispersal or group fidelity. Considering this study in the larger context of other odontocete population studies and studies of connectivity, we suggest genetic differentiation may be mediated by behavior adapted to differing habitat types and niches. © The American Genetic Association 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  4. Population genetics inside a cell: Mutations and mitochondrial genome maintenance

    Goyal, Sidhartha; Shraiman, Boris; Gottschling, Dan

    2012-02-01

    In realistic ecological and evolutionary systems natural selection acts on multiple levels, i.e. it acts on individuals as well as on collection of individuals. An understanding of evolutionary dynamics of such systems is limited in large part due to the lack of experimental systems that can challenge theoretical models. Mitochondrial genomes (mtDNA) are subjected to selection acting on cellular as well as organelle levels. It is well accepted that mtDNA in yeast Saccharomyces cerevisiae is unstable and can degrade over time scales comparable to yeast cell division time. We utilize a recent technology designed in Gottschling lab to extract DNA from populations of aged yeast cells and deep sequencing to characterize mtDNA variation in a population of young and old cells. In tandem, we developed a stochastic model that includes the essential features of mitochondrial biology that provides a null model for expected mtDNA variation. Overall, we find approximately 2% of the polymorphic loci that show significant increase in frequency as cells age providing direct evidence for organelle level selection. Such quantitative study of mtDNA dynamics is absolutely essential to understand the propagation of mtDNA mutations linked to a spectrum of age-related diseases in humans.

  5. Dose-optimal vaccine allocation over multiple populations

    Duijzer, Evelot; Jaarsveld, Willem; Wallinga, Jacco; Dekker, Rommert

    2015-01-01

    textabstractFor a large number of infectious diseases, vaccination is the most effective way to prevent an epidemic. However, the vaccine stockpile is hardly ever sufficient to treat the entire population, which brings about the challenge of vaccine allocation. To aid decision makers facing this challenge, we provide insights into the structure of this problem. We first investigate the dependence of health benefit on the fraction of people that receive vaccination, where we define health bene...

  6. Novel human multiple myeloma cell line UHKT-893

    Uherková, L.; Vančurová, I.; Vyhlídalová, I.; Pleschnerová, M.; Špička, I.; Mihalová, R.; Březinová, J.; Hodný, Zdeněk; Čermáková, K.; Polanská, V.; Marinov, I.; Jedelský, P.L.; Kuželová, K.; Stöckbauer, P.

    2013-01-01

    Roč. 37, č. 3 (2013), s. 320-326 ISSN 0145-2126 Institutional support: RVO:68378050 Keywords : human myeloma cell line * human multiple myeloma * plasma cell * IL-6 dependence * immunoglobulin * free light chain Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.692, year: 2013

  7. Cell elasticity with altered cytoskeletal architectures across multiple cell types.

    Grady, Martha E; Composto, Russell J; Eckmann, David M

    2016-08-01

    The cytoskeleton is primarily responsible for providing structural support, localization and transport of organelles, and intracellular trafficking. The structural support is supplied by actin filaments, microtubules, and intermediate filaments, which contribute to overall cell elasticity to varying degrees. We evaluate cell elasticity in five different cell types with drug-induced cytoskeletal derangements to probe how actin filaments and microtubules contribute to cell elasticity and whether it is conserved across cell type. Specifically, we measure elastic stiffness in primary chondrocytes, fibroblasts, endothelial cells (HUVEC), hepatocellular carcinoma cells (HUH-7), and fibrosarcoma cells (HT 1080) subjected to two cytoskeletal destabilizers: cytochalasin D and nocodazole, which disrupt actin and microtubule polymerization, respectively. Elastic stiffness is measured by atomic force microscopy (AFM) and the disruption of the cytoskeleton is confirmed using fluorescence microscopy. The two cancer cell lines showed significantly reduced elastic moduli values (~0.5kPa) when compared to the three healthy cell lines (~2kPa). Non-cancer cells whose actin filaments were disrupted using cytochalasin D showed a decrease of 60-80% in moduli values compared to untreated cells of the same origin, whereas the nocodazole-treated cells showed no change in elasticity. Overall, we demonstrate actin filaments contribute more to elastic stiffness than microtubules but this result is cell type dependent. Cancer cells behaved differently, exhibiting increased stiffness as well as stiffness variability when subjected to nocodazole. We show that disruption of microtubule dynamics affects cancer cell elasticity, suggesting therapeutic drugs targeting microtubules be monitored for significant elastic changes. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Multiple Discrimination and Immigration: Traces from Institutional, Academic and Populational Discourse

    Miguel S. Valles Martínez

    2017-01-01

    Full Text Available This article focus on the pairing multiple discrimination and immigration, exploring documentation left in political-institutional grounds, academia and people speech. A triple discursive trace is documented (institutional, academic, populational. Main results are: 1 greater use of adjective ?multiple? within political-legal literature on discrimination, being more latent within sociological research; 2 the presence of multiple discrimination forms in institutional, academic and general population language (not always explicitly ; 3 available statistics and surveys do not record the complexity of a sociological and social-legal phenomenon, requering qualitative materials as well (conversational primary discourses from native or immigrant population, and documentary elaborated discourses from institutions or academia.

  9. Cell-based therapeutic strategies for multiple sclerosis.

    Scolding, Neil J; Pasquini, Marcelo; Reingold, Stephen C; Cohen, Jeffrey A

    2017-11-01

    The availability of multiple disease-modifying medications with regulatory approval to treat multiple sclerosis illustrates the substantial progress made in therapy of the disease. However, all are only partially effective in preventing inflammatory tissue damage in the central nervous system and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved questions. Moreover, clinical trials of cell-based therapies present several unique methodological and ethical issues. We summarize here the status of cell-based therapies to treat multiple sclerosis and make consensus recommendations for future research and clinical trials. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

  10. Are There Multiple Populations of Fast Radio Bursts?

    Palaniswamy, Divya; Li, Ye; Zhang, Bing

    2018-02-01

    The repeating FRB 121102 (the “repeater”) shows repetitive bursting activities and was localized in a host galaxy at z = 0.193. On the other hand, despite dozens of hours of telescope time spent on follow-up observations, no other fast radio bursts (FRBs) have been observed to repeat. Yet, it has been speculated that the repeater is the prototype of FRBs, and that other FRBs should show similar repeating patterns. Using the published data, we compare the repeater with other FRBs in the observed time interval (Δt)–flux ratio (S i /S i+1) plane. We find that whereas other FRBs occupy the upper (large S i /S i+1) and right (large Δt) regions of the plane due to the non-detections of other bursts, some of the repeater bursts fall into the lower left region of the plot (short interval and small flux ratio) excluded by the non-detection data of other FRBs. The trend also exists even if one only selects those bursts detectable by the Parkes radio telescope. If other FRBs were similar to the repeater, our simulations suggest that the probability that none of them have been detected to repeat with the current searches would be ∼(10‑4–10‑3). We suggest that the repeater is not representative of the entire FRB population, and that there is strong evidence of more than one population of FRBs.

  11. A critical examination of the numerology of antigen-binding cells: evidence for multiple receptor specificities on single cells.

    Miller, A

    1977-01-01

    The data available from other laboratories as well as our own on the frequency of cells recognizing major histocompatibility antigens or conventional protein and hapten antigens is critically evaluated. The frequency of specific binding for a large number of antigens is sufficiently high to support the idea that at least part of the antigen-binding cell population must have multiple specificities. Our results suggest that these multiple specific cells result from single cells synthesizing and displaying as many as 50-100 species of receptor, each at a frequency of 10(4) per cell. A model involving gene expansion of constant-region genes is suggested and some auxilliary evidence consistent with such C-gene expansion is presented.

  12. Alpha-particles induce autophagy in multiple myeloma cells

    Joelle Marcelle Gaschet

    2015-10-01

    Full Text Available Objectives: Radiations emitted by the radionuclides in radioimmunotherapy (RIT approaches induce direct killing of the targeted cells as well as indirect killing through bystander effect. Our research group is dedicated to the development of α-RIT, i.e RIT using α-particles especially for the treatment of multiple myeloma (MM. γ-irradiation and β-irradiation have been shown to trigger apoptosis in tumor cells. Cell death mode induced by 213Bi α-irradiation appears more controversial. We therefore decided to investigate the effects of 213Bi on MM cell radiobiology, notably cell death mechanisms as well as tumor cell immunogenicity after irradiation.Methods: Murine 5T33 and human LP-1 multiple myeloma (MM cell lines were used to study the effects of such α-particles. We first examined the effects of 213Bi on proliferation rate, double strand DNA breaks, cell cycle and cell death. Then, we investigated autophagy after 213Bi irradiation. Finally, a co-culture of dendritic cells (DC with irradiated tumour cells or their culture media was performed to test whether it would induce DC activation.Results: We showed that 213Bi induces DNA double strand breaks, cell cycle arrest and autophagy in both cell lines but we detected only slight levels of early apoptosis within the 120 hours following irradiation in 5T33 and LP-1. Inhibition of autophagy prevented 213Bi induced inhibition of proliferation in LP-1 suggesting that this mechanism is involved in cell death after irradiation. We then assessed the immunogenicity of irradiated cells and found that irradiated LP-1 can activate DC through the secretion of soluble factor(s, however no increase in membrane or extracellular expression of danger associated molecular patterns (DAMPs was observed after irradiation.Conclusion: This study demonstrates that 213Bi induces mainly necrosis in MM cells, low levels of apoptosis and also autophagy that might be involved in tumor cell death.

  13. Multiple exciton generation in quantum dot-based solar cells

    Goodwin, Heather; Jellicoe, Tom C.; Davis, Nathaniel J. L. K.; Böhm, Marcus L.

    2018-01-01

    Multiple exciton generation (MEG) in quantum-confined semiconductors is the process by which multiple bound charge-carrier pairs are generated after absorption of a single high-energy photon. Such charge-carrier multiplication effects have been highlighted as particularly beneficial for solar cells where they have the potential to increase the photocurrent significantly. Indeed, recent research efforts have proved that more than one charge-carrier pair per incident solar photon can be extracted in photovoltaic devices incorporating quantum-confined semiconductors. While these proof-of-concept applications underline the potential of MEG in solar cells, the impact of the carrier multiplication effect on the device performance remains rather low. This review covers recent advancements in the understanding and application of MEG as a photocurrent-enhancing mechanism in quantum dot-based photovoltaics.

  14. Employment among patients with multiple sclerosis-a population study.

    Hanne Marie Bøe Lunde

    Full Text Available To investigate demographic and clinical factors associated with employment in MS.The study included 213 (89.9% of all MS patients in Sogn and Fjordane County, Western Norway at December 31st 2010. The patients underwent clinical evaluation, structured interviews and completed self-reported questionnaires. Demographic and clinical factors were compared between patients being employed versus patients being unemployed and according to disease course of MS. Logistic regression analysis was used to identify factors independently associated with current employment.After a mean disease duration of almost 19 years, 45% of the population was currently full-time or part- time employed. Patients with relapsing -remitting MS (RRMS had higher employment rate than patients with secondary (SPMS and primary progressive (PPMS. Higher educated MS patients with lower age at onset, shorter disease duration, less severe disability and less fatigue were most likely to be employed.Nearly half of all MS patients were still employed after almost two decades of having MS. Lower age at onset, shorter disease duration, higher education, less fatigue and less disability were independently associated with current employment. These key clinical and demographic factors are important to understand the reasons to work ability in MS. The findings highlight the need for environmental adjustments at the workplace to accommodate individual 's needs in order to improve working ability among MS patients.

  15. Employment among patients with multiple sclerosis-a population study.

    Bøe Lunde, Hanne Marie; Telstad, Wenche; Grytten, Nina; Kyte, Lars; Aarseth, Jan; Myhr, Kjell-Morten; Bø, Lars

    2014-01-01

    To investigate demographic and clinical factors associated with employment in MS. The study included 213 (89.9%) of all MS patients in Sogn and Fjordane County, Western Norway at December 31st 2010. The patients underwent clinical evaluation, structured interviews and completed self-reported questionnaires. Demographic and clinical factors were compared between patients being employed versus patients being unemployed and according to disease course of MS. Logistic regression analysis was used to identify factors independently associated with current employment. After a mean disease duration of almost 19 years, 45% of the population was currently full-time or part- time employed. Patients with relapsing -remitting MS (RRMS) had higher employment rate than patients with secondary (SPMS) and primary progressive (PPMS). Higher educated MS patients with lower age at onset, shorter disease duration, less severe disability and less fatigue were most likely to be employed. Nearly half of all MS patients were still employed after almost two decades of having MS. Lower age at onset, shorter disease duration, higher education, less fatigue and less disability were independently associated with current employment. These key clinical and demographic factors are important to understand the reasons to work ability in MS. The findings highlight the need for environmental adjustments at the workplace to accommodate individual 's needs in order to improve working ability among MS patients.

  16. Ovarian cancer stem cells are enriched in side population and aldehyde dehydrogenase bright overlapping population.

    Kazuyo Yasuda

    Full Text Available Cancer stem-like cells (CSCs/cancer-initiaiting cells (CICs are defined as a small population of cancer cells that have self-renewal capacity, differentiation potential and high tumor-initiating ability. CSCs/CICs of ovarian cancer have been isolated by side population (SP analysis, ALDEFLUOR assay and using cell surface markers. However, these approaches are not definitive markers for CSCs/CICs, and it is necessary to refine recent methods for identifying more highly purified CSCs/CICs. In this study, we analyzed SP cells and aldehyde dehydrogenese bright (ALDH(Br cells from ovarian cancer cells. Both SP cells and ALDH(Br cells exhibited higher tumor-initiating ability and higher expression level of a stem cell marker, sex determining region Y-box 2 (SOX2, than those of main population (MP cells and ALDH(Low cells, respectively. We analyzed an SP and ALDH(Br overlapping population (SP/ALDH(Br, and the SP/ALDH(Br population exhibited higher tumor-initiating ability than that of SP cells or ALDH(Br cells, enabling initiation of tumor with as few as 10(2 cells. Furthermore, SP/ADLH(Br population showed higher sphere-forming ability, cisplatin resistance, adipocyte differentiation ability and expression of SOX2 than those of SP/ALDH(Low, MP/ALDH(Br and MP/ALDH(Low cells. Gene knockdown of SOX2 suppressed the tumor-initiation of ovarian cancer cells. An SP/ALDH(Br population was detected in several gynecological cancer cells with ratios of 0.1% for HEC-1 endometrioid adenocarcinoma cells to 1% for MCAS ovary mucinous adenocarcinoma cells. Taken together, use of the SP and ALDH(Br overlapping population is a promising approach to isolate highly purified CSCs/CICs and SOX2 might be a novel functional marker for ovarian CSCs/CICs.

  17. Impact of assisted reproductive technology on the incidence of multiple-gestation infants: a population perspective

    Scholten, Irma; Chambers, Georgina M.; van Loendersloot, Laura; van der Veen, Fulco; Repping, Sjoerd; Gianotten, Judith; Hompes, Peter G. A.; Ledger, William; Mol, Ben W. J.

    2015-01-01

    To study the value of a population view in assessing assisted reproductive technology (ART) multiple-gestation infants. Descriptive comparison of ART treatment and population statistics in seven developed countries (United States [U.S.], South Korea, United Kingdom, the Netherlands, Australia,

  18. Illegitimate WNT signaling promotes proliferation of multiple myeloma cells

    Derksen, Patrick W. B.; Tjin, Esther; Meijer, Helen P.; Klok, Melanie D.; Mac Gillavry, Harold D.; van Oers, Marinus H. J.; Lokhorst, Henk M.; Bloem, Andries C.; Clevers, Hans; Nusse, Roel; van der Neut, Ronald; Spaargaren, Marcel; Pals, Steven T.

    2004-01-01

    The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also influenced by signals from the environment. In multiple myeloma (MM), the factors and signals coming from the bone marrow microenvironment are possibly even essential for the growth of the tumor cells. As targets for intervention, these signals may be equally important as mutated oncogenes. Given their oncogenic potential, WNT signals form a class of paracrine growth factors that could act to influence MM cell growth. In this paper, we report that MM cells have hallmarks of active WNT signaling, whereas the cells have not undergone detectable mutations in WNT signaling genes such as adenomatous polyposis coli and β-catenin (CTNNB1). We show that the malignant MM plasma cells overexpress β-catenin, including its N-terminally unphosphorylated form, suggesting active β-catenin/T cell factor-mediated transcription. Further accumulation and nuclear localization of β-catenin, and/or increased cell proliferation, was achieved by stimulation of WNT signaling with either Wnt3a, LiCl, or the constitutively active S33Y mutant of β-catenin. In contrast, by blocking WNT signaling by dominant-negative T cell factor, we can interfere with the growth of MM cells. We therefore suggest that MM cells are dependent on an active WNT signal, which may have important implications for the management of this incurable form of cancer. PMID:15067127

  19. The epidermis comprises autonomous compartments maintained by distinct stem cell populations

    Page, Mahalia E; Lombard, Patrick; Ng, Felicia

    2013-01-01

    populations. In contrast, upon wounding, stem cell progeny from multiple compartments acquire lineage plasticity and make permanent contributions to regenerating tissue. We further show that oncogene activation in Lrig1(+ve) cells drives hyperplasia but requires auxiliary stimuli for tumor formation....... In summary, our data demonstrate that epidermal stem cells are lineage restricted during homeostasis and suggest that compartmentalization may constitute a conserved mechanism underlying epithelial tissue maintenance....

  20. Alpha Particles Induce Autophagy in Multiple Myeloma Cells.

    Gorin, Jean-Baptiste; Gouard, Sébastien; Ménager, Jérémie; Morgenstern, Alfred; Bruchertseifer, Frank; Faivre-Chauvet, Alain; Guilloux, Yannick; Chérel, Michel; Davodeau, François; Gaschet, Joëlle

    2015-01-01

    Radiation emitted by the radionuclides in radioimmunotherapy (RIT) approaches induce direct killing of the targeted cells as well as indirect killing through the bystander effect. Our research group is dedicated to the development of α-RIT, i.e., RIT using α-particles especially for the treatment of multiple myeloma (MM). γ-irradiation and β-irradiation have been shown to trigger apoptosis in tumor cells. Cell death mode induced by (213)Bi α-irradiation appears more controversial. We therefore decided to investigate the effects of (213)Bi on MM cell radiobiology, notably cell death mechanisms as well as tumor cell immunogenicity after irradiation. Murine 5T33 and human LP-1 MM cell lines were used to study the effects of such α-particles. We first examined the effects of (213)Bi on proliferation rate, double-strand DNA breaks, cell cycle, and cell death. Then, we investigated autophagy after (213)Bi irradiation. Finally, a coculture of dendritic cells (DCs) with irradiated tumor cells or their culture media was performed to test whether it would induce DC activation. We showed that (213)Bi induces DNA double-strand breaks, cell cycle arrest, and autophagy in both cell lines, but we detected only slight levels of early apoptosis within the 120 h following irradiation in 5T33 and LP-1. Inhibition of autophagy prevented (213)Bi-induced inhibition of proliferation in LP-1 suggesting that this mechanism is involved in cell death after irradiation. We then assessed the immunogenicity of irradiated cells and found that irradiated LP-1 can activate DC through the secretion of soluble factor(s); however, no increase in membrane or extracellular expression of danger-associated molecular patterns was observed after irradiation. This study demonstrates that (213)Bi induces mainly necrosis in MM cells, low levels of apoptosis, and autophagy that might be involved in tumor cell death.

  1. Novel microchip-based tools facilitating live cell imaging and assessment of functional heterogeneity within NK cell populations

    Elin eForslund

    2012-10-01

    Full Text Available Each individual has a heterogeneous pool of NK cells consisting of cells that may be specialized towards specific functional responses such as secretion of cytokines or killing of tumor cells. Many conventional methods are not fit to characterize heterogeneous populations as they measure the average response of all cells. Thus, there is a need for experimental platforms that provide single cell resolution. In addition, there are also transient and stochastic variations in functional responses at the single cell level, calling for methods that allow studies of many events over extended times. This paper presents a versatile microchip platform enabling long-term microscopic studies of individual NK cells interacting with target cells. Each microchip contains an array of microwells, optimized for medium or high-resolution time-lapse imaging of single or multiple NK and target cells, or for screening of thousands of isolated NK-target cell interactions. Individual NK cells confined with target cells in small microwells is a suitable setup for high-content screening and rapid assessment of heterogeneity within populations, while microwells of larger dimensions are appropriate for studies of NK cell migration and sequential interactions with multiple target cells. By combining the chip technology with ultrasonic manipulation, NK and target cells can be forced to interact and positioned with high spatial accuracy within individual microwells. This setup effectively and synchronously creates NK-target conjugates at hundreds of parallel positions in the microchip. Thus, this facilitates assessment of temporal aspects of NK-target cell interactions, e.g. conjugation, immune synapse formation and cytotoxic events. The microchip platform presented here can be used to effectively address questions related to fundamental functions of NK cells that can lead to better understanding of how the behavior of individual cells add up to give a functional response at

  2. Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma

    Mellqvist, Ulf-Henrik; Gimsing, Peter; Hjertner, Oyvind

    2013-01-01

    The Nordic Myeloma Study Group conducted an open randomized trial to compare bortezomib as consolidation therapy given after high-dose therapy and autologous stem cell transplantation (ASCT) with no consolidation in bortezomib-naive patients with newly diagnosed multiple myeloma. Overall, 370...

  3. Automated platform for designing multiple robot work cells

    Osman, N. S.; Rahman, M. A. A.; Rahman, A. A. Abdul; Kamsani, S. H.; Bali Mohamad, B. M.; Mohamad, E.; Zaini, Z. A.; Rahman, M. F. Ab; Mohamad Hatta, M. N. H.

    2017-06-01

    Designing the multiple robot work cells is very knowledge-intensive, intricate, and time-consuming process. This paper elaborates the development process of a computer-aided design program for generating the multiple robot work cells which offer a user-friendly interface. The primary purpose of this work is to provide a fast and easy platform for less cost and human involvement with minimum trial and errors adjustments. The automated platform is constructed based on the variant-shaped configuration concept with its mathematical model. A robot work cell layout, system components, and construction procedure of the automated platform are discussed in this paper where integration of these items will be able to automatically provide the optimum robot work cell design according to the information set by the user. This system is implemented on top of CATIA V5 software and utilises its Part Design, Assembly Design, and Macro tool. The current outcomes of this work provide a basis for future investigation in developing a flexible configuration system for the multiple robot work cells.

  4. A microarray analysis of two distinct lymphatic endothelial cell populations

    Bernhard Schweighofer

    2015-06-01

    Full Text Available We have recently identified lymphatic endothelial cells (LECs to form two morphologically different populations, exhibiting significantly different surface protein expression levels of podoplanin, a major surface marker for this cell type. In vitro shockwave treatment (IVSWT of LECs resulted in enrichment of the podoplaninhigh cell population and was accompanied by markedly increased cell proliferation, as well as 2D and 3D migration. Gene expression profiles of these distinct populations were established using Affymetrix microarray analyses. Here we provide additional details about our dataset (NCBI GEO accession number GSE62510 and describe how we analyzed the data to identify differently expressed genes in these two LEC populations.

  5. Multiple jaw cysts not associated with basal cell nevus syndrome

    Yoon, Suk Ja; Kang, Byung Cheol

    2003-01-01

    We present two cases of multiple jaw cysts not associated with basal cell nevus syndrome. Case 1 : a nine year-old boy visited CNU Hospital for orthodontic treatment and his radiographs showed cystic lesions surrounding the crowns of teeth 13 and 17 respectively, which were diagnosed as dentigerous cysts. Subsequently, two more cysts were found on his follow-up radiographs in 12 and 15 months. The two cysts were determined to be odontogenic keratocysts. The boy had no skeletal abnormalities and no skin lesions associated with basal cell nevus syndrome. Case 2: a fifty-eight year old man had three impacted third molars with pericoronal radiolucencies, which were diagnosed as dentigerous cysts. He had no additional abnormalities associated with basal cell nevus syndrome. Multiple jaw cysts can occur at any age, and periodic radiographic surveillance may be needed for any cases of impacted tooth.

  6. New type of cells with multiple chromosome rearrangements

    Aseeva, Elena A. [National Research Centre for Hematology, Russian Academy of Medical Sciences, Novozykovsky proezd 4a, 125167 Moscow (Russian Federation); Snigiryova, Galina P. [Russian Scientific Centre of Roentgenology and Radiology, ul. Profsoyuznaya 86, 117997 Moscow (Russian Federation); Neverova, Anna L. [National Research Centre for Hematology, Russian Academy of Medical Sciences, Novozykovsky proezd 4a, 125167 Moscow (Russian Federation); Bogomazova, Alexandra N.; Novitskaya, Natalia N.; Khazins, Eva D. [Russian Scientific Centre of Roentgenology and Radiology, ul. Profsoyuznaya 86, 117997 Moscow (Russian Federation); Domracheva, Elena V. [National Research Centre for Hematology, Russian Academy of Medical Sciences, Novozykovsky proezd 4a, 125167 Moscow (Russian Federation)], E-mail: dom@blood.ru

    2010-04-15

    A comparative analysis of the distribution and the frequency of multiaberrant cells (MAC) among lymphocytes in different categories of low dose (up to 0.5 Gy) irradiated people was carried out. The highest MAC frequency was observed in people exposed to {alpha}-radiation (Pu, Rn) and in cosmonauts. This fact allows MAC to be considered as an indicator of a high-energy local exposure. A new type of cells with multiple chromosome rearrangements was discovered in the course of analysis of stable aberrations by the fluorescence in situ hybridization (FISH) method. The biological consequences of MAC formation and possibility of revealing the whole diversity of cells with multiple aberrations by means of modern molecular-cytogenetic methods are discussed.

  7. Multiple jaw cysts not associated with basal cell nevus syndrome

    Yoon, Suk Ja; Kang, Byung Cheol [Chonnam National University College of Medicine, Kwangju (Korea, Republic of)

    2003-09-15

    We present two cases of multiple jaw cysts not associated with basal cell nevus syndrome. Case 1 : a nine year-old boy visited CNU Hospital for orthodontic treatment and his radiographs showed cystic lesions surrounding the crowns of teeth 13 and 17 respectively, which were diagnosed as dentigerous cysts. Subsequently, two more cysts were found on his follow-up radiographs in 12 and 15 months. The two cysts were determined to be odontogenic keratocysts. The boy had no skeletal abnormalities and no skin lesions associated with basal cell nevus syndrome. Case 2: a fifty-eight year old man had three impacted third molars with pericoronal radiolucencies, which were diagnosed as dentigerous cysts. He had no additional abnormalities associated with basal cell nevus syndrome. Multiple jaw cysts can occur at any age, and periodic radiographic surveillance may be needed for any cases of impacted tooth.

  8. Stem cell-like differentiation potentials of endometrial side population cells as revealed by a newly developed in vivo endometrial stem cell assay.

    Kaoru Miyazaki

    Full Text Available Endometrial stem/progenitor cells contribute to the cyclical regeneration of human endometrium throughout a woman's reproductive life. Although the candidate cell populations have been extensively studied, no consensus exists regarding which endometrial population represents the stem/progenitor cell fraction in terms of in vivo stem cell activity. We have previously reported that human endometrial side population cells (ESP, but not endometrial main population cells (EMP, exhibit stem cell-like properties, including in vivo reconstitution of endometrium-like tissues when xenotransplanted into immunodeficient mice. The reconstitution efficiency, however, was low presumably because ESP cells alone could not provide a sufficient microenvironment (niche to support their stem cell activity. The objective of this study was to establish a novel in vivo endometrial stem cell assay employing cell tracking and tissue reconstitution systems and to examine the stem cell properties of ESP through use of this assay.ESP and EMP cells isolated from whole endometrial cells were infected with lentivirus to express tandem Tomato (TdTom, a red fluorescent protein. They were mixed with unlabeled whole endometrial cells and then transplanted under the kidney capsule of ovariectomized immunodeficient mice. These mice were treated with estradiol and progesterone for eight weeks and nephrectomized. All of the grafts reconstituted endometrium-like tissues under the kidney capsules. Immunofluorescence revealed that TdTom-positive cells were significantly more abundant in the glandular, stromal, and endothelial cells of the reconstituted endometrium in mice transplanted with TdTom-labeled ESP cells than those with TdTom-labeled EMP cells.We have established a novel in vivo endometrial stem cell assay in which multi-potential differentiation can be identified through cell tracking during in vivo endometrial tissue reconstitution. Using this assay, we demonstrated that ESP

  9. Smart Energy Management of Multiple Full Cell Powered Applications

    Mohammad S. Alam

    2007-04-23

    In this research project the University of South Alabama research team has been investigating smart energy management and control of multiple fuel cell power sources when subjected to varying demands of electrical and thermal loads together with demands of hydrogen production. This research has focused on finding the optimal schedule of the multiple fuel cell power plants in terms of electric, thermal and hydrogen energy. The optimal schedule is expected to yield the lowest operating cost. Our team is also investigating the possibility of generating hydrogen using photoelectrochemical (PEC) solar cells through finding materials for efficient light harvesting photoanodes. The goal is to develop an efficient and cost effective PEC solar cell system for direct electrolysis of water. In addition, models for hydrogen production, purification, and storage will be developed. The results obtained and the data collected will be then used to develop a smart energy management algorithm whose function is to maximize energy conservation within a managed set of appliances, thereby lowering O/M costs of the Fuel Cell power plant (FCPP), and allowing more hydrogen generation opportunities. The Smart Energy Management and Control (SEMaC) software, developed earlier, controls electrical loads in an individual home to achieve load management objectives such that the total power consumption of a typical residential home remains below the available power generated from a fuel cell. In this project, the research team will leverage the SEMaC algorithm developed earlier to create a neighborhood level control system.

  10. SAHA-induced TRAIL-sensitisation of Multiple Myeloma cells is enhanced in 3D cell culture.

    Arhoma, A; Chantry, A D; Haywood-Small, S L; Cross, N A

    2017-11-15

    Multiple Myeloma (MM) is currently incurable despite many novel therapies. Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) is a potential anti-tumour agent although effects as a single agent are limited. In this study, we investigated whether the Histone Deacetylase (HDAC) inhibitor SAHA can enhance TRAIL-induced apoptosis and target TRAIL resistance in both suspension culture, and 3D cell culture as a model of disseminated MM lesions that form in bone. The effects of SAHA and/or TRAIL in 6 Multiple Myeloma cell lines were assessed in both suspension cultures and in an Alginate-based 3D cell culture model. The effect of SAHA and/or TRAIL was assessed on apoptosis by assessment of nuclear morphology using Hoechst 33342/Propidium Iodide staining. Viable cell number was assessed by CellTiter-Glo luminescence assay, Caspase-8 and -9 activities were measured by Caspase-Glo™ assay kit. TRAIL-resistant cells were generated by culture of RPMI 8226 and NCI-H929 by acute exposure to TRAIL followed by selection of TRAIL-resistant cells. TRAIL significantly induced apoptosis in a dose-dependent manner in OPM-2, RPMI 8226, NCI-H929, U266, JJN-3 MM cell lines and ADC-1 plasma cell leukaemia cells. SAHA amplified TRAIL responses in all lines except OPM-2, and enhanced TRAIL responses were both via Caspase-8 and -9. SAHA treatment induced growth inhibition that further increased in the combination treatment with TRAIL in MM cells. The co-treatment of TRAIL and SAHA reduced viable cell numbers all cell lines. TRAIL responses were further potentiated by SAHA in 3D cell culture in NCI-H929, RPMI 8226 and U266 at lower TRAIL + SAHA doses than in suspension culture. However TRAIL responses in cells that had been selected for TRAIL resistance were not further enhanced by SAHA treatment. SAHA is a potent sensitizer of TRAIL responses in both TRAIL sensitive and resistant cell lines, in both suspension and 3D culture, however SAHA did not sensitise TRAIL-sensitive cell

  11. The effect of multiple paternity on genetic diversity of small populations during and after colonisation.

    Marina Rafajlović

    Full Text Available Genetic variation within and among populations is influenced by the genetic content of the founders and the migrants following establishment. This is particularly true if populations are small, migration rate low and habitats arranged in a stepping-stone fashion. Under these circumstances the level of multiple paternity is critical since multiply mated females bring more genetic variation into founder groups than single mated females. One such example is the marine snail Littorina saxatilis that during postglacial times has invaded mainland refuge areas and thereafter small islands emerging due to isostatic uplift by occasional rafting of multiply mated females. We modelled effects of varying degrees of multiple paternity on the genetic variation of island populations colonised by the founders spreading from the mainland, by quantifying the population heterozygosity during both the transient colonisation process, and after a steady state (with migration has been reached. During colonisation, multiple mating by [Formula: see text] males increased the heterozygosity by [Formula: see text] in comparison with single paternity, while in the steady state the increase was [Formula: see text] compared with single paternity. In the steady state the increase of heterozygosity due to multiple paternity is determined by a corresponding increase in effective population size. During colonisation, by contrast, the increase in heterozygosity is larger and it cannot be explained in terms of the effective population size alone. During the steady-state phase bursts of high genetic variation spread through the system, and far from the mainland this led to short periods of high diversity separated by long periods of low diversity. The size of these fluctuations was boosted by multiple paternity. We conclude that following glacial periods of extirpation, recolonization of isolated habitats by this species has been supported by its high level of multiple paternity.

  12. The Effect of Multiple Paternity on Genetic Diversity of Small Populations during and after Colonisation

    Rafajlović, Marina

    2013-10-28

    Genetic variation within and among populations is influenced by the genetic content of the founders and the migrants following establishment. This is particularly true if populations are small, migration rate low and habitats arranged in a stepping-stone fashion. Under these circumstances the level of multiple paternity is critical since multiply mated females bring more genetic variation into founder groups than single mated females. One such example is the marine snail Littorina saxatilis that during postglacial times has invaded mainland refuge areas and thereafter small islands emerging due to isostatic uplift by occasional rafting of multiply mated females. We modelled effects of varying degrees of multiple paternity on the genetic variation of island populations colonised by the founders spreading from the mainland, by quantifying the population heterozygosity during both the transient colonisation process, and after a steady state (with migration) has been reached. During colonisation, multiple mating by 2-10 males increased the heterozygosity by 10-300% in comparison with single paternity, while in the steady state the increase was 10-50% compared with single paternity. In the steady state the increase of heterozygosity due to multiple paternity is determined by a corresponding increase in effective population size. During colonisation, by contrast, the increase in heterozygosity is larger and it cannot be explained in terms of the effective population size alone. During the steady-state phase bursts of high genetic variation spread through the system, and far from the mainland this led to short periods of high diversity separated by long periods of low diversity. The size of these fluctuations was boosted by multiple paternity. We conclude that following glacial periods of extirpation, recolonization of isolated habitats by this species has been supported by its high level of multiple paternity. 2013 Rafajlovi? et al.

  13. T cells in multiple sclerosis and experimental autoimmune encephalomyelitis.

    Fletcher, J M

    2012-02-01

    Multiple sclerosis (MS) is a demyelinating inflammatory disorder of the central nervous system (CNS), which involves autoimmune responses to myelin antigens. Studies in experimental autoimmune encephalomyelitis (EAE), an animal model for MS, have provided convincing evidence that T cells specific for self-antigens mediate pathology in these diseases. Until recently, T helper type 1 (Th1) cells were thought to be the main effector T cells responsible for the autoimmune inflammation. However more recent studies have highlighted an important pathogenic role for CD4(+) T cells that secrete interleukin (IL)-17, termed Th17, but also IL-17-secreting gammadelta T cells in EAE as well as other autoimmune and chronic inflammatory conditions. This has prompted intensive study of the induction, function and regulation of IL-17-producing T cells in MS and EAE. In this paper, we review the contribution of Th1, Th17, gammadelta, CD8(+) and regulatory T cells as well as the possible development of new therapeutic approaches for MS based on manipulating these T cell subtypes.

  14. Impact of cladribine therapy on changes in circulating dendritic cell subsets, T cells and B cells in patients with multiple sclerosis.

    Mitosek-Szewczyk, Krystyna; Tabarkiewicz, Jacek; Wilczynska, Barbara; Lobejko, Katarzyna; Berbecki, Jerzy; Nastaj, Marcin; Dworzanska, Ewa; Kolodziejczyk, Beata; Stelmasiak, Zbigniew; Rolinski, Jacek

    2013-09-15

    Cladribine causes sustained reduction in peripheral T and B cell populations while sparing other immune cells. We determined two populations of dendritic cells (DCs): namely CD1c(+)/CD19(-) (myeloid DCs) and CD303(+)/CD123(+) (plasmacytoid DCs), CD19(+) B lymphocytes, CD3(+) T lymphocytes and CD4(+) or CD8(+) subpopulations in patients with multiple sclerosis after cladribine therapy. We examined 50 patients with secondary progressive multiple sclerosis (SP MS) according to McDonalds et al.'s criteria, 2001 [15]. Blood samples were collected before the initiation of cladribine therapy and after 1st, 2nd, 3th, 4th and 5th courses of treatment. DC subsets, T and B cells were analyzed by flow cytometry. During cladribine treatment the myeloid DCs CD1c(+)/CD19(-) did not change (p=0.73175), and the plasmacytoid DCs CD303(+)/CD123(+) significantly increased (p=0.00034) which resulted in significant changes in the ratio of myeloid DCs to plasmacytoid DCs (p=0.00273). During therapy, B lymphocyte CD19(+) significantly decreased (p=0.00005) and significant changes in CD4(+) cells (p=0.00191), changes in CD8(+) cells (p=0.05760) and significant changes in CD3(+) (p=0.01822) were found. We noticed significant trend to increase the CD303(+) circulating the dendritic cells. This population produces large amounts of IFN-alfa. We found significant and rapid decrease in B cells and CD4(+) Th cells. Our results suggest two possible ways of beneficial cladribine influence on immune system in MS. Induction of IFN-alfa producing cells and their predominance over BDCA-1(+) DCs, which are associated with cytotoxic response. Additionally, cladribine could influence two populations of lymphocytes: B cells and Th lymphocytes responsible for induction of immune response against myelin antigens. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. T–CELL VACCINE PREPARATION FOR MULTIPLE SCLEROSIS TREATMENT

    I. P. Ivanova

    2005-01-01

    Full Text Available Abstract. A two–stage technology of preparation of T–cell vaccine designated for multiple sclerosis treatment is described. At the first stage myelin–specific lymphocytes undergoe antigen–dependent cultural selection, whereas at the second stage they are grown by means of non–specific stimulation. The vaccine prepared in this way was found to induce specific anti–idiotypic immune response, directed against myelin–reactive T–lymphocytes. The results of 1–year follow–up of 18 vaccinated patients with a cerebral–spinal type of multiple sclerosis indicated the absence of side effects of T–cell vaccination, and suggest the possibility of effective application of this treatment within early stages of disease. (Med. Immunol., 2005, vol.7, № 1, pp 27532

  16. Effect of failures and repairs on multiple cell production lines

    Legato, P.; Bobbio, A.; Roberti, L.

    1989-01-01

    This paper examines a production line composed of multiple stages, or cells, which are passed in sequential order to arrive to the final product. Two possible coordination disciplines are considered, namely: the classical tandem arrangement of sequential working centers with input buffer and the kanban scheme, considered the Japanese shop floor realization of the Just-In-Time (JIT) manifacturing approach. The production line is modelled and analysed by means of Stochastic Petri Nets (SPN). Finally an analysis is made of the possibility that the working cells can incur failure/repair cycles perturbing the production flow of the line and thus reduce performance indices.

  17. Tuning Cell and Tissue Development by Combining Multiple Mechanical Signals.

    Sinha, Ravi; Verdonschot, Nico; Koopman, Bart; Rouwkema, Jeroen

    2017-10-01

    Mechanical signals offer a promising way to control cell and tissue development. It has been established that cells constantly probe their mechanical microenvironment and employ force feedback mechanisms to modify themselves and when possible, their environment, to reach a homeostatic state. Thus, a correct mechanical microenvironment (external forces and mechanical properties and shapes of cellular surroundings) is necessary for the proper functioning of cells. In vitro or in the case of nonbiological implants in vivo, where cells are in an artificial environment, addition of the adequate mechanical signals can, therefore, enable the cells to function normally as in vivo. Hence, a wide variety of approaches have been developed to apply mechanical stimuli (such as substrate stretch, flow-induced shear stress, substrate stiffness, topography, and modulation of attachment area) to cells in vitro. These approaches have not just revealed the effects of the mechanical signals on cells but also provided ways for probing cellular molecules and structures that can provide a mechanistic understanding of the effects. However, they remain lower in complexity compared with the in vivo conditions, where the cellular mechanical microenvironment is the result of a combination of multiple mechanical signals. Therefore, combinations of mechanical stimuli have also been applied to cells in vitro. These studies have had varying focus-developing novel platforms to apply complex combinations of mechanical stimuli, observing the co-operation/competition between stimuli, combining benefits of multiple stimuli toward an application, or uncovering the underlying mechanisms of their action. In general, they provided new insights that could not have been predicted from previous knowledge. We present here a review of several such studies and the insights gained from them, thereby making a case for such studies to be continued and further developed.

  18. Bridging the Timescales of Single-Cell and Population Dynamics

    Jafarpour, Farshid; Wright, Charles S.; Gudjonson, Herman; Riebling, Jedidiah; Dawson, Emma; Lo, Klevin; Fiebig, Aretha; Crosson, Sean; Dinner, Aaron R.; Iyer-Biswas, Srividya

    2018-04-01

    How are granular details of stochastic growth and division of individual cells reflected in smooth deterministic growth of population numbers? We provide an integrated, multiscale perspective of microbial growth dynamics by formulating a data-validated theoretical framework that accounts for observables at both single-cell and population scales. We derive exact analytical complete time-dependent solutions to cell-age distributions and population growth rates as functionals of the underlying interdivision time distributions, for symmetric and asymmetric cell division. These results provide insights into the surprising implications of stochastic single-cell dynamics for population growth. Using our results for asymmetric division, we deduce the time to transition from the reproductively quiescent (swarmer) to the replication-competent (stalked) stage of the Caulobacter crescentus life cycle. Remarkably, population numbers can spontaneously oscillate with time. We elucidate the physics leading to these population oscillations. For C. crescentus cells, we show that a simple measurement of the population growth rate, for a given growth condition, is sufficient to characterize the condition-specific cellular unit of time and, thus, yields the mean (single-cell) growth and division timescales, fluctuations in cell division times, the cell-age distribution, and the quiescence timescale.

  19. Gene expression heterogeneities in embryonic stem cell populations

    Martinez Arias, Alfonso; Brickman, Joshua M

    2011-01-01

    Stem and progenitor cells are populations of cells that retain the capacity to populate specific lineages and to transit this capacity through cell division. However, attempts to define markers for stem cells have met with limited success. Here we consider whether this limited success reflects...... an intrinsic requirement for heterogeneity with stem cell populations. We focus on Embryonic Stem (ES) cells, in vitro derived cell lines from the early embryo that are considered both pluripotent (able to generate all the lineages of the future embryo) and indefinitely self renewing. We examine the relevance...... of recently reported heterogeneities in ES cells and whether these heterogeneities themselves are inherent requirements of functional potency and self renewal....

  20. Velocity landscape correlation resolves multiple flowing protein populations from fluorescence image time series.

    Pandžić, Elvis; Abu-Arish, Asmahan; Whan, Renee M; Hanrahan, John W; Wiseman, Paul W

    2018-02-16

    Molecular, vesicular and organellar flows are of fundamental importance for the delivery of nutrients and essential components used in cellular functions such as motility and division. With recent advances in fluorescence/super-resolution microscopy modalities we can resolve the movements of these objects at higher spatio-temporal resolutions and with better sensitivity. Previously, spatio-temporal image correlation spectroscopy has been applied to map molecular flows by correlation analysis of fluorescence fluctuations in image series. However, an underlying assumption of this approach is that the sampled time windows contain one dominant flowing component. Although this was true for most of the cases analyzed earlier, in some situations two or more different flowing populations can be present in the same spatio-temporal window. We introduce an approach, termed velocity landscape correlation (VLC), which detects and extracts multiple flow components present in a sampled image region via an extension of the correlation analysis of fluorescence intensity fluctuations. First we demonstrate theoretically how this approach works, test the performance of the method with a range of computer simulated image series with varying flow dynamics. Finally we apply VLC to study variable fluxing of STIM1 proteins on microtubules connected to the plasma membrane of Cystic Fibrosis Bronchial Epithelial (CFBE) cells. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. Th17 cells in the pathogenesis of multiple sclerosis

    Marek Juszczak

    2009-10-01

    Full Text Available Th17 cells are a recently described subset of T helper lymphocytes characterized by the production of IL-17 (IL-17A. Since their discovery in 2003, studies on Th17 cells have become increasingly popular among immunologists and they have emerged as key players in the pathogenesis of multiple sclerosis (MS and other autoimmune disorders traditionally attributed to Th1 cells. Murine Th17 lymphocytes differentiate from naive CD4 cells in a specific cytokine environment, which includes TGF- and IL-6 or IL-21, whereas human Th17 cell development requires TGF-, IL-1, and IL-2 in combination with IL-6, IL-21, or IL-23. Th17-related response is additionally enhanced by osteopontin, TNF, and PGE2 and suppressed by IL-25, IL-27, IL-35, and IL-10. Apart from their main cytokine, Th17 cells can also express IL-17F, IL-21, IL-22, TNF, CCL20, and, in humans, IL-26. All of these mediators may contribute to the proinflammatory action of Th17 .cells both in the clearance of various pathogens and in autoimmunity. At least some of these functions are exerted through the induction of neutrophil-recruiting chemokines (CXCL1, CXCL2, CXCL8 by IL-17. Accumulating evidence from studies on mice and humans indicates an important role of Th17 cells in mediating autoimmune neuroinflammation. This has led some immunologists to question the previously exhibited importance of Th1 cells in MS pathology. However, more recent data suggest that both these T-cell subsets are capable of inducing and promoting the disease. Further investigation is required to clarify the role of Th17 cells in the pathogenesis of MS since some of the Th17-related molecules appear as attractive targets for future therapeutic strategies

  2. Efficient cascade multiple heterojunction organic solar cells with inverted structure

    Guo, Tingting; Li, Mingtao; Qiao, Zhenfang; Yu, Leiming; Zhao, Jianhong; Feng, Nianjun; Shi, Peiguang; Wang, Xiaoyan; Pu, Xiaoyun; Wang, Hai

    2018-05-01

    In this work, we demonstrate an efficient cascade multiple heterojunction organic solar cell with inverted structure. By using two donor materials, poly(3-hexylthiosphene) (P3HT) and titanyl phthalocyanine (TiOPc), as well as two acceptor materials, [6,6]-phenyl C61 butyric acid methyl ester (PCBM) and C60, the cascade multiple heterojunctions of P3HT:PCBM/TiOPc:C60/C60 have been constructed. Applying the optimized inverted configuration of FTO/Zinc Tin Oxide (ZTO)/C60 (30 nm)/TiOPc:C60 (1:1.5, 25 nm)/P3HT:PCBM (1:0.8, 100 nm)/MoO3 (4 nm)/Ag, the considerably enhanced open circuit voltage (VOC) and short circuit current (JSC) can be harvested together, and the power conversion efficiency (PCE) is three times higher than that of the control cell with conventional structure. The significant improvements of the inverted cell are mostly due to the broadened spectral absorption and high efficient multi-interface exciton dissociation in the cascade multiple heterojunctions, indicating that the optimized cascade heterojunctions match the inverted structure well.

  3. Progenitor cell populations in the periodontal ligament of mice

    McCulloch, C.A.

    1985-01-01

    Stem cells in a variety of renewal tissues exhibit a slow rate of cell proliferation. The periodontal ligament of mouse molars was examined for the presence of slowly cycling progenitor cells to provide evidence for the existence of stem cells in this tissue. A pulse injection of 3 H-thymidine was administered and mice were sacrificed between 1 hour and 14 days after injection. Analysis of radioautographs using percentage of labeled cells and grain counts demonstrated that a population of label-retaining cells within 10 micron of blood vessels traversed the cell cycle more slowly than proliferating cells located greater than 10 micron from blood vessels. These data suggest that there is a slowly dividing population of progenitor cells in paravascular sites in mouse molar periodontal ligament which may be stem cells

  4. Child Maltreatment Among Singletons and Multiple Births in Japan: A Population-Based Study.

    Yokoyama, Yoshie; Oda, Terumi; Nagai, Noriyo; Sugimoto, Masako; Mizukami, Kenji

    2015-12-01

    The occurrence of multiple births has been recognized as a risk factor for child maltreatment. However, few population-based studies have examined the relationship between multiple births and child maltreatment. This study aimed to evaluate the degree of risk of child maltreatment among singletons and multiple births in Japan and to identify factors associated with increased risk. Using population-based data, we analyzed the database of records on child maltreatment and medical checkups for infants aged 1.5 years filed at Nishinomiya City Public Health Center between April 2007 and March 2011. To protect personal information, the data were transferred to anonymized electronic files for analysis. After adjusting by logistic regression for each associated factor and gestation number, multiples themselves were not associated with the risk of child maltreatment. However, compared with singletons, multiples had a significantly higher rate of risk factors for child maltreatment, including low birth weight and neural abnormality. Moreover, compared with mothers of singleton, mothers of twins had a significantly higher rate of poor health, which is a risk factor of child maltreatment. Multiples were not associated with the risk of child maltreatment. However, compared with singletons, multiples and their mothers had a significantly higher rate of risk factors of child maltreatment.

  5. Multiple origins of outbreak populations of a native insect pest in an agro-ecosystem.

    Kobayashi, T; Sakurai, T; Sakakibara, M; Watanabe, T

    2011-06-01

    Native insects can become epidemic pests in agro-ecosystems. A population genetics approach was applied to analyze the emergence and spread of outbreak populations of native insect species. Outbreaks of the mirid bug, Stenotus rubrovittatus, have rapidly expanded over Japan within the last two decades. To characterize the outbreak dynamics of this species, the genetic structure of local populations was assessed using polymorphisms of the mtDNA COI gene and six microsatellite loci. Results of the population genetic analysis suggested that S. rubrovittatus populations throughout Japan were genetically isolated by geographic distance and separated into three genetic clusters occupying spatially segregated regions. Phylogeographic analysis indicated that the genetic structure of S. rubrovittatus reflected post-glacial colonization. Early outbreaks of S. rubrovittatus in the 1980s occurred independently of genetically isolated populations. The genetic structure of the populations did not fit the pattern of an outbreak expansion, and therefore the data did not support the hypothesis that extensive outbreaks were caused by the dispersal of specific pestiferous populations. Rather, the historical genetic structure prior to the outbreaks was maintained throughout the increase in abundance of the mirid bug. Our study indicated that changes in the agro-environment induced multiple outbreaks of native pest populations. This implies that, given suitable environmental conditions, local populations may have the potential to outbreak even without invasion of populations from other environmentally degraded areas.

  6. Efficient computation of the joint sample frequency spectra for multiple populations.

    Kamm, John A; Terhorst, Jonathan; Song, Yun S

    2017-01-01

    A wide range of studies in population genetics have employed the sample frequency spectrum (SFS), a summary statistic which describes the distribution of mutant alleles at a polymorphic site in a sample of DNA sequences and provides a highly efficient dimensional reduction of large-scale population genomic variation data. Recently, there has been much interest in analyzing the joint SFS data from multiple populations to infer parameters of complex demographic histories, including variable population sizes, population split times, migration rates, admixture proportions, and so on. SFS-based inference methods require accurate computation of the expected SFS under a given demographic model. Although much methodological progress has been made, existing methods suffer from numerical instability and high computational complexity when multiple populations are involved and the sample size is large. In this paper, we present new analytic formulas and algorithms that enable accurate, efficient computation of the expected joint SFS for thousands of individuals sampled from hundreds of populations related by a complex demographic model with arbitrary population size histories (including piecewise-exponential growth). Our results are implemented in a new software package called momi (MOran Models for Inference). Through an empirical study we demonstrate our improvements to numerical stability and computational complexity.

  7. The SUMO project I. A survey of multiple populations in globular clusters

    Monelli, M.; Milone, A. P.; Stetson, P. B.; Marino, A. F.; Cassisi, S.; del Pino Molina, A.; Salaris, M.; Aparicio, A.; Asplund, M.; Grundahl, F.; Piotto, G.; Weiss, A.; Carrera, R.; Cebrián, M.; Murabito, S.; Pietrinferni, A.; Sbordone, L.

    2013-05-01

    We present a general overview and the first results of the SUMO project (a SUrvey of Multiple pOpulations in Globular Clusters). The objective of this survey is the study of multiple stellar populations in the largest sample of globular clusters homogeneously analysed to date. To this aim we obtained high signal-to-noise (S/N > 50) photometry for main sequence stars with mass down to ˜0.5 M⊙ in a large sample of clusters using both archival and proprietary U, B, V and I data from ground-based telescopes. In this paper, we focus on the occurrence of multiple stellar populations in 23 clusters. We define a new photometric index, cU, B, I = (U - B) - (B - I), which turns out to be very effective for identifying multiple sequences along the red giant branch (RGB). We found that in the V-cU, B, I diagram all clusters presented in this paper show broadened or multimodal RGBs, with the presence of two or more components. We found a direct connection with the chemical properties of different sequences, which display different abundances of light elements (O, Na, C, N and Al). The cU, B, I index is also a powerful tool for identifying distinct sequences of stars along the horizontal branch and, for the first time in the case of NGC 104 (47 Tuc), along the asymptotic giant branch. Our results demonstrate that (i) the presence of more than two stellar populations is a common feature amongst globular clusters, as already highlighted in previous work; (ii) multiple sequences with different chemical contents can be easily identified by using standard Johnson photometry obtained with ground-based facilities; (iii) in the study of globular cluster multiple stellar populations the cU, B, I index is an alternative to spectroscopy, and has the advantage of larger statistics.

  8. Multiple Modes of Cell Death Discovered in a Prokaryotic (Cyanobacterial Endosymbiont.

    Weiwen Zheng

    Full Text Available Programmed cell death (PCD is a genetically-based cell death mechanism with vital roles in eukaryotes. Although there is limited consensus on similar death mode programs in prokaryotes, emerging evidence suggest that PCD events are operative. Here we present cell death events in a cyanobacterium living endophytically in the fern Azolla microphylla, suggestive of PCD. This symbiosis is characterized by some unique traits such as a synchronized development, a vertical transfer of the cyanobacterium between plant generations, and a highly eroding cyanobacterial genome. A combination of methods was used to identify cell death modes in the cyanobacterium. Light- and electron microscopy analyses showed that the proportion of cells undergoing cell death peaked at 53.6% (average 20% of the total cell population, depending on the cell type and host developmental stage. Biochemical markers used for early and late programmed cell death events related to apoptosis (Annexin V-EGFP and TUNEL staining assays, together with visualization of cytoskeleton alterations (FITC-phalloidin staining, showed that all cyanobacterial cell categories were affected by cell death. Transmission electron microscopy revealed four modes of cell death: apoptotic-like, autophagic-like, necrotic-like and autolytic-like. Abiotic stresses further enhanced cell death in a dose and time dependent manner. The data also suggest that dynamic changes in the peptidoglycan cell wall layer and in the cytoskeleton distribution patterns may act as markers for the various cell death modes. The presence of a metacaspase homolog (domain p20 further suggests that the death modes are genetically programmed. It is therefore concluded that multiple, likely genetically programmed, cell death modes exist in cyanobacteria, a finding that may be connected with the evolution of cell death in the plant kingdom.

  9. Multiple Modes of Cell Death Discovered in a Prokaryotic (Cyanobacterial) Endosymbiont

    Zheng, Weiwen; Rasmussen, Ulla; Zheng, Siping; Bao, Xiaodong; Chen, Bin; Gao, Yuan; Guan, Xiong; Larsson, John; Bergman, Birgitta

    2013-01-01

    Programmed cell death (PCD) is a genetically-based cell death mechanism with vital roles in eukaryotes. Although there is limited consensus on similar death mode programs in prokaryotes, emerging evidence suggest that PCD events are operative. Here we present cell death events in a cyanobacterium living endophytically in the fern Azolla microphylla, suggestive of PCD. This symbiosis is characterized by some unique traits such as a synchronized development, a vertical transfer of the cyanobacterium between plant generations, and a highly eroding cyanobacterial genome. A combination of methods was used to identify cell death modes in the cyanobacterium. Light- and electron microscopy analyses showed that the proportion of cells undergoing cell death peaked at 53.6% (average 20%) of the total cell population, depending on the cell type and host developmental stage. Biochemical markers used for early and late programmed cell death events related to apoptosis (Annexin V-EGFP and TUNEL staining assays), together with visualization of cytoskeleton alterations (FITC-phalloidin staining), showed that all cyanobacterial cell categories were affected by cell death. Transmission electron microscopy revealed four modes of cell death: apoptotic-like, autophagic-like, necrotic-like and autolytic-like. Abiotic stresses further enhanced cell death in a dose and time dependent manner. The data also suggest that dynamic changes in the peptidoglycan cell wall layer and in the cytoskeleton distribution patterns may act as markers for the various cell death modes. The presence of a metacaspase homolog (domain p20) further suggests that the death modes are genetically programmed. It is therefore concluded that multiple, likely genetically programmed, cell death modes exist in cyanobacteria, a finding that may be connected with the evolution of cell death in the plant kingdom. PMID:23822984

  10. First evidence of multiple populations along the AGB from Strömgren photometry

    Gruyters, Pieter; Casagrande, Luca; Milone, Antonino P.; Hodgkin, Simon T.; Serenelli, Aldo; Feltzing, Sofia

    2017-07-01

    Spectroscopic studies have demonstrated that nearly all Galactic globular clusters (GCs) harbour multiple stellar populations with different chemical compositions. Moreover, colour-magnitude diagrams based exclusively on Strömgrem photometry have allowed us to identify and characterise multiple populations along the RGB of a large number of clusters. In this paper we show for the first time that Strömgren photometry is also very efficient at identifying multiple populations along the AGB, and demonstrate that the AGB of M 3, M 92, NGC 362, NGC 1851, and NGC 6752 are not consistent with a single stellar population. We also provide a catalogue of RGB and AGB stars photometrically identified in these clusters for further spectroscopic follow-up studies. We combined photometry and elemental abundances from the literature for RGB and AGB stars in NGC 6752 where the presence of multiple populations along the AGB has been widely debated. We find that, while the MS, SGB, and RGB host three stellar populations with different helium and light element abundances, only two populations of AGB stars are present in the cluster. These results are consistent with standard evolutionary theory. Based on observations made with the Isaac Newton Telescope operated on the island of La Palma by the Isaac Newton Group in the Spanish Observatorio del Roque de los Muchachos of the Instituto de Astrofísica de Canarias.Full Tables B.1 and B.2 are only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (http://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/603/A37

  11. Genetic and demographic responses of mosquitofish (Gambusia holbrooki) populations exposed to mercury for multiple generations

    Tatara, C.P.; Mulvey, M.; Newman, M.C.

    1999-12-01

    Genetic and demographic responses of mosquitofish were examined after multiple generations of exposure to mercury. Previous studies of acute lethal exposures of mosquitofish to either mercury or arsenic demonstrated a consistent correlation between time to death and genotype at the glucosephosphate isomerase-2 (Gpi-2) locus. A mesocosm study involving mosquitofish populations exposed to mercury for 111 d showed significant female sexual selection and fecundity selection at the Gpi-2 locus. Here the mesocosm study was extended to populations exposed to mercury for several (approx. four) generations. After 2 years, control and mercury-exposed populations met Hardy-Weinberg expectations and showed no evidence of genetic bottlenecks. The mean number of heterozygous loci did not differ significantly between the mercury-exposed and control populations. Significant differences in allele frequencies at the Gpi-2 locus were observed between the mercury-exposed and control populations. Relative to the initial and control allele frequencies, the GPI-2{sup 100} allele frequency was lower, the Gpi-2{sup 66} allele frequency increased, but the Gpi-2{sup 38} allele frequency did not change in mercury-exposed populations. No significant differences were found in standard length, weight, sex ratio, or age class ratio between the control and mercury-exposed populations. Allele frequency changes at the Gpi-2 locus suggest population-level response to chronic mercury exposure. Changes in allele frequency may be useful as indicators of population response to contaminants, provided that the population in question is well understood.

  12. Epidemiology of multiple congenital anomalies in Europe: A EUROCAT population-based registry study

    Calzolari, Elisa; Barisic, Ingeborg; Loane, Maria

    2014-01-01

    BACKGROUND: This study describes the prevalence, associated anomalies, and demographic characteristics of cases of multiple congenital anomalies (MCA) in 19 population-based European registries (EUROCAT) covering 959,446 births in 2004 and 2010. METHODS: EUROCAT implemented a computer algorithm f...

  13. Phylogeographic and population genetic analyses reveal multiple species of Boa and independent origins of insular dwarfism.

    Card, Daren C; Schield, Drew R; Adams, Richard H; Corbin, Andrew B; Perry, Blair W; Andrew, Audra L; Pasquesi, Giulia I M; Smith, Eric N; Jezkova, Tereza; Boback, Scott M; Booth, Warren; Castoe, Todd A

    2016-09-01

    Boa is a Neotropical genus of snakes historically recognized as monotypic despite its expansive distribution. The distinct morphological traits and color patterns exhibited by these snakes, together with the wide diversity of ecosystems they inhabit, collectively suggest that the genus may represent multiple species. Morphological variation within Boa also includes instances of dwarfism observed in multiple offshore island populations. Despite this substantial diversity, the systematics of the genus Boa has received little attention until very recently. In this study we examined the genetic structure and phylogenetic relationships of Boa populations using mitochondrial sequences and genome-wide SNP data obtained from RADseq. We analyzed these data at multiple geographic scales using a combination of phylogenetic inference (including coalescent-based species delimitation) and population genetic analyses. We identified extensive population structure across the range of the genus Boa and multiple lines of evidence for three widely-distributed clades roughly corresponding with the three primary land masses of the Western Hemisphere. We also find both mitochondrial and nuclear support for independent origins and parallel evolution of dwarfism on offshore island clusters in Belize and Cayos Cochinos Menor, Honduras. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Density dependence governs when population responses to multiple stressors are magnified or mitigated.

    Hodgson, Emma E; Essington, Timothy E; Halpern, Benjamin S

    2017-10-01

    Population endangerment typically arises from multiple, potentially interacting anthropogenic stressors. Extensive research has investigated the consequences of multiple stressors on organisms, frequently focusing on individual life stages. Less is known about population-level consequences of exposure to multiple stressors, especially when exposure varies through life. We provide the first theoretical basis for identifying species at risk of magnified effects from multiple stressors across life history. By applying a population modeling framework, we reveal conditions under which population responses from stressors applied to distinct life stages are either magnified (synergistic) or mitigated. We find that magnification or mitigation critically depends on the shape of density dependence, but not the life stage in which it occurs. Stressors are always magnified when density dependence is linear or concave, and magnified or mitigated when it is convex. Using Bayesian numerical methods, we estimated the shape of density dependence for eight species across diverse taxa, finding support for all three shapes. © 2017 by the Ecological Society of America.

  15. T-cell libraries allow simple parallel generation of multiple peptide-specific human T-cell clones.

    Theaker, Sarah M; Rius, Cristina; Greenshields-Watson, Alexander; Lloyd, Angharad; Trimby, Andrew; Fuller, Anna; Miles, John J; Cole, David K; Peakman, Mark; Sewell, Andrew K; Dolton, Garry

    2016-03-01

    Isolation of peptide-specific T-cell clones is highly desirable for determining the role of T-cells in human disease, as well as for the development of therapies and diagnostics. However, generation of monoclonal T-cells with the required specificity is challenging and time-consuming. Here we describe a library-based strategy for the simple parallel detection and isolation of multiple peptide-specific human T-cell clones from CD8(+) or CD4(+) polyclonal T-cell populations. T-cells were first amplified by CD3/CD28 microbeads in a 96U-well library format, prior to screening for desired peptide recognition. T-cells from peptide-reactive wells were then subjected to cytokine-mediated enrichment followed by single-cell cloning, with the entire process from sample to validated clone taking as little as 6 weeks. Overall, T-cell libraries represent an efficient and relatively rapid tool for the generation of peptide-specific T-cell clones, with applications shown here in infectious disease (Epstein-Barr virus, influenza A, and Ebola virus), autoimmunity (type 1 diabetes) and cancer. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  16. Osteoprotegerin is bound, internalized, and degraded by multiple myeloma cells

    Standal, Therese; Seidel, Carina; Hjertner, Øyvind

    2002-01-01

    Multiple myeloma (MM) is a hematologic malignancy characterized by accumulation of plasma cells in the bone marrow (BM). Bone destruction is a complication of the disease and is usually associated with severe morbidity. The balance between receptor activator of nuclear factor-kappaB (NF-kappaB......) ligand and osteoprotegerin (OPG) is of major importance in bone homeostasis. We have recently shown that serum OPG levels are lower in patients with myeloma than in healthy individuals. Here we show that myeloma cells can bind, internalize, and degrade OPG, thereby providing a possible explanation...... for the lower levels of OPG in the BM of patients with MM. This process is dependent on interaction of OPG with heparan sulfates on the myeloma cells. The results suggest a novel biologic mechanism for the bone disease associated with MM and that treatment of the bone disease with OPG lacking the heparin...

  17. Multiple cell common pressure vessel nickel hydrogen battery

    Zagrodnik, Jeffrey P.; Jones, Kenneth R.

    1991-01-01

    A multiple cell common pressure vessel (CPV) nickel hydrogen battery was developed that offers significant weight, volume, cost, and interfacing advantages over the conventional individual pressure vessel (IPV) nickel hydrogen configuration that is currently used for aerospace applications. The baseline CPV design was successfully demonstrated though the testing of a 26 cell prototype, which completed over 7,000 44 percent depth of discharge LEO cycles. Two-cell boilerplate batteries have now exceeded 12,500 LEO cycles in ongoing laboratory tests. CPV batteries using both nominal 5 and 10 inch diameter vessels are currently available. The flexibility of the design allows these diameters to provide a broad capability for a variety of space applications.

  18. Controlling the diversity of cell populations in a stem cell culture

    Heo, Inha; Clevers, Hans

    2015-01-01

    Culturing intestinal stem cells into 3D organoids results in heterogeneous cell populations, reflecting the in vivo cell type diversity. In a recent paper published in Nature, Wang et al. established a culture condition for a highly homogeneous population of intestinal stem cells.

  19. Combining multiple sources of data to inform conservation of Lesser Prairie-Chicken populations

    Ross, Beth; Haukos, David A.; Hagen, Christian A.; Pitman, James

    2018-01-01

    Conservation of small populations is often based on limited data from spatially and temporally restricted studies, resulting in management actions based on an incomplete assessment of the population drivers. If fluctuations in abundance are related to changes in weather, proper management is especially important, because extreme weather events could disproportionately affect population abundance. Conservation assessments, especially for vulnerable populations, are aided by a knowledge of how extreme events influence population status and trends. Although important for conservation efforts, data may be limited for small or vulnerable populations. Integrated population models maximize information from various sources of data to yield population estimates that fully incorporate uncertainty from multiple data sources while allowing for the explicit incorporation of environmental covariates of interest. Our goal was to assess the relative influence of population drivers for the Lesser Prairie-Chicken (Tympanuchus pallidicinctus) in the core of its range, western and southern Kansas, USA. We used data from roadside lek count surveys, nest monitoring surveys, and survival data from telemetry monitoring combined with climate (Palmer drought severity index) data in an integrated population model. Our results indicate that variability in population growth rate was most influenced by variability in juvenile survival. The Palmer drought severity index had no measurable direct effects on adult survival or mean number of offspring per female; however, there were declines in population growth rate following severe drought. Because declines in population growth rate occurred at a broad spatial scale, declines in response to drought were likely due to decreases in chick and juvenile survival rather than emigration outside of the study area. Overall, our model highlights the importance of accounting for environmental and demographic sources of variability, and provides a thorough

  20. On interfaces between cell populations with different mobilities

    Lorenzi, Tommaso

    2016-11-18

    Partial differential equations describing the dynamics of cell population densities from a fluid mechanical perspective can model the growth of avascular tumours. In this framework, we consider a system of equations that describes the interaction between a population of dividing cells and a population of non-dividing cells. The two cell populations are characterised by different mobilities. We present the results of numerical simulations displaying two-dimensional spherical waves with sharp interfaces between dividing and non-dividing cells. Furthermore, we numerically observe how different ratios between the mobilities change the morphology of the interfaces, and lead to the emergence of finger-like patterns of invasion above a threshold. Motivated by these simulations, we study the existence of one-dimensional travelling wave solutions.

  1. Kron 3: a fourth intermediate age cluster in the SMC with evidence of multiple populations

    Hollyhead, K.; Lardo, C.; Kacharov, N.; Bastian, N.; Hilker, M.; Rejkuba, M.; Koch, A.; Grebel, E. K.; Georgiev, I.

    2018-05-01

    We present the results of a spectroscopic study of the intermediate age (≈6.5 Gyr) massive cluster Kron 3 in the Small Magellanic Cloud. We measure CN and CH band strengths (at ≃3839 and 4300 Å, respectively) using VLT FORS2 spectra of 16 cluster members and find a sub-population of five stars enriched in nitrogen. We conclude that this is evidence for multiple populations in Kron 3, the fourth intermediate age cluster, after Lindsay 1, NGC 416 and NGC 339 (ages 6-8 Gyr), to display this phenomenon originally thought to be a unique characteristic of old globular clusters. At ≈6.5 Gyr this is one of the youngest clusters with multiple populations, indicating that the mechanism responsible for their onset must operate until a redshift of at least 0.75, much later than the peak of globular cluster formation at redshift ˜3.

  2. Localized extramedullary relapse after autologous hematopoietic stem cell transplantation in multiple myeloma

    Erkus, Muhan; Meteoglu, Ibrahim; Bolaman, Zahit; Kadikoylu, Gurhan

    2005-01-01

    Extramedullary plasmacytomas are rare manifestation of plasma cell malignancies. After hematopoietic stem cell transplantation HSCT, presentation of localized plasmacytoma with extramedullary growth is very unusual. We report a case of a 56-year-old woman with Dune-Salmon stage IIIA immunoglobulin A-kappa multiple myeloma, which presented 120 days after autologous HSCT with extramedullary plasmacytoma arising from a lymph node in supraclavicular region. The patient had no pretransplant-history related with extramedullary disease. There was no increase of plasma cells in bone marrow or monoclonal protein in urine or serum. Aspiration smears of lymph node revealed a population of plasmacytoid cells at various stages of maturation. The patient was successfully treated with local radiotherapy and has remained progression-free for more than 20 months. (author)

  3. Mechanism for multiplicity of steady states with distinct cell concentration in continuous culture of mammalian cells.

    Yongky, Andrew; Lee, Jongchan; Le, Tung; Mulukutla, Bhanu Chandra; Daoutidis, Prodromos; Hu, Wei-Shou

    2015-07-01

    Continuous culture for the production of biopharmaceutical proteins offers the possibility of steady state operations and thus more consistent product quality and increased productivity. Under some conditions, multiplicity of steady states has been observed in continuous cultures of mammalian cells, wherein with the same dilution rate and feed nutrient composition, steady states with very different cell and product concentrations may be reached. At those different steady states, cells may exhibit a high glycolysis flux with high lactate production and low cell concentration, or a low glycolysis flux with low lactate and high cell concentration. These different steady states, with different cell concentration, also have different productivity. Developing a mechanistic understanding of the occurrence of steady state multiplicity and devising a strategy to steer the culture toward the desired steady state is critical. We establish a multi-scale kinetic model that integrates a mechanistic intracellular metabolic model and cell growth model in a continuous bioreactor. We show that steady state multiplicity exists in a range of dilution rate in continuous culture as a result of the bistable behavior in glycolysis. The insights from the model were used to devise strategies to guide the culture to the desired steady state in the multiple steady state region. The model provides a guideline principle in the design of continuous culture processes of mammalian cells. © 2015 Wiley Periodicals, Inc.

  4. Nestin Reporter Transgene Labels Multiple Central Nervous System Precursor Cells

    Avery S. Walker

    2010-01-01

    Full Text Available Embryonic neuroepithelia and adult subventricular zone (SVZ stem and progenitor cells express nestin. We characterized a transgenic line that expresses enhanced green fluorescent protein (eGFP specified to neural tissue by the second intronic enhancer of the nestin promoter that had several novel features. During embryogenesis, the dorsal telencephalon contained many and the ventral telencephalon few eGFP+ cells. eGFP+ cells were found in postnatal and adult neurogenic regions. eGFP+ cells in the SVZ expressed multiple phenotype markers, glial fibrillary acidic protein, Dlx, and neuroblast-specific molecules suggesting the transgene is expressed through the lineage. eGFP+ cell numbers increased in the SVZ after cortical injury, suggesting this line will be useful in probing postinjury neurogenesis. In non-neurogenic regions, eGFP was strongly expressed in oligodendrocyte progenitors, but not in astrocytes, even when they were reactive. This eGFP+ mouse will facilitate studies of proliferative neuroepithelia and adult neurogenesis, as well as of parenchymal oligodendrocytes.

  5. Incidence of multiple sclerosis among European Economic Area populations, 1985-2009: the framework for monitoring

    2013-01-01

    Background A debate surrounding multiple sclerosis epidemiology has centred on time-related incidence increases and the need of monitoring. The purpose of this study is to reassess multiple sclerosis incidence in the European Economic Area. Methods We conducted a systematic review of literature from 1965 onwards and integrated elements of original research, including requested or completed data by surveys authors and specific analyses. Results The review of 5323 documents yielded ten studies for age- and sex-specific analyses, and 21 studies for time-trend analysis of single data sets. After 1985, the incidence of multiple sclerosis ranged from 1.12 to 6.96 per 100,000 population, was higher in females, tripled with latitude, and doubled with study midpoint year. The north registered increasing trends from the 1960s and 1970s, with a historic drop in the Faroe Islands, and fairly stable data in the period 1980-2000; incidence rose in Italian and French populations in the period 1970-2000, in Evros (Greece) in the 1980s, and in the French West Indies in around 2000. Conclusions We conclude that the increase in multiple sclerosis incidence is only apparent, and that it is not specific to women. Monitoring of multiple sclerosis incidence might be appropriate for the European Economic Area. PMID:23758972

  6. Comparison of multiple transcriptomes exposes unified and divergent features of quiescent and activated skeletal muscle stem cells

    Pietrosemoli, Natalia; Mella, Sébastien; Yennek, Siham

    2017-01-01

    of identifying quiescent markers. Here, we focused on the quiescent cell state and generated new transcriptome profiles that include subfractionations of adult satellite cell populations, and an artificially induced prenatal quiescent state, to identify core signatures for quiescent and proliferating. Methods......Background: Skeletal muscle satellite (stem) cells are quiescent in adult mice and can undergo multiple rounds of proliferation and self-renewal following muscle injury. Several labs have profiled transcripts of myogenic cells during the developmental and adult myogenesis with the aim...... with true in vivo quiescence from those that are first responding genes due to disruption of the stem cell niche....

  7. On interfaces between cell populations with different mobilities

    Lorenzi, Tommaso; Lorz, Alexander; Perthame, Benoit

    2016-01-01

    Partial differential equations describing the dynamics of cell population densities from a fluid mechanical perspective can model the growth of avascular tumours. In this framework, we consider a system of equations that describes the interaction

  8. Pregnancy persistently affects memory T cell populations

    Kieffer, Tom E. C.; Faas, Marijke M.; Scherjon, Sicco A.; Prins, Jelmer R.

    Pregnancy is an immune challenge to the maternal immune system. The effects of pregnancy on maternal immunity and particularly on memory T cells during and after pregnancy are not fully known. This observational study aims to show the short term and the long term effects of pregnancy on the

  9. Emergence of cytotoxic resistance in cancer cell populations: Single-cell mechanisms and population-level consequences

    Lorenzi, Tommaso; Chisholm, Rebecca H.; Lorz, Alexander; Neves de Almeida, Luís; Clairambault, Jean; Larsen, Annette K.; Escargueil, Alexandre

    2016-01-01

    We formulate an individual-based model and a population model of phenotypic evolution, under cytotoxic drugs, in a cancer cell population structured by the expression levels of survival-potential and proliferation-potential. We apply these models to a recently studied experimental system. Our results suggest that mechanisms based on fundamental laws of biology can reversibly push an actively-proliferating, and drug-sensitive, cell population to transition into a weakly-proliferative and drug-tolerant state, which will eventually facilitate the emergence of more potent, proliferating and drug-tolerant cells.

  10. Emergence of cytotoxic resistance in cancer cell populations: Single-cell mechanisms and population-level consequences

    Lorenzi, Tommaso [Centre de Mathématiques et de Leurs Applications, ENS Cachan, CNRS, Cachan 94230 Cedex, France & INRIA-Paris-Rocquencourt, MAMBA Team, Domaine de Voluceau, BP105, 78153 Le Chesnay Cedex (France); Chisholm, Rebecca H. [School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney NSW 2052 (Australia); Lorz, Alexander; Neves de Almeida, Luís; Clairambault, Jean [Sorbonne Universités, UPMC Univ Paris 06, UMR 7598, Laboratoire Jacques-Louis Lions, F-75005, Paris (France); CNRS, UMR 7598, Laboratoire Jacques-Louis Lions, F-75005, Paris (France); INRIA-Paris-Rocquencourt, MAMBA Team, Domaine de Voluceau, BP105, 78153 Le Chesnay Cedex (France); Larsen, Annette K.; Escargueil, Alexandre [Sorbonne Universités, UPMC Univ Paris 06, F-75005, Paris (France); INSERM, UMR-S 938, Laboratory of “Cancer Biology and Therapeutics”, F-75012, Paris (France)

    2016-06-08

    We formulate an individual-based model and a population model of phenotypic evolution, under cytotoxic drugs, in a cancer cell population structured by the expression levels of survival-potential and proliferation-potential. We apply these models to a recently studied experimental system. Our results suggest that mechanisms based on fundamental laws of biology can reversibly push an actively-proliferating, and drug-sensitive, cell population to transition into a weakly-proliferative and drug-tolerant state, which will eventually facilitate the emergence of more potent, proliferating and drug-tolerant cells.

  11. The Mutational Landscape of Circulating Tumor Cells in Multiple Myeloma

    Yuji Mishima

    2017-04-01

    Full Text Available The development of sensitive and non-invasive “liquid biopsies” presents new opportunities for longitudinal monitoring of tumor dissemination and clonal evolution. The number of circulating tumor cells (CTCs is prognostic in multiple myeloma (MM, but there is little information on their genetic features. Here, we have analyzed the genomic landscape of CTCs from 29 MM patients, including eight cases with matched/paired bone marrow (BM tumor cells. Our results show that 100% of clonal mutations in patient BM were detected in CTCs and that 99% of clonal mutations in CTCs were present in BM MM. These include typical driver mutations in MM such as in KRAS, NRAS, or BRAF. These data suggest that BM and CTC samples have similar clonal structures, as discordances between the two were restricted to subclonal mutations. Accordingly, our results pave the way for potentially less invasive mutation screening of MM patients through characterization of CTCs.

  12. Nonequilibrium population dynamics of phenotype conversion of cancer cells.

    Joseph Xu Zhou

    Full Text Available Tumorigenesis is a dynamic biological process that involves distinct cancer cell subpopulations proliferating at different rates and interconverting between them. In this paper we proposed a mathematical framework of population dynamics that considers both distinctive growth rates and intercellular transitions between cancer cell populations. Our mathematical framework showed that both growth and transition influence the ratio of cancer cell subpopulations but the latter is more significant. We derived the condition that different cancer cell types can maintain distinctive subpopulations and we also explain why there always exists a stable fixed ratio after cell sorting based on putative surface markers. The cell fraction ratio can be shifted by changing either the growth rates of the subpopulations (Darwinism selection or by environment-instructed transitions (Lamarckism induction. This insight can help us to understand the dynamics of the heterogeneity of cancer cells and lead us to new strategies to overcome cancer drug resistance.

  13. Concise Review: Stem Cell Population Biology: Insights from Hematopoiesis.

    MacLean, Adam L; Lo Celso, Cristina; Stumpf, Michael P H

    2017-01-01

    Stem cells are fundamental to human life and offer great therapeutic potential, yet their biology remains incompletely-or in cases even poorly-understood. The field of stem cell biology has grown substantially in recent years due to a combination of experimental and theoretical contributions: the experimental branch of this work provides data in an ever-increasing number of dimensions, while the theoretical branch seeks to determine suitable models of the fundamental stem cell processes that these data describe. The application of population dynamics to biology is amongst the oldest applications of mathematics to biology, and the population dynamics perspective continues to offer much today. Here we describe the impact that such a perspective has made in the field of stem cell biology. Using hematopoietic stem cells as our model system, we discuss the approaches that have been used to study their key properties, such as capacity for self-renewal, differentiation, and cell fate lineage choice. We will also discuss the relevance of population dynamics in models of stem cells and cancer, where competition naturally emerges as an influential factor on the temporal evolution of cell populations. Stem Cells 2017;35:80-88. © 2016 AlphaMed Press.

  14. Endothelial progenitor cells display clonal restriction in multiple myeloma

    Braunstein, Marc; Özçelik, Tayfun; Bağişlar, Sevgi; Vakil, Varsha; Smith, Eric LP; Dai, Kezhi; Akyerli, Cemaliye B; Batuman, Olcay A

    2006-01-01

    In multiple myeloma (MM), increased neoangiogenesis contributes to tumor growth and disease progression. Increased levels of endothelial progenitor cells (EPCs) contribute to neoangiogenesis in MM, and, importantly, covary with disease activity and response to treatment. In order to understand the mechanisms responsible for increased EPC levels and neoangiogenic function in MM, we investigated whether these cells were clonal by determining X-chromosome inactivation (XCI) patterns in female patients by a human androgen receptor assay (HUMARA). In addition, EPCs and bone marrow cells were studied for the presence of clonotypic immunoglobulin heavy-chain (IGH) gene rearrangement, which indicates clonality in B cells; thus, its presence in EPCs would indicate a close genetic link between tumor cells in MM and endothelial cells that provide tumor neovascularization. A total of twenty-three consecutive patients who had not received chemotherapy were studied. Screening in 18 patients found that 11 displayed allelic AR in peripheral blood mononuclear cells, and these patients were further studied for XCI patterns in EPCs and hair root cells by HUMARA. In 2 patients whose EPCs were clonal by HUMARA, and in an additional 5 new patients, EPCs were studied for IGH gene rearrangement using PCR with family-specific primers for IGH variable genes (V H ). In 11 patients, analysis of EPCs by HUMARA revealed significant skewing (≥ 77% expression of a single allele) in 64% (n = 7). In 4 of these patients, XCI skewing was extreme (≥ 90% expression of a single allele). In contrast, XCI in hair root cells was random. Furthermore, PCR amplification with V H primers resulted in amplification of the same product in EPCs and bone marrow cells in 71% (n = 5) of 7 patients, while no IGH rearrangement was found in EPCs from healthy controls. In addition, in patients with XCI skewing in EPCs, advanced age was associated with poorer clinical status, unlike patients whose EPCs had random XCI

  15. Detection and Characterization of Circulating Tumour Cells in Multiple Myeloma

    Liangxuan Zhang

    2016-06-01

    Full Text Available Multiple myeloma (MM remains an incurable disease despite recent therapeutic improvements. The ability to detect and characterize MM circulating tumour cells (CTCs in peripheral blood provides an alternative to replace or augment invasive bone marrow (BM biopsies with a simple blood draw, providing real-time, clinically relevant information leading to improved disease manage‐ ment and therapy selection. Here we have developed and qualified an enrichment-free, cell-based immunofluores‐ cence MM CTC assay that utilizes an automated digital pathology algorithm to distinguish MM CTCs from white blood cells (WBCs on the basis of CD138 and CD45 expression levels, as well as a number of morphological parameters. These MM CTCs were further characterized for expression of phospho-ribosomal protein S6 (pS6 as a readout for PI3K/AKT pathway activation. Clinical feasi‐ bility of the assay was established by testing blood samples from a small cohort of patients, where we detected popu‐ lations of both CD138pos and CD138neg MM CTCs. In this study, we developed an immunofluorescent cell-based assay to detect and characterize CTCs in MM.

  16. Multiple squamous cell carcinomas within the head and neck region

    Sato, Katsuro; Hanazawa, Hideyuki; Sato, Yuichiro; Takahashi, Sugata

    2004-01-01

    Clinical features of multiple squamous cell carcinoma (SCC) cases within the head and neck that were treated in our department during the recent 10 years are discussed. Multiple SCCs arose in 6.6% of the cases with primary SCC; 67% of the cases had two carcinomas, and 33% had more than three carcinomas. The most common site of the multiple SCCs was the oral cavity (54%). The most frequent interval between treatment of previous carcinoma and diagnosis of subsequent carcinoma was simultaneous, but more than 5 years' interval was observed in 36% of the patients. The most common initial treatment of the carcinoma was irradiation, but the ratio of surgery increased for subsequent carcinomas. Prognosis of the patients with more than three carcinomas was not worse than that of patients with two carcinomas. Therefore, early diagnosis of the subsequent carcinomas based on careful long-term observation in the head and neck is necessary for follow-up of the patients with SCC of the head and neck. Treatment strategies considering the treatment of subsequent carcinomas are needed for the patients with primary head and neck SCC. (author)

  17. No Evidence for Multiple Stellar Populations in the Low-mass Galactic Globular Cluster E 3

    Salinas, Ricardo; Strader, Jay

    2015-08-01

    Multiple stellar populations are a widespread phenomenon among Galactic globular clusters. Even though the origin of the enriched material from which new generations of stars are produced remains unclear, it is likely that self-enrichment will be feasible only in clusters massive enough to retain this enriched material. We searched for multiple populations in the low mass (M˜ 1.4× {10}4 {M}⊙ ) globular cluster E3, analyzing SOAR/Goodman multi-object spectroscopy centered on the blue cyanogen (CN) absorption features of 23 red giant branch stars. We find that the CN abundance does not present the typical bimodal behavior seen in clusters hosting multistellar populations, but rather a unimodal distribution that indicates the presence of a genuine single stellar population, or a level of enrichment much lower than in clusters that show evidence for two populations from high-resolution spectroscopy. E3 would be the first bona fide Galactic old globular cluster where no sign of self-enrichment is found. Based on observations obtained at the Southern Astrophysical Research (SOAR) Telescope, which is a joint project of the Ministério da Ciência, Tecnologia, e Inovação (MCTI) da República Federativa do Brasil, the US National Optical Astronomy Observatory (NOAO), the University of North Carolina at Chapel Hill (UNC), and Michigan State University (MSU).

  18. Phosphoinositide protein kinase PDPK1 is a crucial cell signaling mediator in multiple myeloma.

    Chinen, Yoshiaki; Kuroda, Junya; Shimura, Yuji; Nagoshi, Hisao; Kiyota, Miki; Yamamoto-Sugitani, Mio; Mizutani, Shinsuke; Sakamoto, Natsumi; Ri, Masaki; Kawata, Eri; Kobayashi, Tsutomu; Matsumoto, Yosuke; Horiike, Shigeo; Iida, Shinsuke; Taniwaki, Masafumi

    2014-12-15

    Multiple myeloma is a cytogenetically/molecularly heterogeneous hematologic malignancy that remains mostly incurable, and the identification of a universal and relevant therapeutic target molecule is essential for the further development of therapeutic strategy. Herein, we identified that 3-phosphoinositide-dependent protein kinase 1 (PDPK1), a serine threonine kinase, is expressed and active in all eleven multiple myeloma-derived cell lines examined regardless of the type of cytogenetic abnormality, the mutation state of RAS and FGFR3 genes, or the activation state of ERK and AKT. Our results revealed that PDPK1 is a pivotal regulator of molecules that are essential for myelomagenesis, such as RSK2, AKT, c-MYC, IRF4, or cyclin Ds, and that PDPK1 inhibition caused the growth inhibition and the induction of apoptosis with the activation of BIM and BAD, and augmented the in vitro cytotoxic effects of antimyeloma agents in myeloma cells. In the clinical setting, PDPK1 was active in myeloma cells of approximately 90% of symptomatic patients at diagnosis, and the smaller population of patients with multiple myeloma exhibiting myeloma cells without active PDPK1 showed a significantly less frequent proportion of the disease stage III by the International Staging System and a significantly more favorable prognosis, including the longer overall survival period and the longer progression-free survival period by bortezomib treatment, than patients with active PDPK1, suggesting that PDPK1 activation accelerates the disease progression and the resistance to treatment in multiple myeloma. Our study demonstrates that PDPK1 is a potent and a universally targetable signaling mediator in multiple myeloma regardless of the types of cytogenetic/molecular profiles. ©2014 American Association for Cancer Research.

  19. Racial disparities in incidence and outcome in multiple myeloma: a population-based study

    Waxman, Adam J.; Mink, Pamela J.; Devesa, Susan S.; Anderson, William F.; Weiss, Brendan M.; Kristinsson, Sigurdur Y.; McGlynn, Katherine A.; Landgren, Ola

    2010-01-01

    Multiple myeloma (MM) is the most common hematologic malignancy in blacks. Some prior studies suggest inferior survival in blacks; others suggest similar survival. Using the original 9 Surveillance, Epidemiology, and End Results registries, we conducted a large-scale population-based study including 5798 black and 28 939 white MM patients diagnosed 1973-2005, followed through 2006. Age-adjusted incidence rates, disease-specific survival, and relative survival rates were calculated by race, ag...

  20. A descriptive study of plasma cell dyscrasias in Egyptian population

    Kassem, N.M.; Kassem, H.A.; EL Zawam, H.; EL Nahas, T.; Abd El Azeeim, H.; Abd El Azeeim; El Husseiny, N.M.

    2014-01-01

    Background: Plasma cell dyscrasias (PCDs) refer to a spectrum of disorders characterized by the monoclonal proliferation of lymphoplasmacytic cells in the bone marrow and, sometimes, tissue deposition of monoclonal immunoglobulins or their components. These disorders include multiple myeloma (MM) and Waldenstrom’s macroglobulinemia, as well as rare conditions such as light-chain deposition disease (LCDD) and heavy-chain diseases (HCDs). The worldwide annual incidence of MM is estimated at 86,000, which is approximately 0.8% of all new cancer cases. Purpose: Our retrospective study aims to highlight the immunologic and epidemiological features of PCDs mainly MM in Egyptian patients and compare our results with those of other populations. Methods: Two hundred seventeen Egyptian patients with PCD were enrolled in the study. Serum, urine protein electrophoresis and immunofixation were used to demonstrate M protein. Results: One hundred thirty-eight patients (63.6%) had IgG monoclonal band, 38 patients (17.5%) had IgA, 12 patients (5.5%) had Waldenstrom’s macroglobulinemia (IgM monoclonal band) and 29 patients (13.4%) were light chain myeloma. One hundred fifty-one (70%) were Kappa chain positive and 66 patients (30%) were lumbda positive. Conventional cytogenetics was available for 40 patients; of them12 patients (30%) showed 13q-. Mean OS was 37.5 months (1-84 months). Survival analysis was statistically insignificant according to age, sex and ISS or type of treatment (P value >0.05). Conclusion: Long term follow up is required to further define the role of different therapeutic lines of treatment including ASCT in the various stages of PCD based on OS data.

  1. A descriptive study of plasma cell dyscrasias in Egyptian population.

    Kassem, Neemat M; El Zawam, Hamdy; Kassem, Heba A; El Nahas, Tamer; El Husseiny, Noha M; El Azeeim, Hamdy Abd

    2014-06-01

    Plasma cell dyscrasias (PCDs) refer to a spectrum of disorders characterized by the monoclonal proliferation of lymphoplasmacytic cells in the bone marrow and, sometimes, tissue deposition of monoclonal immunoglobulins or their components. These disorders include multiple myeloma (MM) and Waldenström's macroglobulinemia, as well as rare conditions such as light-chain deposition disease (LCDD) and heavy-chain diseases (HCDs). The worldwide annual incidence of MM is estimated at 86,000, which is approximately 0.8% of all new cancer cases. Our retrospective study aims to highlight the immunologic and epidemiological features of PCDs mainly MM in Egyptian patients and compare our results with those of other populations. Two hundred seventeen Egyptian patients with PCD were enrolled in the study. Serum, urine protein electrophoresis and immunofixation were used to demonstrate M protein. One hundred thirty-eight patients (63.6%) had IgG monoclonal band, 38 patients (17.5%) had IgA, 12 patients (5.5%) had Waldenström's macroglobulinemia (IgM monoclonal band) and 29 patients (13.4%) were light chain myeloma. One hundred fifty-one (70%) were Kappa chain positive and 66 patients (30%) were lumbda positive. Conventional cytogenetics was available for 40 patients; of them12 patients (30%) showed 13q-. Mean OS was 37.5months (1-84months). Survival analysis was statistically insignificant according to age, sex and ISS or type of treatment (P value>0.05). Long term follow up is required to further define the role of different therapeutic lines of treatment including ASCT in the various stages of PCD based on OS data. Copyright © 2013. Production and hosting by Elsevier B.V.

  2. HIV Cell-to-Cell Spread Results in Earlier Onset of Viral Gene Expression by Multiple Infections per Cell.

    Mikaël Boullé

    2016-11-01

    Full Text Available Cell-to-cell spread of HIV, a directed mode of viral transmission, has been observed to be more rapid than cell-free infection. However, a mechanism for earlier onset of viral gene expression in cell-to-cell spread was previously uncharacterized. Here we used time-lapse microscopy combined with automated image analysis to quantify the timing of the onset of HIV gene expression in a fluorescent reporter cell line, as well as single cell staining for infection over time in primary cells. We compared cell-to-cell spread of HIV to cell-free infection, and limited both types of transmission to a two-hour window to minimize differences due to virus transit time to the cell. The mean time to detectable onset of viral gene expression in cell-to-cell spread was accelerated by 19% in the reporter cell line and by 35% in peripheral blood mononuclear cells relative to cell-free HIV infection. Neither factors secreted by infected cells, nor contact with infected cells in the absence of transmission, detectably changed onset. We recapitulated the earlier onset by infecting with multiple cell-free viruses per cell. Surprisingly, the acceleration in onset of viral gene expression was not explained by cooperativity between infecting virions. Instead, more rapid onset was consistent with a model where the fastest expressing virus out of the infecting virus pool sets the time for infection independently of the other co-infecting viruses.

  3. M13 multiple stellar populations seen with the eyes of Strömgren photometry

    Savino, A.; Massari, D.; Bragaglia, A.; Dalessandro, E.; Tolstoy, E.

    2018-03-01

    We present a photometric study of M13 multiple stellar populations over a wide field of view, covering approximately 6.5 half-light radii, using archival Isaac Newton Telescope observations to build an accurate multiband Strömgren catalogue. The use of the Strömgren index cy permits us to separate the multiple populations of M13 on the basis of their position on the red giant branch. The comparison with medium and high resolution spectroscopic analysis confirms the robustness of our selection criterion. To determine the radial distribution of stars in M13, we complemented our data set with Hubble Space Telescope observations of the cluster core, to compensate for the effect of incompleteness affecting the most crowded regions. From the analysis of the radial distributions, we do not find any significant evidence of spatial segregation. Some residuals may be present in the external regions where we observe only a small number of stars. This finding is compatible with the short dynamical time-scale of M13 and represents, to date, one of the few examples of fully spatially mixed multiple populations in a massive globular cluster.

  4. Experimental depletion of different renal interstitial cell populations

    Bohman, S.O.; Sundelin, B.; Forsum, U.; Tribukait, B.

    1988-01-01

    To define different populations of renal interstitial cells and investigate some aspects of their function, we studied the kidneys of normal rats and rats with hereditary diabetes insipidus (DI, Brattleboro) after experimental manipulations expected to alter the number of interstitial cells. DI rats showed an almost complete loss of interstitial cells in their renal papillae after treatment with a high dose of vasopressin. In spite of the lack of interstitial cells, the animals concentrated their urine to the same extent as vasopressin-treated normal rats, indicating that the renomedullary interstitial cells do not have an important function in concentrating the urine. The interstitial cells returned nearly to normal within 1 week off vasopressin treatment, suggesting a rapid turnover rate of these cells. To further distinguish different populations of interstitial cells, we studied the distribution of class II MHC antigen expression in the kidneys of normal and bone-marrow depleted Wistar rats. Normal rats had abundant class II antigen-positive interstitial cells in the renal cortex and outer medulla, but not in the inner medulla (papilla). Six days after 1000 rad whole body irradiation, the stainable cells were almost completely lost, but electron microscopic morphometry showed a virtually unchanged volume density of interstitial cells in the cortex and outer medulla, as well as the inner medulla. Thus, irradiation abolished the expression of the class II antigen but caused no significant depletion of interstitial cells

  5. Emergence of cytotoxic resistance in cancer cell populations*

    Lorenzi Tommaso

    2015-01-01

    Full Text Available We formulate an individual-based model and an integro-differential model of phenotypic evolution, under cytotoxic drugs, in a cancer cell population structured by the expression levels of survival-potential and proliferation-potential. We apply these models to a recently studied experimental system. Our results suggest that mechanisms based on fundamental laws of biology can reversibly push an actively-proliferating, and drug-sensitive, cell population to transition into a weakly-proliferative and drug-tolerant state, which will eventually facilitate the emergence of more potent, proliferating and drug-tolerant cells.

  6. Dielectrophoretic capture of low abundance cell population using thick electrodes

    Marchalot, Julien; Chateaux, Jean-François; Faivre, Magalie; Mertani, Hichem C.; Ferrigno, Rosaria; Deman, Anne-Laure

    2015-01-01

    Enrichment of rare cell populations such as Circulating Tumor Cells (CTCs) is a critical step before performing analysis. This paper presents a polymeric microfluidic device with integrated thick Carbon-PolyDimethylSiloxane composite (C-PDMS) electrodes designed to carry out dielectrophoretic (DEP) trapping of low abundance biological cells. Such conductive composite material presents advantages over metallic structures. Indeed, as it combines properties of both the matrix and doping particle...

  7. Curcumin mediates anticancer effects by modulating multiple cell signaling pathways.

    Kunnumakkara, Ajaikumar B; Bordoloi, Devivasha; Harsha, Choudhary; Banik, Kishore; Gupta, Subash C; Aggarwal, Bharat B

    2017-08-01

    Curcumin, a component of a spice native to India, was first isolated in 1815 by Vogel and Pelletier from the rhizomes of Curcuma longa (turmeric) and, subsequently, the chemical structure of curcumin as diferuloylmethane was reported by Milobedzka et al. [(1910) 43., 2163-2170]. Since then, this polyphenol has been shown to exhibit antioxidant, anti-inflammatory, anticancer, antiviral, antibacterial, and antifungal activities. The current review primarily focuses on the anticancer potential of curcumin through the modulation of multiple cell signaling pathways. Curcumin modulates diverse transcription factors, inflammatory cytokines, enzymes, kinases, growth factors, receptors, and various other proteins with an affinity ranging from the pM to the mM range. Furthermore, curcumin effectively regulates tumor cell growth via modulation of numerous cell signaling pathways and potentiates the effect of chemotherapeutic agents and radiation against cancer. Curcumin can interact with most of the targets that are modulated by FDA-approved drugs for cancer therapy. The focus of this review is to discuss the molecular basis for the anticancer activities of curcumin based on preclinical and clinical findings. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  8. Human immunodeficiency virus-like particles activate multiple types of immune cells

    Sailaja, Gangadhara; Skountzou, Ioanna; Quan, Fu-Shi; Compans, Richard W.; Kang, Sang-Moo

    2007-01-01

    The rapid spread of human immunodeficiency virus (HIV) worldwide makes it a high priority to develop an effective vaccine. Since live attenuated or inactivated HIV is not likely to be approved as a vaccine due to safety concerns, HIV virus like particles (VLPs) offer an attractive alternative because they are safe due to the lack of a viral genome. Although HIV VLPs have been shown to induce humoral and cellular immune responses, it is important to understand the mechanisms by which they induce such responses and to improve their immunogenicity. We generated HIV VLPs, and VLPs containing Flt3 ligand (FL), a dendritic cell growth factor, to target VLPs to dendritic cells, and investigated the roles of these VLPs in the initiation of adaptive immune responses in vitro and in vivo. We found that HIV-1 VLPs induced maturation of dendritic cells and monocyte/macrophage populations in vitro and in vivo, with enhanced expression of maturation markers and cytokines. Dendritic cells pulsed with VLPs induced activation of splenocytes resulting in increased production of cytokines. VLPs containing FL were found to increase dendritic cells and monocyte/macrophage populations in the spleen when administered to mice. Administration of VLPs induced acute activation of multiple types of cells including T and B cells as indicated by enhanced expression of the early activation marker CD69 and down-regulation of the homing receptor CD62L. VLPs containing FL were an effective form of antigen in activating immune cells via dendritic cells, and immunization with HIV VLPs containing FL resulted in enhanced T helper type 2-like immune responses

  9. Distinct types of glial cells populate the Drosophila antenna

    Jhaveri Dhanisha

    2005-11-01

    Full Text Available Abstract Background The development of nervous systems involves reciprocal interactions between neurons and glia. In the Drosophila olfactory system, peripheral glial cells arise from sensory lineages specified by the basic helix-loop-helix transcription factor, Atonal. These glia wrap around the developing olfactory axons early during development and pattern the three distinct fascicles as they exit the antenna. In the moth Manduca sexta, an additional set of central glia migrate to the base of the antennal nerve where axons sort to their glomerular targets. In this work, we have investigated whether similar types of cells exist in the Drosophila antenna. Results We have used different P(Gal4 lines to drive Green Fluorescent Protein (GFP in distinct populations of cells within the Drosophila antenna. Mz317::GFP, a marker for cell body and perineural glia, labels the majority of peripheral glia. An additional ~30 glial cells detected by GH146::GFP do not derive from any of the sensory lineages and appear to migrate into the antenna from the brain. Their appearance in the third antennal segment is regulated by normal function of the Epidermal Growth Factor receptor and small GTPases. We denote these distinct populations of cells as Mz317-glia and GH146-glia respectively. In the adult, processes of GH146-glial cells ensheath the olfactory receptor neurons directly, while those of the Mz317-glia form a peripheral layer. Ablation of GH146-glia does not result in any significant effects on the patterning of the olfactory receptor axons. Conclusion We have demonstrated the presence of at least two distinct populations of glial cells within the Drosophila antenna. GH146-glial cells originate in the brain and migrate to the antenna along the newly formed olfactory axons. The number of cells populating the third segment of the antenna is regulated by signaling through the Epidermal Growth Factor receptor. These glia share several features of the sorting

  10. Identification of milling and baking quality QTL in multiple soft wheat mapping populations.

    Cabrera, Antonio; Guttieri, Mary; Smith, Nathan; Souza, Edward; Sturbaum, Anne; Hua, Duc; Griffey, Carl; Barnett, Marla; Murphy, Paul; Ohm, Herb; Uphaus, Jim; Sorrells, Mark; Heffner, Elliot; Brown-Guedira, Gina; Van Sanford, David; Sneller, Clay

    2015-11-01

    Two mapping approaches were use to identify and validate milling and baking quality QTL in soft wheat. Two LG were consistently found important for multiple traits and we recommend the use marker-assisted selection on specific markers reported here. Wheat-derived food products require a range of characteristics. Identification and understanding of the genetic components controlling end-use quality of wheat is important for crop improvement. We assessed the underlying genetics controlling specific milling and baking quality parameters of soft wheat including flour yield, softness equivalent, flour protein, sucrose, sodium carbonate, water absorption and lactic acid, solvent retention capacities in a diversity panel and five bi-parental mapping populations. The populations were genotyped with SSR and DArT markers, with markers specific for the 1BL.1RS translocation and sucrose synthase gene. Association analysis and composite interval mapping were performed to identify quantitative trait loci (QTL). High heritability was observed for each of the traits evaluated, trait correlations were consistent over populations, and transgressive segregants were common in all bi-parental populations. A total of 26 regions were identified as potential QTL in the diversity panel and 74 QTL were identified across all five bi-parental mapping populations. Collinearity of QTL from chromosomes 1B and 2B was observed across mapping populations and was consistent with results from the association analysis in the diversity panel. Multiple regression analysis showed the importance of the two 1B and 2B regions and marker-assisted selection for the favorable alleles at these regions should improve quality.

  11. Evolution of the stellar mass function in multiple-population globular clusters

    Vesperini, Enrico; Hong, Jongsuk; Webb, Jeremy J.; D'Antona, Franca; D'Ercole, Annibale

    2018-05-01

    We present the results of a survey of N-body simulations aimed at studying the effects of the long-term dynamical evolution on the stellar mass function (MF) of multiple stellar populations in globular clusters. Our simulations show that if first-(1G) and second-generation (2G) stars have the same initial MF (IMF), the global MFs of the two populations are affected similarly by dynamical evolution and no significant differences between the 1G and 2G MFs arise during the cluster's evolution. If the two populations have different IMFs, dynamical effects do not completely erase memory of the initial differences. Should observations find differences between the global 1G and 2G MFs, these would reveal the fingerprints of differences in their IMFs. Irrespective of whether the 1G and 2G populations have the same global IMF or not, dynamical effects can produce differences between the local (measured at various distances from the cluster centre) 1G and 2G MFs; these differences are a manifestation of the process of mass segregation in populations with different initial structural properties. In dynamically old and spatially mixed clusters, however, differences between the local 1G and 2G MFs can reveal differences between the 1G and 2G global MFs. In general, for clusters with any dynamical age, large differences between the local 1G and 2G MFs are more likely to be associated with differences in the global MF. Our study also reveals a dependence of the spatial mixing rate on the stellar mass, another dynamical consequence of the multiscale nature of multiple-population clusters.

  12. Cerebrospinal fluid B cells correlate with early brain inflammation in multiple sclerosis.

    Bettina Kuenz

    Full Text Available BACKGROUND: There is accumulating evidence from immunological, pathological and therapeutic studies that B cells are key components in the pathophysiology of multiple sclerosis (MS. METHODOLOGY/PRINCIPAL FINDINGS: In this prospective study we have for the first time investigated the differences in the inflammatory response between relapsing and progressive MS by comparing cerebrospinal fluid (CSF cell profiles from patients at the onset of the disease (clinically isolated syndrome, CIS, relapsing-remitting (RR and chronic progressive (CP MS by flow cytometry. As controls we have used patients with other neurological diseases. We have found a statistically significant accumulation of CSF mature B cells (CD19+CD138- and plasma blasts (CD19+CD138+ in CIS and RRMS. Both B cell populations were, however, not significantly increased in CPMS. Further, this accumulation of B cells correlated with acute brain inflammation measured by magnetic resonance imaging and with inflammatory CSF parameters such as the number of CSF leukocytes, intrathecal immunoglobulin M and G synthesis and intrathecal production of matrix metalloproteinase (MMP-9 and the B cell chemokine CxCL-13. CONCLUSIONS: Our data support an important role of CSF B cells in acute brain inflammation in CIS and RRMS.

  13. The reverse effects of random perturbation on discrete systems for single and multiple population models

    Kang, Li; Tang, Sanyi

    2016-01-01

    Highlights: • The discrete single species and multiple species models with random perturbation are proposed. • The complex dynamics and interesting bifurcation behavior have been investigated. • The reverse effects of random perturbation on discrete systems have been discussed and revealed. • The main results can be applied for pest control and resources management. - Abstract: The natural species are likely to present several interesting and complex phenomena under random perturbations, which have been confirmed by simple mathematical models. The important questions are: how the random perturbations influence the dynamics of the discrete population models with multiple steady states or multiple species interactions? and is there any different effects for single species and multiple species models with random perturbation? To address those interesting questions, we have proposed the discrete single species model with two stable equilibria and the host-parasitoid model with Holling type functional response functions to address how the random perturbation affects the dynamics. The main results indicate that the random perturbation does not change the number of blurred orbits of the single species model with two stable steady states compared with results for the classical Ricker model with same random perturbation, but it can strength the stability. However, extensive numerical investigations depict that the random perturbation does not influence the complexities of the host-parasitoid models compared with the results for the models without perturbation, while it does increase the period of periodic orbits doubly. All those confirm that the random perturbation has a reverse effect on the dynamics of the discrete single and multiple population models, which could be applied in reality including pest control and resources management.

  14. Genetic diversity and population structure of Lantana camara in India indicates multiple introductions and gene flow.

    Ray, A; Quader, S

    2014-05-01

    Lantana camara is a highly invasive plant, which has spread over 60 countries and island groups of Asia, Africa and Australia. In India, it was introduced in the early nineteenth century, since when it has expanded and gradually established itself in almost every available ecosystem. We investigated the genetic diversity and population structure of this plant in India in order to understand its introduction, subsequent range expansion and gene flow. A total of 179 individuals were sequenced at three chloroplast loci and 218 individuals were genotyped for six nuclear microsatellites. Both chloroplasts (nine haplotypes) and microsatellites (83 alleles) showed high genetic diversity. Besides, each type of marker confirmed the presence of private polymorphism. We uncovered low to medium population structure in both markers, and found a faint signal of isolation by distance with microsatellites. Bayesian clustering analyses revealed multiple divergent genetic clusters. Taken together, these findings (i.e. high genetic diversity with private alleles and multiple genetic clusters) suggest that Lantana was introduced multiple times and gradually underwent spatial expansion with recurrent gene flow. © 2013 German Botanical Society and The Royal Botanical Society of the Netherlands.

  15. Generation and monitoring of discrete stable random processes using multiple immigration population models

    Matthews, J O; Hopcraft, K I; Jakeman, E [Applied Mathematics Division, School of Mathematical Sciences, University of Nottingham, Nottingham, NG7 2RD (United Kingdom)

    2003-11-21

    Some properties of classical population processes that comprise births, deaths and multiple immigrations are investigated. The rates at which the immigrants arrive can be tailored to produce a population whose steady state fluctuations are described by a pre-selected distribution. Attention is focused on the class of distributions with a discrete stable law, which have power-law tails and whose moments and autocorrelation function do not exist. The separate problem of monitoring and characterizing the fluctuations is studied, analysing the statistics of individuals that leave the population. The fluctuations in the size of the population are transferred to the times between emigrants that form an intermittent time series of events. The emigrants are counted with a detector of finite dynamic range and response time. This is modelled through clipping the time series or saturating it at an arbitrary but finite level, whereupon its moments and correlation properties become finite. Distributions for the time to the first counted event and for the time between events exhibit power-law regimes that are characteristic of the fluctuations in population size. The processes provide analytical models with which properties of complex discrete random phenomena can be explored, and in addition provide generic means by which random time series encompassing a wide range of intermittent and other discrete random behaviour may be generated.

  16. Generation and monitoring of discrete stable random processes using multiple immigration population models

    Matthews, J O; Hopcraft, K I; Jakeman, E

    2003-01-01

    Some properties of classical population processes that comprise births, deaths and multiple immigrations are investigated. The rates at which the immigrants arrive can be tailored to produce a population whose steady state fluctuations are described by a pre-selected distribution. Attention is focused on the class of distributions with a discrete stable law, which have power-law tails and whose moments and autocorrelation function do not exist. The separate problem of monitoring and characterizing the fluctuations is studied, analysing the statistics of individuals that leave the population. The fluctuations in the size of the population are transferred to the times between emigrants that form an intermittent time series of events. The emigrants are counted with a detector of finite dynamic range and response time. This is modelled through clipping the time series or saturating it at an arbitrary but finite level, whereupon its moments and correlation properties become finite. Distributions for the time to the first counted event and for the time between events exhibit power-law regimes that are characteristic of the fluctuations in population size. The processes provide analytical models with which properties of complex discrete random phenomena can be explored, and in addition provide generic means by which random time series encompassing a wide range of intermittent and other discrete random behaviour may be generated

  17. Designing for multiple global user populations: increasing resource allocation efficiency for greater sustainability.

    Nadadur, G; Parkinson, M B

    2012-01-01

    This paper proposes a method to identify opportunities for increasing the efficiency of raw material allocation decisions for products that are simultaneously targeted at multiple user populations around the world. The values of 24 body measures at certain key percentiles were used to estimate the best-fitting anthropometric distributions for female and male adults in nine national populations, which were selected to represent the diverse target markets multinational companies must design for. These distributions were then used to synthesize body measure data for combined populations with a 1:1 female:male ratio. An anthropometric range metric (ARM) was proposed for assessing the variation of these body measures across the populations. At any percentile, ARM values were calculated as the percentage difference between the highest and lowest anthropometric values across the considered user populations. Based on their magnitudes, plots of ARM values computed between the 1st and 99 th percentiles for each body measure were grouped into low, medium, and high categories. This classification of body measures was proposed as a means of selecting the most suitable strategies for designing raw material-efficient products. The findings in this study and the contributions of subsequent work along these lines are expected to help achieve greater efficiencies in resource allocation in global product development.

  18. Comparing population exposure to multiple Washington earthquake scenarios for prioritizing loss estimation studies

    Wood, Nathan J.; Ratliff, Jamie L.; Schelling, John; Weaver, Craig S.

    2014-01-01

    Scenario-based, loss-estimation studies are useful for gauging potential societal impacts from earthquakes but can be challenging to undertake in areas with multiple scenarios and jurisdictions. We present a geospatial approach using various population data for comparing earthquake scenarios and jurisdictions to help emergency managers prioritize where to focus limited resources on data development and loss-estimation studies. Using 20 earthquake scenarios developed for the State of Washington (USA), we demonstrate how a population-exposure analysis across multiple jurisdictions based on Modified Mercalli Intensity (MMI) classes helps emergency managers understand and communicate where potential loss of life may be concentrated and where impacts may be more related to quality of life. Results indicate that certain well-known scenarios may directly impact the greatest number of people, whereas other, potentially lesser-known, scenarios impact fewer people but consequences could be more severe. The use of economic data to profile each jurisdiction’s workforce in earthquake hazard zones also provides additional insight on at-risk populations. This approach can serve as a first step in understanding societal impacts of earthquakes and helping practitioners to efficiently use their limited risk-reduction resources.

  19. Plasma cell morphology in multiple myeloma and related disorders.

    Ribourtout, B; Zandecki, M

    2015-06-01

    Normal and reactive plasma cells (PC) are easy to ascertain on human bone marrow films, due to their small mature-appearing nucleus and large cytoplasm, the latter usually deep blue after Giemsa staining. Cytoplasm is filled with long strands of rough endoplasmic reticulum and one large Golgi apparatus (paranuclear hof), demonstrating that PC are dedicated mainly to protein synthesis and excretion (immunoglobulin). Deregulation of the genome may induce clonal expansion of one PC that will lead to immunoglobulin overproduction and eventually to one among the so-called PC neoplasms. In multiple myeloma (MM), the number of PC is over 10% in most patients studied. Changes in the morphology of myeloma PC may be inconspicuous as compared to normal PC (30-50% patients). In other instances PC show one or several morphological changes. One is related to low amount of cytoplasm, defining lymphoplasmacytoid myeloma (10-15% patients). In other cases (40-50% patients), named immature myeloma cases, nuclear-cytoplasmic asynchrony is observed: presence of one nucleolus, finely dispersed chromatin and/or irregular nuclear contour contrast with a still large and blue (mature) cytoplasm. A peculiar morphological change, corresponding to the presence of very immature PC named plasmablasts, is observed in 10-15% cases. Several prognostic morphological classifications have been published, as mature myeloma is related to favorable outcome and immature myeloma, peculiarly plasmablastic myeloma, is related to dismal prognosis. However, such classifications are no longer included in current prognostic schemes. Changes related to the nucleus are very rare in monoclonal gammopathy of unknown significance (MGUS). In contrast, anomalies related to the cytoplasm of PC, including color (flaming cells), round inclusions (Mott cells, Russell bodies), Auer rod-like or crystalline inclusions, are reported in myeloma cases as well as in MGUS and at times in reactive disorders. They do not correspond

  20. Functional heterogeneity and heritability in CHO cell populations.

    Davies, Sarah L; Lovelady, Clare S; Grainger, Rhian K; Racher, Andrew J; Young, Robert J; James, David C

    2013-01-01

    In this study, we address the hypothesis that it is possible to exploit genetic/functional variation in parental Chinese hamster ovary (CHO) cell populations to isolate clonal derivatives that exhibit superior, heritable attributes for biomanufacturing--new parental cell lines which are inherently more "fit for purpose." One-hundred and ninety-nine CHOK1SV clones were isolated from a donor CHOK1SV parental population by limiting dilution cloning and microplate image analysis, followed by primary analysis of variation in cell-specific proliferation rate during extended deep-well microplate suspension culture of individual clones to accelerate genetic drift in isolated cultures. A subset of 100 clones were comparatively evaluated for transient production of a recombinant monoclonal antibody (Mab) and green fluorescent protein following transfection of a plasmid vector encoding both genes. The heritability of both cell-specific proliferation rate and Mab production was further assessed using a subset of 23 clones varying in functional capability that were subjected to cell culture regimes involving both cryopreservation and extended sub-culture. These data showed that whilst differences in transient Mab production capability were not heritable per se, clones exhibiting heritable variation in specific proliferation rate, endocytotic transfectability and N-glycan processing were identified. Finally, for clonal populations most "evolved" by extended sub-culture in vitro we investigated the relationship between cellular protein biomass content, specific proliferation rate and cell surface N-glycosylation. Rapid-specific proliferation rate was inversely correlated to CHO cell size and protein content, and positively correlated to cell surface glycan content, although substantial clone-specific variation in ability to accumulate cell biomass was evident. Taken together, our data reveal the dynamic nature of the CHO cell functional genome and the potential to evolve and

  1. Trail networks formed by populations of immune cells

    Yang, Taeseok Daniel; Kwon, Tae Goo; Park, Jin-sung; Lee, Kyoung J

    2014-01-01

    Populations of biological cells that communicate with each other can organize themselves to generate large-scale patterns. Examples can be found in diverse systems, ranging from developing embryos, cardiac tissues, chemotaxing ameba and swirling bacteria. The similarity, often shared by the patterns, suggests the existence of some general governing principle. On the other hand, rich diversity and system-specific properties are exhibited, depending on the type of involved cells and the nature of their interactions. The study on the similarity and the diversity constitutes a rapidly growing field of research. Here, we introduce a new class of self-organized patterns of cell populations that we term as ‘cellular trail networks’. They were observed with populations of rat microglia, the immune cells of the brain and the experimental evidence suggested that haptotaxis is the key element responsible for them. The essential features of the observed patterns are well captured by the mathematical model cells that actively crawl and interact with each other through a decomposing but non-diffusing chemical attractant laid down by the cells. Our finding suggests an unusual mechanism of socially cooperative long-range signaling for the crawling immune cells. (paper)

  2. A robust new metric of phenotypic distance to estimate and compare multiple trait differences among populations

    Rebecca SAFRAN, Samuel FLAXMAN, Michael KOPP, Darren E. IRWIN, Derek BRIGGS, Matthew R. EVANS, W. Chris FUNK, David A. GRAY, Eileen A. HEBE

    2012-06-01

    Full Text Available Whereas a rich literature exists for estimating population genetic divergence, metrics of phenotypic trait divergence are lacking, particularly for comparing multiple traits among three or more populations. Here, we review and analyze via simulation Hedges’ g, a widely used parametric estimate of effect size. Our analyses indicate that g is sensitive to a combination of unequal trait variances and unequal sample sizes among populations and to changes in the scale of measurement. We then go on to derive and explain a new, non-parametric distance measure, “Δp”, which is calculated based upon a joint cumulative distribution function (CDF from all populations under study. More precisely, distances are measured in terms of the percentiles in this CDF at which each population’s median lies. Δp combines many desirable features of other distance metrics into a single metric; namely, compared to other metrics, p is relatively insensitive to unequal variances and sample sizes among the populations sampled. Furthermore, a key feature of Δp—and our main motivation for developing it—is that it easily accommodates simultaneous comparisons of any number of traits across any number of populations. To exemplify its utility, we employ Δp to address a question related to the role of sexual selection in speciation: are sexual signals more divergent than ecological traits in closely related taxa? Using traits of known function in closely related populations, we show that traits predictive of reproductive performance are, indeed, more divergent and more sexually dimorphic than traits related to ecological adaptation [Current Zoology 58 (3: 423-436, 2012].

  3. Dinitroaniline herbicide resistance in a multiple-resistant Lolium rigidum population.

    Chen, Jinyi; Yu, Qin; Owen, Mechelle; Han, Heping; Powles, Stephen

    2018-04-01

    The pre-emergence dinitroaniline herbicides (such as trifluralin and pendimethalin) are vital to Australian no-till farming systems. A Lolium rigidum population collected from the Western Australian grain belt with a 12-year trifluralin use history was characterised for resistance to dinitroaniline, acetyl CoA carboxylase (ACCase)- and acetolactate synthase (ALS)-inhibiting herbicides. Target-site resistance mechanisms were investigated. This L. rigidum population exhibited 32-fold resistance to trifluralin, as compared with the susceptible population. It also displayed 12- to 30-fold cross-resistance to other dinitroaniline herbicides (pendimethalin, ethalfluralin and oryzalin). In addition, this population showed multiple resistance to commonly used post-emergence ACCase- and ALS-inhibiting herbicides. Two target-site α-tubulin gene mutations (Val-202-Phe and Thr-239-Ile) previously documented in other dinitroaniline-resistant weed species were identified, and some known target-site mutations in ACCase (Ile-1781-Leu, Asp-2078-Gly and Cys-2088-Arg) and ALS (Pro-197-Gln/Ser) were found in the same population. An agar-based Petri dish screening method was established for the rapid diagnosis of resistance to dinitroaniline herbicides. Evolution of target-site resistance to both pre- and post-emergence herbicides was confirmed in a single L. rigidum population. The α-tubulin mutations Val-202-Phe and Thr-239-Ile, documented here for the first time in L. rigidum, are likely to be responsible for dinitroaniline resistance in this population. Early detection of dinitroaniline herbicide resistance and integrated weed management strategies are needed to maintain the effectiveness of dinitroaniline herbicides. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

  4. Migration, Multiple Sexual Partnerships, and Sexual Concurrency in the Garífuna Population of Honduras.

    Gandhi, Anisha D; Pettifor, Audrey; Barrington, Clare; Marshall, Stephen W; Behets, Frieda; Guardado, Maria Elena; Farach, Nasim; Ardón, Elvia; Paz-Bailey, Gabriela

    2015-09-01

    The Garífuna, an ethnic minority group in Honduras, have been disproportionately affected by HIV. Previous research suggests that migration and high rates of multiple sexual partnerships are major drivers of the epidemic. Using data from a 2012 population-based survey, we assessed whether temporary migration was associated with (1) multiple sexual partnerships and (2) sexual concurrency among Garífuna men and women in Honduras. Among both men and women, temporary migration in the last year was associated with an increased likelihood of multiple sexual partnerships and with concurrency, though only the association between migration and multiple sexual partnerships among men was statistically significant (Adjusted Prevalence Ratio 1.7, 95 % CI 1.2-2.4). Migration may contribute to HIV/STI vulnerability among Garífuna men and women via increases in these sexual risk behaviors. Research conducted among men and women at elevated risk of HIV should continue to incorporate measures of mobility, including history of internal migration.

  5. Destruction of radiation-resistant cell populations by hyperthermia

    Roettinger, E.M.; Gerweck, L.E.

    1979-01-01

    Animal experiments with local hyperthermia have shown that the radiauion dose necessary for the local control of 50% of the tumours examined was essentially reduced by heating to 42,5 0 C. In-vitro experients indicated selective destruction of relatively radiation-resistent cell populations by the combination of hyperthermie and reduced hydrogen ion concentration. Experiments with glioblastoma cells confirmed these results qualitatively, but showed quantitatively considerably lower sensitivity towards hyperthermia. (orig.) 891 MG/orig. 892 RDG [de

  6. Early changes within the lymphocyte population are associated with the development of multiple organ dysfunction syndrome in trauma patients.

    Manson, Joanna; Cole, Elaine; De'Ath, Henry D; Vulliamy, Paul; Meier, Ute; Pennington, Dan; Brohi, Karim

    2016-06-07

    Early survival following severe injury has been improved with refined resuscitation strategies. Multiple organ dysfunction syndrome (MODS) is common among this fragile group of patients leading to prolonged hospital stay and late mortality. MODS after trauma is widely attributed to dysregulated inflammation but the precise mechanics of this response and its influence on organ injury are incompletely understood. This study was conducted to investigate the relationship between early lymphocyte responses and the development of MODS during admission. During a 24-month period, trauma patients were recruited from an urban major trauma centre to an ongoing, observational cohort study. Admission blood samples were obtained within 2 h of injury and before in-hospital intervention, including blood transfusion. The study population was predominantly male with a blunt mechanism of injury. Lymphocyte subset populations including T helper, cytotoxic T cells, NK cells and γδ T cells were identified using flow cytometry. Early cytokine release and lymphocyte count during the first 7 days of admission were also examined. This study demonstrated that trauma patients who developed MODS had an increased population of NK dim cells (MODS vs no MODS: 22 % vs 13 %, p < 0.01) and reduced γδ-low T cells (MODS vs no MODS: 0.02 (0.01-0.03) vs 0.09 (0.06-0.12) × 10^9/L, p < 0.01) at admission. Critically injured patients who developed MODS (n = 27) had higher interferon gamma (IFN-γ) concentrations at admission, compared with patients of matched injury severity and shock (n = 60) who did not develop MODS (MODS vs no MODS: 4.1 (1.8-9.0) vs 1.0 (0.6-1.8) pg/ml, p = 0.01). Lymphopenia was observed within 24 h of injury and was persistent in those who developed MODS. Patients with a lymphocyte count of 0.5 × 10(9)/L or less at 48 h, had a 45 % mortality rate. This study provides evidence of lymphocyte activation within 2 h of injury, as demonstrated by

  7. A probabilistic model for cell population phenotyping using HCS data.

    Edouard Pauwels

    Full Text Available High Content Screening (HCS platforms allow screening living cells under a wide range of experimental conditions and give access to a whole panel of cellular responses to a specific treatment. The outcome is a series of cell population images. Within these images, the heterogeneity of cellular response to the same treatment leads to a whole range of observed values for the recorded cellular features. Consequently, it is difficult to compare and interpret experiments. Moreover, the definition of phenotypic classes at a cell population level remains an open question, although this would ease experiments analyses. In the present work, we tackle these two questions. The input of the method is a series of cell population images for which segmentation and cellular phenotype classification has already been performed. We propose a probabilistic model to represent and later compare cell populations. The model is able to fully exploit the HCS-specific information: "dependence structure of population descriptors" and "within-population variability". The experiments we carried out illustrate how our model accounts for this specific information, as well as the fact that the model benefits from considering them. We underline that these features allow richer HCS data analysis than simpler methods based on single cellular feature values averaged over each well. We validate an HCS data analysis method based on control experiments. It accounts for HCS specificities that were not taken into account by previous methods but have a sound biological meaning. Biological validation of previously unknown outputs of the method constitutes a future line of work.

  8. Assessing Risks to Wildlife Populations from Multiple Stressors: Overview of the Problem and Research Needs.

    Wayne R. Munns, Jr.

    2006-06-01

    Full Text Available Wildlife populations are experiencing increasing pressure from human-induced changes in the landscape. Stressors including agricultural and urban land use, introduced invasive and exotic species, nutrient enrichment, direct human disturbance, and toxic chemicals directly or indirectly influence the quality and quantity of habitat used by terrestrial and aquatic wildlife. Governmental agencies such as the U.S. Environmental Protection Agency are required to assess risks to wildlife populations, in its broadest definition, that result from exposure to these stressors, yet considerable uncertainty exists with respect to how such assessments should be conducted. This uncertainty is compounded by questions concerning the interactive effects of co-occurring stressors, appropriate spatial scales of analysis, extrapolation of response data among species and from organisms to populations, and imperfect knowledge and use of limited data sets. Further, different risk problems require varying degrees of sophistication, methodological refinement, and data quality. These issues suggest a number of research needs to improve methods for wildlife risk assessments, including continued development of population dynamics models to evaluate the effects of multiple stressors at varying spatial scales, methods for extrapolating across endpoints and species with reasonable confidence, stressor-response relations and methods for combining them in predictive and diagnostic assessments, and accessible data sets describing the ecology of terrestrial and aquatic species. Case study application of models and methods for assessing wildlife risk will help to demonstrate their strengths and limitations for solving particular risk problems.

  9. Not a single but multiple populations of GABAergic neurons control sleep.

    Luppi, Pierre-Hervé; Peyron, Christelle; Fort, Patrice

    2017-04-01

    The role of gamma-amino butyric acid (GABA) in sleep induction and maintenance is well accepted since most insomnia treatments target GABAa receptors. However, the population(s) of GABAergic neurons involved in the beneficial effect of GABA on sleep remains to be identified. This is not an easy task since GABAergic neurons are widely distributed in all brain structures. A recently growing number of populations of GABAergic neurons have been involved in sleep control. We first review here possible candidates for inducing non-rapid eye movement (NREM) sleep including the GABAergic neurons of the ventrolateral preoptic area, the parafacial zone in the brainstem, the nucleus accumbens and the cortex. We also discuss the role of several populations of GABAergic neurons in rapid eye movement (REM) sleep control. Indeed, it is well accepted that muscle atonia occurring during REM sleep is due to a GABA/glycinergic hyperpolarization of motoneurons. Recent evidence strongly suggests that these neurons are located in the ventral medullary reticular formation. It has also recently been shown that neurons containing the neuropeptide melanin concentrating hormone and GABA located in the lateral hypothalamic area control REM sleep expression. Finally, a population of REM-off GABAergic neurons located in the ventrolateral periaqueductal gray has been shown to gate REM sleep by inhibiting glutamatergic neurons located in the sublaterodorsal tegmental nucleus. In summary, recent data clearly indicate that multiple populations of GABAergic neurons located throughout the brain from the cortex to the medulla oblongata control NREM and REM sleep. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Antitumoral Effect of Hibiscus sabdariffa on Human Squamous Cell Carcinoma and Multiple Myeloma Cells.

    Malacrida, Alessio; Maggioni, Daniele; Cassetti, Arianna; Nicolini, Gabriella; Cavaletti, Guido; Miloso, Mariarosaria

    2016-10-01

    Cancer is a leading cause of death worldwide. Despite therapeutic improvements, some cancers are still untreatable. Recently there has been an increasing interest in the use of natural substances for cancer prevention and treatment. Hibiscus sabdariffa (HS) is a plant, belonging to Malvaceae family, widespread in South Asia and Central Africa. HS extract (HSE) used in folk medicine, gained researchers' interest thanks to its antioxidant, anti-inflammatory, and chemopreventive properties. In the present study, we initially assessed HSE effect on a panel of human tumor cell lines. Then we focused our study on the following that are most sensitive to HSE action cell lines: Multiple Myeloma (MM) cells (RPMI 8226) and Oral Squamous Cell Carcinoma (OSCC) cells (SCC-25). In both RPMI 8226 and SCC-25 cells, HSE impaired cell growth, exerted a reversible cytostatic effect, and reduced cell motility and invasiveness. We evaluated the involvement of MAPKs ERK1/2 and p38 in HSE effects by using specific inhibitors, U0126 and SB203580, respectively. For both SCC-25 and RPMI 8226, HSE cytostatic effect depends on p38 activation, whereas ERK1/2 modulation is crucial for cell motility and invasiveness. Our results suggest that HSE may be a potential therapeutic agent against MM and OSCC.

  11. High throughput single-cell and multiple-cell micro-encapsulation.

    Lagus, Todd P; Edd, Jon F

    2012-06-15

    Microfluidic encapsulation methods have been previously utilized to capture cells in picoliter-scale aqueous, monodisperse drops, providing confinement from a bulk fluid environment with applications in high throughput screening, cytometry, and mass spectrometry. We describe a method to not only encapsulate single cells, but to repeatedly capture a set number of cells (here we demonstrate one- and two-cell encapsulation) to study both isolation and the interactions between cells in groups of controlled sizes. By combining drop generation techniques with cell and particle ordering, we demonstrate controlled encapsulation of cell-sized particles for efficient, continuous encapsulation. Using an aqueous particle suspension and immiscible fluorocarbon oil, we generate aqueous drops in oil with a flow focusing nozzle. The aqueous flow rate is sufficiently high to create ordering of particles which reach the nozzle at integer multiple frequencies of the drop generation frequency, encapsulating a controlled number of cells in each drop. For representative results, 9.9 μm polystyrene particles are used as cell surrogates. This study shows a single-particle encapsulation efficiency P(k=1) of 83.7% and a double-particle encapsulation efficiency P(k=2) of 79.5% as compared to their respective Poisson efficiencies of 39.3% and 33.3%, respectively. The effect of consistent cell and particle concentration is demonstrated to be of major importance for efficient encapsulation, and dripping to jetting transitions are also addressed. Continuous media aqueous cell suspensions share a common fluid environment which allows cells to interact in parallel and also homogenizes the effects of specific cells in measurements from the media. High-throughput encapsulation of cells into picoliter-scale drops confines the samples to protect drops from cross-contamination, enable a measure of cellular diversity within samples, prevent dilution of reagents and expressed biomarkers, and amplify

  12. Functional heterogeneity of side population cells in skeletal muscle

    Uezumi, Akiyoshi; Ojima, Koichi; Fukada, So-ichiro; Ikemoto, Madoka; Masuda, Satoru; Miyagoe-Suzuki, Yuko; Takeda, Shin'ichi

    2006-01-01

    Skeletal muscle regeneration has been exclusively attributed to myogenic precursors, satellite cells. A stem cell-rich fraction referred to as side population (SP) cells also resides in skeletal muscle, but its roles in muscle regeneration remain unclear. We found that muscle SP cells could be subdivided into three sub-fractions using CD31 and CD45 markers. The majority of SP cells in normal non-regenerating muscle expressed CD31 and had endothelial characteristics. However, CD31 - CD45 - SP cells, which are a minor subpopulation in normal muscle, actively proliferated upon muscle injury and expressed not only several regulatory genes for muscle regeneration but also some mesenchymal lineage markers. CD31 - CD45 - SP cells showed the greatest myogenic potential among three SP sub-fractions, but indeed revealed mesenchymal potentials in vitro. These SP cells preferentially differentiated into myofibers after intramuscular transplantation in vivo. Our results revealed the heterogeneity of muscle SP cells and suggest that CD31 - CD45 - SP cells participate in muscle regeneration

  13. Quantitation of DNA repair in brain cell cultures: implications for autoradiographic analysis of mixed cell populations

    Dambergs, R.; Kidson, C.

    1979-01-01

    Quantitation of DNA repair in the mixed cell population of mouse embryo brain cultures has been assessed by autoradiographic analysis of unscheduled DNA synthesis following UV-irradiation. The proportion of labelled neurons and the grain density over neuronal nuclei were both less than the corresponding values for glial cells. The nuclear geometries of these two classes of cell are very different. Partial correction for the different geometries by relating grain density to nuclear area brought estimates of neuronal and glial DNA repair synthesis more closely in line. These findings have general implications for autoradiographic measurement of DNA repair in mixed cell populations and in differentiated versus dividing cells. (author)

  14. CD34 defines an osteoprogenitor cell population in mouse bone marrow stromal cells

    Abdallah, Basem M; Al-Shammary, Asma; Skagen, Peter

    2015-01-01

    Bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells) and their progenitors have been identified based on retrospective functional criteria. CD markers are employed to define cell populations with distinct functional characteristics. However, defining and pro...

  15. Cell mass and cell cycle dynamics of an asynchronous budding yeast population

    Lencastre Fernandes, Rita; Carlquist, Magnus; Lundin, Luisa

    2013-01-01

    of model predictions for cell property distributions against experimental data is scarce. This study focuses on the experimental and mathematical description of the dynamics of cell size and cell cycle position distributions, of a population of Saccharomyces cerevisiae, in response to the substrate...

  16. Feasibility of mesenchymal stem cell culture expansion for a phase I clinical trial in multiple sclerosis.

    Planchon, Sarah M; Lingas, Karen T; Reese Koç, Jane; Hooper, Brittney M; Maitra, Basabi; Fox, Robert M; Imrey, Peter B; Drake, Kylie M; Aldred, Micheala A; Lazarus, Hillard M; Cohen, Jeffrey A

    2018-01-01

    Multiple sclerosis is an inflammatory, neurodegenerative disease of the central nervous system for which therapeutic mesenchymal stem cell transplantation is under study. Published experience of culture-expanding multiple sclerosis patients' mesenchymal stem cells for clinical trials is limited. To determine the feasibility of culture-expanding multiple sclerosis patients' mesenchymal stem cells for clinical use. In a phase I trial, autologous, bone marrow-derived mesenchymal stem cells were isolated from 25 trial participants with multiple sclerosis and eight matched controls, and culture-expanded to a target single dose of 1-2 × 10 6 cells/kg. Viability, cell product identity and sterility were assessed prior to infusion. Cytogenetic stability was assessed by single nucleotide polymorphism analysis of mesenchymal stem cells from 18 multiple sclerosis patients and five controls. One patient failed screening. Mesenchymal stem cell culture expansion was successful for 24 of 25 multiple sclerosis patients and six of eight controls. The target dose was achieved in 16-62 days, requiring two to three cell passages. Growth rate and culture success did not correlate with demographic or multiple sclerosis disease characteristics. Cytogenetic studies identified changes on one chromosome of one control (4.3%) after extended time in culture. Culture expansion of mesenchymal stem cells from multiple sclerosis patients as donors is feasible. However, culture time should be minimized for cell products designated for therapeutic administration.

  17. Multiple primary malignant neoplasms in a fixed population of A-bomb survivors, 1

    Soda, Midori; Yokoyama, Naokata; Matsuo, Tatsuki; Takagi, Miwako; Kitano, Koei; Toyama, Kyoko; Fujikura, Toshio

    1986-01-01

    In a fixed population (7,564 A-bomb survivors) for Adult Health Study performed until December 1985, 28 A-bomb survivors (5 men and 23 women) were diagnosed as having thyroid cancer, and 79 (including one man) as breast cancer. There was an evident tendency among the group receiving 100 rad or more towards higher incidence of cancers of the thyroid and breast and synchronous or metachronous multiple primaries. The incidence of thyroid cancer tended to be higher in A-bomb survivors less than 20 years of age at the time of exposure; however, this tendency was not seen in the case of breast cancer. The incidence of thyroid cancer - in contrast to breast cancer - tended to decrease from year to year. Multiple primaries were associated with thyroid cancer in 5 A-bomb survivors and breast cancer in 9 A-bomb survivors. Three A-bomb survivors had both thyroid and breast cancers. Among the 11 A-bomb survivors with multiple primaries, nine had received 100 rad or more. (Namekawa, K.)

  18. Does an NKT-cell-based immunotherapeutic approach have a future in multiple myeloma?

    Favreau, Mérédis; Vanderkerken, Karin

    2016-01-01

    Natural killer T (NKT) cells constitute a unique subset of innate-like T lymphocytes which differ from conventional T cells by recognizing lipid antigens presented by the non-polymorphic major histocompatibility complex (MHC) I-like molecule CD1d. Despite being a relatively infrequent population of lymphocytes, NKT cells can respond rapidly upon activation with glycosphingolipids by production of cytokines which aim to polarize different axes of the immune system. Due to their dual effector capacities, NKT cells can play a vital role in cancer immunity, infection, inflammation and autoimmune diseases. It is believed that modulation of their activity towards immune activation can be a useful tool in anti-tumor immunotherapeutic strategies. Here we summarize the characteristics of NKT cells and discuss their involvement in immunosurveillance. Furthermore, an update is given about their role and the progress that has been made in the field of multiple myeloma (MM). Finally, some challenges are discussed that are currently hampering further progress. PMID:26895468

  19. Taxonomic separation of hippocampal networks: principal cell populations and adult neurogenesis

    Roelof Maarten evan Dijk

    2016-03-01

    Full Text Available While many differences in hippocampal anatomy have been described between species, it is typically not clear if they are specific to a particular species and related to functional requirements or if they are shared by species of larger taxonomic units. Without such information, it is difficult to infer how anatomical differences may impact on hippocampal function, because multiple taxonomic levels need to be considered to associate behavioral and anatomical changes. To provide information on anatomical changes within and across taxonomic ranks, we present a quantitative assessment of hippocampal principal cell populations in 20 species or strain groups, with emphasis on rodents, the taxonomic group that provides most animals used in laboratory research. Of special interest is the importance of adult hippocampal neurogenesis in species-specific adaptations relative to other cell populations. Correspondence analysis of cell numbers shows that across taxonomic units, phylogenetically related species cluster together, sharing similar proportions of principal cell populations. CA3 and hilus are strong separators that place rodent species into a tight cluster based on their relatively large CA3 and small hilus while non-rodent species (including humans and non-human primates are placed on the opposite side of the spectrum. Hilus and CA3 are also separators within rodents, with a very large CA3 and rather small hilar cell populations separating mole-rats from other rodents that, in turn, are separated from each other by smaller changes in the proportions of CA1 and granule cells. When adult neurogenesis is included, the relatively small populations of young neurons, proliferating cells and hilar neurons become main drivers of taxonomic separation within rodents. The observations provide challenges to the computational modeling of hippocampal function, suggest differences in the organization of hippocampal information streams in rodent and non

  20. Multiple data sources improve DNA-based mark-recapture population estimates of grizzly bears.

    Boulanger, John; Kendall, Katherine C; Stetz, Jeffrey B; Roon, David A; Waits, Lisette P; Paetkau, David

    2008-04-01

    A fundamental challenge to estimating population size with mark-recapture methods is heterogeneous capture probabilities and subsequent bias of population estimates. Confronting this problem usually requires substantial sampling effort that can be difficult to achieve for some species, such as carnivores. We developed a methodology that uses two data sources to deal with heterogeneity and applied this to DNA mark-recapture data from grizzly bears (Ursus arctos). We improved population estimates by incorporating additional DNA "captures" of grizzly bears obtained by collecting hair from unbaited bear rub trees concurrently with baited, grid-based, hair snag sampling. We consider a Lincoln-Petersen estimator with hair snag captures as the initial session and rub tree captures as the recapture session and develop an estimator in program MARK that treats hair snag and rub tree samples as successive sessions. Using empirical data from a large-scale project in the greater Glacier National Park, Montana, USA, area and simulation modeling we evaluate these methods and compare the results to hair-snag-only estimates. Empirical results indicate that, compared with hair-snag-only data, the joint hair-snag-rub-tree methods produce similar but more precise estimates if capture and recapture rates are reasonably high for both methods. Simulation results suggest that estimators are potentially affected by correlation of capture probabilities between sample types in the presence of heterogeneity. Overall, closed population Huggins-Pledger estimators showed the highest precision and were most robust to sparse data, heterogeneity, and capture probability correlation among sampling types. Results also indicate that these estimators can be used when a segment of the population has zero capture probability for one of the methods. We propose that this general methodology may be useful for other species in which mark-recapture data are available from multiple sources.

  1. Transmissible Plasmids and Integrons Shift Escherichia coli Population Toward Larger Multiple Drug Resistance Numbers.

    Suhartono, Suhartono; Savin, Mary C; Gbur, Edward E

    2018-04-01

    Transmissible plasmids and integrons may play important roles in the persistence and spread of antibiotic-resistant bacteria throughout aquatic environment by accumulating antibiotic resistance genes (ARG). Class 1 and class 2 integron (intI), mobilization (mob), sulfamethoxazole resistance (sul), and trimethoprim resistance (dfr) genes were PCR-amplified and confirmed through DNA sequencing following plasmid extraction from 139 antibiotic-resistant Escherichia coli. E. coli had previously been recovered from wastewater treatment plant effluent and receiving stream water in Northwest Arkansas and isolates had expressed resistance to one to six antibiotics. Almost half of the total isolates (47%) carried putatively transmissible plasmids with mob F12 gene as the most frequently detected mobilization gene. When two or three mob genes were detected per isolate, there was a significant shift in the population toward larger multiple drug resistance (MDR) number. Class 1 and/or 2 integrons were prevalent (46%), and the presence of integron significantly shifted the isolate population toward larger MDR number. More isolates carried single or coexistence of two or three sul genes (99.3%), and single or a combination up to five dfr genes (89.3%) than had exhibited in vitro resistance to the respective antibiotics. These findings indicate not only the role of the wastewater treatment effluent and the stream environment in coaccumulation of ARG with transmissible plasmids and integrons in multiple antibiotic-resistant E. coli populations but also suggest that density of sul and dfr resistance genes within an isolate may serve as a biomarker for mobile MDR in general.

  2. Uncovering multiple populations with washington photometry. I. The globular cluster NGC 1851

    Cummings, Jeffrey D.; Geisler, D.; Villanova, S. [Departamento de Astronomía, Casilla 160-C, Universidad de Concepción (Chile); Carraro, G. [ESO, Alonso de Cordova 3107, Casilla 19001, Santiago de Chile (Chile)

    2014-08-01

    The analysis of multiple populations (MPs) in globular clusters (GCs) has become a forefront area of research in astronomy. Multiple red giant branches (RGBs), subgiant branches (SGBs), and even main sequences (MSs) have now been observed photometrically in many GCs, while broad abundance distributions of certain elements have been detected spectroscopically in most, if not all, GCs. UV photometry has been crucial in discovering and analyzing these MPs, but the Johnson U and the Stromgren and Sloan u filters that have generally been used are relatively inefficient and very sensitive to reddening and atmospheric extinction. In contrast, the Washington C filter is much broader and redder than these competing UV filters, making it far more efficient at detecting MPs and much less sensitive to reddening and extinction. Here, we investigate the use of the Washington system to uncover MPs using only a 1 m telescope. Our analysis of the well-studied GC NGC 1851 finds that the C filter is both very efficient and effective at detecting its previously discovered MPs in the RGB and SGB. Remarkably, we have also detected an intrinsically broad MS best characterized by two distinct but heavily overlapping populations that cannot be explained by binaries, field stars, or photometric errors. The MS distribution is in very good agreement with that seen on the RGB, with ∼30% of the stars belonging to the second population. There is also evidence for two sequences in the red horizontal branch, but this appears to be unrelated to the MPs in this cluster. Neither of these latter phenomena have been observed previously in this cluster. The redder MS stars are also more centrally concentrated than the blue MS. This is the first time MPs in an MS have been discovered from the ground, and using only a 1 m telescope. The Washington system thus proves to be a very powerful tool for investigating MPs, and holds particular promise for extragalactic objects where photons are limited.

  3. Population genetics of the Eastern Hellbender (Cryptobranchus alleganiensis alleganiensis across multiple spatial scales.

    Shem D Unger

    Full Text Available Conservation genetics is a powerful tool to assess the population structure of species and provides a framework for informing management of freshwater ecosystems. As lotic habitats become fragmented, the need to assess gene flow for species of conservation management becomes a priority. The eastern hellbender (Cryptobranchus alleganiensis alleganiensis is a large, fully aquatic paedamorphic salamander. Many populations are experiencing declines throughout their geographic range, yet the genetic ramifications of these declines are currently unknown. To this end, we examined levels of genetic variation and genetic structure at both range-wide and drainage (hierarchical scales. We collected 1,203 individuals from 77 rivers throughout nine states from June 2007 to August 2011. Levels of genetic diversity were relatively high among all sampling locations. We detected significant genetic structure across populations (Fst values ranged from 0.001 between rivers within a single watershed to 0.218 between states. We identified two genetically differentiated groups at the range-wide scale: 1 the Ohio River drainage and 2 the Tennessee River drainage. An analysis of molecular variance (AMOVA based on landscape-scale sampling of basins within the Tennessee River drainage revealed the majority of genetic variation (∼94-98% occurs within rivers. Eastern hellbenders show a strong pattern of isolation by stream distance (IBSD at the drainage level. Understanding levels of genetic variation and differentiation at multiple spatial and biological scales will enable natural resource managers to make more informed decisions and plan effective conservation strategies for cryptic, lotic species.

  4. Multiple loci are associated with white blood cell phenotypes.

    Michael A Nalls

    2011-06-01

    Full Text Available White blood cell (WBC count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2, including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across

  5. Plasma Cell Neoplasms (Including Multiple Myeloma)—Health Professional Version

    There are several types of plasma cell neoplasms, including monoclonal gammopathy of undetermined significance (MGUS), isolated plasmacytoma of the bone, extramedullary plasmacytoma, and multiple myeloma. Find evidence-based information on plasma cell neoplasms treatment, research, and statistics.

  6. FogBank: a single cell segmentation across multiple cell lines and image modalities.

    Chalfoun, Joe; Majurski, Michael; Dima, Alden; Stuelten, Christina; Peskin, Adele; Brady, Mary

    2014-12-30

    sheets with high accuracy. It can be applied to microscopy images of multiple cell lines and a variety of imaging modalities. The code for the segmentation method is available as open-source and includes a Graphical User Interface for user friendly execution.

  7. Heterogeneity of breast cancer stem cells as evidenced with Notch-dependent and Notch-independent populations

    Wong, Nelson K Y; Fuller, Megan; Sung, Sandy; Wong, Fred; Karsan, Aly

    2012-01-01

    Studies have suggested the potential importance of Notch signaling to the cancer stem cell population in some tumors, but it is not known whether all cells in the cancer stem cell fraction require Notch activity. To address this issue, we blocked Notch activity in MCF-7 cells by expressing a dominant-negative MAML-GFP (dnMAML) construct, which inhibits signaling through all Notch receptors, and quantified the effect on tumor-initiating activity. Inhibition of Notch signaling reduced primary tumor sphere formation and side population. Functional quantification of tumor-initiating cell numbers in vivo showed a significant decrease, but not a complete abrogation, of these cells in dnMAML-expressing cells. Interestingly, when assessed in secondary assays in vitro or in vivo, there was no difference in tumor-initiating activity between the dnMAML-expressing cells and control cells. The fact that a subpopulation of dnMAML-expressing cells was capable of forming primary and secondary tumors indicates that there are Notch-independent tumor-initiating cells in the breast cancer cell line MCF-7. Our findings thus provide direct evidence for a heterogeneous cancer stem cell pool, which will require combination therapies against multiple oncogenic pathways to eliminate the tumor-initiating cell population

  8. Dendritic cell, monocyte and T cell activation and response to glatiramer acetate in multiple sclerosis

    Sellebjerg, F; Hesse, D; Limborg, S

    2012-01-01

    , monocytes and dendritic cells (DC) in relation to disease activity in MS patients treated with GA. Methods: Flow cytometry was used to study the activation of CD4+ T cells and T cell subsets (CD25high and CD26high cells), monocytes and DCs in a cross-sectional study of 39 untreated and 29 GA-treated MS......Background: Treatment with glatiramer acetate (GA) modestly decreases disease activity in multiple sclerosis (MS). The mechanism of action is incompletely understood and differences in the response to treatment between individuals may exist. Objective: To study the activation of CD4+ T cells...... (Bonferroni-corrected p=0.0005). The hazard ratio of relapse was 1.32 (95% confidence interval 1.05–1.64) per 1% increase in CD40+ DCs. Patients treated with GA had fewer CD4+ T cells expressing surface markers associated with T helper type 1 effector responses and more CD4+ T cells expressing surface markers...

  9. Regulatory T cells in multiple sclerosis and myasthenia gravis.

    Danikowski, K M; Jayaraman, S; Prabhakar, B S

    2017-06-09

    Multiple sclerosis (MS) is a chronic debilitating disease of the central nervous system primarily mediated by T lymphocytes with specificity to neuronal antigens in genetically susceptible individuals. On the other hand, myasthenia gravis (MG) primarily involves destruction of the neuromuscular junction by antibodies specific to the acetylcholine receptor. Both autoimmune diseases are thought to result from loss of self-tolerance, which allows for the development and function of autoreactive lymphocytes. Although the mechanisms underlying compromised self-tolerance in these and other autoimmune diseases have not been fully elucidated, one possibility is numerical, functional, and/or migratory deficits in T regulatory cells (Tregs). Tregs are thought to play a critical role in the maintenance of peripheral immune tolerance. It is believed that Tregs function by suppressing the effector CD4+ T cell subsets that mediate autoimmune responses. Dysregulation of suppressive and migratory markers on Tregs have been linked to the pathogenesis of both MS and MG. For example, genetic abnormalities have been found in Treg suppressive markers CTLA-4 and CD25, while others have shown a decreased expression of FoxP3 and IL-10. Furthermore, elevated levels of pro-inflammatory cytokines such as IL-6, IL-17, and IFN-γ secreted by T effectors have been noted in MS and MG patients. This review provides several strategies of treatment which have been shown to be effective or are proposed as potential therapies to restore the function of various Treg subsets including Tr1, iTr35, nTregs, and iTregs. Strategies focusing on enhancing the Treg function find importance in cytokines TGF-β, IDO, interleukins 10, 27, and 35, and ligands Jagged-1 and OX40L. Likewise, strategies which affect Treg migration involve chemokines CCL17 and CXCL11. In pre-clinical animal models of experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune myasthenia gravis (EAMG), several strategies

  10. The Not So Simple Globular Cluster ω Cen. I. Spatial Distribution of the Multiple Stellar Populations

    Calamida, A.; Saha, A. [National Optical Astronomy Observatory—AURA, 950 N Cherry Avenue, Tucson, AZ, 85719 (United States); Strampelli, G.; Rest, A. [Space Telescope Science Institute—AURA, 3700 San Martin Drive, Baltimore, MD 21218 (United States); Bono, G.; Ferraro, I.; Iannicola, G. [INAF—Osservatorio Astronomico di Roma—Via Frascati 33, I-00040, Monteporzio Catone, Rome (Italy); Scolnic, D. [The University of Chicago, The Kavli Institute for Cosmological Physics, William Eckhardt Research Center—Suite 499, 5640 South Ellis Avenue, Chicago, IL 60637 (United States); James, D.; Smith, C.; Zenteno, A., E-mail: calamida@noao.edu [Cerro Tololo Inter-American Observatory, Casilla 603, La Serena (Chile)

    2017-04-01

    We present a multi-band photometric catalog of ≈1.7 million cluster members for a field of view of ≈2° × 2° across ω Cen. Photometry is based on images collected with the Dark Energy Camera on the 4 m Blanco telescope and the Advanced Camera for Surveys on the Hubble Space Telescope . The unprecedented photometric accuracy and field coverage allowed us, for the first time, to investigate the spatial distribution of ω Cen multiple populations from the core to the tidal radius, confirming its very complex structure. We found that the frequency of blue main-sequence stars is increasing compared to red main-sequence stars starting from a distance of ≈25′ from the cluster center. Blue main-sequence stars also show a clumpy spatial distribution, with an excess in the northeast quadrant of the cluster pointing toward the direction of the Galactic center. Stars belonging to the reddest and faintest red-giant branch also show a more extended spatial distribution in the outskirts of ω Cen, a region never explored before. Both these stellar sub-populations, according to spectroscopic measurements, are more metal-rich compared to the cluster main stellar population. These findings, once confirmed, make ω Cen the only stellar system currently known where metal-rich stars have a more extended spatial distribution compared to metal-poor stars. Kinematic and chemical abundance measurements are now needed for stars in the external regions of ω Cen to better characterize the properties of these sub-populations.

  11. Multiple factors affect a population of Agassiz's desert tortoise (Gopherus agassizii) in the Northwestern Mojave Desert

    Berry, Kristin H.; Yee, Julie L.; Coble, Ashley A.; Perry, William M.; Shields, Timothy A.

    2013-01-01

    Numerous factors have contributed to declines in populations of the federally threatened Agassiz's Desert Tortoise (Gopherus agassizii) and continue to limit recovery. In 2010, we surveyed a low-density population on a military test facility in the northwestern Mojave Desert of California, USA, to evaluate population status and identify potential factors contributing to distribution and low densities. Estimated densities of live tortoises ranged spatially from 1.2/km2 to 15.1/km2. Although only one death of a breeding-age tortoise was recorded for the 4-yr period prior to the survey, remains of 16 juvenile and immature tortoises were found, and most showed signs of predation by Common Ravens (Corvus corax) and mammals. Predation may have limited recruitment of young tortoises into the adult size classes. To evaluate the relative importance of different types of impacts to tortoises, we developed predictive models for spatially explicit densities of tortoise sign and live tortoises using topography (i.e., slope), predators (Common Raven, signs of mammalian predators), and anthropogenic impacts (distances from paved road and denuded areas, density of ordnance fragments) as covariates. Models suggest that densities of tortoise sign increased with slope and signs of mammalian predators and decreased with Common Ravens, while also varying based on interaction effects involving these predictors as well as distances from paved roads, denuded areas, and ordnance. Similarly, densities of live tortoises varied by interaction effects among distances to denuded areas and paved roads, density of ordnance fragments, and slope. Thus multiple factors predict the densities and distribution of this population.

  12. The essential role of t cells in multiple sclerosis: A reappraisal

    Cris S Constantinescu

    2014-04-01

    Full Text Available Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system in which destruction of myelin and nerve axons has been shown to be mediated by immune mechanisms. Although the focus of research has been traditionally on T cells as key mediators of the immunopathology, more recent efforts at understanding this complex disorder have been directed increasingly at other cellular and humoral elements of the immune response. This review is a reappraisal of the crucial role of T cells, in particular the CD4+ helper T-cell subset, in multiple sclerosis. Recent evidence is discussed underlining the predominant contribution of T-cell-associated genes to the genome-wide association study results of multiple sclerosis susceptibility, the loss of T-cell quiescence in the conversion from clinically isolated syndrome to clinically definite multiple sclerosis, and the fact that T cells represent the main target of effective immunomodulatory and immunosuppressive treatments in multiple sclerosis.

  13. Validation of interphase fluorescence in situ hybridization (iFISH for multiple myeloma using CD138 positive cells

    Renata Kiyomi Kishimoto

    2016-06-01

    Full Text Available ABSTRACT BACKGROUND: Multiple myeloma is a plasma cell neoplasm with acquired genetic abnormalities of clinical and prognostic importance. Multiple myeloma differs from other hematologic malignancies due to a high fraction of low proliferating malignant plasma cells and the paucity of plasma cells in bone marrow aspiration samples, making cytogenetic analysis a challenge. An abnormal karyotype is found in only one-third of patients with multiple myeloma and interphase fluorescence in situ hybridization is the most useful test for studying the chromosomal abnormalities present in almost 90% of cases. However, it is necessary to study the genetic abnormalities in plasma cells after their identification or selection by morphology, immunophenotyping or sorting. Other challenges are the selection of the most informative FISH panel and determining cut-off levels for FISH probes. This study reports the validation of interphase fluorescence in situ hybridization using CD138 positive cells, according to proposed guidelines published by the European Myeloma Network (EMN in 2012. METHOD: Bone marrow samples from patients with multiple myeloma were used to standardize a panel of five probes [1q amplification, 13q14 deletion, 17p deletion, t(4;14, and t(14;16] in CD138+ cells purified by magnetic cell sorting. RESULTS: This test was validated with a low turnaround time and good reproducibility. Five of six samples showed genetic abnormalities. Monosomy/deletion 13 plus t(4;14 were found in two cases. CONCLUSION: This technique together with magnetic cell sorting is effective and can be used in the routine laboratory practice. In addition, magnetic cell sorting provides a pure plasma cell population that allows other molecular and genomic studies.

  14. Distinct retrosplenial cortex cell populations and their spike dynamics during ketamine-induced unconscious state.

    Grace E Fox

    Full Text Available Ketamine is known to induce psychotic-like symptoms, including delirium and visual hallucinations. It also causes neuronal damage and cell death in the retrosplenial cortex (RSC, an area that is thought to be a part of high visual cortical pathways and at least partially responsible for ketamine's psychotomimetic activities. However, the basic physiological properties of RSC cells as well as their response to ketamine in vivo remained largely unexplored. Here, we combine a computational method, the Inter-Spike Interval Classification Analysis (ISICA, and in vivo recordings to uncover and profile excitatory cell subtypes within layers 2&3 and 5&6 of the RSC in mice within both conscious, sleep, and ketamine-induced unconscious states. We demonstrate two distinct excitatory principal cell sub-populations, namely, high-bursting excitatory principal cells and low-bursting excitatory principal cells, within layers 2&3, and show that this classification is robust over the conscious states, namely quiet awake, and natural unconscious sleep periods. Similarly, we provide evidence of high-bursting and low-bursting excitatory principal cell sub-populations within layers 5&6 that remained distinct during quiet awake and sleep states. We further examined how these subtypes are dynamically altered by ketamine. During ketamine-induced unconscious state, these distinct excitatory principal cell subtypes in both layer 2&3 and layer 5&6 exhibited distinct dynamics. We also uncovered different dynamics of local field potential under various brain states in layer 2&3 and layer 5&6. Interestingly, ketamine administration induced high gamma oscillations in layer 2&3 of the RSC, but not layer 5&6. Our results show that excitatory principal cells within RSC layers 2&3 and 5&6 contain multiple physiologically distinct sub-populations, and they are differentially affected by ketamine.

  15. Cell population structure prior to bifurcation predicts efficiency of directed differentiation in human induced pluripotent cells.

    Bargaje, Rhishikesh; Trachana, Kalliopi; Shelton, Martin N; McGinnis, Christopher S; Zhou, Joseph X; Chadick, Cora; Cook, Savannah; Cavanaugh, Christopher; Huang, Sui; Hood, Leroy

    2017-02-28

    Steering the differentiation of induced pluripotent stem cells (iPSCs) toward specific cell types is crucial for patient-specific disease modeling and drug testing. This effort requires the capacity to predict and control when and how multipotent progenitor cells commit to the desired cell fate. Cell fate commitment represents a critical state transition or "tipping point" at which complex systems undergo a sudden qualitative shift. To characterize such transitions during iPSC to cardiomyocyte differentiation, we analyzed the gene expression patterns of 96 developmental genes at single-cell resolution. We identified a bifurcation event early in the trajectory when a primitive streak-like cell population segregated into the mesodermal and endodermal lineages. Before this branching point, we could detect the signature of an imminent critical transition: increase in cell heterogeneity and coordination of gene expression. Correlation analysis of gene expression profiles at the tipping point indicates transcription factors that drive the state transition toward each alternative cell fate and their relationships with specific phenotypic readouts. The latter helps us to facilitate small molecule screening for differentiation efficiency. To this end, we set up an analysis of cell population structure at the tipping point after systematic variation of the protocol to bias the differentiation toward mesodermal or endodermal cell lineage. We were able to predict the proportion of cardiomyocytes many days before cells manifest the differentiated phenotype. The analysis of cell populations undergoing a critical state transition thus affords a tool to forecast cell fate outcomes and can be used to optimize differentiation protocols to obtain desired cell populations.

  16. A national population study of the prevalence of multiple chemical sensitivity.

    Caress, Stanley M; Steinemann, Anne C

    2004-06-01

    The authors conducted a telephone survey of 1054 randomly selected individuals within the continental United States to determine the prevalence of chemical hypersensitivity and the medical diagnosis of multiple chemical sensitivity (MCS) in the American population. The etiology and symptomatology of MCS also were investigated. Results produced a 95% confidence level and a +/-3% margin of error. The authors found that 11.2% of Americans reported an unusual hypersensitivity to common chemical products such as perfume, fresh paint, pesticides, and other petrochemical-based substances, and 2.5% reported they had been medically diagnosed with MCS. Additionally, 31.1% of those sampled reported adverse reactions to fragranced products, and 17.6% experienced breathing difficulties and other health problems when exposed to air fresheners. Although chemical hypersensitivity was more common in women, it affected individuals in all demographic groups studied.

  17. Preconception carrier screening for multiple disorders: evaluation of a screening offer in a Dutch founder population.

    Mathijssen, Inge B; Holtkamp, Kim C A; Ottenheim, Cecile P E; van Eeten-Nijman, Janneke M C; Lakeman, Phillis; Meijers-Heijboer, Hanne; van Maarle, Merel C; Henneman, Lidewij

    2018-02-01

    Technological developments have enabled carrier screening for multiple disorders. This study evaluated experiences with a preconception carrier screening offer for four recessive disorders in a Dutch founder population. Questionnaires were completed by 182 attendees pretesting and posttesting and by 137 non-attendees. Semistructured interviews were conducted with seven of the eight carrier couples. Attendees were mainly informed about the existence of screening by friends/colleagues (49%) and family members (44%). Familiarity with the genetic disorders was high. Knowledge after counseling increased (p influencers (family/friends) can be used to raise awareness of a screening offer. Our findings provide lessons for the implementation of expanded carrier screening panels in other communities and other settings.

  18. A review on stem cell therapy for multiple sclerosis: special focus on human embryonic stem cells.

    Shroff, Geeta

    2018-01-01

    Multiple sclerosis (MS), a complex disorder of the central nervous system (CNS), is characterized with axonal loss underlying long-term progressive disability. Currently available therapies for its management are able to slow down the progression but fail to treat it completely. Moreover, these therapies are associated with major CNS and cardiovascular adverse events, and prolonged use of these treatments may cause life-threatening diseases. Recent research has shown that cellular therapies hold a potential for CNS repair and may be able to provide protection from inflammatory damage caused after injury. Human embryonic stem cell (hESC) transplantation is one of the promising cell therapies; hESCs play an important role in remyelination and help in preventing demylenation of the axons. In this study, an overview of the current knowledge about the unique properties of hESC and their comparison with other cell therapies has been presented for the treatment of patients with MS.

  19. Lattice Boltzmann method with the cell-population equilibrium

    Zhou Xiaoyang; Cheng Bing; Shi Baochang

    2008-01-01

    The central problem of the lattice Boltzmann method (LBM) is to construct a discrete equilibrium. In this paper, a multi-speed 1D cell-model of Boltzmann equation is proposed, in which the cell-population equilibrium, a direct non-negative approximation to the continuous Maxwellian distribution, plays an important part. By applying the explicit one-order Chapman–Enskog distribution, the model reduces the transportation and collision, two basic evolution steps in LBM, to the transportation of the non-equilibrium distribution. Furthermore, 1D dam-break problem is performed and the numerical results agree well with the analytic solutions

  20. Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)—Patient Version

    Plasma cell neoplasms occur when abnormal plasma cells or myeloma cells form tumors in the bones or soft tissues of the body. Multiple myeloma, plasmacytoma, lymphoplasmacytic lymphoma, and monoclonal gammopathy of undetermined significance (MGUS) are different types of plasma cell neoplasms. Find out about risk factors, symptoms, diagnostic tests, prognosis, and treatment for these diseases.

  1. Psidium guajava: A Single Plant for Multiple Health Problems of Rural Indian Population.

    Daswani, Poonam G; Gholkar, Manasi S; Birdi, Tannaz J

    2017-01-01

    The rural population in India faces a number of health problems and often has to rely on local remedies. Psidium guajava Linn. (guava), a tropical plant which is used as food and medicine can be used by rural communities due to its several medicinal properties. A literature search was undertaken to gauge the rural health scenario in India and compile the available literature on guava so as to reflect its usage in the treatment of multiple health conditions prevalent in rural communities. Towards this, electronic databases such as Pubmed, Science Direct, google scholar were scanned. Information on clinical trials on guava was obtained from Cochrane Central Register of Controlled Trials and Clinicaltrial.gov. The literature survey revealed that guava possesses various medicinal properties which have been reported from across the globe in the form of ethnobotanical/ethnopharmacological surveys, laboratory investigations and clinical trials. Besides documenting the safety of guava, the available literature shows that guava is efficacious against the following conditions which rural communities would encounter. (a) Gastrointestinal infections; (b) Malaria; (c)Respiratory infections; (d) Oral/dental infections; (e) Skin infections; (f) Diabetes; (g) Cardiovascular/hypertension; (h) Cancer; (i) Malnutrition; (j) Women problems; (k) Pain; (l) Fever; (m) Liver problems; (n) Kidney problems. In addition, guava can also be useful for treatment of animals and explored for its commercial applications. In conclusion, popularization of guava, can have multiple applications for rural communities.

  2. Multiple genetic variants associated with primary biliary cirrhosis in a Han Chinese population.

    Dong, Ming; Li, Jinxin; Tang, Ruqi; Zhu, Ping; Qiu, Fang; Wang, Chan; Qiu, Jie; Wang, Lan; Dai, Yaping; Xu, Ping; Gao, Yueqiu; Han, Chongxu; Wang, Yongzhong; Wu, Jian; Wu, Xudong; Zhang, Kui; Dai, Na; Sun, Weihao; Zhou, Jianpo; Hu, Zhigang; Liu, Lei; Jiang, Yuzhang; Nie, Jinshan; Zhao, Yi; Gong, Yuhua; Tian, Ye; Ji, Hualiang; Jiao, Zhijun; Jiang, Po; Shi, Xingjuan; Jawed, Rohil; Zhang, Yu; Huang, Qinghai; Li, Enling; Wei, Yiran; Xie, Wei; Zhao, Weifeng; Liu, Xiang; Zhu, Xiang; Qiu, Hong; He, Gengsheng; Chen, Weichang; Seldin, Michael F; Gershwin, M Eric; Liu, Xiangdong; Ma, Xiong

    2015-06-01

    Multiple genome-wide association studies of primary biliary cirrhosis (PBC) in both European and Japanese ancestries have shown significant associations of many genetic loci contributing to the susceptibility to PBC. Major differences in susceptibility loci between these two population groups were observed. In this study, we examined whether the most significant loci observed in either European and/or Japanese cohorts are associated with PBC in a Han Chinese population. In 1070 PBC patients and 1198 controls, we observed highly significant associations at CD80 (rs2293370, P = 2.67 × 10(-8)) and TNFSF15 (rs4979462, P = 3.86 × 10(-8)) and significant associations at 17q12-21 (rs9303277), PDGFB (rs715505), NF-κB1 (rs7665090), IL12RB2 (rs11209050), and STAT4 (rs7574865; all corrected P values rs7574865) was strongly associated after additional control samples were analyzed. Our study is the first large-scale genetic analysis in a Han Chinese PBC cohort. These results do not only reflect that Han Chinese PBC patients share common genetic susceptibility genes with both their Japanese and European counterparts but also suggest a distinctly different genetic susceptibility profile.

  3. Expression of stanniocalcin 1 in thyroid side population cells and thyroid cancer cells.

    Hayase, Suguru; Sasaki, Yoshihito; Matsubara, Tsutomu; Seo, Daekwan; Miyakoshi, Masaaki; Murata, Tsubasa; Ozaki, Takashi; Kakudo, Kennichi; Kumamoto, Kensuke; Ylaya, Kris; Cheng, Sheue-yann; Thorgeirsson, Snorri S; Hewitt, Stephen M; Ward, Jerrold M; Kimura, Shioko

    2015-04-01

    Mouse thyroid side population (SP) cells consist of a minor population of mouse thyroid cells that may have multipotent thyroid stem cell characteristics. However the nature of thyroid SP cells remains elusive, particularly in relation to thyroid cancer. Stanniocalcin (STC) 1 and 2 are secreted glycoproteins known to regulate serum calcium and phosphate homeostasis. In recent years, the relationship of STC1/2 expression to cancer has been described in various tissues. Microarray analysis was carried out to determine genes up- and down-regulated in thyroid SP cells as compared with non-SP cells. Among genes up-regulated, stanniocalcin 1 (STC1) was chosen for study because of its expression in various thyroid cells by Western blotting and immunohistochemistry. Gene expression analysis revealed that genes known to be highly expressed in cancer cells and/or involved in cancer invasion/metastasis were markedly up-regulated in SP cells from both intact as well as partial thyroidectomized thyroids. Among these genes, expression of STC1 was found in five human thyroid carcinoma-derived cell lines as revealed by analysis of mRNA and protein, and its expression was inversely correlated with the differentiation status of the cells. Immunohistochemical analysis demonstrated higher expression of STC1 in the thyroid tumor cell line and thyroid tumor tissues from humans and mice. These results suggest that SP cells contain a population of cells that express genes also highly expressed in cancer cells including Stc1, which warrants further study on the role of SP cells and/or STC1 expression in thyroid cancer.

  4. Anti-CD20 Cell Therapies in Multiple Sclerosis—A Fixed Dosing Schedule for Ocrelizumab is Overkill

    Jagannadha Avasarala

    2017-10-01

    Full Text Available Anti-CD 20 therapies have found significant uses in multiple sclerosis (MS. Based singularly on the accumulated evidence with the use of rituximab (RTX; Rituxan, Genentech, and Biogen in neuroimmunological diseases, ocrelizumab (OCR; Ocrevus, Genentech was developed as a treatment option for MS and selectively targets CD20 B cells, a cell surface antigen found on pre-B cells, mature, and memory B cells, but not on lymphoid stem cells and plasma cells. On the basis of indirect evidence, elimination of the antigen-presenting capabilities and antigen nonspecific immune functions of B cells appear to be central to the therapeutic efficacy of anti-CD20 B-cell therapies. An important question is this—Why does the drug need to be dosed at fixed intervals and not based on a measurable endpoint, such as tracking peripheral CD20 cell counts? There is minimal scientific validity in infusing the drug every 6 months particularly if CD20 cell counts are negligible in the peripheral blood. In this analysis, a case is made for following CD19 cell populations as a surrogate for CD20 cells on a monthly basis to guide OCR redosing parameters and does not follow a scheduled dosing parameter.

  5. Phenotypic and functional profiling of CD4 T cell compartment in distinct populations of healthy adults with different antigenic exposure.

    Sophie Roetynck

    Full Text Available Multiparameter flow cytometry has revealed extensive phenotypic and functional heterogeneity of CD4 T cell responses in mice and humans, emphasizing the importance of assessing multiple aspects of the immune response in correlation with infection or vaccination outcome. The aim of this study was to establish and validate reliable and feasible flow cytometry assays, which will allow us to characterize CD4 T cell population in humans in field studies more fully.We developed polychromatic flow cytometry antibody panels for immunophenotyping the major CD4 T cell subsets as well as broadly characterizing the functional profiles of the CD4 T cells in peripheral blood. We then validated these assays by conducting a pilot study comparing CD4 T cell responses in distinct populations of healthy adults living in either rural or urban Kenya. This study revealed that the expression profile of CD4 T cell activation and memory markers differed significantly between African and European donors but was similar amongst African individuals from either rural or urban areas. Adults from rural Kenya had, however, higher frequencies and greater polyfunctionality among cytokine producing CD4 T cells compared to both urban populations, particularly for "Th1" type of response. Finally, endemic exposure to malaria in rural Kenya may have influenced the expansion of few discrete CD4 T cell populations with specific functional signatures.These findings suggest that environmentally driven T cell activation does not drive the dysfunction of CD4 T cells but is rather associated with greater magnitude and quality of CD4 T cell response, indicating that the level or type of microbial exposure and antigenic experience may influence and shape the functionality of CD4 T cell compartment. Our data confirm that it is possible and mandatory to assess multiple functional attributes of CD4 T cell response in the context of infection.

  6. Increased T cell expression of CD154 (CD40-ligand) in multiple sclerosis

    Jensen, J; Krakauer, M; Sellebjerg, F

    2001-01-01

    CD154 (CD40-ligand, gp39), expressed on activated T cells, is crucial in T cell-dependent immune responses and may be involved in the pathogenesis of multiple sclerosis (MS). We studied cerebro-spinal fluid and peripheral blood T cell expression of CD154 in MS by flow cytometry. Patients with sec......CD154 (CD40-ligand, gp39), expressed on activated T cells, is crucial in T cell-dependent immune responses and may be involved in the pathogenesis of multiple sclerosis (MS). We studied cerebro-spinal fluid and peripheral blood T cell expression of CD154 in MS by flow cytometry. Patients...

  7. Stages of Plasma Cell Neoplasms (Including Multiple Myeloma)

    ... cancer treatment is also called biotherapy or immunotherapy. Immunomodulators are a type of biologic therapy. Thalidomide , lenalidomide , and pomalidomide are immunomodulators used to treat multiple myeloma and other plasma ...

  8. Treatment Options for Plasma Cell Neoplasms (Including Multiple Myeloma)

    ... cancer treatment is also called biotherapy or immunotherapy. Immunomodulators are a type of biologic therapy. Thalidomide , lenalidomide , and pomalidomide are immunomodulators used to treat multiple myeloma and other plasma ...

  9. Expression of genes encoding multi-transmembrane proteins in specific primate taste cell populations.

    Bryan D Moyer

    Full Text Available BACKGROUND: Using fungiform (FG and circumvallate (CV taste buds isolated by laser capture microdissection and analyzed using gene arrays, we previously constructed a comprehensive database of gene expression in primates, which revealed over 2,300 taste bud-associated genes. Bioinformatics analyses identified hundreds of genes predicted to encode multi-transmembrane domain proteins with no previous association with taste function. A first step in elucidating the roles these gene products play in gustation is to identify the specific taste cell types in which they are expressed. METHODOLOGY/PRINCIPAL FINDINGS: Using double label in situ hybridization analyses, we identified seven new genes expressed in specific taste cell types, including sweet, bitter, and umami cells (TRPM5-positive, sour cells (PKD2L1-positive, as well as other taste cell populations. Transmembrane protein 44 (TMEM44, a protein with seven predicted transmembrane domains with no homology to GPCRs, is expressed in a TRPM5-negative and PKD2L1-negative population that is enriched in the bottom portion of taste buds and may represent developmentally immature taste cells. Calcium homeostasis modulator 1 (CALHM1, a component of a novel calcium channel, along with family members CALHM2 and CALHM3; multiple C2 domains; transmembrane 1 (MCTP1, a calcium-binding transmembrane protein; and anoctamin 7 (ANO7, a member of the recently identified calcium-gated chloride channel family, are all expressed in TRPM5 cells. These proteins may modulate and effect calcium signalling stemming from sweet, bitter, and umami receptor activation. Synaptic vesicle glycoprotein 2B (SV2B, a regulator of synaptic vesicle exocytosis, is expressed in PKD2L1 cells, suggesting that this taste cell population transmits tastant information to gustatory afferent nerve fibers via exocytic neurotransmitter release. CONCLUSIONS/SIGNIFICANCE: Identification of genes encoding multi-transmembrane domain proteins

  10. The regrowth kinetic of the surviving population is independent of acute and chronic responses to temozolomide in glioblastoma cell lines

    Silva, Andrew Oliveira; Dalsin, Eloisa; Onzi, Giovana Ravizzoni; Filippi-Chiela, Eduardo Cremonese; Lenz, Guido

    2016-01-01

    Chemotherapy acts on cancer cells by producing multiple effects on a cell population including cell cycle arrest, necrosis, apoptosis and senescence. However, often a subpopulation of cells survives and the behavior of this subpopulation, which is responsible for cancer recurrence, remains obscure. Here we investigated the in vitro short- and long-term responses of six glioblastoma cell lines to clinically relevant doses of temozolomide for 5 days followed by 23 days of recovery, mimicking the standard schedule used in glioblastoma patient for this drug. These cells presented different profiles of sensitivity to temozolomide with varying levels of cell cycle arrest, autophagy and senescence, followed by a regrowth of the surviving cells. The initial reduction in cell number and the subsequent regrowth was analyzed with four new parameters applied to Cumulative Population Doubling (CPD) curves that describe the overall sensitivity of the population and the characteristic of the regrowth: the relative end point CPD (RendCPD); the relative Area Under Curve (rAUC); the Relative Time to Cross a Threshold (RTCT); and the Relative Proliferation Rate (RPR). Surprisingly, the kinetics of regrowth were not predicted by the mechanisms activated after treatment nor by the acute or overall sensitivity. With this study we added new parameters that describe key responses of glioblastoma cell populations to temozolomide treatment. These parameters can also be applied to other cell types and treatments and will help to understand the behavior of the surviving cancer cells after treatment and shed light on studies of cancer resistance and recurrence. - Highlights: • Little is known about the behavior of the glioma cells surviving to TMZ. • The short- and long-term response of six glioma cells lines to TMZ varies considerably. • These glioma cells lines recovered proliferation after therapeutic levels of TMZ. • The growth velocity of the surviving cells was different from the

  11. The regrowth kinetic of the surviving population is independent of acute and chronic responses to temozolomide in glioblastoma cell lines

    Silva, Andrew Oliveira, E-mail: andrewbiomed@gmail.com [Department of Biophysics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS (Brazil); Dalsin, Eloisa, E-mail: dalsineloisa@gmail.com [Department of Biophysics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS (Brazil); Onzi, Giovana Ravizzoni, E-mail: gioonzi@gmail.com [Department of Biophysics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS (Brazil); Center of Biotechnology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS (Brazil); Filippi-Chiela, Eduardo Cremonese, E-mail: eduardochiela@gmail.com [Department of Biophysics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS (Brazil); Lenz, Guido, E-mail: lenz@ufrgs.br [Department of Biophysics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS (Brazil); Center of Biotechnology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS (Brazil)

    2016-11-01

    Chemotherapy acts on cancer cells by producing multiple effects on a cell population including cell cycle arrest, necrosis, apoptosis and senescence. However, often a subpopulation of cells survives and the behavior of this subpopulation, which is responsible for cancer recurrence, remains obscure. Here we investigated the in vitro short- and long-term responses of six glioblastoma cell lines to clinically relevant doses of temozolomide for 5 days followed by 23 days of recovery, mimicking the standard schedule used in glioblastoma patient for this drug. These cells presented different profiles of sensitivity to temozolomide with varying levels of cell cycle arrest, autophagy and senescence, followed by a regrowth of the surviving cells. The initial reduction in cell number and the subsequent regrowth was analyzed with four new parameters applied to Cumulative Population Doubling (CPD) curves that describe the overall sensitivity of the population and the characteristic of the regrowth: the relative end point CPD (RendCPD); the relative Area Under Curve (rAUC); the Relative Time to Cross a Threshold (RTCT); and the Relative Proliferation Rate (RPR). Surprisingly, the kinetics of regrowth were not predicted by the mechanisms activated after treatment nor by the acute or overall sensitivity. With this study we added new parameters that describe key responses of glioblastoma cell populations to temozolomide treatment. These parameters can also be applied to other cell types and treatments and will help to understand the behavior of the surviving cancer cells after treatment and shed light on studies of cancer resistance and recurrence. - Highlights: • Little is known about the behavior of the glioma cells surviving to TMZ. • The short- and long-term response of six glioma cells lines to TMZ varies considerably. • These glioma cells lines recovered proliferation after therapeutic levels of TMZ. • The growth velocity of the surviving cells was different from the

  12. Carrier population control and surface passivation in solar cells

    Cuevas, Andres

    2018-05-02

    Controlling the concentration of charge carriers near the surface is essential for solar cells. It permits to form regions with selective conductivity for either electrons or holes and it also helps to reduce the rate at which they recombine. Chemical passivation of the surfaces is equally important, and it can be combined with population control to implement carrier-selective, passivating contacts for solar cells. This paper discusses different approaches to suppress surface recombination and to manipulate the concentration of carriers by means of doping, work function and charge. It also describes some of the many surface-passivating contacts that are being developed for silicon solar cells, restricted to experiments performed by the authors.

  13. Modelling cell population growth with applications to cancer therapy in human tumour cell lines.

    Basse, Britta; Baguley, Bruce C; Marshall, Elaine S; Wake, Graeme C; Wall, David J N

    2004-01-01

    In this paper we present an overview of the work undertaken to model a population of cells and the effects of cancer therapy. We began with a theoretical one compartment size structured cell population model and investigated its asymptotic steady size distributions (SSDs) (On a cell growth model for plankton, MMB JIMA 21 (2004) 49). However these size distributions are not similar to the DNA (size) distributions obtained experimentally via the flow cytometric analysis of human tumour cell lines (data obtained from the Auckland Cancer Society Research Centre, New Zealand). In our one compartment model, size was a generic term, but in order to obtain realistic steady size distributions we chose size to be DNA content and devised a multi-compartment mathematical model for the cell division cycle where each compartment corresponds to a distinct phase of the cell cycle (J. Math. Biol. 47 (2003) 295). We then incorporated another compartment describing the possible induction of apoptosis (cell death) from mitosis phase (Modelling cell death in human tumour cell lines exposed to anticancer drug paclitaxel, J. Math. Biol. 2004, in press). This enabled us to compare our model to flow cytometric data of a melanoma cell line where the anticancer drug, paclitaxel, had been added. The model gives a dynamic picture of the effects of paclitaxel on the cell cycle. We hope to use the model to describe the effects of other cancer therapies on a number of different cell lines. Copyright 2004 Elsevier Ltd.

  14. Influence of Cell-Cell Interactions on the Population Growth Rate in a Tumor

    Chen, Yong

    2017-12-01

    The understanding of the macroscopic phenomenological models of the population growth at a microscopic level is important to predict the population behaviors emerged from the interactions between the individuals. In this work, we consider the influence of the population growth rate R on the cell-cell interaction in a tumor system and show that, in most cases especially small proliferative probabilities, the regulative role of the interaction will be strengthened with the decline of the intrinsic proliferative probabilities. For the high replication rates of an individual and the cooperative interactions, the proliferative probability almost has no effect. We compute the dependences of R on the interactions between the cells under the approximation of the nearest neighbor in the rim of an avascular tumor. Our results are helpful to qualitatively understand the influence of the interactions between the individuals on the growth rate in population systems. Supported by the National Natural Science Foundation of China under Grant Nos. 11675008 and 21434001

  15. Investigating energy deposition within cell populations using Monte Carlo simulations.

    Oliver, Patricia A K; Thomson, Rowan M

    2018-06-27

    In this work, we develop multicellular models of healthy and cancerous human soft tissues, which are used to investigate energy deposition in subcellular targets, quantify the microdosimetric spread in a population of cells, and determine how these results depend on model details. Monte Carlo (MC) tissue models combining varying levels of detail on different length scales are developed: microscopically-detailed regions of interest (>1500 explicitly-modelled cells) are embedded in bulk tissue phantoms irradiated by photons (20 keV to 1.25 MeV). Specific energy (z; energy imparted per unit mass) is scored in nuclei and cytoplasm compartments using the EGSnrc user-code egs_chamber; specific energy mean, <z>, standard deviation, σz, and distribution, f(z,D), are calculated for a variety of macroscopic doses, D. MC-calculated f(z,D) are compared with normal distributions having the same mean and standard deviation. For mGy doses, there is considerable variation in energy deposition (microdosimetric spread) throughout a cell population: e.g., for 30 keV photons irradiating melanoma with 7.5 μm cell radius and 3 μm nuclear radius, σz/<z> for nuclear targets is 170%, and the fraction of nuclei receiving no energy deposition, fz=0, is 0.31 for a dose of 10 mGy. If cobalt-60 photons are considered instead, then σz/<z> decreases to 84%, and fz=0 decreases to 0.036. These results correspond to randomly arranged cells with cell/nucleus sizes randomly sampled from a normal distribution with a standard deviation of 1 μm. If cells are arranged in a hexagonal lattice and cell/nucleus sizes are uniform throughout the population, then σz/<z> decreases to 106% and 68% for 30 keV and cobalt-60,respectively; fz=0

  16. Multiple insecticide resistance mechanisms in Anopheles gambiae s.l. populations from Cameroon, Central Africa.

    Nwane, Philippe; Etang, Josiane; Chouaїbou, Mouhamadou; Toto, Jean Claude; Koffi, Alphonsine; Mimpfoundi, Rémy; Simard, Frédéric

    2013-02-22

    Increasing incidence of DDT and pyrethroid resistance in Anopheles mosquitoes is seen as a limiting factor for malaria vector control. The current study aimed at an in-depth characterization of An. gambiae s.l. resistance to insecticides in Cameroon, in order to guide malaria vector control interventions. Anopheles gambiae s.l. mosquitoes were collected as larvae and pupae from six localities spread throughout the four main biogeographical domains of Cameroon and reared to adults in insectaries. Standard WHO insecticide susceptibility tests were carried out with 4% DDT, 0.75% permethrin and 0.05% deltamethrin. Mortality rates and knockdown times (kdt50 and kdt95) were determined and the effect of pre-exposure to the synergists DEF, DEM and PBO was assessed. Tested mosquitoes were identified to species and molecular forms (M or S) using PCR-RFLP. The hot ligation method was used to depict kdr mutations and biochemical assays were conducted to assess detoxifying enzyme activities. The An. arabiensis population from Pitoa was fully susceptible to DDT and permethrin (mortality rates>98%) and showed reduced susceptibility to deltamethrin. Resistance to DDT was widespread in An. gambiae s.s. populations and heterogeneous levels of susceptibility to permethrin and deltamethrin were observed. In many cases, prior exposure to synergists partially restored insecticide knockdown effect and increased mortality rates, suggesting a role of detoxifying enzymes in increasing mosquito survival upon challenge by pyrethroids and, to a lower extent DDT. The distribution of kdr alleles suggested a major role of kdr-based resistance in the S form of An. gambiae. In biochemical tests, all but one mosquito population overexpressed P450 activity, whereas baseline GST activity was low and similar in all field mosquito populations and in the control. In Cameroon, multiple resistance mechanisms segregate in the S form of An. gambiae resulting in heterogeneous resistance profiles, whereas in

  17. Transplantation of Human Embryonic Stem Cells in Patients with Multiple Sclerosis and Lyme Disease

    Shroff, Geeta

    2016-01-01

    Case series Patient: Male, 42 ? Female, 30 Final Diagnosis: Human embryonic stem cells showed good therapeutic potential for treatment of multiple sclerosis with lyme disease Symptoms: Fatigue ? weakness in limbs Medication: ? Clinical Procedure: Human embryonic stem cells transplantation Specialty: Transplantology Objective: Rare disease Background: Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease in which the myelin sheath of nerve cells is damaged. It can cause dela...

  18. Molecular purging of multiple myeloma cells by ex-vivo culture and retroviral transduction of mobilized-blood CD34+ cells

    Corneo Gianmarco

    2007-07-01

    Full Text Available Abstract Background Tumor cell contamination of the apheresis in multiple myeloma is likely to affect disease-free and overall survival after autografting. Objective To purge myeloma aphereses from tumor contaminants with a novel culture-based purging method. Methods We cultured myeloma-positive CD34+ PB samples in conditions that retained multipotency of hematopoietic stem cells, but were unfavourable to survival of plasma cells. Moreover, we exploited the resistance of myeloma plasma cells to retroviral transduction by targeting the hematopoietic CD34+ cell population with a retroviral vector carrying a selectable marker (the truncated form of the human receptor for nerve growth factor, ΔNGFR. We performed therefore a further myeloma purging step by selecting the transduced cells at the end of the culture. Results Overall recovery of CD34+ cells after culture was 128.5%; ΔNGFR transduction rate was 28.8% for CD34+ cells and 0% for CD138-selected primary myeloma cells, respectively. Recovery of CD34+ cells after ΔNGFR selection was 22.3%. By patient-specific Ig-gene rearrangements, we assessed a decrease of 0.7–1.4 logs in tumor load after the CD34+ cell selection, and up to 2.3 logs after culture and ΔNGFR selection. Conclusion We conclude that ex-vivo culture and retroviral-mediated transduction of myeloma leukaphereses provide an efficient tumor cell purging.

  19. EEN regulates the proliferation and survival of multiple myeloma cells by potentiating IGF-1 secretion

    Huang, Er-Wen; Xue, Sheng-Jiang; Li, Xiao-Yan; Xu, Suo-Wen; Cheng, Jian-Ding; Zheng, Jin-Xiang; Shi, He; Lv, Guo-Li; Li, Zhi-Gang; Li, Yue; Liu, Chang-Hui; Chen, Xiao-Hui; Liu, Hong; Li, Jie; Liu, Chao

    2014-01-01

    Highlights: • Levels of EEN expression paralleled with the rate of cell proliferation. • EEN was involved in the proliferation and survival of multiple myeloma (MM) cells. • EEN regulated the activity of IGF-1-Akt/mTOR pathway. • EEN regulated proliferation and survival of MM cells by enhancing IGF-1 secretion. - Abstract: The molecular mechanisms of multiple myeloma are not well defined. EEN is an endocytosis-regulating molecule. Here we report that EEN regulates the proliferation and survival of multiple myeloma cells, by regulating IGF-1 secretion. In the present study, we observed that EEN expression paralleled with cell proliferation, EEN accelerated cell proliferation, facilitated cell cycle transition from G1 to S phase by regulating cyclin-dependent kinases (CDKs) pathway, and delayed cell apoptosis via Bcl2/Bax-mitochondrial pathway. Mechanistically, we found that EEN was indispensable for insulin-like growth factor-1 (IGF-1) secretion and the activation of protein kinase B-mammalian target of rapamycin (Akt-mTOR) pathway. Exogenous IGF-1 overcame the phenotype of EEN depletion, while IGF-1 neutralization overcame that of EEN over-expression. Collectively, these data suggest that EEN may play a pivotal role in excessive cell proliferation and insufficient cell apoptosis of bone marrow plasma cells in multiple myeloma. Therefore, EEN may represent a potential diagnostic marker or therapeutic target for multiple myeloma

  20. EEN regulates the proliferation and survival of multiple myeloma cells by potentiating IGF-1 secretion

    Huang, Er-Wen [Guangzhou Institute of Forensic Science, Guangzhou (China); Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou (China); Xue, Sheng-Jiang [Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou (China); Li, Xiao-Yan [Department of Pharmacy, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou (China); Xu, Suo-Wen [Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou (China); Cheng, Jian-Ding; Zheng, Jin-Xiang [Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou (China); Shi, He; Lv, Guo-Li; Li, Zhi-Gang; Li, Yue; Liu, Chang-Hui; Chen, Xiao-Hui; Liu, Hong [Guangzhou Institute of Forensic Science, Guangzhou (China); Li, Jie, E-mail: mdlijie@sina.com [Department of Anaesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou (China); Liu, Chao, E-mail: liuchaogaj@21cn.com [Guangzhou Institute of Forensic Science, Guangzhou (China)

    2014-05-02

    Highlights: • Levels of EEN expression paralleled with the rate of cell proliferation. • EEN was involved in the proliferation and survival of multiple myeloma (MM) cells. • EEN regulated the activity of IGF-1-Akt/mTOR pathway. • EEN regulated proliferation and survival of MM cells by enhancing IGF-1 secretion. - Abstract: The molecular mechanisms of multiple myeloma are not well defined. EEN is an endocytosis-regulating molecule. Here we report that EEN regulates the proliferation and survival of multiple myeloma cells, by regulating IGF-1 secretion. In the present study, we observed that EEN expression paralleled with cell proliferation, EEN accelerated cell proliferation, facilitated cell cycle transition from G1 to S phase by regulating cyclin-dependent kinases (CDKs) pathway, and delayed cell apoptosis via Bcl2/Bax-mitochondrial pathway. Mechanistically, we found that EEN was indispensable for insulin-like growth factor-1 (IGF-1) secretion and the activation of protein kinase B-mammalian target of rapamycin (Akt-mTOR) pathway. Exogenous IGF-1 overcame the phenotype of EEN depletion, while IGF-1 neutralization overcame that of EEN over-expression. Collectively, these data suggest that EEN may play a pivotal role in excessive cell proliferation and insufficient cell apoptosis of bone marrow plasma cells in multiple myeloma. Therefore, EEN may represent a potential diagnostic marker or therapeutic target for multiple myeloma.

  1. Autologous bone marrow Th cells can support multiple myeloma cell proliferation in vitro and in xenografted mice.

    Wang, D; Fløisand, Y; Myklebust, C V; Bürgler, S; Parente-Ribes, A; Hofgaard, P O; Bogen, B; Taskén, K; Tjønnfjord, G E; Schjesvold, F; Dalgaard, J; Tveita, A; Munthe, L A

    2017-10-01

    Multiple myeloma (MM) is a plasma cell malignancy where MM cell growth is supported by the bone marrow (BM) microenvironment with poorly defined cellular and molecular mechanisms. MM cells express CD40, a receptor known to activate autocrine secretion of cytokines and elicit proliferation. Activated T helper (Th) cells express CD40 ligand (CD40L) and BM Th cells are significantly increased in MM patients. We hypothesized that activated BM Th cells could support MM cell growth. We here found that activated autologous BM Th cells supported MM cell growth in a contact- and CD40L-dependent manner in vitro. MM cells had retained the ability to activate Th cells that reciprocated and stimulated MM cell proliferation. Autologous BM Th cells supported MM cell growth in xenografted mice and were found in close contact with MM cells. MM cells secreted chemokines that attracted Th cells, secretion was augmented by CD40-stimulation. Within 14 days of culture of whole BM aspirates in autologous serum, MM cells and Th cells mutually stimulated each other, and MM cells required Th cells for further expansion in vitro and in mice. The results suggest that Th cells may support the expansion of MM cells in patients.

  2. Vipie: web pipeline for parallel characterization of viral populations from multiple NGS samples.

    Lin, Jake; Kramna, Lenka; Autio, Reija; Hyöty, Heikki; Nykter, Matti; Cinek, Ondrej

    2017-05-15

    Next generation sequencing (NGS) technology allows laboratories to investigate virome composition in clinical and environmental samples in a culture-independent way. There is a need for bioinformatic tools capable of parallel processing of virome sequencing data by exactly identical methods: this is especially important in studies of multifactorial diseases, or in parallel comparison of laboratory protocols. We have developed a web-based application allowing direct upload of sequences from multiple virome samples using custom parameters. The samples are then processed in parallel using an identical protocol, and can be easily reanalyzed. The pipeline performs de-novo assembly, taxonomic classification of viruses as well as sample analyses based on user-defined grouping categories. Tables of virus abundance are produced from cross-validation by remapping the sequencing reads to a union of all observed reference viruses. In addition, read sets and reports are created after processing unmapped reads against known human and bacterial ribosome references. Secured interactive results are dynamically plotted with population and diversity charts, clustered heatmaps and a sortable and searchable abundance table. The Vipie web application is a unique tool for multi-sample metagenomic analysis of viral data, producing searchable hits tables, interactive population maps, alpha diversity measures and clustered heatmaps that are grouped in applicable custom sample categories. Known references such as human genome and bacterial ribosomal genes are optionally removed from unmapped ('dark matter') reads. Secured results are accessible and shareable on modern browsers. Vipie is a freely available web-based tool whose code is open source.

  3. Genetic factors and multiple sclerosis in the Moroccan population: a role for HLA class II.

    Ouadghiri, S; El Alaoui Toussi, K; Brick, C; Ait Benhaddou, E H; Benseffaj, N; Benomar, A; El Yahyaoui, M; Essakalli, M

    2013-12-01

    Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system that mainly affects young adults. The association between susceptibility to MS and HLA class II genes, in particular the DRB1*15 allele, has been reported in diverse ethnic groups. The aim of our study was to investigate the distribution of HLA-DRB1* and -DQB1* alleles in Moroccan population and their implication in the susceptibility to the disease. Fifty-seven MS patients were compared to 172 healthy controls unrelated to one another and matched by age, sex and ethnic origin. HLA class II (DRB1* and DQB1*) typing was performed by PCR-SSP and/or Luminex (PCR-SSO). Allelic and haplotypic frequencies, P-values, odds ratio (OR) and 95% confidence interval (CI) were calculated using the software SPSS. A significant increase of DRB1*15 allele frequency (17.6% vs 8.4%, OR=2.67, 95% CI=1.36-5.23, P=0.004) and HLA-DRB1*15-DQB1*06 haplotype (8.8% vs 4.08%, OR=2.78, 95% CI=1.41-5.48, P=0.002) were observed in Moroccan MS patients. No association of the DR15 allele with sex or age at onset was appreciated. Concerning HLA-DQB1* alleles, no significant difference between patients and controls was found. Our results reveal a role for HLA-DRB1*15 allele molecules in the predisposition of Moroccan patients to MS. Although this study should be confirmed on a larger sample size, it analyzes for the first time the possible role of a genetic marker for susceptibility to MS in Moroccan population. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  4. Some considerations in applying stock-recruitment models to multiple-age spawning populations

    Lawler, P.J.

    1988-01-01

    Several approaches used during the Hudson River power plant hearings (1977-1980) to permit quantitative estimation of the impact of power plant operation on the river's striped bass population are presented. The Ricker stock-recruitment model was adopted as a starting point to provide a reasonable working conceptualization of the stock-recruitment processes operating in this river. This model was then modified in a variety of ways to reflect multiple-age spawning by striped bass, and the results were fit to data on the river's commercial striped bass catch and effort, organized to reflect certain average age distribution parameters. Environmental variation in the system, represented in an overall fashion by the spring and summer variation in the river's freshwater flow, and the effect of certain assumed modes of cannibalism were also included in these analyses. Quantitative estimates of the Ricker parameters alpha and beta representing compensatory reserve and density dependent mortality, respectively, in the system were extracted from these fits. In addition, an approach to modeling the influence of certain density-dependent and density-independent growth factors on the various modes of mortality is presented. All of the above procedures are directed toward estimating the change a given impact may induce on the stock-recruitment model parameters alpha and beta. These changes in alpha and beta are used in various equilibrium reduction models to estimate the percentage change in the equilibrium spawning population that, all other things remaining equal, can be expected in the presence of the impact under study. 15 refs., 3 tabs

  5. Searching for multiple stellar populations in the massive, old open cluster Berkeley 39

    Bragaglia, A.; Gratton, R. G.; Carretta, E.; D'Orazi, V.; Sneden, C.; Lucatello, S.

    2012-12-01

    The most massive star clusters include several generations of stars with a different chemical composition (mainly revealed by an Na-O anti-correlation) while low-mass star clusters appear to be chemically homogeneous. We are investigating the chemical composition of several clusters with masses of a few 104 M⊙ to establish the lower mass limit for the multiple stellar population phenomenon. Using VLT/FLAMES spectra we determine abundances of Fe, O, Na, and several other elements (α, Fe-peak, and neutron-capture elements) in the old open cluster Berkeley 39. This is a massive open cluster: M ~ 104 M⊙, approximately at the border between small globular clusters and large open clusters. Our sample size of about 30 stars is one of the largest studied for abundances in any open cluster to date, and will be useful to determine improved cluster parameters, such as age, distance, and reddening when coupled with precise, well-calibrated photometry. We find that Berkeley 39 is slightly metal-poor, ⟨[Fe/H]⟩ = -0.20, in agreement with previous studies of this cluster. More importantly, we do not detect any star-to-star variation in the abundances of Fe, O, and Na within quite stringent upper limits. The rms scatter is 0.04, 0.10, and 0.05 dex for Fe, O, and Na, respectively. This small spread can be entirely explained by the noise in the spectra and by uncertainties in the atmospheric parameters. We conclude that Berkeley 39 is a single-population cluster. Based on observations collected at ESO telescopes under programme 386.B-0009.Tables 2 and 3 are available in electronic form at http://www.aanda.org

  6. Ras proteins have multiple functions in vegetative cells of Dictyostelium.

    Bolourani, Parvin; Spiegelman, George; Weeks, Gerald

    2010-11-01

    During the aggregation of Dictyostelium cells, signaling through RasG is more important in regulating cyclic AMP (cAMP) chemotaxis, whereas signaling through RasC is more important in regulating the cAMP relay. However, RasC is capable of substituting for RasG for chemotaxis, since rasG⁻ cells are only partially deficient in chemotaxis, whereas rasC⁻/rasG⁻ cells are totally incapable of chemotaxis. In this study we have examined the possible functional overlap between RasG and RasC in vegetative cells by comparing the vegetative cell properties of rasG⁻, rasC⁻, and rasC⁻/rasG⁻ cells. In addition, since RasD, a protein not normally found in vegetative cells, is expressed in vegetative rasG⁻ and rasC⁻/rasG⁻ cells and appears to partially compensate for the absence of RasG, we have also examined the possible functional overlap between RasG and RasD by comparing the properties of rasG⁻ and rasC⁻/rasG⁻ cells with those of the mutant cells expressing higher levels of RasD. The results of these two lines of investigation show that RasD is capable of totally substituting for RasG for cytokinesis and growth in suspension, whereas RasC is without effect. In contrast, for chemotaxis to folate, RasC is capable of partially substituting for RasG, but RasD is totally without effect. Finally, neither RasC nor RasD is able to substitute for the role that RasG plays in regulating actin distribution and random motility. These specificity studies therefore delineate three distinct and none-overlapping functions for RasG in vegetative cells.

  7. Specific central nervous system recruitment of HLA-G(+) regulatory T cells in multiple sclerosis.

    Huang, Yu-Hwa; Zozulya, Alla L; Weidenfeller, Christian; Metz, Imke; Buck, Dorothea; Toyka, Klaus V; Brück, Wolfgang; Wiendl, Heinz

    2009-08-01

    We have recently described a novel population of natural regulatory T cells (T(reg)) that are characterized by the expression of HLA-G and may be found at sites of tissue inflammation (HLA-G(pos) T(reg)). Here we studied the role of these cells in multiple sclerosis (MS), a prototypic autoimmune inflammatory disorder of the central nervous system (CNS). Sixty-four patients with different types of MS, 9 patients with other neurological diseases, and 20 healthy donors were included in this study. Inflamed brain lesions from 5 additional untreated MS patients were examined. HLA-G(pos) T(reg) were analyzed in the cerebrospinal fluid (CSF) by flow cytometry and in inflammatory demyelinating lesions of MS brain specimens by immunohistochemistry. Functional capacity was accessed and transmigration was determined using an in vitro model of the human blood-brain barrier (BBB). HLA-G(pos) T(reg) were found enriched in the inflamed CSF of MS patients and in inflammatory demyelinating lesions of MS brain specimens. HLA-G(pos) T(reg) showed a strong propensity to transmigrate across BBB, which was vigorously driven by inflammatory chemokines, and associated with a gain of suppressive capacity upon transmigration. CSF-derived HLA-G(pos) T(reg) of MS patients represented a population of activated central memory activated T cells with an upregulated expression of inflammatory chemokine receptors and exhibiting full suppressive capacity. Unlike natural FoxP3-expressing T(reg), HLA-G(pos) T(reg) derived from peripheral blood were functionally unimpaired in MS. In MS, HLA-G(pos) T(reg) may serve to control potentially destructive immune responses directly at the sites of CNS inflammation and to counterbalance inflammation once specifically recruited to the CNS.

  8. Different aspects of thalidomide treatment and stem cell transplantation in multiple myeloma patients

    Marion, A.M.W. van

    2006-01-01

    Multiple myeloma (MM) is an haematological malignancy caused by an unrestrained proliferation of plasma cells (monoclonally differentiated B-cells), and part of the white blood cell count. This proliferation infiltrates the blood forming skeletal bone marrow, producing osteoclastic factors, causing

  9. Physical status of multiple human papillomavirus genotypes in flow-sorted cervical cancer cells

    Vermeulen, Christine F. W.; Jordanova, Ekaterina S.; Szuhai, Karoly; Kolkman-Uljee, Sandra; Vrede, M. Albert; Peters, Alexander A. W.; Schtturing, Ed; Fleuren, Gert Jan

    Multiple human papilloma virus (HPV) infections have been detected in cervical cancer. To investigate the significance of multiple HPV infections, we studied their prevalence in cancer samples from a low-risk (Dutch) and a high-risk (Surinamese) population and the correlation of HPV infection with

  10. Activation of endogenous neural stem cells for multiple sclerosis therapy

    Michailidou, I.; de Vries, H.E.; Hol, E.M.; van Strien, M.E.

    2015-01-01

    Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, leading to severe neurological deficits. Current MS treatment regimens, consist of immunomodulatory agents aiming to reduce the rate of relapses. However, these agents are usually insufficient to treat chronic

  11. The Peculiar Radial Distribution of Multiple Populations in the Massive Globular Cluster M80

    Dalessandro, E.; Cadelano, M.; Vesperini, E.; Salaris, M.; Ferraro, F. R.; Lanzoni, B.; Raso, S.; Hong, J.; Webb, J. J.; Zocchi, A.

    2018-05-01

    We present a detailed analysis of the radial distribution of light-element multiple populations (LE-MPs) in the massive and dense globular cluster M80, based on a combination of UV and optical Hubble Space Telescope data. Surprisingly, we find that first-generation (FG) stars (FG) are significantly more centrally concentrated than extreme second-generation (SG) stars out to ∼2.5r h from the cluster center. To understand the origin of such peculiar behavior, we used a set of N-body simulations following the long-term dynamical evolution of LE-MPs. We find that, given the advanced dynamical state of the cluster, the observed difference does not depend on the primordial relative distributions of FG and SG stars. On the contrary, a difference of ∼0.05–0.10 M ⊙ between the average masses of the two subpopulations is needed to account for the observed radial distributions. We argue that such a mass difference might be the result of the higher He abundance of SG stars (of the order of ΔY ∼ 0.05–0.06) with respect to FG stars. Interestingly, we find that a similar He variation is necessary to reproduce the horizontal branch morphology of M80. These results demonstrate that differences in mass among LE-MPs, due to different He content, should be properly taken into account for a correct interpretation of their radial distribution, at least in dynamically evolved systems.

  12. A Multiple-star Combined Solution Program - Application to the Population II Binary μ Cas

    Gudehus, D. H.

    2001-05-01

    A multiple-star combined-solution computer program which can simultaneously fit astrometric, speckle, and spectroscopic data, and solve for the orbital parameters, parallax, proper motion, and masses has been written and is now publicly available. Some features of the program are the ability to scale the weights at run time, hold selected parameters constant, handle up to five spectroscopic subcomponents for the primary and the secondary each, account for the light travel time across the system, account for apsidal motion, plot the results, and write the residuals in position to a standard file for further analysis. The spectroscopic subcomponent data can be represented by reflex velocities and/or by independent measurements. A companion editing program which can manage the data files is included in the package. The program has been applied to the Population II binary μ Cas to derive improved masses and an estimate of the primordial helium abundance. The source code, executables, sample data files, and documentation for OpenVMS and Unix, including Linux, are available at http://www.chara.gsu.edu/\\rlap\\ \\ gudehus/binary.html.

  13. Application of Multiple-Population Genetic Algorithm in Optimizing the Train-Set Circulation Plan Problem

    Yu Zhou

    2017-01-01

    Full Text Available The train-set circulation plan problem (TCPP belongs to the rolling stock scheduling (RSS problem and is similar to the aircraft routing problem (ARP in airline operations and the vehicle routing problem (VRP in the logistics field. However, TCPP involves additional complexity due to the maintenance constraint of train-sets: train-sets must conduct maintenance tasks after running for a certain time and distance. The TCPP is nondeterministic polynomial hard (NP-hard. There is no available algorithm that can obtain the optimal global solution, and many factors such as the utilization mode and the maintenance mode impact the solution of the TCPP. This paper proposes a train-set circulation optimization model to minimize the total connection time and maintenance costs and describes the design of an efficient multiple-population genetic algorithm (MPGA to solve this model. A realistic high-speed railway (HSR case is selected to verify our model and algorithm, and, then, a comparison of different algorithms is carried out. Furthermore, a new maintenance mode is proposed, and related implementation requirements are discussed.

  14. Romidepsin targets multiple survival signaling pathways in malignant T cells

    Valdez, B C; Brammer, J E; Li, Y; Murray, D; Liu, Y; Hosing, C; Nieto, Y; Champlin, R E; Andersson, B S

    2015-01-01

    Romidepsin is a cyclic molecule that inhibits histone deacetylases. It is Food and Drug Administration-approved for treatment of cutaneous and peripheral T-cell lymphoma, but its precise mechanism of action against malignant T cells is unknown. To better understand the biological effects of romidepsin in these cells, we exposed PEER and SUPT1 T-cell lines, and a primary sample from T-cell lymphoma patient (Patient J) to romidepsin. We then examined the consequences in some key oncogenic signaling pathways. Romidepsin displayed IC 50 values of 10.8, 7.9 and 7.0 nm in PEER, SUPT1 and Patient J cells, respectively. Strong inhibition of histone deacetylases and demethylases, increased production of reactive oxygen species and decreased mitochondrial membrane potential were observed, which may contribute to the observed DNA-damage response and apoptosis. The stress-activated protein kinase/c-Jun N-terminal kinase signaling pathway and unfolded protein response in the endoplasmic reticulum were activated, whereas the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) and β-catenin pro-survival pathways were inhibited. The decreased level of β-catenin correlated with the upregulation of its inhibitor SFRP1 through romidepsin-mediated hypomethylation of its gene promoter. Our results provide new insights into how romidepsin invokes malignant T-cell killing, show evidence of its associated DNA hypomethylating activity and offer a rationale for the development of romidepsin-containing combination therapies

  15. CELL POPULATION KINETICS OF EXCISED ROOTS OF PISUM SATIVUM

    Van't Hof, Jack

    1965-01-01

    The cell population kinetics of excised, cultured pea roots was studied with the use of tritiated thymidine and colchicine to determine (1) the influence of excision, (2) the influence of sucrose concentration, (3) the average mitotic cycle duration, and (4) the duration of mitosis and the G 1, S, and G 2 periods of interphase.1 The results indicate that the process of excision causes a drop in the frequency of mitotic figures when performed either at the beginning of the culture period or after 100 hours in culture. This initial decrease in frequency of cell division is independent of sucrose concentration, but the subsequent rise in frequency of division, after 12 hours in culture, is dependent upon sucrose concentration. Two per cent sucrose maintains the shortest mitotic cycle duration. The use of colchicine indicated an average cycle duration of 20 hours, whereas the use of tritiated thymidine produced an average cycle duration of 17 hours. PMID:5857253

  16. Cell dualism: presence of cells with alternative membrane potentials in growing populations of bacteria and yeasts.

    Ivanov, Volodymyr; Rezaeinejad, Saeid; Chu, Jian

    2013-10-01

    It is considered that all growing cells, for exception of acidophilic bacteria, have negatively charged inside cytoplasmic membrane (Δψ⁻-cells). Here we show that growing populations of microbial cells contain a small portion of cells with positively charged inside cytoplasmic membrane (Δψ⁺-cells). These cells were detected after simultaneous application of the fluorescent probes for positive membrane potential (anionic dye DIBAC⁻) and membrane integrity (propidium iodide, PI). We found in exponentially growing cell populations of Escherichia coli and Saccharomyces cerevisiae that the content of live Δψ⁻-cells was 93.6 ± 1.8 % for bacteria and 90.4 ± 4.0 % for yeasts and the content of live Δψ⁺-cells was 0.9 ± 0.3 % for bacteria and 2.4 ± 0.7 % for yeasts. Hypothetically, existence of Δψ⁺-cells could be due to short-term, about 1 min for bacteria and 5 min for yeasts, change of membrane potential from negative to positive value during the cell cycle. This change has been shown by the reversions of K⁺, Na⁺, and Ca²⁺ ions fluxes across the cell membrane during synchronous yeast culture. The transformation of Δψ(⁻-cells to Δψ⁺-cells can be explained by slow influx of K⁺ ions into Δψ⁻-cell to the trigger level of K⁺ concentration ("compression of potassium spring"), which is forming "alternative" Δψ⁺-cell for a short period, following with fast efflux of K⁺ ions out of Δψ⁺-cell ("release of potassium spring") returning cell to normal Δψ⁻ state. We anticipate our results to be a starting point to reveal the biological role of cell dualism in form of Δψ⁻- and Δψ⁺- cells.

  17. Sickle cell disease in tribal populations in India.

    Colah, Roshan B; Mukherjee, Malay B; Martin, Snehal; Ghosh, Kanjaksha

    2015-05-01

    The sickle gene is widespread among many tribal population groups in India with prevalence of heterozygotes varying from 1-40 per cent. Co-inheritance of the sickle gene with β-thalassaemia, HbD Punjab and glucose-6-phosphate dehydrogenase (G6PD) deficiency has also been reported. Most of the screening programmes in India now use high performance liquid chromatography (HPLC) analysis although the solubility test is also sensitive and cheap. Sickle cell disease (SCD) among tribal populations is generally milder than among non-tribal groups with fewer episodes of painful crises, infections, acute chest syndrome and need for hospitalization. This has partly been attributed to the very high prevalence of α-thalassaemia among these tribes as well as higher foetal haemoglobin levels. However, the clinical presentation is variable with many cases having a severe presentation. There is not much information available on maternal and perinatal outcome in tribal women with sickle cell disease. Newborn screening programmes for SCD have recently been initiated in Maharashtra, Gujarat, Orissa and Chattisgarh and monitoring these birth cohorts will help to understand the natural history of SCD in India. Prenatal diagnosis is acceptable by tribal families in India. The Indian Council of Medical Research and the National Rural Health Mission in different States are undertaking outreach programmes for better management and control of the disease.

  18. Red Cell Alloantibodies in Multiple Transfused Thalassaemia Patients.

    Chaudhari, C N

    2011-01-01

    Thalassaemia major patients require lifelong transfusion support due to which they are prone for alloimmunization to foreign RBCs. Alloimmunization can be prevented by extended phenotype match blood transfusion. The study was conducted to know the extent of problem of alloimmunization and to find important red cell antibodies in thalassaemia patients. A cross-sectional study was conducted. A total of 32 thalassaemia patients were enrolled. The specimen was subjected to red cell alloantibody and autoantibody by column gel agglutination technique. R 1 (w) R 1 , R 2 R 2 , rr (papaine and non papain) and 11 cell panel reagent cells were used in screening and identification of alloantibodies respectively. Six (18.8 %) subjects were alloimmunized. All alloimmunized subjects were recipient of more than 20 units of transfusion. Total seven clinically significant alloantibodies were identified. Anti E and anti c were commonest antibodies in four (12.5%) patients. Red cell alloimmunization is an important risk in thalassaemia patient. 71.4% of alloantibodies were anti E and anti c type. Extended phenotype match blood transfusion for Rh-c and Rh-E antigens or level 2 antigen matching stringency needs to be explored in preventing alloimmunization in thalassaemia patients.

  19. Single cell genomics indicates horizontal gene transfer and viral infections in a deep subsurface Firmicutes population

    Jessica eLabonté

    2015-04-01

    Full Text Available A major fraction of Earth's prokaryotic biomass dwells in the deep subsurface, where cellular abundances per volume of sample are lower, metabolism is slower, and generation times are longer than those in surface terrestrial and marine environments. How these conditions impact biotic interactions and evolutionary processes is largely unknown. Here we employed single cell genomics to analyze cell-to-cell genome content variability and signatures of horizontal gene transfer (HGT and viral infections in five cells of Candidatus Desulforudis audaxviator, which were collected from a three km-deep fracture water in the 2.9 Ga-old Witwatersrand Basin of South Africa. Between 0 and 32 % of genes recovered from single cells were not present in the original, metagenomic assembly of Desulforudis, which was obtained from a neighboring subsurface fracture. We found a transposable prophage, a retron, multiple clustered regularly interspaced short palindromic repeats (CRISPRs and restriction-modification systems, and an unusually high frequency of transposases in the analyzed single cell genomes. This indicates that recombination, HGT and viral infections are prevalent evolutionary events in the studied population of microorganisms inhabiting a highly stable deep subsurface environment.

  20. Biologic characteristics of the side population of human small cell lung cancer cell line H446.

    Wang, Bo; Yang, Huan; Huang, Yu-Zheng; Yan, Ru-Hong; Liu, Fen-Ju; Zhang, Jun-Ning

    2010-03-01

    Recently, the theory of cancer stem cells (CSCs) has presented new targets and orientations for tumor therapy. The major difficulties in researching CSCs include their isolation and purification. The aim of this study is to identify and characterize the side population (SP) cells in small cell lung cancer (SCLC) cell line H446, which lays the foundation for the isolation and purification of CSCs. Fluorescence-activated cell sorting (FACS) was used to sort SP and non-SP (NSP) cells from H446. Both subgroups were cultivated to survey the capacity to form into suspended tumor cell spheres. Reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR were used to evaluate the expression levels of the mRNA of CD133, ABCG2, and nucleostemin in both subgroups. The capacity of proliferation and the differences in drug resistance of both subgroups and unsorted cells were tested by the MTT method. The differentiation ability of both subgroups was determined by FACS. Proliferation was determined by subcutaneous tumor formation in nude mice. The percent of Hoechst 33342 negative cells was about (5.1 +/- 0.2)% in H446 by fluorescence microscopy. The percent of SP cells was (6.3 +/- 0.1)% by flow cytometry. SP cells had a stronger capability of forming into tumor spheres than NSP cells. The mRNA expression levels of ABCG2, CD133, and nucleostemin in SP cells were 21.60 +/- 0.26, 7.10 +/- 0.14, and 1.02 +/- 0.08 folds higher than that in NSP cells (P 0.05, respectively). In vivo, SP cells showed better proliferative ability and tougher viability when treated with drugs. SP cells can differentiate into NSP cells, but NSP cells cannot differentiate into SP cells. SP cells had a greater ability to form tumors. The H446 cell line contained some SP cells with stem cell properties. CD133 and ABCG2 may be cancer stem cell markers of SCLC.

  1. Joint modeling and registration of cell populations in cohorts of high-dimensional flow cytometric data.

    Saumyadipta Pyne

    Full Text Available In biomedical applications, an experimenter encounters different potential sources of variation in data such as individual samples, multiple experimental conditions, and multivariate responses of a panel of markers such as from a signaling network. In multiparametric cytometry, which is often used for analyzing patient samples, such issues are critical. While computational methods can identify cell populations in individual samples, without the ability to automatically match them across samples, it is difficult to compare and characterize the populations in typical experiments, such as those responding to various stimulations or distinctive of particular patients or time-points, especially when there are many samples. Joint Clustering and Matching (JCM is a multi-level framework for simultaneous modeling and registration of populations across a cohort. JCM models every population with a robust multivariate probability distribution. Simultaneously, JCM fits a random-effects model to construct an overall batch template--used for registering populations across samples, and classifying new samples. By tackling systems-level variation, JCM supports practical biomedical applications involving large cohorts. Software for fitting the JCM models have been implemented in an R package EMMIX-JCM, available from http://www.maths.uq.edu.au/~gjm/mix_soft/EMMIX-JCM/.

  2. Incorporating Multiple Energy Relay Dyes in Liquid Dye-Sensitized Solar Cells

    Yum, Jun-Ho; Hardin, Brian E.; Hoke, Eric T.; Baranoff, Etienne; Zakeeruddin, Shaik M.; Nazeeruddin, Mohammad K.; Torres, Tomas; McGehee, Michael D.; Grä tzel, Michael

    2011-01-01

    Panchromatic response is essential to increase the light-harvesting efficiency in solar conversion systems. Herein we show increased light harvesting from using multiple energy relay dyes inside dye-sensitized solar cells. Additional photoresponse

  3. Significance of adipose tissue-derived stem cells regulate CD4+ T cell immune in the treatment of multiple sclerosis

    Yong-lin XIE

    2014-10-01

    Full Text Available Adipose tissue-derived stem cells (ADSCs are genetically engineered seed cells with immunomodulatory effects, widely used in the treatment of autoimmune diseases. This article focuses on the immunomodulatory effects of adipose tissue-derived stem cells on CD4+ T cell subsets, including T helper cell (Th 1, 2, 17 and regulatory T cell (Treg, and its clinical significance in the treatment of multiple sclerosis. doi: 10.3969/j.issn.1672-6731.2014.10.005

  4. Dielectrophoretic capture of low abundance cell population using thick electrodes.

    Marchalot, Julien; Chateaux, Jean-François; Faivre, Magalie; Mertani, Hichem C; Ferrigno, Rosaria; Deman, Anne-Laure

    2015-09-01

    Enrichment of rare cell populations such as Circulating Tumor Cells (CTCs) is a critical step before performing analysis. This paper presents a polymeric microfluidic device with integrated thick Carbon-PolyDimethylSiloxane composite (C-PDMS) electrodes designed to carry out dielectrophoretic (DEP) trapping of low abundance biological cells. Such conductive composite material presents advantages over metallic structures. Indeed, as it combines properties of both the matrix and doping particles, C-PDMS allows the easy and fast integration of conductive microstructures using a soft-lithography approach while preserving O2 plasma bonding properties of PDMS substrate and avoiding a cumbersome alignment procedure. Here, we first performed numerical simulations to demonstrate the advantage of such thick C-PDMS electrodes over a coplanar electrode configuration. It is well established that dielectrophoretic force ([Formula: see text]) decreases quickly as the distance from the electrode surface increases resulting in coplanar configuration to a low trapping efficiency at high flow rate. Here, we showed quantitatively that by using electrodes as thick as a microchannel height, it is possible to extend the DEP force influence in the whole volume of the channel compared to coplanar electrode configuration and maintaining high trapping efficiency while increasing the throughput. This model was then used to numerically optimize a thick C-PDMS electrode configuration in terms of trapping efficiency. Then, optimized microfluidic configurations were fabricated and tested at various flow rates for the trapping of MDA-MB-231 breast cancer cell line. We reached trapping efficiencies of 97% at 20 μl/h and 78.7% at 80 μl/h, for 100 μm thick electrodes. Finally, we applied our device to the separation and localized trapping of CTCs (MDA-MB-231) from a red blood cells sample (concentration ratio of 1:10).

  5. Derivation of keratinocytes from chicken embryonic stem cells: Establishment and characterization of differentiated proliferative cell populations

    Mathilde Couteaudier

    2015-03-01

    Full Text Available A common challenge in avian cell biology is the generation of differentiated cell-lines, especially in the keratinocyte lineage. Only a few avian cell-lines are available and very few of them show an interesting differentiation profile. During the last decade, mammalian embryonic stem cell-lines were shown to differentiate into almost all lineages, including keratinocytes. Although chicken embryonic stem cells had been obtained in the 1990s, few differentiation studies toward the ectodermal lineage were reported. Consequently, we explored the differentiation of chicken embryonic stem cells toward the keratinocyte lineage by using a combination of stromal induction, ascorbic acid, BMP4 and chicken serum. During the induction period, we observed a downregulation of pluripotency markers and an upregulation of epidermal markers. Three homogenous cell populations were derived, which were morphologically similar to chicken primary keratinocytes, displaying intracellular lipid droplets in almost every pavimentous cell. These cells could be serially passaged without alteration of their morphology and showed gene and protein expression profiles of epidermal markers similar to chicken primary keratinocytes. These cells represent an alternative to the isolation of chicken primary keratinocytes, being less cumbersome to handle and reducing the number of experimental animals used for the preparation of primary cells.

  6. Circulating CD4+CXCR5+ T cells contribute to proinflammatory responses in multiple ways in coronary artery disease.

    Ding, Ru; Gao, Wenwu; He, Zhiqing; Wu, Feng; Chu, Yang; Wu, Jie; Ma, Lan; Liang, Chun

    2017-11-01

    Coronary artery disease (CAD) is a common subtype of cardiovascular disease. The major contributing event is atherosclerosis, which is a progressive inflammatory condition resulting in the thickening of the arterial wall and the formation of atheromatous plaques. Recent evidence suggests that circulating CD4 + CXCR5 + T cells can contribute to inflammatory reactions. In this study, the frequency, phenotype, and function of circulating CD4 + CXCR5 + T cells in CAD patients were examined. Data showed that circulating CD4 + CXCR5 + T cells in CAD patients were enriched with a PD-1 + CCR7 - subset, which was previously identified as the most potent in B cell help. The CD4 + CXCR5 + T cells in CAD patients also secreted significantly higher levels of IFN-γ, IL-17A, and IL-21 than those from healthy controls. Depleting the PD-1 + population significantly reduced the cytokine secretion. Interestingly, the CD4 + CXCR5 + PD-1 - T cells significantly upregulated PD-1 following anti-CD3/CD28 or SEB stimulation. CD4 + CXCR5 + T cells from CAD patients also demonstrated more potent capacity to stimulate B cell inflammation than those from healthy individuals. The phosphorylation of STAT1 and STAT3 were significantly higher in B cells incubated with CD4 + CXCR5 + T cells from CAD than controls. The IL-6 and IFN-γ expression were also significantly higher in B cells incubated with CD4 + CXCR5 + T cells from CAD. Together, this study demonstrated that CAD patients presented a highly activated CD4 + CXCR5 + T cell subset that could contribute to proinflammatory responses in multiple ways. The possibility of using CD4 + CXCR5 + T cells as a therapeutic target should therefore be examined in CAD patients. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Patterns of genetic diversity of the cryptogenic red alga Polysiphonia morrowii (Ceramiales, Rhodophyta) suggest multiple origins of the Atlantic populations.

    Geoffroy, Alexandre; Destombe, Christophe; Kim, Byeongseok; Mauger, Stéphane; Raffo, María Paula; Kim, Myung Sook; Le Gall, Line

    2016-08-01

    The red alga Polysiphonia morrowii, native to the North Pacific (Northeast Asia), has recently been reported worldwide. To determine the origin of the French and Argentine populations of this introduced species, we compared samples from these two areas with samples collected in Korea and at Hakodate, Japan, the type locality of the species. Combined analyses of chloroplastic (rbcL) and mitochondrial (cox1) DNA revealed that the French and Argentine populations are closely related and differ substantially from the Korean and Japanese populations. The genetic structure of P. morrowii populations from South Atlantic and North Atlantic, which showed high haplotype diversity compared with populations from the North Pacific, suggested the occurrence of multiple introduction events from areas outside of the so-called native regions. Although similar, the French and Argentine populations are not genetically identical. Thus, the genetic structure of these two introduced areas may have been modified by cryptic and recurrent introduction events directly from Asia or from other introduced areas that act as introduction relays. In addition, the large number of private cytoplasmic types identified in the two introduced regions strongly suggests that local populations of P. morrowii existed before the recent detection of these invasions. Our results suggest that the most likely scenario is that the source population(s) of the French and Argentine populations was not located only in the North Pacific and/or that P. morrowii is a cryptogenic species.

  8. Semiautomatic bladder segmentation on CBCT using a population-based model for multiple-plan ART of bladder cancer

    Chai, Xiangfei; van Herk, Marcel; Betgen, Anja; Hulshof, Maarten; Bel, Arjan

    2012-01-01

    The aim of this study is to develop a novel semiautomatic bladder segmentation approach for selecting the appropriate plan from the library of plans for a multiple-plan adaptive radiotherapy (ART) procedure. A population-based statistical bladder model was first built from a training data set (95

  9. Prognostic impact of circulating plasma cells in patients with multiple myeloma: implications for plasma cell leukemia definition.

    Granell, Miquel; Calvo, Xavier; Garcia-Guiñón, Antoni; Escoda, Lourdes; Abella, Eugènia; Martínez, Clara Mª; Teixidó, Montserrat; Gimenez, Mª Teresa; Senín, Alicia; Sanz, Patricia; Campoy, Desirée; Vicent, Ana; Arenillas, Leonor; Rosiñol, Laura; Sierra, Jorge; Bladé, Joan; de Larrea, Carlos Fernández

    2017-06-01

    The presence of circulating plasma cells in patients with multiple myeloma is considered a marker for highly proliferative disease. In the study herein, the impact of circulating plasma cells assessed by cytology on survival of patients with multiple myeloma was analyzed. Wright-Giemsa stained peripheral blood smears of 482 patients with newly diagnosed myeloma or plasma cell leukemia were reviewed and patients were classified into 4 categories according to the percentage of circulating plasma cells: 0%, 1-4%, 5-20%, and plasma cell leukemia with the following frequencies: 382 (79.2%), 83 (17.2%), 12 (2.5%) and 5 (1.0%), respectively. Median overall survival according to the circulating plasma cells group was 47, 50, 6 and 14 months, respectively. At multivariate analysis, the presence of 5 to 20% circulating plasma cells was associated with a worse overall survival (relative risk 4.9, 95% CI 2.6-9.3) independently of age, creatinine, the Durie-Salmon system stage and the International Staging System (ISS) stage. Patients with ≥5% circulating plasma cells had lower platelet counts (median 86×10 9 /L vs 214×10 9 /L, P <0.0001) and higher bone marrow plasma cells (median 53% vs 36%, P =0.004). The presence of ≥5% circulating plasma cells in patients with multiple myeloma has a similar adverse prognostic impact as plasma cell leukemia. Copyright© Ferrata Storti Foundation.

  10. Multiple Modes of Communication between Neurons and Oligodendrocyte Precursor Cells

    Maldonado, Paloma P; Angulo, María Cecilia

    The surprising discovery of bona fide synapses between neurons and oligodendrocytes precursor cells (OPCs) 15 years ago placed these progenitors as real partners of neurons in the CNS. The role of these synapses has not been established yet, but a main hypothesis is that neuron-OPC synaptic activity

  11. Multiple helminth infection of the skin causes lymphocyte hypo-responsiveness mediated by Th2 conditioning of dermal myeloid cells.

    Peter C Cook

    2011-03-01

    Full Text Available Infection of the mammalian host by schistosome larvae occurs via the skin, although nothing is known about the development of immune responses to multiple exposures of schistosome larvae, and/or their excretory/secretory (E/S products. Here, we show that multiple (4x exposures, prior to the onset of egg laying by adult worms, modulate the skin immune response and induce CD4(+ cell hypo-responsiveness in the draining lymph node, and even modulate the formation of hepatic egg-induced granulomas. Compared to mice exposed to a single infection (1x, dermal cells from multiply infected mice (4x, were less able to support lymph node cell proliferation. Analysis of dermal cells showed that the most abundant in 4x mice were eosinophils (F4/80(+MHC-II(-, but they did not impact the ability of antigen presenting cells (APC to support lymphocyte proliferation to parasite antigen in vitro. However, two other cell populations from the dermal site of infection appear to have a critical role. The first comprises arginase-1(+, Ym-1(+ alternatively activated macrophage-like cells, and the second are functionally compromised MHC-II(hi cells. Through the administration of exogenous IL-12 to multiply infected mice, we show that these suppressive myeloid cell phenotypes form as a consequence of events in the skin, most notably an enrichment of IL-4 and IL-13, likely resulting from an influx of RELMα-expressing eosinophils. We further illustrate that the development of these suppressive dermal cells is dependent upon IL-4Rα signalling. The development of immune hypo-responsiveness to schistosome larvae and their effect on the subsequent response to the immunopathogenic egg is important in appreciating how immune responses to helminth infections are modulated by repeated exposure to the infective early stages of development.

  12. Multiple mesodermal lineage differentiation of Apodemus sylvaticus embryonic stem cells in vitro

    Yu Weihua

    2010-06-01

    Full Text Available Abstract Background Embryonic stem (ES cells have attracted significant attention from researchers around the world because of their ability to undergo indefinite self-renewal and produce derivatives from the three cell lineages, which has enormous value in research and clinical applications. Until now, many ES cell lines of different mammals have been established and studied. In addition, recently, AS-ES1 cells derived from Apodemus sylvaticus were established and identified by our laboratory as a new mammalian ES cell line. Hence further research, in the application of AS-ES1 cells, is warranted. Results Herein we report the generation of multiple mesodermal AS-ES1 lineages via embryoid body (EB formation by the hanging drop method and the addition of particular reagents and factors for induction at the stage of EB attachment. The AS-ES1 cells generated separately in vitro included: adipocytes, osteoblasts, chondrocytes and cardiomyocytes. Histochemical staining, immunofluorescent staining and RT-PCR were carried out to confirm the formation of multiple mesodermal lineage cells. Conclusions The appropriate reagents and culture milieu used in mesodermal differentiation of mouse ES cells also guide the differentiation of in vitro AS-ES1 cells into distinct mesoderm-derived cells. This study provides a better understanding of the characteristics of AS-ES1 cells, a new species ES cell line and promotes the use of Apodemus ES cells as a complement to mouse ES cells in future studies.

  13. Global gene expression and comparison between multiple populations in the mouse epidermis

    Anders Patrik Gunnarsson

    2016-07-01

    Our data shows that flow cytometry using multicolor panels can identify further subsets of cells within the epidermis and also highlights a marked discrepancy in gene expression between directly isolated cells and tissue cultured cells.

  14. Comparison of tumor biology of two distinct cell sub-populations in lung cancer stem cells.

    Wang, Jianyu; Sun, Zhiwei; Liu, Yongli; Kong, Liangsheng; Zhou, Shixia; Tang, Junlin; Xing, Hongmei Rosie

    2017-11-14

    Characterization of the stem-like properties of cancer stem cells (CSCs) remain indirect and qualitative, especially the ability of CSCs to undergo asymmetric cell division for self renewal and differentiation, a unique property of cells of stem origin. It is partly due to the lack of stable cellular models of CSCs. In this study, we developed a new approach for CSC isolation and purification to derive a CSC-enriched cell line (LLC-SE). By conducting five consecutive rounds of single cell cloning using the LLC-SE cell line, we obtained two distinct sub-population of cells within the Lewis lung cancer CSCs that employed largely symmetric division for self-renewal (LLC-SD) or underwent asymmetric division for differentiation (LLC-ASD). LLC-SD and LLC-ASD cell lines could be stably passaged in culture and be distinguished by cell morphology, stem cell marker, spheroid formation and subcutaneous tumor initiation efficiency, as well as orthotopic lung tumor growth, progression and survival. The ability LLC-ASD cells to undergo asymmetric division was visualized and quantified by the asymmetric segregation of labeled BrdU and NUMB to one of the two daughter cells in anaphase cell division. The more stem-like LLC-SD cells exhibited higher capacity for tumorigenesis and progression and shorter survival. As few as 10 LLC-SD could initiate subcutaneous tumor growth when transplanted to the athymic mice. Collectively, these observations suggest that the SD-type of cells appear to be on the top of the hierarchical order of the CSCs. Furthermore, they have lead to generated cellular models of CSC self-renewal for future mechanistic investigations.

  15. Clonal cell populations unresponsive to radiosensitization induced by telomerase inhibition

    Ju, Yeun-Jin; Shin, Hyun-Jin; Park, Jeong-Eun; Juhn, Kyoung-Mi; Woo, Seon Rang; Kim, Hee-Young; Han, Young-Hoon; Hwang, Sang-Gu; Hong, Sung-Hee; Kang, Chang-Mo; Yoo, Young-Do; Park, Won-Bong; Cho, Myung-Haing; Park, Gil Hong; Lee, Kee-Ho

    2010-01-01

    Research highlights: → In our present manuscript, we have clearly showed an interesting but problematic obstacle of a radiosensitization strategy based on telomerase inhibition by showing that: Clonal population unresponsive to this radiosensitization occasionally arise. → The telomere length of unsensitized clones was reduced, as was that of most sensitized clones. → The unsensitized clones did not show chromosome end fusion which was noted in all sensitized clones. → P53 status is not associated with the occurrence of unsensitized clone. → Telomere end capping in unsensitized clone is operative even under telomerase deficiency. -- Abstract: A combination of a radiotherapeutic regimen with telomerase inhibition is valuable when tumor cells are to be sensitized to radiation. Here, we describe cell clones unresponsive to radiosensitization after telomere shortening. After extensive division of individual transformed clones of mTERC -/- cells, about 22% of clones were unresponsive to radiosensitization even though telomerase action was inhibited. The telomere lengths of unsensitized mTERC -/- clones were reduced, as were those of most sensitized clones. However, the unsensitized clones did not exhibit chromosomal end-to-end fusion to the extent noted in all sensitized clones. Thus, a defense mechanism preventing telomere erosion is operative even when telomeres become shorter under conditions of telomerase deficiency, and results in unresponsiveness to the radiosensitization generally mediated by telomere shortening.

  16. Increasing cell culture population doublings for long-term growth of finite life span human cell cultures

    Stampfer, Martha R; Garbe, James C

    2015-02-24

    Cell culture media formulations for culturing human epithelial cells are herein described. Also described are methods of increasing population doublings in a cell culture of finite life span human epithelial cells and prolonging the life span of human cell cultures. Using the cell culture media disclosed alone and in combination with addition to the cell culture of a compound associated with anti-stress activity achieves extended growth of pre-stasis cells and increased population doublings and life span in human epithelial cell cultures.

  17. Ascl1 (Mash1) lineage cells contribute to discrete cell populations in CNS architecture.

    Kim, Euiseok J; Battiste, James; Nakagawa, Yasushi; Johnson, Jane E

    2008-08-01

    Ascl1 (previously Mash1) is a bHLH transcription factor essential for neuronal differentiation and specification in the nervous system. Although it has been studied for its role in several neural lineages, the full complement of lineages arising from Ascl1 progenitor cells remains unknown. Using an inducible Cre-flox genetic fate-mapping strategy, Ascl1 lineages were determined throughout the brain. Ascl1 is present in proliferating progenitor cells but these cells are actively differentiating as evidenced by rapid migration out of germinal zones. Ascl1 lineage cells contribute to distinct cell types in each major brain division: the forebrain including the cerebral cortex, olfactory bulb, hippocampus, striatum, hypothalamus, and thalamic nuclei, the midbrain including superior and inferior colliculi, and the hindbrain including Purkinje and deep cerebellar nuclei cells and cells in the trigeminal sensory system. Ascl1 progenitor cells at early stages in each CNS region preferentially become neurons, and at late stages they become oligodendrocytes. In conclusion, Ascl1-expressing progenitor cells in the brain give rise to multiple, but not all, neuronal subtypes and oligodendrocytes depending on the temporal and spatial context, consistent with a broad role in neural differentiation with some subtype specification.

  18. Yeast cells contain a heterogeneous population of peroxisomes that segregate asymmetrically during cell division

    Kumar, Sanjeev; de Boer, Rinse; van der Klei, Ida J

    2018-01-01

    Here we used fluorescence microscopy and a peroxisome-targeted tandem fluorescent protein timer to determine the relative age of peroxisomes in yeast. Our data indicate that yeast cells contain a heterogeneous population of relatively old and younger peroxisomes. During budding the peroxisome

  19. The Effect of Multiple Paternity on Genetic Diversity of Small Populations during and after Colonisation

    Rafajlović, Marina; Eriksson, Anders; Rimark, Anna; Hintz-Saltin, Sara; Charrier, Gré gory; Panova, Marina; André , Carl; Johannesson, Kerstin; Mehlig, Bernhard

    2013-01-01

    Genetic variation within and among populations is influenced by the genetic content of the founders and the migrants following establishment. This is particularly true if populations are small, migration rate low and habitats arranged in a stepping

  20. Multiple bubbles in a Hele-Shaw cell

    Vasconcelos, G.L.

    1994-01-01

    A new class of exact solutions is reported for an infinite stream of identical groups of bubbles moving with a constant velocity U in a Hele-Shaw cell when surface tension is neglected. It is suggested that the existence of these solutions might explain some of the complex behavior observed in recent experiments on rising bubbles in a Hele-Shaw cell. Solutions for a finite number of bubbles in a channel are also obtained. In this case, it is shown that solutions with an arbitrary bubble velocity U>V, where V is the fluid velocity at infinity, can in general be obtained from a simple transformation of the solutions for U=2V

  1. Intracranial Tumor Cell Migration and the Development of Multiple Brain Metastases in Malignant Melanoma

    Trude G. Simonsen

    2016-06-01

    Full Text Available INTRODUCTION: A majority of patients with melanoma brain metastases develop multiple lesions, and these patients show particularly poor prognosis. To develop improved treatment strategies, detailed insights into the biology of melanoma brain metastases, and particularly the development of multiple lesions, are needed. The purpose of this preclinical investigation was to study melanoma cell migration within the brain after cell injection into a well-defined intracerebral site. METHODS: A-07, D-12, R-18, and U-25 human melanoma cells transfected with green fluorescent protein were injected stereotactically into the right cerebral hemisphere of nude mice. Moribund mice were killed and autopsied, and the brain was evaluated by fluorescence imaging or histological examination. RESULTS: Intracerebral inoculation of melanoma cells produced multiple lesions involving all regions of the brain, suggesting that the cells were able to migrate over substantial distances within the brain. Multiple modes of transport were identified, and all transport modes were observed in all four melanoma lines. Thus, the melanoma cells were passively transported via the flow of cerebrospinal fluid in the meninges and ventricles, they migrated actively along leptomeningeal and brain parenchymal blood vessels, and they migrated actively along the surfaces separating different brain compartments. CONCLUSION: Migration of melanoma cells after initial arrest, extravasation, and growth at a single location within the brain may contribute significantly to the development of multiple melanoma brain metastases.

  2. Autologous hematopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: comparison with secondary progressive multiple sclerosis.

    Casanova, Bonaventura; Jarque, Isidro; Gascón, Francisco; Hernández-Boluda, Juan Carlos; Pérez-Miralles, Francisco; de la Rubia, Javier; Alcalá, Carmen; Sanz, Jaime; Mallada, Javier; Cervelló, Angeles; Navarré, Arantxa; Carcelén-Gadea, María; Boscá, Isabel; Gil-Perotin, Sara; Solano, Carlos; Sanz, Miguel Angel; Coret, Francisco

    2017-07-01

    The main objective of our work is to describe the long-term results of myeloablative autologous hematopoietic stem cell transplant (AHSCT) in multiple sclerosis patients. Patients that failed to conventional therapies for multiple sclerosis (MS) underwent an approved protocol for AHSCT, which consisted of peripheral blood stem cell mobilization with cyclophosphamide and granulocyte colony-stimulating factor (G-CSF), followed by a conditioning regimen of BCNU, Etoposide, Ara-C, Melphalan IV, plus Rabbit Thymoglobulin. Thirty-eight MS patients have been transplanted since 1999. Thirty-one patients have been followed for more than 2 years (mean 8.4 years). There were 22 relapsing-remitting multiple sclerosis (RRMS) patients and 9 secondary progressive multiple sclerosis (SPMS) patients. No death related to AHSCT. A total of 10 patients (32.3%) had at least one relapse during post-AHSCT evolution, 6 patients in the RRMS group (27.2%) and 4 in the SPMS group (44.4%). After AHSCT, 7 patients (22.6%) experienced progression of disability, all within SP form. By contrast, no patients with RRMS experienced worsening of disability after a median follow-up of 5.4 years, 60% of them showed a sustained reduction in disability (SRD), defined as the improvement of 1.0 point in the expanded disability status scale (EDSS) sustains for 6 months (0.5 in cases of EDSS ≥ 5.5). The only clinical variable that predicted a poor response to AHSCT was a high EDSS in the year before transplant. AHSCT using the BEAM-ATG scheme is safe and efficacious to control the aggressive forms of RRMS.

  3. Collective synchronization of self/non-self discrimination in T cell activation, across multiple spatio-temporal scales

    Altan-Bonnet, Gregoire

    The immune system is a collection of cells whose function is to eradicate pathogenic infections and malignant tumors while protecting healthy tissues. Recent work has delineated key molecular and cellular mechanisms associated with the ability to discriminate self from non-self agents. For example, structural studies have quantified the biophysical characteristics of antigenic molecules (those prone to trigger lymphocyte activation and a subsequent immune response). However, such molecular mechanisms were found to be highly unreliable at the individual cellular level. We will present recent efforts to build experimentally validated computational models of the immune responses at the collective cell level. Such models have become critical to delineate how higher-level integration through nonlinear amplification in signal transduction, dynamic feedback in lymphocyte differentiation and cell-to-cell communication allows the immune system to enforce reliable self/non-self discrimination at the organism level. In particular, we will present recent results demonstrating how T cells tune their antigen discrimination according to cytokine cues, and how competition for cytokine within polyclonal populations of cells shape the repertoire of responding clones. Additionally, we will present recent theoretical and experimental results demonstrating how competition between diffusion and consumption of cytokines determine the range of cell-cell communications within lymphoid organs. Finally, we will discuss how biochemically explicit models, combined with quantitative experimental validation, unravel the relevance of new feedbacks for immune regulations across multiple spatial and temporal scales.

  4. A millifluidic study of cell-to-cell heterogeneity in growth-rate and cell-division capability in populations of isogenic cells of Chlamydomonas reinhardtii.

    Shima P Damodaran

    Full Text Available To address possible cell-to-cell heterogeneity in growth dynamics of isogenic cell populations of Chlamydomonas reinhardtii, we developed a millifluidic drop-based device that not only allows the analysis of populations grown from single cells over periods of a week, but is also able to sort and collect drops of interest, containing viable and healthy cells, which can be used for further experimentation. In this study, we used isogenic algal cells that were first synchronized in mixotrophic growth conditions. We show that these synchronized cells, when placed in droplets and kept in mixotrophic growth conditions, exhibit mostly homogeneous growth statistics, but with two distinct subpopulations: a major population with a short doubling-time (fast-growers and a significant subpopulation of slowly dividing cells (slow-growers. These observations suggest that algal cells from an isogenic population may be present in either of two states, a state of restricted division and a state of active division. When isogenic cells were allowed to propagate for about 1000 generations on solid agar plates, they displayed an increased heterogeneity in their growth dynamics. Although we could still identify the original populations of slow- and fast-growers, drops inoculated with a single progenitor cell now displayed a wider diversity of doubling-times. Moreover, populations dividing with the same growth-rate often reached different cell numbers in stationary phase, suggesting that the progenitor cells differed in the number of cell divisions they could undertake. We discuss possible explanations for these cell-to-cell heterogeneities in growth dynamics, such as mutations, differential aging or stochastic variations in metabolites and macromolecules yielding molecular switches, in the light of single-cell heterogeneities that have been reported among isogenic populations of other eu- and prokaryotes.

  5. Lack of CD4+ T cell percent decrease in alemtuzumab-treated multiple sclerosis patients with persistent relapses.

    Rolla, Simona; De Mercanti, Stefania Federica; Bardina, Valentina; Horakova, Dana; Habek, Mario; Adamec, Ivan; Cocco, Eleonora; Annovazzi, Pietro; Vladic, Anton; Novelli, Francesco; Durelli, Luca; Clerico, Marinella

    2017-12-15

    Alemtuzumab, a highly effective treatment for relapsing remitting multiple sclerosis (RRMS), induces lymphopenia especially of CD4+ T cells. Here, we report the atypical CD4+ T population behaviour of two patients with persistent disease activity despite repeated alemtuzumab treatments. Whereas lymphocytes count decreased and fluctuated accordingly to alemtuzumab administration, their CD4+ cell percentage was not or just mildly affected and was slightly below the lowest normal limit already before alemtuzumab. These cases anticipate further studies aimed to investigate whether the evaluation of the CD4+ cell percentage could represent a helpful tool to address the individual clinical response to alemtuzumab. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  6. Use of Multicolor Flow Cytometry for Isolation of Specific Cell Populations Deriving from Differentiated Human Embryonic Stem Cells

    Mengarelli, Isabella; Fryga, Andrew; Barberi, Tiziano

    2016-01-01

    Flow Cytometry-Sorting (FCM-Sorting) is a technique commonly used to identify and isolate specific types of cells from a heterogeneous population of live cells. Here we describe a multicolor flow cytometry technique that uses five distinct cell surface antigens to isolate four live populations with

  7. Development of a population of cancer cells: Observation and modeling by a Mixed Spatial Evolutionary Games approach.

    Świerniak, Andrzej; Krześlak, Michał; Student, Sebastian; Rzeszowska-Wolny, Joanna

    2016-09-21

    Living cells, like whole living organisms during evolution, communicate with their neighbors, interact with the environment, divide, change their phenotypes, and eventually die. The development of specific ways of communication (through signaling molecules and receptors) allows some cellular subpopulations to survive better, to coordinate their physiological status, and during embryonal development to create tissues and organs or in some conditions to become tumors. Populations of cells cultured in vitro interact similarly, also competing for space and nutrients and stimulating each other to better survive or to die. The results of these intercellular interactions of different types seem to be good examples of biological evolutionary games, and have been the subjects of simulations by the methods of evolutionary game theory where individual cells are treated as players. Here we present examples of intercellular contacts in a population of living human cancer HeLa cells cultured in vitro and propose an evolutionary game theory approach to model the development of such populations. We propose a new technique termed Mixed Spatial Evolutionary Games (MSEG) which are played on multiple lattices corresponding to the possible cellular phenotypes which gives the possibility of simulating and investigating the effects of heterogeneity at the cellular level in addition to the population level. Analyses performed with MSEG suggested different ways in which cellular populations develop in the case of cells communicating directly and through factors released to the environment. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. A novel Multiple-Marker Method for the Early Diagnosis of Oral Squamous Cell Carcinoma

    Jutta Ries

    2009-01-01

    Full Text Available Objective: Melanoma associated antigens-A (MAGE-A expression is highly specific to cancer cells. Thus, they can be the most suitable targets for the diagnosis of malignancy. The aim of this study was to evaluate the sensitivity of multiple MAGE-A expression analysis for the diagnosis of oral squamous cell carcinoma (OSCC.

  9. A population dynamics analysis of the interaction between adaptive regulatory T cells and antigen presenting cells.

    David Fouchet

    Full Text Available BACKGROUND: Regulatory T cells are central actors in the maintenance of tolerance of self-antigens or allergens and in the regulation of the intensity of the immune response during infections by pathogens. An understanding of the network of the interaction between regulatory T cells, antigen presenting cells and effector T cells is starting to emerge. Dynamical systems analysis can help to understand the dynamical properties of an interaction network and can shed light on the different tasks that can be accomplished by a network. METHODOLOGY AND PRINCIPAL FINDINGS: We used a mathematical model to describe a interaction network of adaptive regulatory T cells, in which mature precursor T cells may differentiate into either adaptive regulatory T cells or effector T cells, depending on the activation state of the cell by which the antigen was presented. Using an equilibrium analysis of the mathematical model we show that, for some parameters, the network has two stable equilibrium states: one in which effector T cells are strongly regulated by regulatory T cells and another in which effector T cells are not regulated because the regulatory T cell population is vanishingly small. We then simulate different types of perturbations, such as the introduction of an antigen into a virgin system, and look at the state into which the system falls. We find that whether or not the interaction network switches from the regulated (tolerant state to the unregulated state depends on the strength of the antigenic stimulus and the state from which the network has been perturbed. CONCLUSION/SIGNIFICANCE: Our findings suggest that the interaction network studied in this paper plays an essential part in generating and maintaining tolerance against allergens and self-antigens.

  10. Modeling the Potential Effects of New Tobacco Products and Policies: A Dynamic Population Model for Multiple Product Use and Harm

    Vugrin, Eric D.; Rostron, Brian L.; Verzi, Stephen J.; Brodsky, Nancy S.; Brown, Theresa J.; Choiniere, Conrad J.; Coleman, Blair N.; Paredes, Antonio; Apelberg, Benjamin J.

    2015-01-01

    Background Recent declines in US cigarette smoking prevalence have coincided with increases in use of other tobacco products. Multiple product tobacco models can help assess the population health impacts associated with use of a wide range of tobacco products. Methods and Findings We present a multi-state, dynamical systems population structure model that can be used to assess the effects of tobacco product use behaviors on population health. The model incorporates transition behaviors, such as initiation, cessation, switching, and dual use, related to the use of multiple products. The model tracks product use prevalence and mortality attributable to tobacco use for the overall population and by sex and age group. The model can also be used to estimate differences in these outcomes between scenarios by varying input parameter values. We demonstrate model capabilities by projecting future cigarette smoking prevalence and smoking-attributable mortality and then simulating the effects of introduction of a hypothetical new lower-risk tobacco product under a variety of assumptions about product use. Sensitivity analyses were conducted to examine the range of population impacts that could occur due to differences in input values for product use and risk. We demonstrate that potential benefits from cigarette smokers switching to the lower-risk product can be offset over time through increased initiation of this product. Model results show that population health benefits are particularly sensitive to product risks and initiation, switching, and dual use behaviors. Conclusion Our model incorporates the variety of tobacco use behaviors and risks that occur with multiple products. As such, it can evaluate the population health impacts associated with the introduction of new tobacco products or policies that may result in product switching or dual use. Further model development will include refinement of data inputs for non-cigarette tobacco products and inclusion of health

  11. Enrichment of skin-derived neural precursor cells from dermal cell populations by altering culture conditions.

    Bayati, Vahid; Gazor, Rohoullah; Nejatbakhsh, Reza; Negad Dehbashi, Fereshteh

    2016-01-01

    As stem cells play a critical role in tissue repair, their manipulation for being applied in regenerative medicine is of great importance. Skin-derived precursors (SKPs) may be good candidates for use in cell-based therapy as the only neural stem cells which can be isolated from an accessible tissue, skin. Herein, we presented a simple protocol to enrich neural SKPs by monolayer adherent cultivation to prove the efficacy of this method. To enrich neural SKPs from dermal cell populations, we have found that a monolayer adherent cultivation helps to increase the numbers of neural precursor cells. Indeed, we have cultured dermal cells as monolayer under serum-supplemented (control) and serum-supplemented culture, followed by serum free cultivation (test) and compared. Finally, protein markers of SKPs were assessed and compared in both experimental groups and differentiation potential was evaluated in enriched culture. The cells of enriched culture concurrently expressed fibronectin, vimentin and nestin, an intermediate filament protein expressed in neural and skeletal muscle precursors as compared to control culture. In addition, they possessed a multipotential capacity to differentiate into neurogenic, glial, adipogenic, osteogenic and skeletal myogenic cell lineages. It was concluded that serum-free adherent culture reinforced by growth factors have been shown to be effective on proliferation of skin-derived neural precursor cells (skin-NPCs) and drive their selective and rapid expansion.

  12. Characterization of CD4+ T cell-mediated cytotoxicity in patients with multiple myeloma.

    Zhang, Xiaole; Gao, Lei; Meng, Kai; Han, Chunting; Li, Qiang; Feng, Zhenjun; Chen, Lei

    2018-05-01

    Multiple myeloma (MM) is an incurable cancer characterized by the development of malignant plasma cells. The CD8 T cell-mediated cytotoxicity is considered a major player in antitumor immunity, but in MM patients, the CD8 T cells displayed senescence markers and were functionally impaired. To investigate whether cytotoxic CD4 T cells could act as a treatment alternative in MM, we examined the frequency and function of naturally occurring cytotoxic CD4 T cells in MM patients. The cytotoxic CD4 T cells were identified as granzyme-A, granzyme B-, and perforin-expressing CD4 T cells, and their frequencies were significantly upregulated in MM patients when compared with healthy controls. The frequencies of cytotoxic CD4 T cells in MM patients were not associated with the frequencies of cytotoxic CD8 T cells, but were negatively associated with disease severity. Interestingly, the expression levels of inhibitory molecules, including PD-1 and CTLA-4, were significantly lower in cytotoxic CD4 T cells than in cytotoxic CD8 T cells. When co-incubated with autologous CD38 + CD138 + plasma cells, CD4 T cells were capable of eliminating plasma cells with varying degrees of efficacy. In MM patients, the frequency of circulating plasma cells was negatively correlated with the frequency of cytotoxic CD4 T cells. Therefore, CD4 T cell-mediated cytotoxicity existed naturally in MM patients and could potentially act as an option in antitumor therapies. Copyright © 2018 Elsevier Inc. All rights reserved.

  13. A CASE REPORT OF MULTIPLE PRIMARY SQUAMOUS CELL CARCINOMAS OF THE OVARY AND SIGMOID COLON

    A. B. Villert

    2016-01-01

    Full Text Available Squamous cell ovarian and sigmoid colon carcinomas are extremely rare malignancies. Because of their rarity, it is difficult to investigate the clinical characteristics and prognosis of patients with theses malignancies, and therefore, the increased interest in each clinical case report is highly relevant. Multiple primary squamous cell ovarian and sigmoid colon carcinomas are the subject of discussion and differential diagnosis of sigmoid colon cancer with secondary ovarian cancer. Histopathological and clinical characteristics of the tumors were present and evidences in favor of the multiple primary malignancies were given. The association of squamous cell ovarian and sigmoid colon carcinomas with human papilloma virus type 16 was shown.

  14. Multiple Modes of Communication between Neurons and Oligodendrocyte Precursor Cells.

    Maldonado, Paloma P; Angulo, María Cecilia

    2015-06-01

    The surprising discovery of bona fide synapses between neurons and oligodendrocytes precursor cells (OPCs) 15 years ago placed these progenitors as real partners of neurons in the CNS. The role of these synapses has not been established yet, but a main hypothesis is that neuron-OPC synaptic activity is a signaling pathway controlling OPC proliferation/differentiation, influencing the myelination process. However, new evidences describing non-synaptic mechanisms of communication between neurons and OPCs have revealed that neuron-OPC interactions are more complex than expected. The activation of extrasynaptic receptors by ambient neurotransmitter or local spillover and the ability of OPCs to sense neuronal activity through a potassium channel suggest that distinct modes of communication mediate different functions of OPCs in the CNS. This review discusses different mechanisms used by OPCs to interact with neurons and their potential roles during postnatal development and in brain disorders. © The Author(s) 2014.

  15. Multiple populations within globular clusters in Early-type galaxies Exploring their effect on stellar initial mass function estimates

    Chantereau, W.; Usher, C.; Bastian, N.

    2018-05-01

    It is now well-established that most (if not all) ancient globular clusters host multiple populations, that are characterised by distinct chemical features such as helium abundance variations along with N-C and Na-O anti-correlations, at fixed [Fe/H]. These very distinct chemical features are similar to what is found in the centres of the massive early-type galaxies and may influence measurements of the global properties of the galaxies. Additionally, recent results have suggested that M/L variations found in the centres of massive early-type galaxies might be due to a bottom-heavy stellar initial mass function. We present an analysis of the effects of globular cluster-like multiple populations on the integrated properties of early-type galaxies. In particular, we focus on spectral features in the integrated optical spectrum and the global mass-to-light ratio that have been used to infer variations in the stellar initial mass function. To achieve this we develop appropriate stellar population synthesis models and take into account, for the first time, an initial-final mass relation which takes into consideration a varying He abundance. We conclude that while the multiple populations may be present in massive early-type galaxies, they are likely not responsible for the observed variations in the mass-to-light ratio and IMF sensitive line strengths. Finally, we estimate the fraction of stars with multiple populations chemistry that come from disrupted globular clusters within massive ellipticals and find that they may explain some of the observed chemical patterns in the centres of these galaxies.

  16. Multiple co morbid conditions in patient with Mast Cell Activation Syndrome

    2017-10-26

    conditions in patient \\\\·ith Mast Cell Activation Syndron1e Sb. GRANT NUMBER Sc. PROGRAM.ELEMENT NUMBER 6. AUTHOR(S) Sd. PROJECT NUMBER Maj Sofia...13. SUPPLEMENTARY NOTES 14. ABSTRACT Multiple co-n1orhid conditions in patient \\Vith Mast Cell Activation Syndrotne Sofia M. Szari.MD. and James...Defense. !NTR()D{JCT!ON: Mast cell activation disorders {MCAD) have been associated \\Vilh Connective Tissue Disorders (CTD) and orthostatic

  17. Cannabinoids synergize with carfilzomib, reducing multiple myeloma cells viability and migration

    Nabissi, Massimo; Morelli, Maria Beatrice; Offidani, Massimo; Amantini, Consuelo; Gentili, Silvia; Soriani, Alessandra; Cardinali, Claudio; Leoni, Pietro; Santoni, Giorgio

    2016-01-01

    Several studies showed a potential anti-tumor role for cannabinoids, by modulating cell signaling pathways involved in cancer cell proliferation, chemo-resistance and migration. Cannabidiol (CBD) was previously noted in multiple myeloma (MM), both alone and in synergy with the proteasome inhibitor bortezomib, to induce cell death. In other type of human cancers, the combination of CBD with ?9-tetrahydrocannabinol (THC) was found to act synergistically with other chemotherapeutic drugs suggest...

  18. Deficient Fas expression by CD4+ CCR5+ T cells in multiple sclerosis

    Julià, Eva; Montalban, Xavier; Al-Zayat, Hammad

    2006-01-01

    OBJECTIVE: To evaluate whether T cells expressing CCR5 and CXCR3 from multiple sclerosis (MS) patients are more resistant to apoptosis. METHODS: Expression of CD69, TNF-R1, Fas, FasL, bcl-2, and bax was investigated in 41 MS patients and 12 healthy controls by flow cytometry in CD4+ and CD8+ T...... cells expressing CCR5 and CXCR3. RESULTS: In MS patients, the percentage of CD69 was increased and Fas expression decreased in CD4+ CCR5+ T cells. INTERPRETATION: The lower Fas expression in activated CD4+ CCR5+ T cells might contribute to disease pathogenesis by prolonging cell survival and favoring...

  19. [Multiplicity of B microchromosomes in a Siberian population of mice Apodemus peninsulae (2n = 48 + 4-30 B chromosomes)].

    Borisov, Iu M; Afanas'ev, A G; Lebedev, T T; Bochkarev, M N

    2010-06-01

    Differentiation of four Siberian populations of East-Asian (Korean) field mice (Apodemus peninsulae) inhabiting the basin of the mid-stream of the Yenisei River was carried out according to the variants of the B chromosome system. A multiplicity of B microchromosomes (from 4 to 30) was found for the first time in all 26 mice from the left shore of the Yenisei River in the mid-stream area. All of them probably belong to a population with B microchromosomes. It is likely that in this population further reorganization of B microchromosomes into B macrochromosomes typical of this species does not occur. Two mice from this population had a large number of B chromosomes (26) earlier not observed in this species. In one mouse, the modal number of B microchromosomes was 30. This is a new maximum number of B chromosomes in this mouse species.

  20. T Cell Epitope Immunotherapy Induces a CD4+ T Cell Population with Regulatory Activity

    Verhoef Adrienne

    2005-01-01

    Full Text Available Background Synthetic peptides, representing CD4+ T cell epitopes, derived from the primary sequence of allergen molecules have been used to down-regulate allergic inflammation in sensitised individuals. Treatment of allergic diseases with peptides may offer substantial advantages over treatment with native allergen molecules because of the reduced potential for cross-linking IgE bound to the surface of mast cells and basophils. Methods and Findings In this study we address the mechanism of action of peptide immunotherapy (PIT in cat-allergic, asthmatic patients. Cell-division-tracking dyes, cell-mixing experiments, surface phenotyping, and cytokine measurements were used to investigate immunomodulation in peripheral blood mononuclear cells (PBMCs after therapy. Proliferative responses of PBMCs to allergen extract were significantly reduced after PIT. This was associated with modified cytokine profiles generally characterised by an increase in interleukin-10 and a decrease in interleukin-5 production. CD4+ cells isolated after PIT were able to actively suppress allergen-specific proliferative responses of pretreatment CD4neg PBMCs in co-culture experiments. PIT was associated with a significant increase in surface expression of CD5 on both CD4+ and CD8+ PBMCs. Conclusion This study provides evidence for the induction of a population of CD4+ T cells with suppressor/regulatory activity following PIT. Furthermore, up-regulation of cell surface levels of CD5 may contribute to reduced reactivity to allergen.

  1. Germ Cell Cancer and Multiple Relapses: Toxicity and Survival

    Lauritsen, Jakob; Kier, Maria G.G.; Mortensen, Mette S.

    2015-01-01

    Purpose: A small number of patients with germ cell cancer (GCC) receive more than one line of treatment for disseminated disease. The purpose of this study was to evaluate late toxicity and survival in an unselected cohort of patients who experienced relapse after receiving first-line treatment...... for disseminated disease. Methods: From the Danish Testicular Cancer database, we identified all patients who received more than one line of treatment for disseminated disease. Information about late toxicity and mortality was obtained by means of linkage to national registers. Prognostic factors for relapse......, compared with patients treated with only orchiectomy, had an increased risk for a second cancer (hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.5), major cardiovascular disease (HR, 1.9; 95% CI, 1.0 to 3.3), pulmonary disease (HR, 2.0; 95% CI, 1.0 to 3.8), GI disease (HR, 7.3; 95% CI, 3.6 to 14.8), renal...

  2. Dystroglycan versatility in cell adhesion: a tale of multiple motifs

    Winder Steve J

    2010-02-01

    Full Text Available Abstract Dystroglycan is a ubiquitously expressed heterodimeric adhesion receptor. The extracellular α-subunit makes connections with a number of laminin G domain ligands including laminins, agrin and perlecan in the extracellular matrix and the transmembrane β-subunit makes connections to the actin filament network via cytoskeletal linkers including dystrophin, utrophin, ezrin and plectin, depending on context. Originally discovered as part of the dystrophin glycoprotein complex of skeletal muscle, dystroglycan is an important adhesion molecule and signalling scaffold in a multitude of cell types and tissues and is involved in several diseases. Dystroglycan has emerged as a multifunctional adhesion platform with many interacting partners associating with its short unstructured cytoplasmic domain. Two particular hotspots are the cytoplasmic juxtamembrane region and at the very carboxy terminus of dystroglycan. Regions which between them have several overlapping functions: in the juxtamembrane region; a nuclear localisation signal, ezrin/radixin/moesin protein, rapsyn and ERK MAP Kinase binding function, and at the C terminus a regulatory tyrosine governing WW, SH2 and SH3 domain interactions. We will discuss the binding partners for these motifs and how their interactions and regulation can modulate the involvement of dystroglycan in a range of different adhesion structures and functions depending on context. Thus dystroglycan presents as a multifunctional scaffold involved in adhesion and adhesion-mediated signalling with its functions under exquisite spatio-temporal regulation.

  3. T-cell receptor Vα and Cα alleles associated with multiple sclerosis and myasthenia gravis

    Oksenberg, J.R.; Cavalli-Sforza, L.L.; Steinman, L.; Sherritt, M.; Bernard, C.C.; Begovich, A.B.; Erlich, H.A.

    1989-01-01

    Polymorphic markers in genes encoding the α chain of the human T-cell receptor (TcR) have been detected by Southern blot analysis in Pss I digests. Polymorphic bands were observed at 6.3 and 2.0 kilobases (kb) with frequencies of 0.30 and 0.44, respectively, in the general population. Using the polymerase chain reaction (PCR) method, the authors amplified selected sequences derived from the full-length TcR α cDNA probe. These PcR products were used as specific probes to demonstrate that the 6.3-kb polymorphic fragment hybridizes to the variable (V)-region probe and the 2.0-kb fragment hybridizes to the constant (C)-region probe. Segregation of the polymorphic bands was analyzed in family studies. To look for associations between these markers and autoimmune diseases, the authors have studied the restriction fragment length polymorphism distribution of the Pss I markers in patients with multiple sclerosis, myasthenia gravis, and Graves disease. Significant differences in the frequency of the polymorphic V α and C α markers were identified between patients and healthy individuals

  4. Multiple human papilloma virus infections predominant in squamous cell cervical carcinoma in Bandung

    Edhyana Sahiratmadja

    2014-04-01

    Full Text Available Background Persistent infection of high risk genotypes of human papilloma virus (hrHPV has been established as the etiological cause for cervical cancer, and the most prevalent genotypes that infect the cervical tissue are HPV-16 and HPV-18. However, HPV genotype profile has been shown to differ according to geographical distribution across the globe. The present study aimed to determine the HPV genotype distribution in cervical cancer patients from Bandung, Indonesia. Methods During the period of July – November 2010 viral DNA was extracted from randomly chosen cervical cancer biopsies and subjected to genotype determination using the diagnostic linear array genotyping test (Roche. The distribution of HPV genotypes was explored and the prevalence of HPV genotypes was mapped. Results Of 96 cervical cancer tissue samples, 76 (79.2% were histopathologically classified as squamous cell cervical carcinoma. Due to the high cost of HPV genotyping tests, only twenty-five samples were randomly genotyped. Almost 90% of the cervical cancer patients were multiply infected with HPV-16 in combination with HPV-18, HPV-45, or HPV-52. The HPV-16 genotype had the highest prevalence, all samples being infected with HPV-16. Conclusion The cervical cancer cases were predominantly infected by multiple hrHPVs with HPV-16 as the major genotype among other hrHPVs, supporting the carcinogenic role of this hrHPV. Therefore, screening for hrHPVs in the general population is urgently needed as a means of early detection of cervical cancer.

  5. Multiple human papilloma virus infections predominant in squamous cell cervical carcinoma in Bandung

    Edhyana Sahiratmadja

    2015-12-01

    Full Text Available BACKGROUND Persistent infection of high risk genotypes of human papilloma virus (hrHPV has been established as the etiological cause for cervical cancer, and the most prevalent genotypes that infect the cervical tissue are HPV-16 and HPV-18. However, HPV genotype profile has been shown to differ according to geographical distribution across the globe. The present study aimed to determine the HPV genotype distribution in cervical cancer patients from Bandung, Indonesia. METHODS During the period of July – November 2010 viral DNA was extracted from randomly chosen cervical cancer biopsies and subjected to genotype determination using the diagnostic linear array genotyping test (Roche. The distribution of HPV genotypes was explored and the prevalence of HPV genotypes was mapped. RESULTS Of 96 cervical cancer tissue samples, 76 (79.2% were histopathologically classified as squamous cell cervical carcinoma. Due to the high cost of HPV genotyping tests, only twenty-five samples were randomly genotyped. Almost 90% of the cervical cancer patients were multiply infected with HPV-16 in combination with HPV-18, HPV-45, or HPV-52. The HPV-16 genotype had the highest prevalence, all samples being infected with HPV-16. CONCLUSION The cervical cancer cases were predominantly infected by multiple hrHPVs with HPV-16 as the major genotype among other hrHPVs, supporting the carcinogenic role of this hrHPV. Therefore, screening for hrHPVs in the general population is urgently needed as a means of early detection of cervical cancer.

  6. The population of Indonesia : regional demographic scenarios using a multiregional method and multiple data sources

    Muhidin, Salahudin

    2002-01-01

    This study attempts to contribute on the understanding of regional population dynamics in Indonesia. It outlines a detailed analysis of the changes in regional demographic variables during the last three decades. It provides an assessment of the past population projections, as well as the advantages

  7. A computational model incorporating neural stem cell dynamics reproduces glioma incidence across the lifespan in the human population.

    Roman Bauer

    Full Text Available Glioma is the most common form of primary brain tumor. Demographically, the risk of occurrence increases until old age. Here we present a novel computational model to reproduce the probability of glioma incidence across the lifespan. Previous mathematical models explaining glioma incidence are framed in a rather abstract way, and do not directly relate to empirical findings. To decrease this gap between theory and experimental observations, we incorporate recent data on cellular and molecular factors underlying gliomagenesis. Since evidence implicates the adult neural stem cell as the likely cell-of-origin of glioma, we have incorporated empirically-determined estimates of neural stem cell number, cell division rate, mutation rate and oncogenic potential into our model. We demonstrate that our model yields results which match actual demographic data in the human population. In particular, this model accounts for the observed peak incidence of glioma at approximately 80 years of age, without the need to assert differential susceptibility throughout the population. Overall, our model supports the hypothesis that glioma is caused by randomly-occurring oncogenic mutations within the neural stem cell population. Based on this model, we assess the influence of the (experimentally indicated decrease in the number of neural stem cells and increase of cell division rate during aging. Our model provides multiple testable predictions, and suggests that different temporal sequences of oncogenic mutations can lead to tumorigenesis. Finally, we conclude that four or five oncogenic mutations are sufficient for the formation of glioma.

  8. Evaluating the status of individuals and populations: Advantages of multiple approaches and time scales: Chapter 6

    Monson, Daniel H.; Bowen, Lizabeth

    2015-01-01

    The assessment of population status is a central goal of applied wildlife research and essential to the field of wildlife conservation. “Population status” has a number of definitions, the most widely used having to do with the current trajectory of the population (i.e., growing, stable, or declining), or the probability of persistence (i.e., extinction risk), perhaps without any specific knowledge as to the factors driving a population’s dynamics. In contrast, a population’s status relative to the carrying capacity of the environment (K) is an ecologically-based definition that explicitly provides information about a major mechanism of population control. That is, it relates to the relative per capita availability of resources to individuals in a population, which can also be used to infer the state of the environment itself.

  9. Dissection of Recombination Attributes for Multiple Maize Populations Using a Common SNP Assay

    Haiying Guan

    2017-11-01

    Full Text Available Recombination is a vital characteristic for quantitative trait loci mapping and breeding to enhance the yield potential of maize. However, recombination characteristics in globally used segregating populations have never been evaluated at similar genetic marker densities. This study aimed to divulge the characteristics of recombination events, recombinant chromosomal segments, and recombination frequency for four dissimilar populations. These populations were doubled haploid (DH, recombination inbred line (RIL, intermated B73xMo17 (IBM, and multi-parent advanced generation inter-cross (MAGIC, using the Illumina MaizeSNP50 BeadChip to provide markers. Our results revealed that the average number of recombination events was 16, 41, 72, and 86 per line in DH, RIL, IBM, and MAGIC populations, respectively. Accordingly, the average length of recombinant chromosomal segments was 84.8, 47.3, 29.2, and 20.4 Mb in DH, RIL, IBM, and MAGIC populations, respectively. Furtherly, the recombination frequency varied in different genomic regions and population types [DH (0–12.7 cM/Mb, RIL (0–15.5 cM/Mb, IBM (0–24.1 cM/Mb, MAGIC (0–42.3 cM/Mb]. Utilizing different sub-sets of lines, the recombination bin number and size were analyzed in each population. Additionally, different sub-sets of markers and lines were employed to estimate the recombination bin number and size via formulas for relationship in these populations. The relationship between recombination events and recombination bin length was also examined. Our results contribute to determining the most suitable number of genetic markers, lines in each population, and population type for successful mapping and breeding.

  10. POOR HEMOPOIETIC STEM CELL MOBILIZERS IN MULTIPLE MYELOMA : A SINGLE INSTITUTION EXPERIENCE

    Guillermo Jose Ruiz-Delgado

    2010-06-01

    Full Text Available In a single institution, in a group of 28 myeloma patients deemed eligible for autologous transplant, stem cell mobilization was attempted using filgrastim: 26 individuals were given 31 autografts employing 1-4 (median three apheresis sessions, to obtain a target stem cell dose of 1 x 106 CD34 viable cells / Kg of the recipient. The median number of grafted CD34 cells was 7.56 x 106  / Kg of the recipient; the range being 0.92 to 14.8.  By defining as poor mobilizers individuals in which a cell collection of 1 x 106 CD34 viable cells / Kg was better (80% at 80 months than those grafted with < 1 x 106 CD34 viable cells / Kg (67% at 76 months. Methods to improve stem cell mobilization are needed and may result in obtaining better results when autografting multiple myeloma patients.

  11. Programming strategy for efficient modeling of dynamics in a population of heterogeneous cells

    Hald, Bjørn Olav; Hendriksen, Morten; Sørensen, Preben Graae

    2013-01-01

    Heterogeneity is a ubiquitous property of biological systems. Even in a genetically identical population of a single cell type, cell-to-cell differences are observed. Although the functional behavior of a given population is generally robust, the consequences of heterogeneity are fairly unpredict...

  12. The fairness, predictive validity and acceptability of multiple mini interview in an internationally diverse student population- a mixed methods study

    Kelly, Maureen E.; Dowell, Jon; Husbands, Adrian; Newell, John; O'Flynn, Siun; Kropmans, Thomas; Dunne, Fidelma P.; Murphy, Andrew W.

    2014-01-01

    Background International medical students, those attending medical school outside of their country of citizenship, account for a growing proportion of medical undergraduates worldwide. This study aimed to establish the fairness, predictive validity and acceptability of Multiple Mini Interview (MMI) in an internationally diverse student population. Methods This was an explanatory sequential, mixed methods study. All students in First Year Medicine, National University of Ireland Galway 2012 we...

  13. [Multiple decrement tables of changes in the marital status of the population of Poland (1982-1984)].

    Kedelski, M; Golata, E

    1986-01-01

    Official Polish data for the period 1982-1984 are used to construct multiple decrement tables of changes in marital status for the population of a hypothetical cohort over the course of its life history. The data are analyzed separately by sex with respect to the probabilities of change in marital status, the characteristics of the life cycle, and the expectation of life by marital status category. (SUMMARY IN ENG AND RUS)

  14. The CEA−/lo colorectal cancer cell population harbors cancer stem cells and metastatic cells

    Zhang, Bo; Mu, Lei; Huang, Kaiyu; Zhao, Hui; Ma, Chensen; Li, Xiaolan; Tao, Deding; Gong, Jianping; Qin, Jichao

    2016-01-01

    Serum carcinoembryonic antigen (CEA) is the most commonly used tumor marker in a variety of cancers including colorectal cancer (CRC) for tumor diagnosis and monitoring. Recent studies have shown that colonic crypt cells expressing little or no CEA may enrich for stem cells. Numerous studies have clearly shown that there exist CRC patients with normal serum CEA levels during tumor progression or even tumor relapse, although CEA itself is considered to promote metastasis and block cell differentiation. These seemingly contradictory observations prompted us to investigate, herein, the biological properties as well as tumorigenic and metastatic capacity of CRC cells that express high (CEA+) versus low CEA (CEA−/lo) levels of CEA. Our findings show that the abundance of CEA−/lo cells correlate with poor differentiation and poor prognosis, and moreover, CEA−/lo cells form more spheres in vitro, generate more tumors and exhibit a higher potential in developing liver and lung metastases than corresponding CEA+ cells. Applying RNAi-mediated approach, we found that IGF1R mediated tumorigenic and capacity of CEA−/lo cells but did not mediate those of CEA+ cells. Notably, our data demonstrated that CEA molecule was capable of protecting CEA−/lo cells from anoikis, implying that CEA+ cells, although themselves possessing less tumorigenic and metastatic capacity, may promote metastasis of CEA−/lo cells via secreting CEA molecule. Our observations suggest that, besides targeting CEA molecule, CEA−/lo cells may represent a critical source of tumor progression and metastasis, and should therefore be the target of future therapies. PMID:27813496

  15. Evaluation of Personal and Built Environment Attributes to Physical Activity: A Multilevel Analysis on Multiple Population-Based Data Sources

    Wei Yang

    2012-01-01

    Full Text Available Background. Studies have documented that built environment factors potentially promote or impede leisure time physical activity (LTPA. This study explored the relationship between multiple built environment factors and individual characteristics on LTPA. Methods. Multiple data sources were utilized including individual level data for health behaviors and health status from the Nevada Behavioral Risk Factor Surveillance System (BRFSS and community level data from different data sources including indicators for recreation facilities, safety, air quality, commute time, urbanization, population density, and land mix level. Mixed model logistic regression and geographic information system (GIS spatial analysis were conducted. Results. Among 6,311 respondents, 24.4% reported no LTPA engagement during the past 30 days. No engagement in LTPA was significantly associated with (1 individual factors: older age, less education, lower income, being obesity, and low life satisfaction and (2 community factors: more commute time, higher crime rate, urban residence, higher population density, but not for density and distance to recreation facilities, air quality, and land mix. Conclusions. Multiple data systems including complex population survey and spatial analysis are valuable tools on health and built environment studies.

  16. Serological prevalence of celiac disease in Brazilian population of multiple sclerosis, neuromyelitis optica and myelitis.

    de Oliveira, Pérola; de Carvalho, Daniel Rocha; Brandi, Ivar Viana; Pratesi, Riccardo

    2016-09-01

    Comorbidity of celiac disease with demyelinating diseases of the central nervous system has been reported since the 1960s. The objective of this study was to determine the serological prevalence of celiac disease in the largest series of patients diagnosed with multiple sclerosis, neuromyelitis optica, or myelitis. A prevalence study was conducted with patients evaluated at Sarah Network of Rehabilitation Hospitals between March 2012 and September 2013. They were previously diagnosed with multiple sclerosis, neuromyelitis optica, or idiopathic myelitis. The serum levels of antibodies against tissue transglutaminase and endomysium were assessed. Of the 379 patients evaluated, 249 (65.70%) were diagnosed with multiple sclerosis, 37 (9.56%) with neuromyelitis optica, and 96 (24.54%) with idiopathic myelitis. Two patients (0.53%), one with multiple sclerosis and other with myelitis, tested positive for both antibodies. Our study do not confirm the relationship between celiac serological antibodies with multiple sclerosis, neuromyelitis optica and inflammatory myelitis of an unknown etiology. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. A population-based study of effect of multiple birth on infant mortality in Nigeria

    Uthman Mubashir B

    2008-09-01

    Full Text Available Abstract Background Multi-foetal pregnancies and multiple births including twins and higher order multiples births such as triplets and quadruplets are high-risk pregnancy and birth. These high-risk groups contribute to the higher rate of childhood mortality especially during early period of life. Methods We examined the relationship between multiple births and infant mortality using univariable and multivariable survival regression procedure with Weibull hazard function, controlling for child's sex, birth order, prenatal care, delivery assistance; mother's age at child birth, nutritional status, education level; household living conditions and several other risk factors. Results Children born multiple births were more than twice as likely to die during infancy as infants born singleton (hazard ratio = 2.19; 95% confidence interval: 1.50, 3.19 holding other factors constant. Maternal education and household asset index were associated with lower risk of infant mortality. Conclusion Multiple births are strongly negatively associated with infant survival in Nigeria independent of other risk factors. Mother's education played a protective role against infant death. This evidence suggests that improving maternal education may be key to improving child survival in Nigeria. A well-educated mother has a better chance of satisfying important factors that can improve infant survival: the quality of infant feeding, general care, household sanitation, and adequate use of preventive and curative health services.

  18. Making sense of snapshot data: ergodic principle for clonal cell populations.

    Thomas, Philipp

    2017-11-01

    Population growth is often ignored when quantifying gene expression levels across clonal cell populations. We develop a framework for obtaining the molecule number distributions in an exponentially growing cell population taking into account its age structure. In the presence of generation time variability, the average acquired across a population snapshot does not obey the average of a dividing cell over time, apparently contradicting ergodicity between single cells and the population. Instead, we show that the variation observed across snapshots with known cell age is captured by cell histories, a single-cell measure obtained from tracking an arbitrary cell of the population back to the ancestor from which it originated. The correspondence between cells of known age in a population with their histories represents an ergodic principle that provides a new interpretation of population snapshot data. We illustrate the principle using analytical solutions of stochastic gene expression models in cell populations with arbitrary generation time distributions. We further elucidate that the principle breaks down for biochemical reactions that are under selection, such as the expression of genes conveying antibiotic resistance, which gives rise to an experimental criterion with which to probe selection on gene expression fluctuations. © 2017 The Author(s).

  19. Statistics and methodology of multiple cell upset characterization under heavy ion irradiation

    Zebrev, G.I.; Gorbunov, M.S.; Useinov, R.G.; Emeliyanov, V.V.; Ozerov, A.I.; Anashin, V.S.; Kozyukov, A.E.; Zemtsov, K.S.

    2015-01-01

    Mean and partial cross-section concepts and their connections to multiplicity and statistics of multiple cell upsets (MCUs) in highly-scaled digital memories are introduced and discussed. The important role of the experimental determination of the upset statistics is emphasized. It was found that MCU may lead to quasi-linear dependence of cross-sections on linear energy transfer (LET). A new form of function for interpolation of mean cross-section dependences on LET has been proposed

  20. Killing multiple myeloma cells with the small molecule 3-bromopyruvate: implications for therapy.

    Majkowska-Skrobek, Grażyna; Augustyniak, Daria; Lis, Paweł; Bartkowiak, Anna; Gonchar, Mykhailo; Ko, Young H; Pedersen, Peter L; Goffeau, Andre; Ułaszewski, Stanisław

    2014-07-01

    The small molecule 3-bromopyruvate (3-BP), which has emerged recently as the first member of a new class of potent anticancer agents, was tested for its capacity to kill multiple myeloma (MM) cancer cells. Human MM cells (RPMI 8226) begin to lose viability significantly within 8 h of incubation in the presence of 3-BP. The Km (0.3 mmol/l) for intracellular accumulation of 3-BP in MM cells is 24 times lower than that in control cells (7.2 mmol/l). Therefore, the uptake of 3-BP by MM cells is significantly higher than that by peripheral blood mononuclear cells. Further, the IC50 values for human MM cells and control peripheral blood mononuclear cells are 24 and 58 µmol/l, respectively. Therefore, specificity and selectivity of 3-BP toward MM cancer cells are evident on the basis of the above. In MM cells the transcription levels of the gene encoding the monocarboxylate transporter MCT1 is significantly amplified compared with control cells. The level of intracellular ATP in MM cells decreases by over 90% within 1 h after addition of 100 µmol/l 3-BP. The cytotoxicity of 3-BP, exemplified by a marked decrease in viability of MM cells, is potentiated by the inhibitor of glutathione synthesis buthionine sulfoximine. In addition, the lack of mutagenicity and its superior capacity relative to Glivec to kill MM cancer cells are presented in this study.

  1. CHOOSING A HEALTH INSTITUTION WITH MULTIPLE CORRESPONDENCE ANALYSIS AND CLUSTER ANALYSIS IN A POPULATION BASED STUDY

    ASLI SUNER

    2013-06-01

    Full Text Available Multiple correspondence analysis is a method making easy to interpret the categorical variables given in contingency tables, showing the similarities, associations as well as divergences among these variables via graphics on a lower dimensional space. Clustering methods are helped to classify the grouped data according to their similarities and to get useful summarized data from them. In this study, interpretations of multiple correspondence analysis are supported by cluster analysis; factors affecting referred health institute such as age, disease group and health insurance are examined and it is aimed to compare results of the methods.

  2. Coordinated learning of grid cell and place cell spatial and temporal properties: multiple scales, attention and oscillations.

    Grossberg, Stephen; Pilly, Praveen K

    2014-02-05

    A neural model proposes how entorhinal grid cells and hippocampal place cells may develop as spatial categories in a hierarchy of self-organizing maps (SOMs). The model responds to realistic rat navigational trajectories by learning both grid cells with hexagonal grid firing fields of multiple spatial scales, and place cells with one or more firing fields, that match neurophysiological data about their development in juvenile rats. Both grid and place cells can develop by detecting, learning and remembering the most frequent and energetic co-occurrences of their inputs. The model's parsimonious properties include: similar ring attractor mechanisms process linear and angular path integration inputs that drive map learning; the same SOM mechanisms can learn grid cell and place cell receptive fields; and the learning of the dorsoventral organization of multiple spatial scale modules through medial entorhinal cortex to hippocampus (HC) may use mechanisms homologous to those for temporal learning through lateral entorhinal cortex to HC ('neural relativity'). The model clarifies how top-down HC-to-entorhinal attentional mechanisms may stabilize map learning, simulates how hippocampal inactivation may disrupt grid cells, and explains data about theta, beta and gamma oscillations. The article also compares the three main types of grid cell models in the light of recent data.

  3. Adult T-cell leukemia/lymphoma presenting multiple lymphomatous polyposis

    Akira Hokama; Nobuyuki Takasu; Jiro Fujita; Takeaki Tomoyose; Yu-ichi Yamamoto; Takako Watanabe; Tetsuo Hirata; Fukunori Kinjo; Seiya Kato; Koichi Ohshima; Hiroshi Uezato

    2008-01-01

    Multiple lymphomatous polyposis (HLP) is an unusual form of non-Hodgkin's lymphoma characterized by polyps throughout the gastrointestinal tract. It has been reported that most MLP are observed in cases with mantle cell lymphoma of B-cell type. We herein present a case of a 66-year-old man with adult T-cell leukemia/lymphoma (ATLL). Colonoscopy revealed MLP throughout the colon and histopathological findings of ATLL cell infiltration. The patient died despite combination of chemotherapy. The literature of manifestations of colonic involvement of ATLL is reviewed and the importance of endoscopic evaluation to differentiate ATLL intestinal lesions from opportunistic infectious enterocolitis is discussed.

  4. CD4 T cell activation and disease activity at onset of multiple sclerosis

    Jensen, J; Langkilde, Annika Reynberg; Fenst, C

    2004-01-01

    We studied CD4 T cell activation in patients with clinically isolated syndromes (CIS) suggesting an initial attack of multiple sclerosis. The percentage of blood CD26+ CD4 T cells was increased in these patients, and correlated with magnetic resonance imaging disease activity and clinical disease...... severity. In contrast, the percentage of CD25+ CD4 T cells in cerebrospinal fluid correlated negatively with the cerebrospinal fluid concentration of myelin basic protein and the presence of IgG oligoclonal bands. These results suggest that distinct systemic and intrathecal T cell activation states...

  5. Phenotypic switching of populations of cells in a stochastic environment

    Hufton, Peter G.; Lin, Yen Ting; Galla, Tobias

    2018-02-01

    In biology phenotypic switching is a common bet-hedging strategy in the face of uncertain environmental conditions. Existing mathematical models often focus on periodically changing environments to determine the optimal phenotypic response. We focus on the case in which the environment switches randomly between discrete states. Starting from an individual-based model we derive stochastic differential equations to describe the dynamics, and obtain analytical expressions for the mean instantaneous growth rates based on the theory of piecewise-deterministic Markov processes. We show that optimal phenotypic responses are non-trivial for slow and intermediate environmental processes, and systematically compare the cases of periodic and random environments. The best response to random switching is more likely to be heterogeneity than in the case of deterministic periodic environments, net growth rates tend to be higher under stochastic environmental dynamics. The combined system of environment and population of cells can be interpreted as host-pathogen interaction, in which the host tries to choose environmental switching so as to minimise growth of the pathogen, and in which the pathogen employs a phenotypic switching optimised to increase its growth rate. We discuss the existence of Nash-like mutual best-response scenarios for such host-pathogen games.

  6. A POPULATION OF VERY HOT SUPER-EARTHS IN MULTIPLE-PLANET SYSTEMS SHOULD BE UNCOVERED BY KEPLER

    Schlaufman, Kevin C.; Lin, D. N. C.; Ida, S.

    2010-01-01

    We simulate a Kepler-like observation of a theoretical exoplanet population and show that the observed orbital period distribution of the Kepler giant planet candidates is best matched by an average stellar specific dissipation function Q' * in the interval 10 6 ∼ * ∼ 7 . In that situation, the few super-Earths that are driven to orbital periods of P < 1 day by dynamical interactions in multiple-planet systems will survive tidal disruption for a significant fraction of the main-sequence lifetimes of their stellar hosts. Consequently, though these very hot super-Earths are not characteristic of the overall super-Earth population, their substantial transit probability implies that they should be significant contributors to the full super-Earth population uncovered by Kepler. As a result, the CoRoT-7 system may be the first representative of a population of very hot super-Earths that we suggest should be found in multiple-planet systems preferentially orbiting the least-dissipative stellar hosts in the Kepler sample.

  7. Concept of multiple-cell cavity for axion dark matter search

    Jeong, Junu; Youn, SungWoo; Ahn, Saebyeok; Kim, Jihn E.; Semertzidis, Yannis K.

    2018-02-01

    In cavity-based axion dark matter search experiments exploring high mass regions, multiple-cavity design is under consideration as a method to increase the detection volume within a given magnet bore. We introduce a new idea, referred to as a multiple-cell cavity, which provides various benefits including a larger detection volume, simpler experimental setup, and easier phase-matching mechanism. We present the characteristics of this concept and demonstrate the experimental feasibility with an example of a double-cell cavity.

  8. Directional genetic selection by pulp mill effluent on multiple natural populations of three-spined stickleback (Gasterosteus aculeatus).

    Lind, Emma E; Grahn, Mats

    2011-05-01

    Contamination can cause a rapid environmental change which may require populations to respond with evolutionary changes. To evaluate the effects of pulp mill effluents on population genetics, we sampled three-spined sticklebacks (Gasterosteus aculeatus) near four pulp mills and four adjacent reference sites and analyzed Amplified Fragment Length Polymorphism (AFLP) to compare genetic variability. A fine scale genetic structure was detected and samples from polluted sites separated from reference sites in multidimensional scaling plots (Pselection. When removing 13 F(ST)-outlier loci, significant at the Pselective agent on natural populations of G. aculeatus, causing a convergence in genotype composition change at multiple sites in an open environment. © The Author(s) 2011. This article is published with open access at Springerlink.com

  9. Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2-dependent regulatory dendritic cell population.

    Zhang, Bin; Liu, Rui; Shi, Dan; Liu, Xingxia; Chen, Yuan; Dou, Xiaowei; Zhu, Xishan; Lu, Chunhua; Liang, Wei; Liao, Lianming; Zenke, Martin; Zhao, Robert C H

    2009-01-01

    Mesenchymal stem cells (MSCs), in addition to their multilineage differentiation, exert immunomodulatory effects on immune cells, even dendritic cells (DCs). However, whether they influence the destiny of full mature DCs (maDCs) remains controversial. Here we report that MSCs vigorously promote proliferation of maDCs, significantly reduce their expression of Ia, CD11c, CD80, CD86, and CD40 while increasing CD11b expression. Interestingly, though these phenotypes clearly suggest their skew to immature status, bacterial lipopolysaccharide (LPS) stimulation could not reverse this trend. Moreover, high endocytosic capacity, low immunogenicity, and strong immunoregulatory function of MSC-treated maDCs (MSC-DCs) were also observed. Furthermore we found that MSCs, partly via cell-cell contact, drive maDCs to differentiate into a novel Jagged-2-dependent regulatory DC population and escape their apoptotic fate. These results further support the role of MSCs in preventing rejection in organ transplantation and treatment of autoimmune disease.

  10. A 'Rosetta Stone' to Interpret the UV-HST Photometry of Multiple Stellar Populations in Globular Clusters

    Renzini, Alvio

    2011-10-01

    In this proposal we intend to firmly identify the chemical species responsible for the UV and UV-optical color differences exhibited by the multiple stellar populations harboured by two Galactic globular clusters: omega Centauri and 47 Tucanae, one with highly helium enriched sub-populations {omega Centauri}, the other not.We plan to collect ultraviolet STIS spectra for stars in the crowded cores of the clusters, where HST photometry is already available for thousands of stars in more than 10 filters, from F225W to F850LP. This WFC3+ACS photometric database has allowed us to show that UV colors are remarkably effective in separating the different cluster sub-populations, and with the proposed STIS spectroscopy we can quantify the chemical abundance differences among such sub-populations, most notably in Nitrogen and Oxygen. The resulting calibration of the UV colors in terms of CNO abundances will provide a new effective tool for the chemical characterization of large numbers of globular cluster stars belonging to the various sub-populations in each cluster, and to better isolate the specific role of the helium abundance.The plan is to observe at least one star for each of the main principal stellar sub-populations in each of the two clusters. These objects are selected on the basis of their accurate photometry and astrometry already in hand, based on existing UV-HST images.

  11. Multiple disease resistance to fungal and oomycete pathogens using a recombinant inbred line population in pepper

    Incorporating disease resistance into cultivars is a primary focus of modern breeding programs. Resistance to pathogens is often introgressed from landrace or wild individuals with poor fruit quality into commercial-quality cultivars. Sites of multiple disease resistance (MDR) are regions or “hotspo...

  12. Multiple resistances against diseases and insects in a breeding population of pinus pinaster

    Alejandr Solla; Maria Vivas; Elena Cubera; Luis Sampedro; Xoaquin Moreira; Esther Merlo; Raul de la Mata; Rafael Zas

    2012-01-01

    The different plant defenses existing within a given taxon have been commonly assumed to trade-off among each other because of both evolutionary and physiological reasons. The higher the efficiency of a single defensive trait, the lower selective pressure for other redundant defenses expected. On the other hand, production of multiple defenses might be...

  13. Ontogenetic specialism in predators with multiple niche shifts prevents predator population recovery and establishment

    van Leeuwen, A.; Huss, M.; Gårdmark, A.; de Roos, A.M.

    2014-01-01

    The effects of ontogenetic niche shifts on community structure and dynamics are underexplored, despite the occurrence of such shifts in the majority of animal species. We studied the form of niche shifts in a predator that exhibits multiple ontogenetic niche shifts, and analyzed how this life

  14. A preliminary study measuring the number of T-cell receptor-rearrangement excision circles (TRECs) in peripheral blood T-cell populations of A-bomb survivors and control populations

    Kubo, Yoshiko; Yamaoka, Mika; Kusunoki, Yoichiro

    2006-01-01

    More than a half century after damage of the immune systems by the radiation from A-bomb, we can still observe significant decreases in the percentages of naieve CD4 and CD8 T cells among the survivors. To investigate whether the observed decreases in the naieve T-cell populations may have resulted from reduction in thymic T-cell production ability of survivors, we established a real-time polymerase chain reaction (PCR) method to examine the number of T-cell receptor-rearrangement excision circles (TRECs) in peripheral blood CD4 and CD8 T-cell populations. The real-time PCR quantitatively detected TREC sequences with a good reproducibility in human laboratory controls. In the 445 survivors so far been examined, multiple regression analysis indicated that the number of TRECs in the CD4 T-cell fraction was significantly higher in females than in males and decreased significantly with age in both males and females. This analysis also suggested a possible dose-dependent decrease in the number of TRECs in the CD4 T-cell fraction of the survivors who were less than 20 years of age at the time of bombing (p=0.09). A similar statistically significant trend for gender difference or age was observed in the CD8 T-cell fraction of the survivors. However, there was no effect of radiation exposure on the number of TRECs in the CD8-T cell fraction. The results indicate the possibility that A-bomb radiation exposure may have induced a long-term impairment in thymic CD4 T-cell production. Further investigations in a larger study population are necessary to test this hypothesis. (author)

  15. A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci.

    Rand, Kristin A; Song, Chi; Dean, Eric; Serie, Daniel J; Curtin, Karen; Sheng, Xin; Hu, Donglei; Huff, Carol Ann; Bernal-Mizrachi, Leon; Tomasson, Michael H; Ailawadhi, Sikander; Singhal, Seema; Pawlish, Karen; Peters, Edward S; Bock, Cathryn H; Stram, Alex; Van Den Berg, David J; Edlund, Christopher K; Conti, David V; Zimmerman, Todd; Hwang, Amie E; Huntsman, Scott; Graff, John; Nooka, Ajay; Kong, Yinfei; Pregja, Silvana L; Berndt, Sonja I; Blot, William J; Carpten, John; Casey, Graham; Chu, Lisa; Diver, W Ryan; Stevens, Victoria L; Lieber, Michael R; Goodman, Phyllis J; Hennis, Anselm J M; Hsing, Ann W; Mehta, Jayesh; Kittles, Rick A; Kolb, Suzanne; Klein, Eric A; Leske, Cristina; Murphy, Adam B; Nemesure, Barbara; Neslund-Dudas, Christine; Strom, Sara S; Vij, Ravi; Rybicki, Benjamin A; Stanford, Janet L; Signorello, Lisa B; Witte, John S; Ambrosone, Christine B; Bhatti, Parveen; John, Esther M; Bernstein, Leslie; Zheng, Wei; Olshan, Andrew F; Hu, Jennifer J; Ziegler, Regina G; Nyante, Sarah J; Bandera, Elisa V; Birmann, Brenda M; Ingles, Sue A; Press, Michael F; Atanackovic, Djordje; Glenn, Martha J; Cannon-Albright, Lisa A; Jones, Brandt; Tricot, Guido; Martin, Thomas G; Kumar, Shaji K; Wolf, Jeffrey L; Deming Halverson, Sandra L; Rothman, Nathaniel; Brooks-Wilson, Angela R; Rajkumar, S Vincent; Kolonel, Laurence N; Chanock, Stephen J; Slager, Susan L; Severson, Richard K; Janakiraman, Nalini; Terebelo, Howard R; Brown, Elizabeth E; De Roos, Anneclaire J; Mohrbacher, Ann F; Colditz, Graham A; Giles, Graham G; Spinelli, John J; Chiu, Brian C; Munshi, Nikhil C; Anderson, Kenneth C; Levy, Joan; Zonder, Jeffrey A; Orlowski, Robert Z; Lonial, Sagar; Camp, Nicola J; Vachon, Celine M; Ziv, Elad; Stram, Daniel O; Hazelett, Dennis J; Haiman, Christopher A; Cozen, Wendy

    2016-12-01

    Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry-European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4 Correlated variants in 7p15.3 clustered around an enhancer at the 3' end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10 -7 ) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7 CONCLUSIONS: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609-18. ©2016 AACR. ©2016 American Association for Cancer Research.

  16. Medullospheres from DAOY, UW228 and ONS-76 cells: increased stem cell population and proteomic modifications.

    Zanini, Cristina; Ercole, Elisabetta; Mandili, Giorgia; Salaroli, Roberta; Poli, Alice; Renna, Cristiano; Papa, Valentina; Cenacchi, Giovanna; Forni, Marco

    2013-01-01

    Medulloblastoma (MB) is an aggressive pediatric tumor of the Central Nervous System (CNS) usually treated according to a refined risk stratification. The study of cancer stem cells (CSC) in MB is a promising approach aimed at finding new treatment strategies. The CSC compartment was studied in three characterized MB cell lines (DAOY, UW228 and ONS-76) grown in standard adhesion as well as being grown as spheres, which enables expansion of the CSC population. MB cell lines, grown in adherence and as spheres, were subjected to morphologic analysis at the light and electron microscopic level, as well as cytofluorimetric determinations. Medullospheres (MBS) were shown to express increasingly immature features, along with the stem cells markers: CD133, Nestin and β-catenin. Proteomic analysis highlighted the differences between MB cell lines, demonstrating a unique protein profile for each cell line, and minor differences when grown as spheres. In MBS, MALDI-TOF also identified some proteins, that have been linked to tumor progression and resistance, such as Nucleophosmin (NPM). In addition, immunocytochemistry detected Sox-2 as a stemness marker of MBS, as well as confirming high NPM expression. Culture conditioning based on low attachment flasks and specialized medium may provide new data on the staminal compartment of CNS tumors, although a proteomic profile of CSC is still elusive for MB.

  17. Medullospheres from DAOY, UW228 and ONS-76 cells: increased stem cell population and proteomic modifications.

    Cristina Zanini

    Full Text Available BACKGROUND: Medulloblastoma (MB is an aggressive pediatric tumor of the Central Nervous System (CNS usually treated according to a refined risk stratification. The study of cancer stem cells (CSC in MB is a promising approach aimed at finding new treatment strategies. METHODOLOGY/PRINCIPAL FINDINGS: The CSC compartment was studied in three characterized MB cell lines (DAOY, UW228 and ONS-76 grown in standard adhesion as well as being grown as spheres, which enables expansion of the CSC population. MB cell lines, grown in adherence and as spheres, were subjected to morphologic analysis at the light and electron microscopic level, as well as cytofluorimetric determinations. Medullospheres (MBS were shown to express increasingly immature features, along with the stem cells markers: CD133, Nestin and β-catenin. Proteomic analysis highlighted the differences between MB cell lines, demonstrating a unique protein profile for each cell line, and minor differences when grown as spheres. In MBS, MALDI-TOF also identified some proteins, that have been linked to tumor progression and resistance, such as Nucleophosmin (NPM. In addition, immunocytochemistry detected Sox-2 as a stemness marker of MBS, as well as confirming high NPM expression. CONCLUSIONS/SIGNIFICANCE: Culture conditioning based on low attachment flasks and specialized medium may provide new data on the staminal compartment of CNS tumors, although a proteomic profile of CSC is still elusive for MB.

  18. HIF-1α inhibition blocks the cross talk between multiple myeloma plasma cells and tumor microenvironment

    Borsi, Enrica, E-mail: enrica.borsi2@unibo.it [Department of Experimental Diagnostic and Specialty Medicine (DIMES), “L. and A. Seràgnoli”, Bologna University School of Medicine, S. Orsola' s University Hospital (Italy); Perrone, Giulia [Fondazione IRCCS Istituto Nazionale dei Tumori, Hematology Department, Via Venezian 1, 20133 Milano (Italy); Terragna, Carolina; Martello, Marina; Zamagni, Elena; Tacchetti, Paola; Pantani, Lucia; Brioli, Annamaria; Dico, Angela Flores; Zannetti, Beatrice Anna; Rocchi, Serena; Cavo, Michele [Department of Experimental Diagnostic and Specialty Medicine (DIMES), “L. and A. Seràgnoli”, Bologna University School of Medicine, S. Orsola' s University Hospital (Italy)

    2014-11-01

    Multiple myeloma (MM) is a malignant disorder of post-germinal center B cells, characterized by the clonal proliferation of malignant plasma cells (PCs) within the bone marrow (BM). The reciprocal and complex interactions that take place between the different compartments of BM and the MM cells result in tumor growth, angiogenesis, bone disease, and drug resistance. Given the importance of the BM microenvironment in MM pathogenesis, we investigated the possible involvement of Hypoxia-Inducible transcription Factor-1 alpha (HIF-1α) in the PCs-bone marrow stromal cells interplay. To test this hypothesis, we used EZN-2968, a 3rd generation antisense oligonucleotide against HIF-1α, to inhibit HIF-1α functions. Herein, we provide evidence that the interaction between MM cells and BM stromal cells is drastically reduced upon HIF-1α down-modulation. Notably, we showed that upon exposure to HIF-1α inhibitor, neither the incubation with IL-6 nor the co-culture with BM stromal cells were able to revert the anti-proliferative effect induced by EZN-2968. Moreover, we observed a down-modulation of cytokine-induced signaling cascades and a reduction of MM cells adhesion capability to the extracellular matrix proteins in EZN-2968-treated samples. Taken together, these results strongly support the concept that HIF-1α plays a critical role in the interactions between bone BM cells and PCs in Multiple Myeloma. - Highlights: • HIF-1α inhibition induces a mild apoptotic cell death. • Down-modulation of cytokine-induced signaling cascades upon HIF-1α inhibition. • Reduced interaction between MM cells and BMSCs upon HIF-1α down-modulation. • Reduced PCs adhesion to the extracellular matrix protein induced by EZN-2968. • HIF-1α inhibition may be an attractive therapeutic strategy for Multiple Myeloma.

  19. Stellar metallicity variations across spiral arms in disk galaxies with multiple populations

    Khoperskov, S.; Di Matteo, P.; Haywood, M.; Combes, F.

    2018-03-01

    This Letter studies the formation of azimuthal metallicity variations in the disks of spiral galaxies in the absence of initial radial metallicity gradients. Using high-resolution N-body simulations, we model composite stellar discs, made of kinematically cold and hot stellar populations, and study their response to spiral arm perturbations. We find that, as expected, disk populations with different kinematics respond differently to a spiral perturbation, with the tendency for dynamically cooler populations to show a larger fractional contribution to spiral arms than dynamically hotter populations. By assuming a relation between kinematics and metallicity, namely the hotter the population, the more metal-poor it is, this differential response to the spiral arm perturbations naturally leads to azimuthal variations in the mean metallicity of stars in the simulated disk. Thus, azimuthal variations in the mean metallicity of stars across a spiral galaxy are not necessarily a consequence of the reshaping, by radial migration, of an initial radial metallicity gradient. They indeed arise naturally also in stellar disks which have initially only a negative vertical metallicity gradient.

  20. Linear time algorithms to construct populations fitting multiple constraint distributions at genomic scales.

    Siragusa, Enrico; Haiminen, Niina; Utro, Filippo; Parida, Laxmi

    2017-10-09

    Computer simulations can be used to study population genetic methods, models and parameters, as well as to predict potential outcomes. For example, in plant populations, predicting the outcome of breeding operations can be studied using simulations. In-silico construction of populations with pre-specified characteristics is an important task in breeding optimization and other population genetic studies. We present two linear time Simulation using Best-fit Algorithms (SimBA) for two classes of problems where each co-fits two distributions: SimBA-LD fits linkage disequilibrium and minimum allele frequency distributions, while SimBA-hap fits founder-haplotype and polyploid allele dosage distributions. An incremental gap-filling version of previously introduced SimBA-LD is here demonstrated to accurately fit the target distributions, allowing efficient large scale simulations. SimBA-hap accuracy and efficiency is demonstrated by simulating tetraploid populations with varying numbers of founder haplotypes, we evaluate both a linear time greedy algoritm and an optimal solution based on mixed-integer programming. SimBA is available on http://researcher.watson.ibm.com/project/5669.

  1. Label-free morphology-based prediction of multiple differentiation potentials of human mesenchymal stem cells for early evaluation of intact cells.

    Hiroto Sasaki

    Full Text Available Precise quantification of cellular potential of stem cells, such as human bone marrow-derived mesenchymal stem cells (hBMSCs, is important for achieving stable and effective outcomes in clinical stem cell therapy. Here, we report a method for image-based prediction of the multiple differentiation potentials of hBMSCs. This method has four major advantages: (1 the cells used for potential prediction are fully intact, and therefore directly usable for clinical applications; (2 predictions of potentials are generated before differentiation cultures are initiated; (3 prediction of multiple potentials can be provided simultaneously for each sample; and (4 predictions of potentials yield quantitative values that correlate strongly with the experimental data. Our results show that the collapse of hBMSC differentiation potentials, triggered by in vitro expansion, can be quantitatively predicted far in advance by predicting multiple potentials, multi-lineage differentiation potentials (osteogenic, adipogenic, and chondrogenic and population doubling potential using morphological features apparent during the first 4 days of expansion culture. In order to understand how such morphological features can be effective for advance predictions, we measured gene-expression profiles of the same early undifferentiated cells. Both senescence-related genes (p16 and p21 and cytoskeleton-related genes (PTK2, CD146, and CD49 already correlated to the decrease of potentials at this stage. To objectively compare the performance of morphology and gene expression for such early prediction, we tested a range of models using various combinations of features. Such comparison of predictive performances revealed that morphological features performed better overall than gene-expression profiles, balancing the predictive accuracy with the effort required for model construction. This benchmark list of various prediction models not only identifies the best morphological feature

  2. Complex heterogeneous tissue constructs containing multiple cell types prepared by inkjet printing technology.

    Xu, Tao; Zhao, Weixin; Zhu, Jian-Ming; Albanna, Mohammad Z; Yoo, James J; Atala, Anthony

    2013-01-01

    This study was designed to develop a versatile method for fabricating complex and heterogeneous three-dimensional (3D) tissue constructs using simultaneous ink-jetting of multiple cell types. Human amniotic fluid-derived stem cells (hAFSCs), canine smooth muscle cells (dSMCs), and bovine aortic endothelial cells (bECs), were separately mixed with ionic cross-linker calcium chloride (CaCl(2)), loaded into separate ink cartridges and printed using a modified thermal inkjet printer. The three cell types were delivered layer-by-layer to pre-determined locations in a sodium alginate-collagen composite located in a chamber under the printer. The reaction between CaCl(2) and sodium alginate resulted in a rapid formation of a solid composite gel and the printed cells were anchored in designated areas within the gel. The printing process was repeated for several cycles leading to a complex 3D multi-cell hybrid construct. The biological functions of the 3D printed constructs were evaluated in vitro and in vivo. Each of the printed cell types maintained their viability and normal proliferation rates, phenotypic expression, and physiological functions within the heterogeneous constructs. The bioprinted constructs were able to survive and mature into functional tissues with adequate vascularization in vivo. These findings demonstrate the feasibility of fabricating complex heterogeneous tissue constructs containing multiple cell types using inkjet printing technology. Copyright © 2012 Elsevier Ltd. All rights reserved.

  3. A developmentally plastic adult mouse kidney cell line spontaneously generates multiple adult kidney structures

    Webb, Carol F.; Ratliff, Michelle L.; Powell, Rebecca; Wirsig-Wiechmann, Celeste R.; Lakiza, Olga; Obara, Tomoko

    2015-01-01

    Despite exciting new possibilities for regenerative therapy posed by the ability to induce pluripotent stem cells, recapitulation of three-dimensional kidneys for repair or replacement has not been possible. ARID3a-deficient mouse tissues generated multipotent, developmentally plastic cells. Therefore, we assessed the adult mouse ARID3a−/− kidney cell line, KKPS5, which expresses renal progenitor surface markers as an alternative cell source for modeling kidney development. Remarkably, these cells spontaneously developed into multicellular nephron-like structures in vitro, and engrafted into immunocompromised medaka mesonephros, where they formed mouse nephron structures. These data implicate KKPS5 cells as a new model system for studying kidney development. - Highlights: • An ARID3a-deficient mouse kidney cell line expresses multiple progenitor markers. • This cell line spontaneously forms multiple nephron-like structures in vitro. • This cell line formed mouse kidney structures in immunocompromised medaka fish kidneys. • Our data identify a novel model system for studying kidney development

  4. A developmentally plastic adult mouse kidney cell line spontaneously generates multiple adult kidney structures

    Webb, Carol F., E-mail: carol-webb@omrf.org [Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK (United States); Immunobiology and Cancer Research, Oklahoma Medical Research Foundation, Oklahoma City, OK (United States); Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK (United States); Ratliff, Michelle L., E-mail: michelle-ratliff@omrf.org [Immunobiology and Cancer Research, Oklahoma Medical Research Foundation, Oklahoma City, OK (United States); Powell, Rebecca, E-mail: rebeccapowell@gmail.com [Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK (United States); Wirsig-Wiechmann, Celeste R., E-mail: celeste-wirsig@ouhsc.edu [Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK (United States); Lakiza, Olga, E-mail: olga-lakiza@ouhsc.edu [Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK (United States); Obara, Tomoko, E-mail: tomoko-obara@ouhsc.edu [Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK (United States)

    2015-08-07

    Despite exciting new possibilities for regenerative therapy posed by the ability to induce pluripotent stem cells, recapitulation of three-dimensional kidneys for repair or replacement has not been possible. ARID3a-deficient mouse tissues generated multipotent, developmentally plastic cells. Therefore, we assessed the adult mouse ARID3a−/− kidney cell line, KKPS5, which expresses renal progenitor surface markers as an alternative cell source for modeling kidney development. Remarkably, these cells spontaneously developed into multicellular nephron-like structures in vitro, and engrafted into immunocompromised medaka mesonephros, where they formed mouse nephron structures. These data implicate KKPS5 cells as a new model system for studying kidney development. - Highlights: • An ARID3a-deficient mouse kidney cell line expresses multiple progenitor markers. • This cell line spontaneously forms multiple nephron-like structures in vitro. • This cell line formed mouse kidney structures in immunocompromised medaka fish kidneys. • Our data identify a novel model system for studying kidney development.

  5. Production of Multiple Growth Factors by a Newly Established Human Thyroid Carcinoma Cell Line

    Yoshida, Yataro; Ohashi, Kensaku; Sano, Emiko; Kobayashi, Hisataka; Endo, Keigo; Naruto, Masanobu; Nakamura, Toru

    1992-01-01

    A multiple growth factor‐producing tumor cell line (NIM‐1) was newly established from a patient with thyroid cancer and remarkable neutrophilia. NIM‐1 cells also caused severe neutrophilia in nude mice bearing tumors. NIM‐1‐conditioned medium (NIM‐1CM) contained activities that supported not only granulocyte, macrophage and eosinophil colony formation of human bone marrow cells but also the growth of colony‐stimulating factor (CSF)‐dependent cell lines, NFS60‐KX and TF‐1. Northern blot hybridization analysis revealed the constitutive expression of granulocyte‐CSF (G‐CSF), granulocyte/macrophage‐CSF (GM‐CSF) and interleukin(IL)‐6 mRNAs in NIM‐1 cells. Enzyme‐linked immunosorbent assays (ELISA) using NIM‐1CM also confirmed the production of IL‐la and a small amount of IL‐1β besides G‐CSF, GM‐CSF and IL‐6 in NIM‐1 cells. In addition, unexpected production of IL‐11 in NIM‐1 cells was detected by northern blot hybridization analysis and by bioassay using an IL‐11‐dependent cell line. Therefore, NIM‐1 cell line is shown to produce multiple cytokines including potentially megakaryopoietic growth factors such as GM‐CSF, IL‐6 and IL‐11. PMID:1372885

  6. Lin28a is a putative factor in regulating cancer stem cell-like properties in side population cells of oral squamous cell carcinoma

    Hayashi, S.; Tanaka, J.; Okada, S.; Isobe, T.; Yamamoto, G.; Yasuhara, R.; Irie, T.; Akiyama, C.; Kohno, Y.; Tachikawa, T.; Mishima, K., E-mail: mishima-k@dent.showa-u.ac.jp

    2013-05-01

    Cancer stem cells (CSCs) are among the target cells of cancer therapy because they are uniquely involved in both cancer progression and sensitivity to chemotherapeutic agents. We identified side population (SP) cells, which are known to be an enriched population of CSC, in five oral squamous cell carcinoma (OSCC) cells (SCC9, SCC25, TOSCC7, TOSCC17, and TOSCC23). The percentages of SP cells ranged from 0% to 3.3%, with TOSCC23 cells showing the highest percentages of SP cells (3.3% of the total cell population). The SP cells isolated from TOSCC23 cells also showed greater cell proliferation and invasion compared to non-SP (MP) cells. Therefore, our initial findings suggested that SP cells were enriched for CSC-like cells. Furthermore, DNA microarray analysis revealed that the expression of cell proliferation-related and anti-apoptotic genes was greater in SP cells compared to MP cells. We focused on Lin28a, which showed the highest expression (approximately 22-fold) among the upregulated genes. The overexpression of Lin28a in TOSCC23 cells increased their proliferation, colony formation, and invasion. These findings suggest that Lin28a is an appropriate CSC target molecule for OSCC treatment - Highlights: ► Lin28a is a SP cell-specific factor in oral squamous cell carcinoma (OSCC) cells. ► SP cells in OSCC cells show cancer stem cell-like properties. ► Lin28a regulates OSCC proliferative and invasive activities.

  7. Lin28a is a putative factor in regulating cancer stem cell-like properties in side population cells of oral squamous cell carcinoma

    Hayashi, S.; Tanaka, J.; Okada, S.; Isobe, T.; Yamamoto, G.; Yasuhara, R.; Irie, T.; Akiyama, C.; Kohno, Y.; Tachikawa, T.; Mishima, K.

    2013-01-01

    Cancer stem cells (CSCs) are among the target cells of cancer therapy because they are uniquely involved in both cancer progression and sensitivity to chemotherapeutic agents. We identified side population (SP) cells, which are known to be an enriched population of CSC, in five oral squamous cell carcinoma (OSCC) cells (SCC9, SCC25, TOSCC7, TOSCC17, and TOSCC23). The percentages of SP cells ranged from 0% to 3.3%, with TOSCC23 cells showing the highest percentages of SP cells (3.3% of the total cell population). The SP cells isolated from TOSCC23 cells also showed greater cell proliferation and invasion compared to non-SP (MP) cells. Therefore, our initial findings suggested that SP cells were enriched for CSC-like cells. Furthermore, DNA microarray analysis revealed that the expression of cell proliferation-related and anti-apoptotic genes was greater in SP cells compared to MP cells. We focused on Lin28a, which showed the highest expression (approximately 22-fold) among the upregulated genes. The overexpression of Lin28a in TOSCC23 cells increased their proliferation, colony formation, and invasion. These findings suggest that Lin28a is an appropriate CSC target molecule for OSCC treatment - Highlights: ► Lin28a is a SP cell-specific factor in oral squamous cell carcinoma (OSCC) cells. ► SP cells in OSCC cells show cancer stem cell-like properties. ► Lin28a regulates OSCC proliferative and invasive activities

  8. Systematic identification of yeast cell cycle transcription factors using multiple data sources

    Li Wen-Hsiung

    2008-12-01

    Full Text Available Abstract Background Eukaryotic cell cycle is a complex process and is precisely regulated at many levels. Many genes specific to the cell cycle are regulated transcriptionally and are expressed just before they are needed. To understand the cell cycle process, it is important to identify the cell cycle transcription factors (TFs that regulate the expression of cell cycle-regulated genes. Results We developed a method to identify cell cycle TFs in yeast by integrating current ChIP-chip, mutant, transcription factor binding site (TFBS, and cell cycle gene expression data. We identified 17 cell cycle TFs, 12 of which are known cell cycle TFs, while the remaining five (Ash1, Rlm1, Ste12, Stp1, Tec1 are putative novel cell cycle TFs. For each cell cycle TF, we assigned specific cell cycle phases in which the TF functions and identified the time lag for the TF to exert regulatory effects on its target genes. We also identified 178 novel cell cycle-regulated genes, among which 59 have unknown functions, but they may now be annotated as cell cycle-regulated genes. Most of our predictions are supported by previous experimental or computational studies. Furthermore, a high confidence TF-gene regulatory matrix is derived as a byproduct of our method. Each TF-gene regulatory relationship in this matrix is supported by at least three data sources: gene expression, TFBS, and ChIP-chip or/and mutant data. We show that our method performs better than four existing methods for identifying yeast cell cycle TFs. Finally, an application of our method to different cell cycle gene expression datasets suggests that our method is robust. Conclusion Our method is effective for identifying yeast cell cycle TFs and cell cycle-regulated genes. Many of our predictions are validated by the literature. Our study shows that integrating multiple data sources is a powerful approach to studying complex biological systems.

  9. Analysis of multiple types of human cells subsequent to bioprinting with electrospraying technology.

    Xin, Yu; Chai, Gang; Zhang, Ting; Wang, Xiangsheng; Qu, Miao; Tan, Andy; Bogari, Melia; Zhu, Ming; Lin, Li; Hu, Qingxi; Liu, Yuanyuan; Zhang, Yan

    2016-12-01

    The aim of the present study was to investigate bioprinting with electrospraying technology using multiple types of human cell suspensions as bio-ink, in order to lay the initial foundations for the application of the bioprinting technology in tissue engineering. In the current study, six types of human cells were selected and cultured, including human fibroblasts, human adipose-derived stem cells (hADSCs), human periodontal ligament cells (HPDLCs), adult human retinal pigment epithelial cells (ARPE-19), human umbilical vascular endothelial cells (HUVECs) and human gastric epithelial cell line (GES-1). Each cell type was divided into two groups, the experimental and control group. All the experimental group cells were electrosprayed using an electrospraying printer (voltage, 15 kV; flow rate, 150 µl/min) and collected in a petri dish placed 15 cm away from the needle (needle diameter, 0.5 mm). Subsequently, cell viability was detected by flow cytometry with a Live/Dead Viability kit. In addition, the cell morphological characteristics were observed with a phase-contrast microscope after 6 h of culturing in order to obtain adherent cells, while cell proliferation was analyzed using a Cell Counting Kit-8 assay. The control groups, without printing, were subjected to the same procedures as the experimental groups. The results of the cell viability and proliferation assays indicated a statistically significant difference after printing between the experiments and control groups only for the hADSCs (P0.05). In addition, there were no observable differences between all experimental and the control groups at any examined time point in the terms of cell morphological characteristics. In conclusion, bioprinting based on electrospraying technology demonstrated no distinct negative effect on cell vitality, proliferation and morphology in the present study, and thus the application of this novel technology to cell printing may provide a promising method in tissue engineering.

  10. A Case of Mature Natural Killer-Cell Neoplasm Manifesting Multiple Choroidal Lesions: Primary Intraocular Natural Killer-Cell Lymphoma

    Yoshiaki Tagawa

    2015-11-01

    Full Text Available Purpose: Natural killer (NK cell neoplasm is a rare disease that follows an acute course and has a poor prognosis. It usually emerges from the nose and appears in the ocular tissue as a metastasis. Herein, we describe a case of NK-cell neoplasm in which the eye was considered to be the primary organ. Case: A 50-year-old female displayed bilateral anterior chamber cells, vitreous opacity, bullous retinal detachment, and multiple white choroidal mass lesions. Although malignant lymphoma or metastatic tumor was suspected, various systemic examinations failed to detect any positive results. A vitrectomy was performed OS; however, histocytological analyses from the vitreous sample showed no definite evidence of malignancy, and IL-10 concentration was low. Enlarged choroidal masses were fused together. Three weeks after the first visit, the patient suddenly developed an attack of fever, night sweat, and hepatic dysfunction, and 5 days later, she passed away due to multiple organ failure. Immunohistochemisty and in situ hybridization revealed the presence of atypical cells positive for CD3, CD56, and Epstein-Barr virus-encoded RNAs, resulting in the diagnosis of NK-cell neoplasm. With the characteristic clinical course, we concluded that this neoplasm was a primary intraocular NK-cell lymphoma. Conclusions: This is the first report to describe primary intraocular NK-cell neoplasm. When we encounter atypical choroidal lesions, we should consider the possibility of NK-cell lymphoma, even though it is a rare disease.

  11. High Throughput Single-cell and Multiple-cell Micro-encapsulation

    Lagus, Todd P.; Edd, Jon F.

    2012-01-01

    Microfluidic encapsulation methods have been previously utilized to capture cells in picoliter-scale aqueous, monodisperse drops, providing confinement from a bulk fluid environment with applications in high throughput screening, cytometry, and mass spectrometry. We describe a method to not only encapsulate single cells, but to repeatedly capture a set number of cells (here we demonstrate one- and two-cell encapsulation) to study both isolation and the interactions between cells in groups of ...

  12. Modeling the effector - regulatory T cell cross-regulation reveals the intrinsic character of relapses in Multiple Sclerosis

    Torrealdea Javier

    2011-07-01

    Full Text Available Abstract Background The relapsing-remitting dynamics is a hallmark of autoimmune diseases such as Multiple Sclerosis (MS. Although current understanding of both cellular and molecular mechanisms involved in the pathogenesis of autoimmune diseases is significant, how their activity generates this prototypical dynamics is not understood yet. In order to gain insight about the mechanisms that drive these relapsing-remitting dynamics, we developed a computational model using such biological knowledge. We hypothesized that the relapsing dynamics in autoimmunity can arise through the failure in the mechanisms controlling cross-regulation between regulatory and effector T cells with the interplay of stochastic events (e.g. failure in central tolerance, activation by pathogens that are able to trigger the immune system. Results The model represents five concepts: central tolerance (T-cell generation by the thymus, T-cell activation, T-cell memory, cross-regulation (negative feedback between regulatory and effector T-cells and tissue damage. We enriched the model with reversible and irreversible tissue damage, which aims to provide a comprehensible link between autoimmune activity and clinical relapses and active lesions in the magnetic resonances studies in patients with Multiple Sclerosis. Our analysis shows that the weakness in this negative feedback between effector and regulatory T-cells, allows the immune system to generate the characteristic relapsing-remitting dynamics of autoimmune diseases, without the need of additional environmental triggers. The simulations show that the timing at which relapses appear is highly unpredictable. We also introduced targeted perturbations into the model that mimicked immunotherapies that modulate effector and regulatory populations. The effects of such therapies happened to be highly dependent on the timing and/or dose, and on the underlying dynamic of the immune system. Conclusion The relapsing dynamic in MS

  13. Petiveria alliacea extracts uses multiple mechanisms to inhibit growth of human and mouse tumoral cells

    Urue?a, Claudia; Cifuentes, Claudia; Casta?eda, Diana; Arango, Amparo; Kaur, Punit; Asea, Alexzander; Fiorentino, Susana

    2008-01-01

    Abstract Background There is ethnopharmacological evidence that Petiveria alliacea can have antitumor activity; however, the mechanism of its cytotoxic activity is not well understood. We assessed multiple in vitro biological activities of an ethyl acetate soluble plant fraction over several tumor cell lines. Methods Tumor cell lines were evaluated using the following tests: trypan blue exclusion test, MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide], flow cytometry, cytosk...

  14. Effects of Voltage-Gated K+ Channel on Cell Proliferation in Multiple Myeloma

    Wei Wang

    2014-01-01

    Full Text Available Objective. To study the effects and underlying mechanisms of voltage-gated K+ channels on the proliferation of multiple myeloma cells. Methods. RPMI-8226 MM cell line was used for the experiments. Voltage-gated K+ currents and the resting potential were recorded by whole-cell patch-clamp technique. RT-PCR detected Kv channel mRNA expression. Cell viability was analyzed with MTT assay. Cell counting system was employed to monitor cell proliferation. DNA contents and cell volume were analyzed by flow cytometry. Results. Currents recorded in RPMI-8226 cells were confirmed to be voltage-gated K+ channels. A high level of Kv1.3 mRNA was detected but no Kv3.1 mRNA was detected in RPMI-8226 cells. Voltage-gated K+ channel blocker 4-aminopyridine (4-AP (2 mM depolarized the resting potential from −42 ± 1.7 mV to −31.8 ± 2.8 mV (P0.05. Conclusions. In RPMI-8226, voltage-gated K+ channels are involved in proliferation and cell cycle progression its influence on the resting potential and cell volume may be responsible for this process; the inhibitory effect of the voltage-gated K+ channel blocker on RPMI-8226 cell proliferation is a phase-specific event.

  15. Psychological well-being in people with multiple sclerosis in an Iranian population

    Dehnavi, Sedigheh Rezaei; Heidarian, Fatemeh; Ashtari, Fereshteh; Shaygannejad, Vahid

    2015-01-01

    Background: To date, few results on well-being in individuals with neurological disease have been published, while several studies in other groups have indicated that well-being may not be the only absence of psychological distress, but also positive psychological function. The aim of the present study was to compare the psychological well-being (PWB) between the people with Multiple sclerosis (MS) and normal individuals and identify correlated demographic factors to PWB in people with MS dis...

  16. Population-based colorectal cancer screening by fecal immunochemical testing over multiple rounds

    van der Vlugt, M.

    2017-01-01

    Colorectal cancer (CRC) is one of the major causes of death in the Netherlands, accounting for over 5100 deaths in 2015. Population screening aims to detect CRC or its precursors, advanced adenoma, in an early phase, thereby reducing CRC morbidity and mortality. A recent observational study

  17. Establishing multiple omics baselines for three Southeast Asian populations in the Singapore Integrative Omics Study.

    Saw, Woei-Yuh; Tantoso, Erwin; Begum, Husna; Zhou, Lihan; Zou, Ruiyang; He, Cheng; Chan, Sze Ling; Tan, Linda Wei-Lin; Wong, Lai-Ping; Xu, Wenting; Moong, Don Kyin Nwe; Lim, Yenly; Li, Bowen; Pillai, Nisha Esakimuthu; Peterson, Trevor A; Bielawny, Tomasz; Meikle, Peter J; Mundra, Piyushkumar A; Lim, Wei-Yen; Luo, Ma; Chia, Kee-Seng; Ong, Rick Twee-Hee; Brunham, Liam R; Khor, Chiea-Chuen; Too, Heng Phon; Soong, Richie; Wenk, Markus R; Little, Peter; Teo, Yik-Ying

    2017-09-21

    The Singapore Integrative Omics Study provides valuable insights on establishing population reference measurement in 364 Chinese, Malay, and Indian individuals. These measurements include > 2.5 millions genetic variants, 21,649 transcripts expression, 282 lipid species quantification, and 284 clinical, lifestyle, and dietary variables. This concept paper introduces the depth of the data resource, and investigates the extent of ethnic variation at these omics and non-omics biomarkers. It is evident that there are specific biomarkers in each of these platforms to differentiate between the ethnicities, and intra-population analyses suggest that Chinese and Indians are the most biologically homogeneous and heterogeneous, respectively, of the three groups. Consistent patterns of correlations between lipid species also suggest the possibility of lipid tagging to simplify future lipidomics assays. The Singapore Integrative Omics Study is expected to allow the characterization of intra-omic and inter-omic correlations within and across all three ethnic groups through a systems biology approach.The Singapore Genome Variation projects characterized the genetics of Singapore's Chinese, Malay, and Indian populations. The Singapore Integrative Omics Study introduced here goes further in providing multi-omic measurements in individuals from these populations, including genetic, transcriptome, lipidome, and lifestyle data, and will facilitate the study of common diseases in Asian communities.

  18. Imaging of multiple myeloma and related monoclonal plasma cell diseases. An update

    Weber, Marc-Andre; Delorme, Stefan; Hillengass, Jens

    2014-01-01

    Multiple myeloma is a hematologic disorder characterized by the infiltration and proliferation of monoclonal plasma cells mainly in the bone marrow. The main symptoms are hypercalcemia, renal impairment, cytopenia/anemia and bone disease - summarized as CRAB-criteria. Symptomatic multiple myeloma is consistently preceded by asymptomatic premalignant stages called monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Staging of multiple myeloma is based on the measurement of the monoclonal protein in serum and urine as well as the assessment of impairment of hematopoiesis, renal function and mineralized bone. In the last decade the development of novel therapeutic agents has led to an increase in response rates and survival time of patients with multiple myeloma, which further stresses the value of response assessment by imaging. Cross sectional imaging like MRI and CT is currently replacing conventional radiological surveys in the initial work-up and follow-up of patients with monoclonal plasma cell diseases. The added value of MRI is to improve initial staging by unraveling a diffuse infiltration of bone marrow by plasma cells, a focal pattern or a combination of both. Furthermore, a complete remission of myeloma confirmed by MRI and CT goes along with a better prognosis compared to a complete response based only on serological parameters.

  19. Yessotoxin as a Tool to Study Induction of Multiple Cell Death Pathways

    Mónica Suárez Korsnes

    2012-07-01

    Full Text Available This work proposes to use the marine algal toxin yessotoxin (YTX to establish reference model experiments to explore medically valuable effects from induction of multiple cell death pathways. YTX is one of few toxins reported to make such induction. It is a small molecule compound which at low concentrations can induce apoptosis in primary cultures, many types of cells and cell lines. It can also induce a non-apoptotic form of programmed cell death in BC3H1 myoblast cell lines. The present contribution reviews arguments that this type of induction may have principal interest outside this particular example. One principal effect of medical interest may be that cancer cells will not so easily adapt to the synergistic effects from induction of more than one death pathway as compared to induction of only apoptosis.

  20. Raman spectroscopy differentiates between sensitive and resistant multiple myeloma cell lines

    Franco, Domenico; Trusso, Sebastiano; Fazio, Enza; Allegra, Alessandro; Musolino, Caterina; Speciale, Antonio; Cimino, Francesco; Saija, Antonella; Neri, Fortunato; Nicolò, Marco S.; Guglielmino, Salvatore P. P.

    2017-12-01

    Current methods for identifying neoplastic cells and discerning them from their normal counterparts are often nonspecific and biologically perturbing. Here, we show that single-cell micro-Raman spectroscopy can be used to discriminate between resistant and sensitive multiple myeloma cell lines based on their highly reproducible biomolecular spectral signatures. In order to demonstrate robustness of the proposed approach, we used two different cell lines of multiple myeloma, namely MM.1S and U266B1, and their counterparts MM.1R and U266/BTZ-R subtypes, resistant to dexamethasone and bortezomib, respectively. Then, micro-Raman spectroscopy provides an easily accurate and noninvasive method for cancer detection for both research and clinical environments. Characteristic peaks, mostly due to different DNA/RNA ratio, nucleic acids, lipids and protein concentrations, allow for discerning the sensitive and resistant subtypes. We also explored principal component analysis (PCA) for resistant cell identification and classification. Sensitive and resistant cells form distinct clusters that can be defined using just two principal components. The identification of drug-resistant cells by confocal micro-Raman spectroscopy is thus proposed as a clinical tool to assess the development of resistance to glucocorticoids and proteasome inhibitors in myeloma cells.

  1. Endothelial Progenitor Cell Fraction Contained in Bone Marrow-Derived Mesenchymal Stem Cell Populations Impairs Osteogenic Differentiation

    Fabian Duttenhoefer

    2015-01-01

    Full Text Available In bone tissue engineering (TE endothelial cell-osteoblast cocultures are known to induce synergies of cell differentiation and activity. Bone marrow mononucleated cells (BMCs are a rich source of mesenchymal stem cells (MSCs able to develop an osteogenic phenotype. Endothelial progenitor cells (EPCs are also present within BMC. In this study we investigate the effect of EPCs present in the BMC population on MSCs osteogenic differentiation. Human BMCs were isolated and separated into two populations. The MSC population was selected through plastic adhesion capacity. EPCs (CD34+ and CD133+ were removed from the BMC population and the resulting population was named depleted MSCs. Both populations were cultured over 28 days in osteogenic medium (Dex+ or medium containing platelet lysate (PL. MSC population grew faster than depleted MSCs in both media, and PL containing medium accelerated the proliferation for both populations. Cell differentiation was much higher in Dex+ medium in both cases. Real-time RT-PCR revealed upregulation of osteogenic marker genes in depleted MSCs. Higher values of ALP activity and matrix mineralization analyses confirmed these results. Our study advocates that absence of EPCs in the MSC population enables higher osteogenic gene expression and matrix mineralization and therefore may lead to advanced bone neoformation necessary for TE constructs.

  2. What Population Reveals about Individual Cell Identity: Single-Cell Parameter Estimation of Models of Gene Expression in Yeast.

    Artémis Llamosi

    2016-02-01

    Full Text Available Significant cell-to-cell heterogeneity is ubiquitously observed in isogenic cell populations. Consequently, parameters of models of intracellular processes, usually fitted to population-averaged data, should rather be fitted to individual cells to obtain a population of models of similar but non-identical individuals. Here, we propose a quantitative modeling framework that attributes specific parameter values to single cells for a standard model of gene expression. We combine high quality single-cell measurements of the response of yeast cells to repeated hyperosmotic shocks and state-of-the-art statistical inference approaches for mixed-effects models to infer multidimensional parameter distributions describing the population, and then derive specific parameters for individual cells. The analysis of single-cell parameters shows that single-cell identity (e.g. gene expression dynamics, cell size, growth rate, mother-daughter relationships is, at least partially, captured by the parameter values of gene expression models (e.g. rates of transcription, translation and degradation. Our approach shows how to use the rich information contained into longitudinal single-cell data to infer parameters that can faithfully represent single-cell identity.

  3. N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation

    Groen, Richard W. J.; de Rooij, Martin F. M.; Kocemba, Kinga A.; Reijmers, Rogier M.; de Haan-Kramer, Anneke; Overdijk, Marije B.; Aalders, Linda; Rozemuller, Henk; Martens, Anton C. M.; Bergsagel, P. Leif; Kersten, Marie José; Pals, Steven T.; Spaargaren, Marcel

    2011-01-01

    Multiple myeloma is a hematologic malignancy characterized by a clonal expansion of malignant plasma cells in the bone marrow, which is accompanied by the development of osteolytic lesions and/or diffuse osteopenia. The intricate bi-directional interaction with the bone marrow microenvironment plays

  4. N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation

    Groen, R.W.J.; de Rooij, M.F.M.; Kocemba, K.A.; Reijmers, R.M.; de Haan-Kramer, A.; Overdijk, M.B.; Aalders, L.; Rozemuller, H.; Martens, A.C.M.; Bergsagel, P.L.; Kersten, M.J.; Pals, S.T.; Spaargaren, M.

    2011-01-01

    Background Multiple myeloma is a hematologic malignancy characterized by a clonal expansion of malignant plasma cells in the bone marrow, which is accompanied by the development of osteolytic lesions and/or diffuse osteopenia. The intricate bi-directional interaction with the bone marrow

  5. Two tickets to paradise: multiple dispersal events in the founding of hoary bat populations in Hawai'i

    Russell, Amy L.; Pinzari, Corinna A.; Vonhof, Maarten J.; Olival, Kevin J.; Bonaccorso, Frank

    2015-01-01

    The Hawaiian islands are an extremely isolated oceanic archipelago, and their fauna has long served as models of dispersal in island biogeography. While molecular data have recently been applied to investigate the timing and origin of dispersal events for several animal groups including birds, insects, and snails, these questions have been largely unaddressed in Hawai'i's only native terrestrial mammal, the Hawaiian hoary bat, Lasiurus cinereus semotus. Here, we use molecular data to test the hypotheses that (1) Hawaiian L. c. semotus originated via dispersal from North American populations of L. c. cinereus rather than from South American L. c. villosissimus, and (2) modern Hawaiian populations were founded from a single dispersal event. Contrary to the latter hypothesis, our mitochondrial data support a biogeographic history of multiple, relatively recent dispersals of hoary bats from North America to the Hawaiian islands. Coalescent demographic analyses of multilocus data suggest that modern populations of Hawaiian hoary bats were founded no more than 10 kya. Our finding of multiple evolutionarily significant units in Hawai'i highlights information that should be useful for re-evaluation of the conservation status of hoary bats in Hawai'i.

  6. Optimization of carrier multiplication for more effcient solar cells: the case of Sn quantum dots.

    Allan, Guy; Delerue, Christophe

    2011-09-27

    We present calculations of impact ionization rates, carrier multiplication yields, and solar-power conversion efficiencies in solar cells based on quantum dots (QDs) of a semimetal, α-Sn. Using these results and previous ones on PbSe and PbS QDs, we discuss a strategy to select QDs with the highest carrier multiplication rate for more efficient solar cells. We suggest using QDs of materials with a close to zero band gap and a high multiplicity of the bands in order to favor the relaxation of photoexcited carriers by impact ionization. Even in that case, the improvement of the maximum solar-power conversion efficiency appears to be a challenging task. © 2011 American Chemical Society

  7. Population pharmacokinetics of artesunate and dihydroartemisinin following single- and multiple-dosing of oral artesunate in healthy subjects

    Kirsch Lee E

    2009-12-01

    Full Text Available Abstract Background The population pharmacokinetics of artesunate (AS and its active metabolite dihydroartemisinin (DHA were studied in healthy subjects receiving single- or multiple-dosing of AS orally either in combination with pyronaridine (PYR or as a monotherapy with or without food. Methods Data from 118 concentration-time profiles arising from 91 healthy Korean subjects were pooled from four Phase I clinical studies. Subjects received 2-5 mg/kg of single- and multiple-dosing of oral AS either in combination with PYR or as a monotherapy with or without food. Plasma AS and DHA were measured simultaneously using a validated liquid chromatography- mass spectrometric method with a lower limit of quantification of 1 ng/mL for both AS and DHA. Nonlinear mixed-effect modelling was used to obtain the pharmacokinetic and variability (inter-individual and residual variability parameter estimates. Results A novel parent-metabolite pharmacokinetic model consisting of a dosing compartment, a central compartment for AS, a central compartment and a peripheral compartment for DHA was developed. AS and DHA data were modelled simultaneously assuming stoichiometric conversion to DHA. AS was rapidly absorbed with a population estimate of absorption rate constant (Ka of 3.85 h-1. The population estimates of apparent clearance (CL/F and volume of distribution (V2/F for AS were 1190 L/h with 36.2% inter-individual variability (IIV and 1210 L with 57.4% IIV, respectively. For DHA, the population estimates of apparent clearance (CLM/F and central volume of distribution (V3/F were 93.7 L/h with 28% IIV and 97.1 L with 30% IIV, respectively. The population estimates of apparent inter-compartmental clearance (Q/F and peripheral volume of distribution (V4/F for DHA were 5.74 L/h and 18.5 L, respectively. Intake of high-fat and high-caloric meal prior to the drug administration resulted in 84% reduction in Ka. Body weight impacted CLM/F, such that a unit change in

  8. Characterization of γδ regulatory T cells from peripheral blood in patients with multiple myeloma

    Ma, Yongyong; Lei, Huyi; Tan, Jie; Xuan, Li; Wu, Xiuli; Liu, Qifa

    2016-01-01

    γδ regulatory T cells are able to inhibit the activation and function of T cells involved in antigen-specific immune responses. This study aimed to investigate the potential role of γδ regulatory T cells in inhibiting anti-tumor immune responses in patients diagnosed as multiple myeloma (MM). We measured the levels of γδ T cells, the distribution and clonally amplified TCR Vγ and VδT cells in peripheral blood of healthy donors, patients recently diagnosed with MM, and MM patients in remission cohorts. In addition, we evaluated the ability of γδ regulatory T cells to inhibit the proliferation of CD4+CD25- T cells and detected the expression of immunoregulatory-associated molecules. We found that the levels of γδ regulatory T cells from the peripheral blood in patients of MM were significantly higher than those in healthy donors. Comparison of γδT regulatory cells function in MM and healthy donors showed similarly inhibitory effects on the proliferation of T cells. Additionally, TLR8 expression level increased significantly in MM patients compared to healthy donors, while the expression levels of Foxp3, CD25, CTLA4, GITR, GATA3 and Tbet in MM patients and healthy donors showed no significant difference. Taken together, our study reveals the potential role of γδ regulatory T cells in inhibiting anti-tumor immune responses in MM patients.

  9. Targeting poly (ADP-ribose polymerase partially contributes to bufalin-induced cell death in multiple myeloma cells.

    He Huang

    Full Text Available Despite recent pharmaceutical advancements in therapeutic drugs, multiple myeloma (MM remains an incurable disease. Recently, ploy(ADP-ribose polymerase 1 (PARP1 has been shown as a potentially promising target for MM therapy. A previous report suggested bufalin, a component of traditional Chinese medicine ("Chan Su", might target PARP1. However, this hypothesis has not been verified. We here showed that bufalin could inhibit PARP1 activity in vitro and reduce DNA-damage-induced poly(ADP-ribosylation in MM cells. Molecular docking analysis revealed that the active site of bufalin interaction is within the catalytic domain of PAPR1. Thus, PARP1 is a putative target of bufalin. Furthermore, we showed, for the first time that the proliferation of MM cell lines (NCI-H929, U266, RPMI8226 and MM.1S and primary CD138(+ MM cells could be inhibited by bufalin, mainly via apoptosis and G2-M phase cell cycle arrest. MM cell apoptosis was confirmed by apoptotic cell morphology, Annexin-V positive cells, and the caspase3 activation. We further evaluated the role of PARP1 in bufalin-induced apoptosis, discovering that PARP1 overexpression partially suppressed bufalin-induced cell death. Moreover, bufalin can act as chemosensitizer to enhance the cell growth-inhibitory effects of topotecan, camptothecin, etoposide and vorinostat in MM cells. Collectively, our data suggest that bufalin is a novel PARP1 inhibitor and a potentially promising therapeutic agent against MM alone or in combination with other drugs.

  10. The genealogy of sequences containing multiple sites subject to strong selection in a subdivided population.

    Nordborg, Magnus; Innan, Hideki

    2003-03-01

    A stochastic model for the genealogy of a sample of recombining sequences containing one or more sites subject to selection in a subdivided population is described. Selection is incorporated by dividing the population into allelic classes and then conditioning on the past sizes of these classes. The past allele frequencies at the selected sites are thus treated as parameters rather than as random variables. The purpose of the model is not to investigate the dynamics of selection, but to investigate effects of linkage to the selected sites on the genealogy of the surrounding chromosomal region. This approach is useful for modeling strong selection, when it is natural to parameterize the past allele frequencies at the selected sites. Several models of strong balancing selection are used as examples, and the effects on the pattern of neutral polymorphism in the chromosomal region are discussed. We focus in particular on the statistical power to detect balancing selection when it is present.

  11. Global Existence Analysis of Cross-Diffusion Population Systems for Multiple Species

    Chen, Xiuqing; Daus, Esther S.; Jüngel, Ansgar

    2018-02-01

    The existence of global-in-time weak solutions to reaction-cross-diffusion systems for an arbitrary number of competing population species is proved. The equations can be derived from an on-lattice random-walk model with general transition rates. In the case of linear transition rates, it extends the two-species population model of Shigesada, Kawasaki, and Teramoto. The equations are considered in a bounded domain with homogeneous Neumann boundary conditions. The existence proof is based on a refined entropy method and a new approximation scheme. Global existence follows under a detailed balance or weak cross-diffusion condition. The detailed balance condition is related to the symmetry of the mobility matrix, which mirrors Onsager's principle in thermodynamics. Under detailed balance (and without reaction) the entropy is nonincreasing in time, but counter-examples show that the entropy may increase initially if detailed balance does not hold.

  12. Homeostasis of peripheral CD4+ T cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers

    Almeida, Afonso R. M.; Legrand, Nicolas; Papiernik, Martine; Freitas, António A.

    2002-01-01

    We show that the lymphoid hyperplasia observed in IL-2Ralpha- and IL-2-deficient mice is due to the lack of a population of regulatory cells essential for CD4 T cell homeostasis. In chimeras reconstituted with bone marrow cells from IL-2Ralpha-deficient donors, restitution of a population of

  13. Male behaviors reveal multiple pherotypes within vine mealybug Planococcus ficus (Signoret) (Hemiptera; Pseudococcidae) populations

    Kol-Maimon, Hofit; Levi-Zada, Anat; Franco, José Carlos; Dunkelblum, Ezra; Protasov, Alex; Eliyaho, Miriam; Mendel, Zvi

    2010-12-01

    The vine mealybug (VM) females collected in Israel produce two sex pheromone compounds: lavandulyl senecioate (LS) and ( S)-lavandulyl isovalerate (LI). The males display ambiguous behavior to LI: repulsion in the vineyard and attraction of laboratory-reared males. We addressed the question of individual male behavior, i.e., do males respond to both LS and LI, or might they display a distinct response to each of the two pheromone compounds. We compared male pherotype frequencies between wild-caught and laboratory-reared populations. Then, we examined the relationship between pherotype composition and male capture rates in pheromone traps. Finally, we addressed the heredity of the pherotypes. The Israeli VM populations contain nine different male pherotypes, as defined according to the male behavior to pheromone compounds. The studied Portuguese populations included five of the nine pherotypes; none of the Portuguese males were attracted to LI. It seems that the high frequency of males that were attracted to LI is related to dense VM populations. It is hypothesized that selection for the male pherotypes, I males, those that respond to LI, occur under high-density rearing conditions. This may result from shorter development times of males and females that produce more I male pherotypes. The lower relative frequency of trapping of males in LI-baited traps than expected from the percentage determined in a Petri dish arena suggests that males that respond solely to LS (S males) are better fliers. The results also suggest that the pherotype trait is inherited by both sexes of the VM.

  14. Forecasting the Relative and Cumulative Effects of Multiple Stressors on At-risk Populations

    2011-08-01

    applied to model populations of Ord’s kangaroo rat, Spotted Owls, and elk. Although the model was recently demonstrated to members of the DoD...C. C. Peterson, I. R. Wallis, K. H. Berry, and K. A. Nagy. 1998. Effects of climatic variation on field metabolism and water relations of desert...simulation experiment with endangered kangaroo rats. International Association for Landscape Ecology Annual Meeting, April 2009. A. 2 A. 3

  15. Clinical Features in a Danish Population-Based Cohort of Probable Multiple System Atrophy Patients

    Starhof, Charlotte; Korbo, Lise; Lassen, Christina Funch

    2016-01-01

    Background: Multiple system atrophy (MSA) is a rare, sporadic and progressive neurodegenerative disorder. We aimed to describe the clinical features of Danish probable MSA patients, evaluate their initial response to dopaminergic therapy and examine mortality. Methods: From the Danish National...... the criteria for probable MSA. We recorded clinical features, examined differences by MSA subtype and used Kaplan-Meier survival analysis to examine mortality. Results: The mean age at onset of patients with probable MSA was 60.2 years (range 36-75 years) and mean time to wheelchair dependency was 4.7 years...

  16. Multiple Ethnic Origins of Mitochondrial DNA Lineages for the Population of Mauritius

    Betancor, Eva; Suárez, Nicolás M.; Calaon, Diego; Čaval, Saša; Janoo, Anwar; Pestano, Jose

    2014-01-01

    This article reports on the first genetic assessment of the contemporary Mauritian population. Small island nodes such as Mauritius played a critical role in historic globalization processes and revealing high-resolution details of labour sourcing is crucial in order to better understand early-modern diaspora events. Mauritius is a particularly interesting case given detailed historic accounts attesting to European (Dutch, French and British), African and Asian points of origin. Ninety-seven samples were analysed for mitochondrial DNA to begin unravelling the complex dynamics of the island's modern population. In corroboration with general demographic information, the majority of maternal lineages were derived from South Asia (58.76%), with Malagasy (16.60%), East/Southeast Asian (11.34%) and Sub-Saharan African (10.21%) also making significant contributions. This study pinpoints specific regional origins for the South Asian genetic contribution, showing a greater influence on the contemporary population from northern and southeast India. Moreover, the analysis of lineages related to the slave trade demonstrated that Madagascar and East Asia were the main centres of origin, with less influence from West Africa. PMID:24676463

  17. Stem cell mobilization with cyclophosphamide overcomes the suppressive effect of lenalidomide therapy on stem cell collection in multiple myeloma.

    Mark, Tomer; Stern, Jessica; Furst, Jessica R; Jayabalan, David; Zafar, Faiza; LaRow, April; Pearse, Roger N; Harpel, John; Shore, Tsiporah; Schuster, Michael W; Leonard, John P; Christos, Paul J; Coleman, Morton; Niesvizky, Ruben

    2008-07-01

    A total of 28 treatment-naïve patients with stage II or III multiple myeloma (MM) were treated with the combination of clarithromycin, lenalidomide, and dexamethasone (BiRD). Stem cells were collected following granulocyte-colony stimulating factor (G-CSF) or cyclophosphamide (Cy) plus G-CSF mobilization at maximum response. Sufficient stem cells for 2 autologous stem cell transplants were collected from all patients mobilized with Cy plus G-CSF, versus 33% mobilized with G-CSF alone (P < .0001). The duration of prior lenalidomide therapy did not correlate with success of stem cell harvests (P = .91). In conclusion, Cy can be added to G-CSF for stem cell mobilization to successfully overcome the suppressive effect of prior treatment with lenalidomide.

  18. Gemcitabine radiosensitizes multiple myeloma cells to low let, but not high let, irradiation

    Supiot, Stephane; Thillays, Francois; Rio, Emmanuel; Gouard, Sebastien; Morgenstern, Alfred; Bruchertseifer, Frank; Mahe, Marc-Andre; Chatal, Jean-Francois; Davodeau, Francois; Cherel, Michel

    2007-01-01

    The radiosensitizing properties of gemcitabine in relation to low Linear Energy Transfer (LET) particles (Cobalt 60) and high-LET particles (alpha-RIT 213 Bi-radiolabeled CHX-DTPA-B-B4) were analyzed. Three multiple myeloma cell lines (LP1, RPMI 8226, U266) were irradiated with or without 10 nM gemcitabine 24 h prior to radiation. Gemcitabine led to radiosensitization of LP1 and U266 cells with low-LET (Radiation Enhancement Ratio: 1.55 and 1.49, respectively) but did not radiosensitize any cell line when combined with high-LET

  19. Multiple growth hormone-binding proteins are expressed on insulin-producing cells

    Møldrup, A; Billestrup, N; Thorn, N A

    1989-01-01

    The insulin-producing rat islet tumor cell line, RIN-5AH, expresses somatogen binding sites and responds to GH by increased proliferation and insulin production. Affinity cross-linking shows that RIN-5AH cells contain two major GH-binding subunits of Mr 100-130K (110K), which appear to exist as d....... It is concluded that the RIN-5AH cells have multiple GH-binding proteins which may mediate signals for either proliferation and/or insulin production....

  20. Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle.

    Feillet, Céline; Krusche, Peter; Tamanini, Filippo; Janssens, Roel C; Downey, Mike J; Martin, Patrick; Teboul, Michèle; Saito, Shoko; Lévi, Francis A; Bretschneider, Till; van der Horst, Gijsbertus T J; Delaunay, Franck; Rand, David A

    2014-07-08

    Daily synchronous rhythms of cell division at the tissue or organism level are observed in many species and suggest that the circadian clock and cell cycle oscillators are coupled. For mammals, despite known mechanistic interactions, the effect of such coupling on clock and cell cycle progression, and hence its biological relevance, is not understood. In particular, we do not know how the temporal organization of cell division at the single-cell level produces this daily rhythm at the tissue level. Here we use multispectral imaging of single live cells, computational methods, and mathematical modeling to address this question in proliferating mouse fibroblasts. We show that in unsynchronized cells the cell cycle and circadian clock robustly phase lock each other in a 1:1 fashion so that in an expanding cell population the two oscillators oscillate in a synchronized way with a common frequency. Dexamethasone-induced synchronization reveals additional clock states. As well as the low-period phase-locked state there are distinct coexisting states with a significantly higher period clock. Cells transition to these states after dexamethasone synchronization. The temporal coordination of cell division by phase locking to the clock at a single-cell level has significant implications because disordered circadian function is increasingly being linked to the pathogenesis of many diseases, including cancer.

  1. Pro-apoptotic protein Noxa regulates memory T cell population size and protects against lethal immunopathology

    Wensveen, Felix M.; Klarenbeek, Paul L.; van Gisbergen, Klaas P. J. M.; Pascutti, Maria F.; Derks, Ingrid A. M.; van Schaik, Barbera D. C.; ten Brinke, Anja; de Vries, Niek; Cekinovic, Durdica; Jonjic, Stipan; van Lier, René A. W.; Eldering, Eric

    2013-01-01

    Memory T cells form a highly specific defense layer against reinfection with previously encountered pathogens. In addition, memory T cells provide protection against pathogens that are similar, but not identical to the original infectious agent. This is because each T cell response harbors multiple

  2. A sub-population of circulating porcine gammadelta T cells can act as professional antigen presenting cells.

    Takamatsu, H-H; Denyer, M S; Wileman, T E

    2002-09-10

    A sub-population of circulating porcine gammadelta T cells express cell surface antigens associated with antigen presenting cells (APCs), and are able to take up soluble antigen very effectively. Functional antigen presentation by gammadelta T cells to memory helper T cells was studied by inbred pig lymphocytes immunised with ovalbumin (OVA). After removing all conventional APCs from the peripheral blood of immunised pigs, the remaining lymphocytes still proliferated when stimulated with OVA. When gammadelta T cells were further depleted, OVA specific proliferation was abolished, but reconstitution with gammadelta T cells restored proliferation. The proliferation was blocked by monoclonal antibodies (mAb) against MHC class II or CD4, and by pre-treatment of gammadelta T cells with chloroquine. These results indicate that a sub-population of circulating porcine gammadelta T cells act as APCs and present antigen via MHC class II.

  3. Influence of Multiple Infection and Relatedness on Virulence: Disease Dynamics in an Experimental Plant Population and Its Castrating Parasite

    Buono, Lorenza; López-Villavicencio, Manuela; Shykoff, Jacqui A.; Snirc, Alodie; Giraud, Tatiana

    2014-01-01

    The level of parasite virulence, i.e., the decrease in host's fitness due to a pathogen, is expected to depend on several parameters, such as the type of the disease (e.g., castrating or host-killing) and the prevalence of multiple infections. Although these parameters have been extensively studied theoretically, few empirical data are available to validate theoretical predictions. Using the anther smut castrating disease on Silene latifolia caused by Microbotryum lychnidis-dioicae, we studied the dynamics of multiple infections and of different components of virulence (host death, non-recovery and percentage of castrated stems) during the entire lifespan of the host in an experimental population. We monitored the number of fungal genotypes within plants and their relatedness across five years, using microsatellite markers, as well as the rates of recovery and host death in the population. The mean relatedness among genotypes within plants remained at a high level throughout the entire host lifespan despite the dynamics of the disease, with recurrent new infections. Recovery was lower for plants with multiple infections compared to plants infected by a single genotype. As expected for castrating parasites, M. lychnidis-dioicae did not increase host mortality. Mortality varied across years but was generally lower for plants that had been diseased the preceding year. This is one of the few studies to have empirically verified theoretical expectations for castrating parasites, and to show particularly i) that castrated hosts live longer, suggesting that parasites can redirect resources normally used in reproduction to increase host lifespan, lengthening their transmission phase, and ii) that multiple infections increase virulence, here in terms of non-recovery and host castration. PMID:24892951

  4. Apoptotic effects of non-edible parts of Punica granatum on human multiple myeloma cells.

    Kiraz, Yağmur; Neergheen-Bhujun, Vidushi S; Rummun, Nawraj; Baran, Yusuf

    2016-02-01

    Multiple myeloma is of great concern since existing therapies are unable to cure this clinical condition. Alternative therapeutic approaches are mandatory, and the use of plant extracts is considered interesting. Punica granatum and its derived products were suggested as potential anticancer agents due to the presence of bioactive compounds. Thus, polypenolic-rich extracts of the non-edible parts of P. granatum were investigated for their antiproliferative and apoptotic effects on U266 multiple myeloma cells. We demonstrated that there were dose-dependent decreases in the proliferation of U266 cells in response to P. granatum extracts. Also, exposure to the extracts triggered apoptosis with significant increases in loss of mitochondrial membrane potential in U266 cells exposed to the leaves and stem extracts, while the flower extract resulted in slight increases in loss of MMP. These results were confirmed by Annexin-V analysis. These results documented the cytotoxic and apoptotic effects of P. granatum extracts on human U266 multiple myeloma cells via disruption of mitochondrial membrane potential and increasing cell cycle arrest. The data suggest that the extracts can be envisaged in cancer chemoprevention and call for further exploration into the potential application of these plant parts.

  5. A Population of Very-Hot Super-Earths in Multiple-Planet Systems Should be Uncovered by Kepler

    Schlaufman, Kevin C.; Lin, D. N. C.; Ida, S.

    2010-01-01

    We simulate a Kepler-like observation of a theoretical exoplanet population and we show that the observed orbital period distribution of the Kepler giant planet candidates is best matched by an average stellar specific dissipation function Q_* in the interval 10^6 ~< Q_* ~< 10^7. In that situation, the few super-Earths that are driven to orbital periods P < 1 day by dynamical interactions in multiple-planet systems will survive tidal disruption for a significant fraction of the main-sequence ...

  6. The influence of pregnancy on disability from multiple sclerosis: a population-based study in Middlesex County, Ontario.

    Weinshenker, B G; Hader, W; Carriere, W; Baskerville, J; Ebers, G C

    1989-11-01

    We analyzed the effect of pregnancy on long-term disability resulting from multiple sclerosis in 185 women ascertained through a retrospective population-based survey of MS in Middlesex County, Ontario, Canada. There was no association between disability and total number of term pregnancies, timing of pregnancy relative to onset of MS, or either onset or worsening of MS in relation to a pregnancy. The mean number of pregnancies both before and after onset of MS was no different among groups stratified according to disability. This study addresses some of the difficulties inherent in studying the effect of pregnancy on disability resulting from MS.

  7. Survival and Functionality of Human Induced Pluripotent Stem Cell-Derived Oligodendrocytes in a Nonhuman Primate Model for Multiple Sclerosis

    Thiruvalluvan, Arun; Czepiel, Marcin; Kap, Yolanda A.; Mantingh-Otter, Ietje; Vainchtein, Ilia; Kuipers, Jeroen; Bijlard, Marjolein; Baron, Wia; Giepmans, Ben; Brueck, Wolfgang; 'T Hart, Bert A.; Boddeke, Erik; Copray, Sjef

    2016-01-01

    : Fast remyelination by endogenous oligodendrocyte precursor cells (OPCs) is essential to prevent axonal and subsequent retrograde neuronal degeneration in demyelinating lesions in multiple sclerosis (MS). In chronic lesions, however, the remyelination capacity of OPCs becomes insufficient. Cell

  8. CD146/MCAM defines functionality of human bone marrow stromal stem cell populations

    Harkness, Linda; Zaher, Walid; Ditzel, Nicholas

    2016-01-01

    BACKGROUND: Identification of surface markers for prospective isolation of functionally homogenous populations of human skeletal (stromal, mesenchymal) stem cells (hMSCs) is highly relevant for cell therapy protocols. Thus, we examined the possible use of CD146 to subtype a heterogeneous hMSC...... population. METHODS: Using flow cytometry and cell sorting, we isolated two distinct hMSC-CD146(+) and hMSC-CD146(-) cell populations from the telomerized human bone marrow-derived stromal cell line (hMSC-TERT). Cells were examined for differences in their size, shape and texture by using high...... and adipocytes on the basis of gene expression and protein production of lineage-specific markers. In vivo, hMSC-CD146(+) and hMSC-CD146(-) cells formed bone and bone marrow organ when implanted subcutaneously in immune-deficient mice. Bone was enriched in hMSC-CD146(-) cells (12.6 % versus 8.1 %) and bone...

  9. Genotyping of human lice suggests multiple emergencies of body lice from local head louse populations.

    Wenjun Li

    Full Text Available BACKGROUND: Genetic analyses of human lice have shown that the current taxonomic classification of head lice (Pediculus humanus capitis and body lice (Pediculus humanus humanus does not reflect their phylogenetic organization. Three phylotypes of head lice A, B and C exist but body lice have been observed only in phylotype A. Head and body lice have different behaviours and only the latter have been involved in outbreaks of infectious diseases including epidemic typhus, trench fever and louse borne recurrent fever. Recent studies suggest that body lice arose several times from head louse populations. METHODS AND FINDINGS: By introducing a new genotyping technique, sequencing variable intergenic spacers which were selected from louse genomic sequence, we were able to evaluate the genotypic distribution of 207 human lice. Sequence variation of two intergenic spacers, S2 and S5, discriminated the 207 lice into 148 genotypes and sequence variation of another two intergenic spacers, PM1 and PM2, discriminated 174 lice into 77 genotypes. Concatenation of the four intergenic spacers discriminated a panel of 97 lice into 96 genotypes. These intergenic spacer sequence types were relatively specific geographically, and enabled us to identify two clusters in France, one cluster in Central Africa (where a large body louse outbreak has been observed and one cluster in Russia. Interestingly, head and body lice were not genetically differentiated. CONCLUSIONS: We propose a hypothesis for the emergence of body lice, and suggest that humans with both low hygiene and head louse infestations provide an opportunity for head louse variants, able to ingest a larger blood meal (a required characteristic of body lice, to colonize clothing. If this hypothesis is ultimately supported, it would help to explain why poor human hygiene often coincides with outbreaks of body lice. Additionally, if head lice act as a reservoir for body lice, and that any social degradation in

  10. CALCULUS FROM THE PAST: MULTIPLE DELAY SYSTEMS ARISING IN CANCER CELL MODELLING

    WAKE, G. C.; BYRNE, H. M.

    2013-01-01

    Nonlocal calculus is often overlooked in the mathematics curriculum. In this paper we present an interesting new class of nonlocal problems that arise from modelling the growth and division of cells, especially cancer cells, as they progress through the cell cycle. The cellular biomass is assumed to be unstructured in size or position, and its evolution governed by a time-dependent system of ordinary differential equations with multiple time delays. The system is linear and taken to be autonomous. As a result, it is possible to reduce its solution to that of a nonlinear matrix eigenvalue problem. This method is illustrated by considering case studies, including a model of the cell cycle developed recently by Simms, Bean and Koeber. The paper concludes by explaining how asymptotic expressions for the distribution of cells across the compartments can be determined and used to assess the impact of different chemotherapeutic agents. Copyright © 2013 Australian Mathematical Society.

  11. Characterization of annual disease progression of multiple sclerosis patients: A population-based study

    Freilich, Jonatan; Manouchehrinia, Ali; Trusheim, Mark

    2017-01-01

    Previous research characterizing factors influencing multiple sclerosis (MS) disease progression has typically been based on time to disease milestones (Kaplan-Meier, Cox hazard regression, etc.). A limitation of these methods is the handling of the often large groups of patients not reaching...... the milestone. To characterize clinical factors influencing MS disease progression as annual transitions from each Expanded Disability Status Scale (EDSS). The annual progression of 11,964 patients from the Swedish MS Registry was analysed with 10 multinomial logistic regressions, that is, one for transition...... from each full EDSS with explanatory variables age, sex, age at onset, time in current EDSS, highest prior EDSS, MS course and treatment. All factors (except sex) investigated had statistically significant impacts on transitions from at least one EDSS. However, significance and size of the effect...

  12. Patterns of cervical coinfection with multiple human papilloma virus types in a screening population in Denmark

    Goldman, Bryan; Rebolj, Matejka; Rygaard, Carsten

    2013-01-01

    Patterns of cervical human papillomavirus (HPV) infection suggest that HPV genotypes are not independent of each other. This may be explained by risk factors common to all HPV infections, but type-specific biological factors may also play a role. This raises the question of whether widespread use...... of the quadrivalent vaccine (covering HPV6, 11, 16, 18) may indirectly affect the prevalence of any non-vaccine types. Routine screening samples from 5014 Danish women were tested for 35 HPV genotypes (including 13 high-risk) using the Genomica CLART(®) HPV2 kit, which is a low-density microarray based on PCR...... amplification. Simulation studies were performed both under independence between genotypes and under a common dependence structure as would arise from common risk factors, and simulation results were compared to observed coinfection patterns. Overall HPV prevalence was 37.4%, with multiple infections in 17...

  13. 3-Bromopyruvate inhibits cell proliferation and induces apoptosis in CD133+ population in human glioma.

    Xu, Dong-Qiang; Tan, Xiao-Yu; Zhang, Bao-Wei; Wu, Tao; Liu, Ping; Sun, Shao-Jun; Cao, Yin-Guang

    2016-03-01

    The study was aimed to investigate the role of 3-bromopyruvate in inhibition of CD133+ U87 human glioma cell population growth. The results demonstrated that 3-bromopyruvate inhibited the viability of both CD133+ and parental cells derived from U87 human glioma cell line. However, the 3-bromopyruvate-induced inhibition in viability was more prominent in CD133+ cells at 10 μM concentration after 48 h. Treatment of CD133+ cells with 3-bromopyruvate caused reduction in cell population and cell size, membrane bubbling, and degradation of cell membranes. Hoechst 33258 staining showed condensation of chromatin material and fragmentation of DNA in treated CD133+ cells after 48 h. 3-Bromopyruvate inhibited the migration rate of CD133+ cells significantly compared to the parental cells. Flow cytometry revealed that exposure of CD133+ cells to 3-bromopyruvate increased the cell population in S phase from 24.5 to 37.9 % with increase in time from 12 to 48 h. In addition, 3-bromopyruvate significantly enhanced the expression of Bax and cleaved caspase 3 in CD133+ cells compared to the parental cells. Therefore, 3-bromopyruvate is a potent chemotherapeutic agent for the treatment of glioma by targeting stem cells selectively.

  14. Detection and characterization of side population in Ewing's sarcoma SK-ES-1 cells in vitro

    Yang, Min; Zhang, Rui; Yan, Ming; Ye, Zhengxu; Liang, Wei; Luo, Zhuojing

    2010-01-01

    Dye exclusion is a valuable technique to isolate cancer stem cells (CSCs) based on an ability of stem cell to efflux fluorescent DNA-binding dye, especially for tumors without unique surface markers. It has been proven that side population (SP) cells that exclude Hoechst 33342 dye are enriched with stem-like cells in several cancer cell lines. In this study, we isolated and characterized SP cells from human Ewing's sarcoma cell line SK-ES-1 in vitro. SP cells were detected in SK-ES-1 and comprised 1.2% of total cell population. Only SP cells had the capacity to regenerate both SP and non-SP cells. The proliferation rates were similar between SP and non-SP cells. However, the clonogenicity and invasiveness of SP cells were significantly higher than that of non-SP cells. Further characterization of this SP phenotype presented other properties. SP cells exhibited increased multi-drug resistance and the ATP binding cassette protein (ABC) transporters were up-regulated in SP population. These findings suggest that SP cells derived from Ewing's sarcoma play the critical role in tumor metastasis and recurrence and might be an ideal target for clinical therapy.

  15. Multiple maternal origins of native modern and ancient horse populations in China.

    Lei, C Z; Su, R; Bower, M A; Edwards, C J; Wang, X B; Weining, S; Liu, L; Xie, W M; Li, F; Liu, R Y; Zhang, Y S; Zhang, C M; Chen, H

    2009-12-01

    To obtain more knowledge of the origin and genetic diversity of domestic horses in China, this study provides a comprehensive analysis of mitochondrial DNA (mtDNA) D-loop sequence diversity from nine horse breeds in China in conjunction with ancient DNA data and evidence from archaeological and historical records. A 247-bp mitochondrial D-loop sequence from 182 modern samples revealed a total of 70 haplotypes with a high level of genetic diversity. Seven major mtDNA haplogroups (A-G) and 16 clusters were identified for the 182 Chinese modern horses. In the present study, nine 247-bp mitochondrial D-loop sequences of ancient remains of Bronze Age horse from the Chifeng region of Inner Mongolia in China (c. 4000-2000a bp) were used to explore the origin and diversity of Chinese modern horses and the phylogenetic relationship between ancient and modern horses. The nine ancient horses carried seven haplotypes with rich genetic diversity, which were clustered together with modern individuals among haplogroups A, E and F. Modern domestic horse and ancient horse data support the multiple origins of domestic horses in China. This study supports the argument that multiple successful events of horse domestication, including separate introductions of wild mares into the domestic herds, may have occurred in antiquity, and that China cannot be excluded from these events. Indeed, the association of Far Eastern mtDNA types to haplogroup F was highly significant using Fisher's exact test of independence (P = 0.00002), lending support for Chinese domestication of this haplogroup. High diversity and all seven mtDNA haplogroups (A-G) with 16 clusters also suggest that further work is necessary to shed more light on horse domestication in China.

  16. Quality of life after multiple trauma: validation and population norm of the Polytrauma Outcome (POLO) chart.

    Lefering, R; Tecic, T; Schmidt, Y; Pirente, N; Bouillon, B; Neugebauer, E

    2012-08-01

    Due to an increasing number of survivors after multiple injuries in Western countries, the health-related quality of life (QoL) is considered to be an important outcome parameter. Up to now, measuring instruments used in this field lacked validity and comparability. Within 6 years, our working group developed a new modular instrument, called the Polytrauma Outcome (POLO) chart. This study documents the validation of the trauma-specific module specifically designed for trauma patients, the Trauma Outcome Profile (TOP). A total of 172 multiply injured patients (mean Injury Severity Score [ISS] 26.7) recruited from eight trauma centres participating in the German Trauma Registry were compared with 166 marginally injured patients (mean ISS 3.9). The mean follow-up was 24.2 and 26.4 months, respectively. The validation questionnaires used were the Beck Depression Inventory (BDI), the State-Trait Anxiety Inventory (STAI), Impact of Event Scale-Revised (IES-R), Social Support Questionnaire (F-SOZU-K-22), Barthel Index of Activities of Daily Living (ADL) and the Short Form Health Survey (SF-36). The internal consistency of the different dimensions of QoL assessed with the TOP was good. Factor analysis provides evidence of the construct validity of the questionnaire. Correlation with external measures gives evidence of criterion validity for the various dimensions of QoL and similar exceedance of proposed cut-off points within TOP and external measures is verified. The TOP module is a reliable and valid instrument to assess health-related QoL in patients with multiple injuries. It can be used stand-alone or as part of the POLO chart together with the Glasgow Outcome Scale (GOS), the EuroQoL and the SF-36 as a regular systematic follow-up instrument.

  17. Multiple transfused thalassemia major: Ocular manifestations in a hospital-based population

    Taneja Rashi

    2010-01-01

    Full Text Available Purpose: To study the ocular manifestations in multiple transfused beta-thalassemia major patients and assess the ocular side-effects of iron chelating agents. Materials and Methods: In this prospective observational study, 45 multiple transfused beta-thalassemia major children between six months and 21 years of age were enrolled and assigned groups according to the treatment regimens suggested. Group A received only blood transfusions, Group B blood transfusions with subcutaneous desferrioxamine, Group C blood transfusions with desferrioxamine and oral deferriprone and Group D blood transfusions with deferriprone. Ocular status at the time of enrolment was documented. Subjects were observed quarterly for one year for changes in ocular status arising due to the disease process and due to iron chelation therapy. Children with hemoglobinopathies other than beta-thalassemia major, congenital ocular anomalies and anemia due to other causes were excluded. Results: Ocular involvement was observed in 58% of patients. Lenticular opacities were the most common ocular finding (44%, followed by decreased visual acuity (33%. An increased occurrence of ocular changes was observed with increase of serum ferritin and serum iron levels as well as with higher number of blood transfusions received. Desferrioxamine seemed to have a protective influence on retinal pigment epithelium (RPE mottling. Occurrence of lenticular opacities and RPE degeneration correlated positively with use of desferrioxamine and deferriprone respectively. Follow-up of patients for one year did not reveal any change in ocular status. Conclusion: Regular ocular examinations can aid in preventing, delaying or ameliorating the ocular complications of thalassemia.

  18. Genetic Factors Associated with Risk and Disability Progression of Multiple Sclerosis in Slovak Population

    Hanysova Sandra

    2017-08-01

    Full Text Available Objective: The aim of our study was to determine the relation of particular genetic variants in selected genes (GSTM1, GSTT1 null genotypes; rs1695 GSTP1; rs10735781 EVI5 to the risk of multiple sclerosis (MS development and find out the possible association with disease disability progression rate. Material and methods: Our study included 202 MS patients and 174 healthy control volunteers. MS patients were divided according to disability progression rate to three groups - slowly progressing, mid-rate progressing and rapidly progressing. All DNA samples were isolated from venous blood. Genotyping was performed by PCR-RFLP and multiplex PCR. Results: Our analysis showed that GSTT1 null genotype (OR 0.56; 95%CI 0.33 -0.95; p=0.04 and GSTM1, GSTT1 double null genotype (OR 0.32; 95%CI 0.14 - 0.74; p=0.006 are potentially protective in relation to MS. We observed similar result in GSTT1 null genotype in association with mid-rate progression (OR 0.48; 95%CI 0.24 - 0.97; p=0.05. Frequency of GSTM1 and GSTT1 double null genotype is significantly lower in subgroup of MS patients with progression rate defined as slow (OR 0.22; 95%CI 0.05 - 0.98; p=0.05 and middle (OR 0.33; 95%CI 0.11 - 0.99; p=0.045. We did not show any significant association of genetic changes rs1695 in GSTP1 and rs10735781 in EVI5 with MS or rate of disease progression. Conclusions: Genetic basis of multiple sclerosis is still not fully elucidated. Further research may clarify our results and confirm the value of studied factors for clinical practice.

  19. Factors Influencing Quality of Life for Disabled and Nondisabled Elderly Population: The Results of a Multiple Correspondence Analysis

    M. Avolio

    2013-01-01

    Full Text Available Objectives. The aim of our study is to examine the role of some factors (sociodemographic patterns, social relationship support, and trust in healthcare actors on structure of quality of life among the Italian elderly population, by stratifying according to presence or absence of disability. Methods. Using data of the Italian National Institute of Statistics (ISTAT survey, we obtained a sample of 25,183 Italian people aged 65+ years. Multiple Correspondence Analysis (MCA was used to test such a relationship. Results. By applying the MCA between disabled and nondisabled elderly population, we identified three dimensions: “demographic structure and social contacts,” “social relationships,” “trust in the Italian National Health Services (INHS.” Furthermore, the difference in trust on the INHS and its actors was seen among disabled and non-disabled elderly population. Conclusions. Knowledge on the concept of quality of life and its application to the elderly population either with or without disability should make a difference in both people’s life and policies and practices affecting life. New domains, such as information and trusting relationships both within and towards the care network’s nodes, are likely to play an important role in this relationship.

  20. Antidepressant Drug Treatment in Association with Multiple Sclerosis Disease-Modifying Therapy: Using Explorys in the MS Population.

    Mirsky, Matthew M; Marrie, Ruth Ann; Rae-Grant, Alexander

    2016-01-01

    Background: The Explorys Enterprise Performance Management (EPM) database contains de-identified clinical data for 50 million patients. Multiple sclerosis (MS) disease-modifying therapies (DMTs), specifically interferon beta (IFNβ) treatments, may potentiate depression. Conflicting data have emerged, and a large-scale claims-based study by Patten et al. did not support such an association. This study compares the results of Patten et al. with those using the EPM database. Methods: "Power searches" were built to test the relationship between antidepressant drug use and DMT in the MS population. Searches were built to produce a cohort of individuals diagnosed as having MS in the past 3 years taking a specific DMT who were then given any antidepressant drug. The antidepressant drug therapy prevalence was tested in the MS population on the following DMTs: IFNβ-1a, IFNβ-1b, combined IFNβ, glatiramer acetate, natalizumab, fingolimod, and dimethyl fumarate. Results: In patients with MS, the rate of antidepressant drug use in those receiving DMTs was 40.60% to 44.57%. The rate of antidepressant drug use for combined IFNβ DMTs was 41.61% (males: 31.25%-39.62%; females: 43.10%-47.33%). Antidepressant drug use peaked in the group aged 45 to 54 years for five of six DMTs. Conclusions: We found no association between IFNβ treatment and antidepressant drug use in the MS population compared with other DMTs. The EPM database has been validated against the Patten et al. data for future use in the MS population.

  1. Reducing bias in population and landscape genetic inferences: the effects of sampling related individuals and multiple life stages.

    Peterman, William; Brocato, Emily R; Semlitsch, Raymond D; Eggert, Lori S

    2016-01-01

    In population or landscape genetics studies, an unbiased sampling scheme is essential for generating accurate results, but logistics may lead to deviations from the sample design. Such deviations may come in the form of sampling multiple life stages. Presently, it is largely unknown what effect sampling different life stages can have on population or landscape genetic inference, or how mixing life stages can affect the parameters being measured. Additionally, the removal of siblings from a data set is considered best-practice, but direct comparisons of inferences made with and without siblings are limited. In this study, we sampled embryos, larvae, and adult Ambystoma maculatum from five ponds in Missouri, and analyzed them at 15 microsatellite loci. We calculated allelic richness, heterozygosity and effective population sizes for each life stage at each pond and tested for genetic differentiation (F ST and D C ) and isolation-by-distance (IBD) among ponds. We tested for differences in each of these measures between life stages, and in a pooled population of all life stages. All calculations were done with and without sibling pairs to assess the effect of sibling removal. We also assessed the effect of reducing the number of microsatellites used to make inference. No statistically significant differences were found among ponds or life stages for any of the population genetic measures, but patterns of IBD differed among life stages. There was significant IBD when using adult samples, but tests using embryos, larvae, or a combination of the three life stages were not significant. We found that increasing the ratio of larval or embryo samples in the analysis of genetic distance weakened the IBD relationship, and when using D C , the IBD was no longer significant when larvae and embryos exceeded 60% of the population sample. Further, power to detect an IBD relationship was reduced when fewer microsatellites were used in the analysis.

  2. A genetics-based approach confirms immune associations with life history across multiple populations of an aquatic vertebrate (Gasterosteus aculeatus).

    Whiting, James R; Magalhaes, Isabel S; Singkam, Abdul R; Robertson, Shaun; D'Agostino, Daniele; Bradley, Janette E; MacColl, Andrew D C

    2018-06-20

    Understanding how wild immune variation covaries with other traits can reveal how costs and trade-offs shape immune evolution in the wild. Divergent life history strategies may increase or alleviate immune costs, helping shape immune variation in a consistent, testable way. Contrasting hypotheses suggest that shorter life histories may alleviate costs by offsetting them against increased mortality; or increase the effect of costs if immune responses are traded off against development or reproduction. We investigated the evolutionary relationship between life history and immune responses within an island radiation of three-spined stickleback, with discrete populations of varying life histories and parasitism. We sampled two short-lived, two long-lived and an anadromous population using qPCR to quantify current immune profile and RAD-seq data to study the distribution of immune variants within our assay genes and across the genome. Short-lived populations exhibited significantly increased expression of all assay genes, which was accompanied by a strong association with population-level variation in local alleles and divergence in a gene that may be involved in complement pathways. In addition, divergence around the eda gene in anadromous fish is likely associated with increased inflammation. A wider analysis of 15 populations across the island revealed that immune genes across the genome show evidence of having diverged alongside life history strategies. Parasitism and reproductive investment were also important sources of variation for expression, highlighting the caution required when assaying immune responses in the wild. These results provide strong, gene-based support for current hypotheses linking life history and immune variation across multiple populations of a vertebrate model. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  3. Reducing bias in population and landscape genetic inferences: the effects of sampling related individuals and multiple life stages

    William Peterman

    2016-03-01

    Full Text Available In population or landscape genetics studies, an unbiased sampling scheme is essential for generating accurate results, but logistics may lead to deviations from the sample design. Such deviations may come in the form of sampling multiple life stages. Presently, it is largely unknown what effect sampling different life stages can have on population or landscape genetic inference, or how mixing life stages can affect the parameters being measured. Additionally, the removal of siblings from a data set is considered best-practice, but direct comparisons of inferences made with and without siblings are limited. In this study, we sampled embryos, larvae, and adult Ambystoma maculatum from five ponds in Missouri, and analyzed them at 15 microsatellite loci. We calculated allelic richness, heterozygosity and effective population sizes for each life stage at each pond and tested for genetic differentiation (FST and DC and isolation-by-distance (IBD among ponds. We tested for differences in each of these measures between life stages, and in a pooled population of all life stages. All calculations were done with and without sibling pairs to assess the effect of sibling removal. We also assessed the effect of reducing the number of microsatellites used to make inference. No statistically significant differences were found among ponds or life stages for any of the population genetic measures, but patterns of IBD differed among life stages. There was significant IBD when using adult samples, but tests using embryos, larvae, or a combination of the three life stages were not significant. We found that increasing the ratio of larval or embryo samples in the analysis of genetic distance weakened the IBD relationship, and when using DC, the IBD was no longer significant when larvae and embryos exceeded 60% of the population sample. Further, power to detect an IBD relationship was reduced when fewer microsatellites were used in the analysis.

  4. A stem cell medium containing neural stimulating factor induces a pancreatic cancer stem-like cell-enriched population

    WATANABE, YUSAKU; YOSHIMURA, KIYOSHI; YOSHIKAWA, KOICHI; TSUNEDOMI, RYOICHI; SHINDO, YOSHITARO; MATSUKUMA, SOU; MAEDA, NORIKO; KANEKIYO, SHINSUKE; SUZUKI, NOBUAKI; KURAMASU, ATSUO; SONODA, KOUHEI; TAMADA, KOJI; KOBAYASHI, SEI; SAYA, HIDEYUKI; HAZAMA, SHOICHI; OKA, MASAAKI

    2014-01-01

    Cancer stem cells (CSCs) have been studied for their self-renewal capacity and pluripotency, as well as their resistance to anticancer therapy and their ability to metastasize to distant organs. CSCs are difficult to study because their population is quite low in tumor specimens. To overcome this problem, we established a culture method to induce a pancreatic cancer stem-like cell (P-CSLC)-enriched population from human pancreatic cancer cell lines. Human pancreatic cancer cell lines established at our department were cultured in CSC-inducing media containing epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), leukemia inhibitory factor (LIF), neural cell survivor factor-1 (NSF-1), and N-acetylcysteine. Sphere cells were obtained and then transferred to a laminin-coated dish and cultured for approximately two months. The surface markers, gene expression, aldehyde dehydrogenase (ALDH) activity, cell cycle, and tumorigenicity of these induced cells were examined for their stem cell-like characteristics. The population of these induced cells expanded within a few months. The ratio of CD24high, CD44high, epithelial specific antigen (ESA) high, and CD44variant (CD44v) high cells in the induced cells was greatly enriched. The induced cells stayed in the G0/G1 phase and demonstrated mesenchymal and stemness properties. The induced cells had high tumorigenic potential. Thus, we established a culture method to induce a P-CSLCenriched population from human pancreatic cancer cell lines. The CSLC population was enriched approximately 100-fold with this method. Our culture method may contribute to the precise analysis of CSCs and thus support the establishment of CSC-targeting therapy. PMID:25118635

  5. Use of Pearson's Chi-Square for Testing Equality of Percentile Profiles across Multiple Populations.

    Johnson, William D; Beyl, Robbie A; Burton, Jeffrey H; Johnson, Callie M; Romer, Jacob E; Zhang, Lei

    2015-08-01

    In large sample studies where distributions may be skewed and not readily transformed to symmetry, it may be of greater interest to compare different distributions in terms of percentiles rather than means. For example, it may be more informative to compare two or more populations with respect to their within population distributions by testing the hypothesis that their corresponding respective 10 th , 50 th , and 90 th percentiles are equal. As a generalization of the median test, the proposed test statistic is asymptotically distributed as Chi-square with degrees of freedom dependent upon the number of percentiles tested and constraints of the null hypothesis. Results from simulation studies are used to validate the nominal 0.05 significance level under the null hypothesis, and asymptotic power properties that are suitable for testing equality of percentile profiles against selected profile discrepancies for a variety of underlying distributions. A pragmatic example is provided to illustrate the comparison of the percentile profiles for four body mass index distributions.

  6. Imbalance of placental regulatory T cell and Th17 cell population dynamics in the FIV-infected pregnant cat

    Boudreaux Crystal E

    2012-05-01

    Full Text Available Abstract Background An appropriate balance in placental regulatory T cells (Tregs, an immunosuppressive cell population, and Th17 cells, a pro-inflammatory cell population, is essential in allowing tolerance of the semi-allogeneic fetus. TGF-β and IL-6 are cytokines that promote differentiation of Tregs and Th17 cells from a common progenitor; aberrant expression of the cytokines may perturb the balance in the two cell populations. We previously reported a pro-inflammatory placental environment with decreased levels of FoxP3, a Treg marker, and increased levels of IL-6 in the placentas of FIV-infected cats at early pregnancy. Thus, we hypothesized that FIV infection in the pregnant cat causes altered placental Treg and Th17 cell populations, possibly resulting in placental inflammation. Methods We examined the effect of FIV infection on Treg and Th17 populations in placentas at early pregnancy using quantitative confocal microscopy to measure FoxP3 or RORγ, a Th17 marker, and qPCR to quantify expression of the key cytokines TGF-β and IL-6. Results FoxP3 and RORγ were positively correlated in FIV-infected placentas at early pregnancy, but not placentas from normal cats, indicating virus-induced alteration in the balance of these cell populations. In control cats the expression of IL-6 and RORγ was positively correlated as predicted, but this relationship was disrupted in infected animals. TGF-β was reduced in infected queens, an occurrence that could dysregulate both Treg and Th17 cell populations. Co-expression analyses revealed a highly significant positive correlation between IL-6 and TGF-β expression in control animals that did not occur in infected animals. Conclusion Collectively, these data point toward potential disruption in the balance of Treg and Th17 cell populations that may contribute to FIV-induced inflammation in the feline placenta.

  7. Variants in multiple genes polymorphism association analysis of COPD in the Chinese Li population

    Ding Y

    2015-07-01

    Full Text Available Yipeng Ding,1,* Danlei Yang,2,3,* Long Zhou,4 Junxu Xu,5 Yu Chen,5 Ping He,1 Jinjian Yao,1 Jiannan Chen,1 Huan Niu,1 Pei Sun,1 Tianbo Jin4 1Department of Emergency, People’s Hospital of Hainan Province, Haikou, Hainan, 2Department of Respiratory and Critical Care Medicine, Tongji Hospital, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Medical College, 3Department of Science and Technology, Huazhong University, Wuhan, 4School of Life Sciences, Northwest University, Xi’an, 5Department of Respiration Emergency, The Third People’s Hospital of Haikou, Haikou, Hainan, People’s Republic of China *These authors contributed equally to this work Background: It is known that the contribution of risk alleles to chronic obstructive pulmonary disease (COPD may vary between populations. Further, previous studies involving various ethnic groups have revealed associations between COPD and genetic polymorphisms in families with sequence similarity 13, member A (FAM13A, micro-RNA 2054 (MIR2054, SET domain containing protein 7 (SETD7, ring finger protein 150 (RNF150, hedgehog interacting protein (HHIP, and vascular endothelial growth factor A (VEGFA. Our objective was to explore the association between these gene polymorphism and COPD in members of Chinese Li minority population.Materials and methods: The Chinese Li population case–control study was conducted to assess genetic associations with COPD risk. Seven single nucleotide polymorphisms (SNPs located on chromosome 4, including FAM13A, MIR2054, SETD7, RNF150, and HHIP, and nine SNPs in the VEGFA gene were genotyped among 234 cases and 240 controls using Sequenom Mass-ARRAY® platform. Linkage disequilibrium (LD analysis was performed using Haploview software and the associations of the SNP frequencies with COPD were analyzed using chi-square (χ2 tests, genetic models analysis, and haplotype analysis.Results: By χ2 we found the minor allele “G” of rs17050782 was with increased

  8. Cell surface glycan engineering of neural stem cells augments neurotropism and improves recovery in a murine model of multiple sclerosis

    Merzaban, Jasmeen S.

    2015-09-13

    Neural stem cell (NSC)-based therapies offer potential for neural repair in central nervous system (CNS) inflammatory and degenerative disorders. Typically, these conditions present with multifocal CNS lesions making it impractical to inject NSCs locally, thus mandating optimization of vascular delivery of the cells to involved sites. Here, we analyzed NSCs for expression of molecular effectors of cell migration and found that these cells are natively devoid of E-selectin ligands. Using glycosyltransferase-programmed stereosubstitution (GPS), we glycan engineered the cell surface of NSCs ("GPS-NSCs") with resultant enforced expression of the potent E-selectin ligand HCELL (hematopoietic cell E-/L-selectin ligand) and of an E-selectin-binding glycoform of neural cell adhesion molecule ("NCAM-E"). Following intravenous (i.v.) injection, short-term homing studies demonstrated that, compared with buffer-treated (control) NSCs, GPS-NSCs showed greater neurotropism. Administration of GPS-NSC significantly attenuated the clinical course of experimental autoimmune encephalomyelitis (EAE), with markedly decreased inflammation and improved oligodendroglial and axonal integrity, but without evidence of long-term stem cell engraftment. Notably, this effect of NSC is not a universal property of adult stem cells, as administration of GPS-engineered mouse hematopoietic stem/progenitor cells did not improve EAE clinical course. These findings highlight the utility of cell surface glycan engineering to boost stem cell delivery in neuroinflammatory conditions and indicate that, despite the use of a neural tissue-specific progenitor cell population, neural repair in EAE results from endogenous repair and not from direct, NSC-derived cell replacement.

  9. Transforming growth factor alpha (TGFα regulates granulosa cell tumor (GCT cell proliferation and migration through activation of multiple pathways.

    Cheng Wang

    Full Text Available Granulosa cell tumors (GCTs are the most common ovarian estrogen producing tumors, leading to symptoms of excessive estrogen such as endometrial hyperplasia and endometrial adenocarcinoma. These tumors have malignant potential and often recur. The etiology of GCT is unknown. TGFα is a potent mitogen for many different cells. However, its function in GCT initiation, progression and metastasis has not been determined. The present study aims to determine whether TGFα plays a role in the growth of GCT cells. KGN cells, which are derived from an invasive GCT and have many features of normal granulosa cells, were used as the cellular model. Immunohistochemistry, Western blot and RT-PCR results showed that the ErbB family of receptors is expressed in human GCT tissues and GCT cell lines. RT-PCR results also indicated that TGFα and EGF are expressed in the human granulosa cells and the GCT cell lines, suggesting that TGFα might regulate GCT cell function in an autocrine/paracrine manner. TGFα stimulated KGN cell DNA synthesis, cell proliferation, cell viability, cell cycle progression, and cell migration. TGFα rapidly activated EGFR/PI3K/Akt and mTOR pathways, as indicated by rapid phosphorylation of Akt, TSC2, Rictor, mTOR, P70S6K and S6 proteins following TGFα treatment. TGFα also rapidly activated the EGFR/MEK/ERK pathway, and P38 MAPK pathways, as indicated by the rapid phosphorylation of EGFR, MEK, ERK1/2, P38, and CREB after TGFα treatment. Whereas TGFα triggered a transient activation of Akt, it induced a sustained activation of ERK1/2 in KGN cells. Long-term treatment of KGN cells with TGFα resulted in a significant increase in cyclin D2 and a decrease in p27/Kip1, two critical regulators of granulosa cell proliferation and granulosa cell tumorigenesis. In conclusion, TGFα, via multiple signaling pathways, regulates KGN cell proliferation and migration and may play an important role in the growth and metastasis of GCTs.

  10. Single Cell Dynamics Causes Pareto-Like Effect in Stimulated T Cell Populations.

    Cosette, Jérémie; Moussy, Alice; Onodi, Fanny; Auffret-Cariou, Adrien; Neildez-Nguyen, Thi My Anh; Paldi, Andras; Stockholm, Daniel

    2015-12-09

    Cell fate choice during the process of differentiation may obey to deterministic or stochastic rules. In order to discriminate between these two strategies we used time-lapse microscopy of individual murine CD4 + T cells that allows investigating the dynamics of proliferation and fate commitment. We observed highly heterogeneous division and death rates between individual clones resulting in a Pareto-like dominance of a few clones at the end of the experiment. Commitment to the Treg fate was monitored using the expression of a GFP reporter gene under the control of the endogenous Foxp3 promoter. All possible combinations of proliferation and differentiation were observed and resulted in exclusively GFP-, GFP+ or mixed phenotype clones of very different population sizes. We simulated the process of proliferation and differentiation using a simple mathematical model of stochastic decision-making based on the experimentally observed parameters. The simulations show that a stochastic scenario is fully compatible with the observed Pareto-like imbalance in the final population.

  11. An Evaluation of Population Density Mapping and Built up Area Estimates in Sri Lanka Using Multiple Methodologies

    Engstrom, R.; Soundararajan, V.; Newhouse, D.

    2017-12-01

    In this study we examine how well multiple population density and built up estimates that utilize satellite data compare in Sri Lanka. The population relationship is examined at the Gram Niladhari (GN) level, the lowest administrative unit in Sri Lanka from the 2011 census. For this study we have two spatial domains, the whole country and a 3,500km2 sub-sample, for which we have complete high spatial resolution imagery coverage. For both the entire country and the sub-sample we examine how consistent are the existing publicly available measures of population constructed from satellite imagery at predicting population density? For just the sub-sample we examine how well do a suite of values derived from high spatial resolution satellite imagery predict population density and how does our built up area estimate compare to other publicly available estimates. Population measures were obtained from the Sri Lankan census, and were downloaded from Facebook, WorldPoP, GPW, and Landscan. Percentage built-up area at the GN level was calculated from three sources: Facebook, Global Urban Footprint (GUF), and the Global Human Settlement Layer (GHSL). For the sub-sample we have derived a variety of indicators from the high spatial resolution imagery. Using deep learning convolutional neural networks, an object oriented, and a non-overlapping block, spatial feature approach. Variables calculated include: cars, shadows (a proxy for building height), built up area, and buildings, roof types, roads, type of agriculture, NDVI, Pantex, and Histogram of Oriented Gradients (HOG) and others. Results indicate that population estimates are accurate at the higher, DS Division level but not necessarily at the GN level. Estimates from Facebook correlated well with census population (GN correlation of 0.91) but measures from GPW and WorldPop are more weakly correlated (0.64 and 0.34). Estimates of built-up area appear to be reliable. In the 32 DSD-subsample, Facebook's built- up area measure

  12. Characterization of the multiple drug resistance phenotype expressed by tumour cells following in vitro exposure to fractionated X-irradiation

    Hill, B.T.; McClean, S.; Hosking, L.; Shellard, S.; Dempke, W.; Whelan, R.

    1992-01-01

    The major clinical problem of the emergence of drug resistant tumor cell populations is recognized in patients previously treated with antitumor drugs and with radiotherapy. It is proposed that, although radiation-induced vascular fibrosis may limit drug delivery to the tumor, exposure to radiation may 'induce' or 'select for' drug resistance. This hypothesis was examined by establishing in vitro model systems to investigate the resistance phenotype of tumor cells following exposure to X-rays. Characteristically tumor cells surviving exposure to a series of fractions of X-irradiation are shown to have consistently expressed resistance to multiple drugs, including the Vinca alkaloids and the epipodophyllotoxins. Currently this research is aimed at determining whether distinctive resistance mechanisms operate depending on whether resistance results following drug or X-ray exposure. Initial results indicate that whilst some common mechanisms operate, drug resistant tumor cells identified following exposure to X-irradiation appear to exhibit a novel multidrug resistance phenotype. (author). 13 refs., 1 tab

  13. Stem Cell Physics. Multiple-Laser-Beam Treatment of Parkinson's Disease

    Stefan, V.

    2013-03-01

    A novel method for the treatment of Parkinson's disease is proposed. Pluripotent stem cells are laser cultured, using ultrashort wavelength, (around 0.1 micron-ultraviolet radiation-with intensities of a few mW/cm2) , multiple laser beams.[2] The multiple-energy laser photons[3] interact with the neuron DNA molecules to be cloned. The laser created dopaminergic substantia nigra neurons can be, (theoretically), laser transplanted, (a higher focusing precision as compared to a syringe method), into the striatum or substantia nigra regions of the brain, or both. Supported by Nikola Tesla Labs, Stefan University.

  14. T cells in multiple myeloma display features of exhaustion and senescence at the tumor site

    Claudia Zelle-Rieser

    2016-11-01

    Full Text Available Abstract Background Multiple myeloma is an incurable plasma cell malignancy that is mostly restricted to the bone marrow. Cancer-induced dysfunction of cytotoxic T cells at the tumor site may be responsible for immune evasion and therapeutical failure of immunotherapies. Therefore, enhanced knowledge about the actual status of T cells in myeloma bone marrow is urgently needed. Here, we assessed the expression of inhibitory molecules PD-1, CTLA-4, 2B4, CD160, senescence marker CD57, and CD28 on T cells of naive and treated myeloma patients in the bone marrow and peripheral blood and collected data on T cell subset distribution in both compartments. In addition, T cell function concerning proliferation and expression of T-bet, IL-2, IFNγ, and CD107a was investigated after in vitro stimulation by CD3/CD28. Finally, data was compared to healthy, age-matched donor T cells from both compartments. Methods Multicolor flow cytometry was utilized for the analyses of surface molecules, intracellular staining of cytokines was also performed by flow cytometry, and proliferation was assessed by 3H-thymidine incorporation. Statistical analyses were performed utilizing unpaired T test and Mann-Whitney U test. Results We observed enhanced T cell exhaustion and senescence especially at the tumor site. CD8+ T cells expressed several molecules associated with T cell exhaustion (PD-1, CTLA-4, 2B4, CD160 and T cell senescence (CD57, lack of CD28. This phenotype was associated with lower proliferative capacity and impaired function. Despite a high expression of the transcription factor T-bet, CD8+ T cells from the tumor site failed to produce IFNγ after CD3/CD28 in vitro restimulation and displayed a reduced ability to degranulate in response to T cell stimuli. Notably, the percentage of senescent CD57+CD28− CD8+ T cells was significantly lower in treated myeloma patients when compared to untreated patients. Conclusions T cells from the bone marrow of myeloma

  15. Andrographolide inhibits multiple myeloma cells by inhibiting the TLR4/NF-κB signaling pathway.

    Gao, Hui; Wang, Jianrong

    2016-02-01

    Andrographolide is an active component from the extract of Andrographis paniculata [(Burm.f) Nees], a medicinal plant from the Acanthaceae family. Pharmacological studies have revealed that andrographolide possesses anti-bacterial, anti-inflammatory, anti-viral, immune regulatory and hepatoprotective properties, and is efficacious in the treatment of cardiovascular diseases, while exhibiting low toxicity and low cost. The present study aimed to determine the inhibitory effects of andrographolide on the growth of multiple myeloma (MM) cells and its possible impact on the Toll-like receptor (TLR)4/nuclear factor (NF)-κB signaling pathway. Cell proliferation was detected using an MTT assay, cellular apoptosis was measured using flow cytometry, and caspase-9/3 activation were assessed using colorimetric assay kits. Furthermore, TLR4 and NF-κB protein expression was determined by western blot analysis. The results revealed that andrographolide reduced the proliferation, while increasing cellular apoptosis and caspase-9/3 activation of MM cells, in addition to downregulating the expression of TLR4 and NF-κB protein. Of note, TLR4- or NF-κB-targeting small-interfering (si)RNA enhanced the andrographolide-induced inhibition of cell proliferation and induction of apoptosis of MM cells. The results of the present study therefore suggested that andrographolide inhibited multiple myeloma cells via the TLR4/NF-κB signaling pathway.

  16. Online unsupervised formation of cell assemblies for the encoding of multiple cognitive maps.

    Salihoglu, Utku; Bersini, Hugues; Yamaguchi, Yoko; Molter, Colin

    2009-01-01

    Since their introduction sixty years ago, cell assemblies have proved to be a powerful paradigm for brain information processing. After their introduction in artificial intelligence, cell assemblies became commonly used in computational neuroscience as a neural substrate for content addressable memories. However, the mechanisms underlying their formation are poorly understood and, so far, there is no biologically plausible algorithms which can explain how external stimuli can be online stored in cell assemblies. We addressed this question in a previous paper [Salihoglu, U., Bersini, H., Yamaguchi, Y., Molter, C., (2009). A model for the cognitive map formation: Application of the retroaxonal theory. In Proc. IEEE international joint conference on neural networks], were, based on biologically plausible mechanisms, a novel unsupervised algorithm for online cell assemblies' creation was developed. The procedure involved simultaneously, a fast Hebbian/anti-Hebbian learning of the network's recurrent connections for the creation of new cell assemblies, and a slower feedback signal which stabilized the cell assemblies by learning the feedforward input connections. Here, we first quantify the role played by the retroaxonal feedback mechanism. Then, we show how multiple cognitive maps, composed by a set of orthogonal input stimuli, can be encoded in the network. As a result, when facing a previously learned input, the system is able to retrieve the cognitive map it belongs to. As a consequence, ambiguous inputs which could belong to multiple cognitive maps can be disambiguated by the knowledge of the context, i.e. the cognitive map.

  17. Isolation and Multiple Differentiation Potential Assessment of Human Gingival Mesenchymal Stem Cells

    Yuan Gao

    2014-11-01

    Full Text Available The aim of this study was to isolate human mesenchymal stem cells (MSCs from the gingiva (GMSCs and confirm their multiple differentiation potentials, including the odontogenic lineage. GMSCs, periodontal ligament stem cells (PDLSCs and dermal stem cells (DSCs cultures were analyzed for cell shape, cell cycle, colony-forming unit-fibroblast (CFU-F and stem cell markers. Cells were then induced for osteogenic and adipogenic differentiation and analyzed for differentiation markers (alkaline phosphatase (ALP activity, mineralization nodule formation and Runx2, ALP, osteocalcin (OCN and collagen I expressions for the osteogenic differentiation, and lipid vacuole formation and PPARγ-2 expression for the adipogenic differentiation. Besides, the odontogenic differentiation potential of GMSCs induced with embryonic tooth germ cell-conditioned medium (ETGC-CM was observed. GMSCs, PDLSCs and DSCs were all stromal origin. PDLSCs showed much higher osteogenic differentiation ability but lower adipogenic differentiation potential than DSCs. GMSCs showed the medial osteogenic and adipogenic differentiation potentials between those of PDLSCs and DSCs. GMSCs were capable of expressing the odontogenic genes after ETGC-CM induction. This study provides evidence that GMSCs can be used in tissue engineering/regeneration protocols as an approachable stem cell source.

  18. Simultaneous Measurement of Multiple Mechanical Properties of Single Cells Using AFM by Indentation and Vibration.

    Zhang, Chuang; Shi, Jialin; Wang, Wenxue; Xi, Ning; Wang, Yuechao; Liu, Lianqing

    2017-12-01

    The mechanical properties of cells, which are the main characteristics determining their physical performance and physiological functions, have been actively studied in the fields of cytobiology and biomedical engineering and for the development of medicines. In this study, an indentation-vibration-based method is proposed to simultaneously measure the mechanical properties of cells in situ, including cellular mass (m), elasticity (k), and viscosity (c). The proposed measurement method is implemented based on the principle of forced vibration stimulated by simple harmonic force using an atomic force microscope (AFM) system integrated with a piezoelectric transducer as the substrate vibrator. The corresponding theoretical model containing the three mechanical properties is derived and used to perform simulations and calculations. Living and fixed human embryonic kidney 293 (HEK 293) cells were subjected to indentation and vibration to measure and compare their mechanical parameters and verify the proposed approach. The results that the fixed sample cells are more viscous and elastic than the living sample cells and the measured mechanical properties of cell are consistent within, but not outside of the central region of the cell, are in accordance with the previous studies. This work provides an approach to simultaneous measurement of the multiple mechanical properties of single cells using an integrated AFM system based on the principle force vibration and thickness-corrected Hertz model. This study should contribute to progress in biomedical engineering, cytobiology, medicine, early diagnosis, specific therapy and cell-powered robots.

  19. The novel immunotoxin HM1.24-ETA′ induces apoptosis in multiple myeloma cells

    Staudinger, M; Glorius, P; Burger, R; Kellner, C; Klausz, K; Günther, A; Repp, R; Klapper, W; Gramatzki, M; Peipp, M

    2014-01-01

    Despite new treatment modalities, the clinical outcome in a substantial number of patients with multiple myeloma (MM) has yet to be improved. Antibody-based targeted therapies for myeloma patients could make use of the HM1.24 antigen (CD317), a surface molecule overexpressed on malignant plasma cells and efficiently internalized. Here, a novel immunotoxin, HM1.24-ETA′, is described. HM1.24-ETA′ was generated by genetic fusion of a CD317-specific single-chain Fv (scFv) antibody and a truncated variant of Pseudomonas aeruginosa exotoxin A (ETA′). HM1.24-ETA′ inhibited growth of interleukin 6 (IL-6)-dependent and -independent myeloma cell lines. Half-maximal growth inhibition was observed at concentrations as low as 0.3 nM. Target cell killing occurred via induction of apoptosis and was unaffected in co-culture experiments with bone marrow stromal cells. HM1.24-ETA′ efficiently triggered apoptosis of freshly isolated/cryopreserved cells of patients with plasma cell leukemia and MM and was active in a preclinical severe combined immunodeficiency (SCID) mouse xenograft model. Importantly, HM1.24-ETA′ was not cytotoxic against CD317-positive cells from healthy tissue (monocytes, human umbilical vein endothelial cells). These results indicate that CD317 may represent a promising target structure for specific and efficient immunotoxin therapy for patients with plasma cell tumors

  20. Positive association of vitamin D receptor gene variations with multiple sclerosis in South East Iranian population.

    Narooie-Nejad, Mehrnaz; Moossavi, Maryam; Torkamanzehi, Adam; Moghtaderi, Ali

    2015-01-01

    Among the factors postulated to play a role in MS susceptibility, the role of vitamin D is outstanding. Since the function of vitamin D receptor (VDR) represents the effect of vitamin D on the body and genetic variations in VDR gene may affect its function, we aim to highlight the association of two VDR gene polymorphisms with MS susceptibility. In current study, we recruited 113 MS patients and 122 healthy controls. TaqI (rs731236) and ApaI (rs7975232) genetic variations in these two groups were evaluated using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. All genotype and allele frequencies in both variations showed association with the disease status. However, to find the definite connection between genetic variations in VDR gene and MS disease in a population of South East of Iran, more researches on gene structure and its function with regard to patients' conditions are required.

  1. Cytosine methylation alteration in natural populations of Leymus chinensis induced by multiple abiotic stresses.

    Yingjie Yu

    Full Text Available BACKGROUND: Human activity has a profound effect on the global environment and caused frequent occurrence of climatic fluctuations. To survive, plants need to adapt to the changing environmental conditions through altering their morphological and physiological traits. One known mechanism for phenotypic innovation to be achieved is environment-induced rapid yet inheritable epigenetic changes. Therefore, the use of molecular techniques to address the epigenetic mechanisms underpinning stress adaptation in plants is an important and challenging topic in biological research. In this study, we investigated the impact of warming, nitrogen (N addition, and warming+nitrogen (N addition stresses on the cytosine methylation status of Leymus chinensis Tzvel. at the population level by using the amplified fragment length polymorphism (AFLP, methylation-sensitive amplified polymorphism (MSAP and retrotransposon based sequence-specific amplification polymorphism (SSAP techniques. METHODOLOGY/PRINCIPAL FINDINGS: Our results showed that, although the percentages of cytosine methylation changes in SSAP are significantly higher than those in MSAP, all the treatment groups showed similar alteration patterns of hypermethylation and hypomethylation. It meant that the abiotic stresses have induced the alterations in cytosine methylation patterns, and the levels of cytosine methylation changes around the transposable element are higher than the other genomic regions. In addition, the identification and analysis of differentially methylated loci (DML indicated that the abiotic stresses have also caused targeted methylation changes at specific loci and these DML might have contributed to the capability of plants in adaptation to the abiotic stresses. CONCLUSIONS/SIGNIFICANCE: Our results demonstrated that abiotic stresses related to global warming and nitrogen deposition readily evoke alterations of cytosine methylation, and which may provide a molecular basis for rapid

  2. Cytosine Methylation Alteration in Natural Populations of Leymus chinensis Induced by Multiple Abiotic Stresses

    Yu, Yingjie; Yang, Xuejiao; Wang, Huaying; Shi, Fengxue; Liu, Ying; Liu, Jushan; Li, Linfeng; Wang, Deli; Liu, Bao

    2013-01-01

    Background Human activity has a profound effect on the global environment and caused frequent occurrence of climatic fluctuations. To survive, plants need to adapt to the changing environmental conditions through altering their morphological and physiological traits. One known mechanism for phenotypic innovation to be achieved is environment-induced rapid yet inheritable epigenetic changes. Therefore, the use of molecular techniques to address the epigenetic mechanisms underpinning stress adaptation in plants is an important and challenging topic in biological research. In this study, we investigated the impact of warming, nitrogen (N) addition, and warming+nitrogen (N) addition stresses on the cytosine methylation status of Leymus chinensis Tzvel. at the population level by using the amplified fragment length polymorphism (AFLP), methylation-sensitive amplified polymorphism (MSAP) and retrotransposon based sequence-specific amplification polymorphism (SSAP) techniques. Methodology/Principal Findings Our results showed that, although the percentages of cytosine methylation changes in SSAP are significantly higher than those in MSAP, all the treatment groups showed similar alteration patterns of hypermethylation and hypomethylation. It meant that the abiotic stresses have induced the alterations in cytosine methylation patterns, and the levels of cytosine methylation changes around the transposable element are higher than the other genomic regions. In addition, the identification and analysis of differentially methylated loci (DML) indicated that the abiotic stresses have also caused targeted methylation changes at specific loci and these DML might have contributed to the capability of plants in adaptation to the abiotic stresses. Conclusions/Significance Our results demonstrated that abiotic stresses related to global warming and nitrogen deposition readily evoke alterations of cytosine methylation, and which may provide a molecular basis for rapid adaptation by

  3. B cells are multifunctional players in multiple sclerosis pathogenesis: insights from therapeutic interventions

    Nele eClaes

    2015-12-01

    Full Text Available Multiple sclerosis (MS is a severe disease of the central nervous system (CNS characterized by autoimmune inflammation and neurodegeneration. Historically, damage to the CNS was thought to be mediated predominantly by activated pro-inflammatory T cells. B cell involvement in the pathogenesis of MS was solely attributed to autoantibody production. The first clues for the involvement of antibody-independent B cell functions in MS pathology came from positive results in clinical trials of the B cell depleting treatment rituximab in patients with relapsing-remitting (RR MS. The survival of antibody-secreting plasma cells and decrease in T cell numbers indicated the importance of other B cell functions in MS such as antigen presentation, costimulation and cytokine production. Rituximab provided us with an example of how clinical trials can lead to new research opportunities concerning B cell biology. Moreover, analysis of the antibody-independent B cell functions in MS has gained interest since these trials. Limited information is present on the effects of current immunomodulatory therapies on B cell functions, although effects of both first-line (interferon, glatiramer acetate, dimethyl fumarate and teriflunomide, second-line (fingolimod, natalizumab and even third-line (monoclonal antibody therapies treatments on B cell subtype distribution, expression of functional surface markers and secretion of different cytokines by B cells have been studied to some extent. In this review, we summarize the effects of different MS related treatments on B cell functions that have been described up to now in order to find new research opportunities and contribute to the understanding of the pathogenesis of MS.

  4. Cross-cultural adaptation and validation of the 12-item Multiple Sclerosis Walking Scale (MSWS-12 for the Brazilian population

    Bruna E. M. Marangoni

    2012-12-01

    Full Text Available Gait impairment is reported by 85% of patients with multiple sclerosis (MS as main complaint. In 2003, Hobart et al. developed a scale for walking known as The 12-item Multiple Sclerosis Walking Scale (MSWS-12, which combines the perspectives of patients with psychometric methods. OBJECTIVE: This study aimed to cross-culturally adapt and validate the MSWS-12 for the Brazilian population with MS. METHODS: This study included 116 individuals diagnosed with MS, in accordance with McDonald's criteria. The steps of the adaptation process included translation, back-translation, review by an expert committee and pretesting. A test and retest of MSWS-12/BR was made for validation, with comparison with another scale (MSIS-29/BR and another test (T25FW. RESULTS: The Brazilian version of MSWS-12/BR was shown to be similar to the original. The results indicate that MSWS-12/BR is a reliable and reproducible scale. CONCLUSIONS: MSWS-12/BR has been adapted and validated, and it is a reliable tool for the Brazilian population.

  5. Determination of the populations and structures of multiple conformers in an ensemble from NMR data: Multiple-copy refinement of nucleic acid structures using floating weights

    Goerler, Adrian; Ulyanov, Nikolai B.; James, Thomas L.

    2000-01-01

    A new algorithm is presented for determination of structural conformers and their populations based on NMR data. Restrained Metropolis Monte Carlo simulations or restrained energy minimizations are performed for several copies of a molecule simultaneously. The calculations are restrained with dipolar relaxation rates derived from measured NOE intensities via complete relaxation matrix analysis. The novel feature of the algorithm is that the weights of individual conformers are determined in every refinement step, by the quadratic programming algorithm, in such a way that the restraint energy is minimized. Its design ensures that the calculated populations of the individual conformers are based only on experimental restraints. Presence of internally inconsistent restraints is the driving force for determination of distinct multiple conformers. The method is applied to various simulated test systems. Conformational calculations on nucleic acids are carried out using generalized helical parameters with the program DNAminiCarlo. From different mixtures of A- and B-DNA, minor fractions as low as 10% could be determined with restrained energy minimization. For B-DNA with three local conformers (C2'-endo, O4'-exo, C3'-endo), the minor O4'-exo conformer could not be reliably determined using NOE data typically measured for DNA. The other two conformers, C2'-endo and C3'-endo, could be reproduced by Metropolis Monte Carlo simulated annealing. The behavior of the algorithm in various situations is analyzed, and a number of refinement protocols are discussed. Prior to application of this algorithm to each experimental system, it is suggested that the presence of internal inconsistencies in experimental data be ascertained. In addition, because the performance of the algorithm depends on the type of conformers involved and experimental data available, it is advisable to carry out test calculations with simulated data modeling each experimental system studied

  6. Characterisation of cellular adhesion reinforcement by multiple bond force spectroscopy in alveolar epithelial cells.

    Nguyen, Ngoc-Minh; Angely, Christelle; Andre Dias, Sofia; Planus, Emmanuelle; Filoche, Marcel; Pelle, Gabriel; Louis, Bruno; Isabey, Daniel

    2017-07-01

    Integrin-mediated adhesion is a key process by which cells physically connect with their environment, and express sensitivity and adaptation through mechanotransduction. A critical step of cell adhesion is the formation of the first bonds which individually generate weak contacts (∼tens pN) but can sustain thousand times higher forces (∼tens nN) when associated. We propose an experimental validation by multiple bond force spectroscopy (MFS) of a stochastic model predicting adhesion reinforcement permitted by non-cooperative, multiple bonds on which force is homogeneously distributed (called parallel bond configuration). To do so, spherical probes (diameter: 6.6 μm), specifically coated by RGD-peptide to bind integrins, are used to statically indent and homogenously stretch the multiple bonds created for short contact times (2 s) between the bead and the surface of epithelial cells (A549). Using different separation speeds (v = 2, 5, 10 μm/s) and measuring cellular Young's modulus as well as the local stiffness preceding local rupture events, we obtain cell-by-cell the effective loading rates both at the global cell level and at the local level of individual constitutive bonds. Local rupture forces are in the range: f*=60-115 pN , whereas global rupture (detachment) forces reach F*=0.8-1.7 nN . Global and local rupture forces both exhibit linear dependencies with the effective loading rate, the slopes of these two linear relationships providing an estimate of the number of independent integrin bonds constituting the tested multiple bond structure (∼12). The MFS method enables to validate the reinforcement of integrin-mediated adhesion induced by the multiple bond configuration in which force is homogeneously distributed amongst parallel bonds. Local rupture events observed in the course of a spectroscopy manoeuver (MFS) lead to rupture force values considered in the literature as single-integrin bonds. Adhesion reinforcement permitted by the parallel

  7. Rationally engineered nanoparticles target multiple myeloma cells, overcome cell-adhesion-mediated drug resistance, and show enhanced efficacy in vivo

    Kiziltepe, T; Ashley, J D; Stefanick, J F; Qi, Y M; Alves, N J; Handlogten, M W; Suckow, M A; Navari, R M; Bilgicer, B

    2012-01-01

    In the continuing search for effective cancer treatments, we report the rational engineering of a multifunctional nanoparticle that combines traditional chemotherapy with cell targeting and anti-adhesion functionalities. Very late antigen-4 (VLA-4) mediated adhesion of multiple myeloma (MM) cells to bone marrow stroma confers MM cells with cell-adhesion-mediated drug resistance (CAM-DR). In our design, we used micellar nanoparticles as dynamic self-assembling scaffolds to present VLA-4-antagonist peptides and doxorubicin (Dox) conjugates, simultaneously, to selectively target MM cells and to overcome CAM-DR. Dox was conjugated to the nanoparticles through an acid-sensitive hydrazone bond. VLA-4-antagonist peptides were conjugated via a multifaceted synthetic procedure for generating precisely controlled number of targeting functionalities. The nanoparticles were efficiently internalized by MM cells and induced cytotoxicity. Mechanistic studies revealed that nanoparticles induced DNA double-strand breaks and apoptosis in MM cells. Importantly, multifunctional nanoparticles overcame CAM-DR, and were more efficacious than Dox when MM cells were cultured on fibronectin-coated plates. Finally, in a MM xenograft model, nanoparticles preferentially homed to MM tumors with ∼10 fold more drug accumulation and demonstrated dramatic tumor growth inhibition with a reduced overall systemic toxicity. Altogether, we demonstrate the disease driven engineering of a nanoparticle-based drug delivery system, enabling the model of an integrative approach in the treatment of MM

  8. Cell characteristics of a multiple alloy nano-dots memory structure

    Bea, Ji Chel; Lee, Kang-Wook; Tanaka, Tetsu; Koyanagi, Mitsumasa; Song, Yun Heub; Lee, Gae-Hun

    2009-01-01

    A multiple alloy metal nano-dots memory using FN tunneling was investigated in order to confirm its structural possibility for future flash memory. In this work, a multiple FePt nano-dots device with a high work function (∼5.2 eV) and extremely high dot density (∼1.2 × 10 13 cm −2 ) was fabricated. Its structural effect for multiple layers was evaluated and compared to the one with a single layer in terms of the cell characteristics and reliability. We confirm that MOS capacitor structures with two to four multiple FePt nano-dot layers provide a larger threshold voltage window and better retention characteristics. Furthermore, it was also revealed that several process parameters for block oxide and inter-tunnel oxide between the nano-dot layers are very important to improve the efficiency of electron injection into multiple nano-dots. From these results, it is expected that a multiple FePt nano-dots memory using Fowler–Nordheim (FN) tunneling could be a candidate structure for future flash memory

  9. NF-kappa B modulation is involved in celastrol induced human multiple myeloma cell apoptosis.

    Haiwen Ni

    Full Text Available Celastrol is an active compound extracted from the root bark of the traditional Chinese medicine Tripterygium wilfordii Hook F. To investigate the effect of celastrol on human multiple myeloma cell cycle arrest and apoptosis and explore its molecular mechanism of action. The activity of celastrol on LP-1 cell proliferation was detected by WST-8 assay. The celastrol-induced cell cycle arrest was analyzed by flow cytometry after propidium iodide staining. Nuclear translocation of the nuclear factor kappa B (NF-κB was observed by fluorescence microscope. Celastrol inhibited cell proliferation of LP-1 myeloma cell in a dose-dependent manner with IC50 values of 0.8817 µM, which was mediated through G1 cell cycle arrest and p27 induction. Celastrol induced apoptosis in LP-1 and RPMI 8226 myeloma cells in a time and dose dependent manner, and it involved Caspase-3 activation and NF-κB pathway. Celastrol down-modulated antiapoptotic proteins including Bcl-2 and survivin expression. The expression of NF-κB and IKKa were decreased after celastrol treatment. Celastrol effectively blocked the nuclear translocation of the p65 subunit and induced human multiple myeloma cell cycle arrest and apoptosis by p27 upregulation and NF-kB modulation. It has been demonstrated that the effect of celastrol on NF-kB was HO-1-independent by using zinc protoporphyrin-9 (ZnPPIX, a selective heme oxygenase inhibitor. From the results, it could be inferred that celastrol may be used as a NF-kB inhibitor to inhibit myeloma cell proliferation.

  10. Codivergence and multiple host species use by fig wasp populations of the Ficus pollination mutualism

    McLeish Michael J

    2012-01-01

    Full Text Available Abstract Background The interaction between insects and plants takes myriad forms in the generation of spectacular diversity. In this association a species host range is fundamental and often measured using an estimate of phylogenetic concordance between species. Pollinating fig wasps display extreme host species specificity, but the intraspecific variation in empirical accounts of host affiliation has previously been underestimated. In this investigation, lineage delimitation and codiversification tests are used to generate and discuss hypotheses elucidating on pollinating fig wasp associations with Ficus. Results Statistical parsimony and AMOVA revealed deep divergences at the COI locus within several pollinating fig wasp species that persist on the same host Ficus species. Changes in branching patterns estimated using the generalized mixed Yule coalescent test indicated lineage duplication on the same Ficus species. Conversely, Elisabethiella and Alfonsiella fig wasp species are able to reproduce on multiple, but closely related host fig species. Tree reconciliation tests indicate significant codiversification as well as significant incongruence between fig wasp and Ficus phylogenies. Conclusions The findings demonstrate more relaxed pollinating fig wasp host specificity than previously appreciated. Evolutionarily conservative host associations have been tempered by horizontal transfer and lineage duplication among closely related Ficus species. Independent and asynchronistic diversification of pollinating fig wasps is best explained by a combination of both sympatric and allopatric models of speciation. Pollinator host preference constraints permit reproduction on closely related Ficus species, but uncertainty of the frequency and duration of these associations requires better resolution.

  11. Psychological well-being in people with multiple sclerosis in an Iranian population

    Sedigheh Rezaei Dehnavi

    2015-01-01

    Full Text Available Background: To date, few results on well-being in individuals with neurological disease have been published, while several studies in other groups have indicated that well-being may not be the only absence of psychological distress, but also positive psychological function. The aim of the present study was to compare the psychological well-being (PWB between the people with Multiple sclerosis (MS and normal individuals and identify correlated demographic factors to PWB in people with MS disorder. Materials and Methods: A case-control study was performed in July 2012 on 55 people with MS who were referred to MS clinic (located at the Kashani Hospital, Isfahan Neurosciences Research Centre and 83 normal individuals with matched mean of age, level of education, and gender. The participants filled up the 18-item Ryff′s PWB and demographic profile. The data were analyzed by SPSS software based on the independent t-test, and ANOVA. Results: There is significant different in all PWB dimensions between people with MS and normal groups. There were no significant differences in PWB in people with MS in relation to gender and marital status, but individuals with higher level of education scored higher in total PWB, positive relationship with others and purpose in life. Conclusion: People with MS are at risk of lower level of PWB. Interventional programs for improving PWB are strongly recommended.

  12. Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells

    Zub, Kamila Anna; Sousa, Mirta Mittelstedt Leal de; Sarno, Antonio

    2015-01-01

    of the AKR1C family involved in prostaglandin synthesis contribute to the resistant phenotype. Finally, selected metabolic and oxidative stress response enzymes were targeted by inhibitors, several of which displayed a selective cytotoxicity against the melphalan-resistant cells and should be further...... and pathways not previously associated with melphalan resistance in multiple myeloma cells, including a metabolic switch conforming to the Warburg effect (aerobic glycolysis), and an elevated oxidative stress response mediated by VEGF/IL8-signaling. In addition, up-regulated aldo-keto reductase levels...

  13. Divergent migration within lake sturgeon (Acipenser fulvescens) populations: Multiple distinct patterns exist across an unrestricted migration corridor

    Kessel, Steven T.; Hondorp, Darryl W.; Holbrook, Christopher; Boase, James C.; Chiotti, Justin A.; Thomas, Michael V.; Wills, Todd C.; Roseman, Edward; Drouin, Richard; Krueger, Charles C.

    2018-01-01

    Population structure, distribution, abundance, and dispersal arguably underpin the entire field of animal ecology, with consequences for regional species persistence, and provision of ecosystem services. Divergent migration behaviours among individuals or among populations is an important aspect of the ecology of highly-mobile animals, allowing populations to exploit spatially- or temporally-distributed food and space resources.This study investigated the spatial ecology of lake sturgeon (Acipenser fulvescens) within the barrier free Huron-Erie Corridor (HEC), which connects Lake Huron and Lake Erie of the North American Laurentian Great Lakes.Over six years (2011 – 2016), movements of 268 lake sturgeon in the HEC were continuously monitored across the Great Lakes using acoustic telemetry (10 yr battery life acoustic transmitters). Five distinct migration behaviours were identified with hierarchical cluster analysis, based on the phenology and duration of river and lake use.Lake sturgeon in the HEC were found to contain a high level of intraspecific divergent migration, including partial migration with the existence of residents. Specific behaviours included year-round river residency and multiple lake-migrant behaviours that involved movements between lakes and rivers. Over 85% of individuals were assign to migration behaviours as movements were consistently repeated over the study, which suggested migration behaviours were consistent and persistent in lake sturgeon. Differential use of specific rivers or lakes by acoustic-tagged lake sturgeon further subdivided individuals into 14 “contingents” (spatiotemporally segregated subgroups).Contingents associated with one river (Detroit or St. Clair) were rarely detected in the other river, which confirmed that lake sturgeon in the Detroit and St. Clair represent two semi-independent populations that could require separate management consideration for their conservation. The distribution of migration behaviours

  14. Cyclic AMP induces apoptosis in multiple myeloma cells and inhibits tumor development in a mouse myeloma model

    Follin-Arbelet, Virginie; Hofgaard, Peter O; Hauglin, Harald; Naderi, Soheil; Sundan, Anders; Blomhoff, Rune; Bogen, Bjarne; Blomhoff, Heidi K

    2011-01-01

    Multiple myeloma is an incurable disease requiring the development of effective therapies which can be used clinically. We have elucidated the potential for manipulating the cAMP signaling pathway as a target for inhibiting the growth of multiple myeloma cells. As a model system, we primarily used the murine multiple myeloma cell line MOPC315 which can be grown both in vivo and in vitro. Human multiple myeloma cell lines U266, INA-6 and the B-cell precursor acute lymphoblastic leukemia cell line Reh were used only for in vitro studies. Cell death was assessed by flow cytometry and western blot analysis after treatment with cAMP elevating agents (forskolin, prostaglandin E2 and rolipram) and cAMP analogs. We followed tumor growth in vivo after forskolin treatment by imaging DsRed-labelled MOPC315 cells transplanted subcutaneously in BALB/c nude mice. In contrast to the effect on Reh cells, 50 μM forskolin more than tripled the death of MOPC315 cells after 24 h in vitro. Forskolin induced cell death to a similar extent in the human myeloma cell lines U266 and INA-6. cAMP-mediated cell death had all the typical hallmarks of apoptosis, including changes in the mitochondrial membrane potential and cleavage of caspase 3, caspase 9 and PARP. Forskolin also inhibited the growth of multiple myeloma cells in a mouse model in vivo. Elevation of intracellular levels of cAMP kills multiple myeloma cells in vitro and inhibits development of multiple myeloma in vivo. This strongly suggests that compounds activating the cAMP signaling pathway may be useful in the field of multiple myeloma

  15. HOX and TALE signatures specify human stromal stem cell populations from different sources.

    Picchi, Jacopo; Trombi, Luisa; Spugnesi, Laura; Barachini, Serena; Maroni, Giorgia; Brodano, Giovanni Barbanti; Boriani, Stefano; Valtieri, Mauro; Petrini, Mario; Magli, Maria Cristina

    2013-04-01

    Human stromal stem cell populations reside in different tissues and anatomical sites, however a critical question related to their efficient use in regenerative medicine is whether they exhibit equivalent biological properties. Here, we compared cellular and molecular characteristics of stromal stem cells derived from the bone marrow, at different body sites (iliac crest, sternum, and vertebrae) and other tissues (dental pulp and colon). In particular, we investigated whether homeobox genes of the HOX and TALE subfamilies might provide suitable markers to identify distinct stromal cell populations, as HOX proteins control cell positional identity and, together with their co-factors TALE, are involved in orchestrating differentiation of adult tissues. Our results show that stromal populations from different sources, although immunophenotypically similar, display distinct HOX and TALE signatures, as well as different growth and differentiation abilities. Stromal stem cells from different tissues are characterized by specific HOX profiles, differing in the number and type of active genes, as well as in their level of expression. Conversely, bone marrow-derived cell populations can be essentially distinguished for the expression levels of specific HOX members, strongly suggesting that quantitative differences in HOX activity may be crucial. Taken together, our data indicate that the HOX and TALE profiles provide positional, embryological and hierarchical identity of human stromal stem cells. Furthermore, our data suggest that cell populations derived from different body sites may not represent equivalent cell sources for cell-based therapeutical strategies for regeneration and repair of specific tissues. Copyright © 2012 Wiley Periodicals, Inc.

  16. Multiple Sclerosis Walking Scale-12, translation, adaptation and validation for the Persian language population.

    Nakhostin Ansari, Noureddin; Naghdi, Soofia; Mohammadi, Roghaye; Hasson, Scott

    2015-02-01

    The Multiple Sclerosis Walking Scale-12 (MSWS-12) is a multi-item rating scale used to assess the perspectives of patients about the impact of MS on their walking ability. The aim of this study was to examine the reliability and validity of the MSWS-12 in Persian speaking patients with MS. The MSWS-12 questionnaire was translated into Persian language according to internationally adopted standards involving forward-backward translation, reviewed by an expert committee and tested on the pre-final version. In this cross-sectional study, 100 participants (50 patients with MS and 50 healthy subjects) were included. The MSWS-12 was administered twice 7 days apart to 30 patients with MS for test and retest reliability. Internal consistency reliability was Cronbach's α 0.96 for test and 0.97 for retest. There were no significant floor or ceiling effects. Test-retest reliability was excellent (intraclass correlation coefficient [ICC] agreement of 0.98, 95% CI, 0.95-0.99) confirming the reproducibility of the Persian MSWS-12. Construct validity using known group methods was demonstrated through a significant difference in the Persian MSWS-12 total score between the patients with MS and healthy subjects. Factor analysis extracted 2 latent factors (79.24% of the total variance). A second factor analysis suggested the 9-item Persian MSWS as a unidimensional scale for patients with MS. The Persian MSWS-12 was found to be valid and reliable for assessing walking ability in Persian speaking patients with MS. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. Tumourigenic canine osteosarcoma cell lines associated with frizzled-6 up-regulation and enhanced side population cell frequency.

    de Sá Rodrigues, L C; Holmes, K E; Thompson, V; Newton, M A; Stein, T J

    2017-03-01

    An increased serum alkaline phosphatase concentration is known to be associated with a negative prognosis in canine and human osteosarcoma. To expand upon previous studies regarding the biological relevance of increased serum alkaline phosphatase as a negative prognostic factor, xenogeneic heterotopic transplants were performed using six canine primary osteosarcoma cell lines generated from patients with differing serum alkaline phosphatase concentrations (three normal and three increased). Three of the six cell lines were capable of generating tumours and tumour formation was independent of the serum alkaline phosphatase status of the cell line. Microarray analysis identified 379 genes as being differentially expressed between the tumourigenic and non-tumourigenic cell lines. Frizzled-6 was upregulated to the greatest extent (7.78-fold) in tumourigenic cell lines compared with non-tumourigenic cell lines. Frizzled-6, a co-receptor for Wnt ligands has been associated with enhanced tumour-initiating cells and poor prognosis for other tumours. The increased expression of frizzled-6 was confirmed by quantitative reverse transcription polymerase chain reaction (QPCR) and Western blot analysis. Additionally, the tumourigenic cell lines also had an increase in the percentage of side population cells compared with non-tumourigenic cell lines (5.89% versus 1.58%, respectively). There were no differences in tumourigenicity, frizzled-6 or percentage of side population cells noted between osteosarcoma cell lines generated from patients of differing serum alkaline phosphatase concentration. However, to our knowledge this is the first study to identified frizzled-6 as a possible marker of osteosarcoma cell populations with enhanced tumourigenicity and side population cells. Future work will focus on defining the role of frizzled-6 in osteosarcoma tumourigenesis and tumour-initiating cells. © 2015 John Wiley & Sons Ltd.

  18. Research advances on the multiple uses of Moringa oleifera: A sustainable alternative for socially neglected population.

    Brilhante, Raimunda Sâmia Nogueira; Sales, Jamille Alencar; Pereira, Vandbergue Santos; Castelo-Branco, Débora de Souza Collares Maia; Cordeiro, Rossana de Aguiar; de Souza Sampaio, Célia Maria; de Araújo Neto Paiva, Manoel; Santos, João Bosco Feitosa Dos; Sidrim, José Júlio Costa; Rocha, Marcos Fábio Gadelha

    2017-07-01

    Moringa oleifera Lam (Moringaceae) is a plant with high nutritional and medicinal value. Native to India, it is now widely distributed throughout tropical and subtropical regions of the world. Its different parts are sources of proteins, vitamins and minerals and present different pharmacological and biotechnological potential. Moreover, M. oleifera seeds are widely used in water and effluent treatment, for their coagulation, flocculation and sedimentation properties, their ability of improving water quality, by reducing organic matter and microbial load, with special applicability in intensive animal production systems, such as aquaculture. In addition, due to its high nutritional value and several medicinal properties, this tree may act as a nutritional and medical alternative for socially neglected populations. In this context, this review gathers information on M. oleifera, emphasizing its chemical constituents, nutritional, pharmacological and antimicrobial properties, applications in the treatment of water effluents, and ecological and social aspects. Copyright © 2017 Hainan Medical University. Production and hosting by Elsevier B.V. All rights reserved.

  19. Analysing the Influence of the Spontaneous Aneuploidy Frequency on the Cell Population System Cultivation

    G. A. Nefedov

    2015-01-01

    Full Text Available The paper provides a qualitative analysis of M.S. Vinogradova's nonlinear model for dynamics of the cell population system. This system describes the stem cells cultivation in vitro under resource constraints. The system consists of two populations, namely: population of normal cells and population of abnormal cells. Resource constraints are considered as linear dependences of mitosis parameters on the normalized densities of each population.One of the key parameters that effects on the realization of the system evolution scenarios is a parameter that determines a share of the normal cells, which pass, when dividing, into population of the abnormal cells. The paper analyses both the existence conditions of the rest points and the changes of the evolution scenarios of population system with changing abovementioned parameter and other system parameters held fixed. It is shown that there is a saddle-node bifurcation in the system; the bifurcation value of the parameter is found. The paper shows the interval of parameter values in which the favorable scenarios of population system evolution are implemented. It also presents results of mathematical modeling.

  20. T regulatory cells are markers of disease activity in multiple sclerosis patients.

    Dacia Dalla Libera

    Full Text Available FoxP3⁺ Treg cells are believed to play a role in the occurrence of autoimmunity and in the determination of clinical recurrences. Contradictory reports are, however, available describing frequency and function of Treg cells during autoimmune diseases. We examined, by both polychromatic flow cytometry, and real-time RT-PCR, several Treg markers in peripheral blood mononuclear cells from patients with multiple sclerosis (MS, an autoimmune disease affecting the central nervous system. We found that Tregs, as defined by CD25, CD39, FoxP3, CTLA4, and GITR expression, were significantly decreased in stable MS patients as compared to healthy donors, but, surprisingly, restored to normal levels during an acute clinical attack. We conclude that Treg cells are not involved in causing clinical relapses, but rather react to inflammation in the attempt to restore homeostasis.

  1. Modifications of S-phase cell distribution in the intestinal crypts after multiple daily fractionation

    Becciolini, A; Cremonini, D; Fabbrica, D; Balzi, M [Florence Univ. (Italy). Ist. di Radiologia

    1983-01-01

    The effects obtained by multiple daily fractionation (3 Gy x2 or 3 Gy x2x2) on the distribution of S-phase cells along the crypt of the small intestine were investigated. The frequency of labelled cell distribution was reduced at early intervals; then the proliferating compartment gradually extended to the villus junctions. During recovery labelled cell frequency in the lower half of the crypts returned to control levels, while labelled cells were present in the differentiating area. With lower total dose modifications were milder and, as early as 72 h before exposure, distribution was already similar to controls. Invertase activity showed an initial increase and a higher reduction during acute damage when fractionation with higher doses was used. A lack of return to normal activity was present even 11 days after exposure when, however, the characteristic circadian pattern was observed.

  2. Late post-irradiation phenomena in mammalain cell populations. Pt. 2. Intraclonal recovery in sublines isolated from X-irradiated L5178Y-S cell populations

    Beer, J.Z.

    1975-01-01

    Clonal analysis of L5178Y-S cell populations irradiated with 300 rads of X-rays indicates occurence of cell sublines with considerably prolonged mean doubling times up to 22 h as compared to 10-11 h for control. Subsequent observations of growth of the handicapped sublines derived from single cells showed capability of all more than 100 studied sublines to recover normal proliferative activity. This process of intraclonal recovery required in many cases longer periods of time, corresponding to many tens, sometimes more than 200, generations. Late intraclonal recovery was further analysed by subcloning. It was found that although cytochemically assayed viability of the handicapped sublines was normal, cloning efficiency strongly depended on the stage of the recovery process. The recovery processes occuring in clones isolated from irradiated cell populations were compared with analogous processes occuring in slowly growing sublines isolated from non-irradiated cell cultures. Marked differences in kinetics of these processes show that either they are different in sublines derived from irradiated and non-irradiated cell populations or that the mechanisms of the late intraclonal recovery are affected by radiation. The results presented allow to conclude that gradual post-irradiation recovery of growth depends primarily on formation, in the developing populations, of cells with higher proliferative activities. Possible nature of the recovery processes is discussed in the light of available information on mammalian somatic cell variants with altered drug or temperature sensitivity, or with nutritional requirements. A sequence is proposed of changes leading from radiation-induced disturbance of the normably existing equilibrium between three basic cell subpopulations to ultimate restoration of this equilibrium. (author)

  3. Topological defects in confined populations of spindle-shaped cells

    Duclos, Guillaume; Erlenkämper, Christoph; Joanny, Jean-François; Silberzan, Pascal

    2017-01-01

    Most spindle-shaped cells (including smooth muscles and sarcomas) organize in vivo into well-aligned `nematic’ domains, creating intrinsic topological defects that may be used to probe the behaviour of these active nematic systems. Active non-cellular nematics have been shown to be dominated by activity, yielding complex chaotic flows. However, the regime in which live spindle-shaped cells operate, and the importance of cell-substrate friction in particular, remains largely unexplored. Using in vitro experiments, we show that these active cellular nematics operate in a regime in which activity is effectively damped by friction, and that the interaction between defects is controlled by the system’s elastic nematic energy. Due to the activity of the cells, these defects behave as self-propelled particles and pairwise annihilate until all displacements freeze as cell crowding increases. When confined in mesoscopic circular domains, the system evolves towards two identical +1/2 disclinations facing each other. The most likely reduced positions of these defects are independent of the size of the disk, the cells’ activity or even the cell type, but are well described by equilibrium liquid crystal theory. These cell-based systems thus operate in a regime more stable than other active nematics, which may be necessary for their biological function.

  4. Encapsulation of Multiple Microalgal Cells via a Combination of Biomimetic Mineralization and LbL Coating

    Minjeong Kim

    2018-02-01

    Full Text Available The encapsulation of living cells is appealing for its various applications to cell-based sensors, bioreactors, biocatalysts, and bioenergy. In this work, we introduce the encapsulation of multiple microalgal cells in hollow polymer shells of rhombohedral shape by the following sequential processes: embedding of microalgae in CaCO3 crystals; layer-by-layer (LbL coating of polyelectrolytes; and removal of sacrificial crystals. The microcapsule size was controlled by the alteration of CaCO3 crystal size, which is dependent on CaCl2/Na2CO3 concentration. The microalgal cells could be embedded in CaCO3 crystals by a two-step process: heterogeneous nucleation of crystal on the cell surface followed by cell embedment by the subsequent growth of crystal. The surfaces of the microalgal cells were highly favorable for the crystal growth of calcite; thus, micrometer-sized microalgae could be perfectly occluded in the calcite crystal without changing its rhombohedral shape. The surfaces of the microcapsules, moreover, could be decorated with gold nanoparticles, Fe3O4 magnetic nanoparticles, and carbon nanotubes (CNTs, by which we would expect the functionalities of a light-triggered release, magnetic separation, and enhanced mechanical and electrical strength, respectively. This approach, entailing the encapsulation of microalgae in semi-permeable and hollow polymer microcapsules, has the potential for application to microbial-cell immobilization for high-biomass-concentration cultivation as well as various other bioapplications.

  5. Encapsulation of Multiple Microalgal Cells via a Combination of Biomimetic Mineralization and LbL Coating.

    Kim, Minjeong; Choi, Myoung Gil; Ra, Ho Won; Park, Seung Bin; Kim, Yong-Joo; Lee, Kyubock

    2018-02-13

    The encapsulation of living cells is appealing for its various applications to cell-based sensors, bioreactors, biocatalysts, and bioenergy. In this work, we introduce the encapsulation of multiple microalgal cells in hollow polymer shells of rhombohedral shape by the following sequential processes: embedding of microalgae in CaCO₃ crystals; layer-by-layer (LbL) coating of polyelectrolytes; and removal of sacrificial crystals. The microcapsule size was controlled by the alteration of CaCO₃ crystal size, which is dependent on CaCl₂/Na₂CO₃ concentration. The microalgal cells could be embedded in CaCO₃ crystals by a two-step process: heterogeneous nucleation of crystal on the cell surface followed by cell embedment by the subsequent growth of crystal. The surfaces of the microalgal cells were highly favorable for the crystal growth of calcite; thus, micrometer-sized microalgae could be perfectly occluded in the calcite crystal without changing its rhombohedral shape. The surfaces of the microcapsules, moreover, could be decorated with gold nanoparticles, Fe₃O₄ magnetic nanoparticles, and carbon nanotubes (CNTs), by which we would expect the functionalities of a light-triggered release, magnetic separation, and enhanced mechanical and electrical strength, respectively. This approach, entailing the encapsulation of microalgae in semi-permeable and hollow polymer microcapsules, has the potential for application to microbial-cell immobilization for high-biomass-concentration cultivation as well as various other bioapplications.

  6. Small Molecules Affect Human Dental Pulp Stem Cell Properties Via Multiple Signaling Pathways

    Al-Habib, Mey; Yu, Zongdong

    2013-01-01

    One fundamental issue regarding stem cells for regenerative medicine is the maintenance of stem cell stemness. The purpose of the study was to test whether small molecules can enhance stem cell properties of mesenchymal stem cells (MSCs) derived from human dental pulp (hDPSCs), which have potential for multiple clinical applications. We identified the effects of small molecules (Pluripotin (SC1), 6-bromoindirubin-3-oxime and rapamycin) on the maintenance of hDPSC properties in vitro and the mechanisms involved in exerting the effects. Primary cultures of hDPSCs were exposed to optimal concentrations of these small molecules. Treated hDPSCs were analyzed for their proliferation, the expression levels of pluripotent and MSC markers, differentiation capacities, and intracellular signaling activations. We found that small molecule treatments decreased cell proliferation and increased the expression of STRO-1, NANOG, OCT4, and SOX2, while diminishing cell differentiation into odonto/osteogenic, adipogenic, and neurogenic lineages in vitro. These effects involved Ras-GAP-, ERK1/2-, and mTOR-signaling pathways, which may preserve the cell self-renewal capacity, while suppressing differentiation. We conclude that small molecules appear to enhance the immature state of hDPSCs in culture, which may be used as a strategy for adult stem cell maintenance and extend their capacity for regenerative applications. PMID:23573877

  7. Involvement of multiple myeloma cell-derived exosomes in osteoclast differentiation

    Raimondi, Lavinia; De Luca, Angela; Amodio, Nicola; Manno, Mauro; Raccosta, Samuele; Taverna, Simona; Bellavia, Daniele; Naselli, Flores; Fontana, Simona; Schillaci, Odessa; Giardino, Roberto; Fini, Milena; Tassone, Pierfrancesco; Santoro, Alessandra; De Leo, Giacomo; Giavaresi, Gianluca; Alessandro, Riccardo

    2015-01-01

    Bone disease is the most frequent complication in multiple myeloma (MM) resulting in osteolytic lesions, bone pain, hypercalcemia and renal failure. In MM bone disease the perfect balance between bone-resorbing osteoclasts (OCs) and bone-forming osteoblasts (OBs) activity is lost in favour of OCs, thus resulting in skeletal disorders. Since exosomes have been described for their functional role in cancer progression, we here investigate whether MM cell-derived exosomes may be involved in OCs differentiation. We show that MM cells produce exosomes which are actively internalized by Raw264.7 cell line, a cellular model of osteoclast formation. MM cell-derived exosomes positively modulate pre-osteoclast migration, through the increasing of CXCR4 expression and trigger a survival pathway. MM cell-derived exosomes play a significant pro-differentiative role in murine Raw264.7 cells and human primary osteoclasts, inducing the expression of osteoclast markers such as Cathepsin K (CTSK), Matrix Metalloproteinases 9 (MMP9) and Tartrate-resistant Acid Phosphatase (TRAP). Pre-osteoclast treated with MM cell-derived exosomes differentiate in multinuclear OCs able to excavate authentic resorption lacunae. Similar results were obtained with exosomes derived from MM patient's sera. Our data indicate that MM-exosomes modulate OCs function and differentiation. Further studies are needed to identify the OCs activating factors transported by MM cell-derived exosomes. PMID:25944696

  8. Cytokinetically quiescent (G0/G1) human multiple myeloma cells are susceptible to simultaneous inhibition of Chk1 and MEK1/2.

    Pei, Xin-Yan; Dai, Yun; Youssefian, Leena E; Chen, Shuang; Bodie, Wesley W; Takabatake, Yukie; Felthousen, Jessica; Almenara, Jorge A; Kramer, Lora B; Dent, Paul; Grant, Steven

    2011-11-10

    Effects of Chk1 and MEK1/2 inhibition were investigated in cytokinetically quiescent multiple myeloma (MM) and primary CD138(+) cells. Coexposure to the Chk1 and MEK1/2 inhibitors AZD7762 and selumetinib (AZD6244) robustly induced apoptosis in various MM cells and CD138(+) primary samples, but spared normal CD138(-) and CD34(+) cells. Furthermore, Chk1/MEK1/2 inhibitor treatment of asynchronized cells induced G(0)/G(1) arrest and increased apoptosis in all cell-cycle phases, including G(0)/G(1). To determine whether this regimen is active against quiescent G(0)/G(1) MM cells, cells were cultured in low-serum medium to enrich the G(0)/G(1) population. G(0)/G(1)-enriched cells exhibited diminished sensitivity to conventional agents (eg, Taxol and VP-16) but significantly increased susceptibility to Chk1 ± MEK1/2 inhibitors or Chk1 shRNA knock-down. These events were associated with increased γH2A.X expression/foci formation and Bim up-regulation, whereas Bim shRNA knock-down markedly attenuated lethality. Immunofluorescent analysis of G(0)/G(1)-enriched or primary MM cells demonstrated colocalization of activated caspase-3 and the quiescent (G(0)) marker statin, a nuclear envelope protein. Finally, Chk1/MEK1/2 inhibition increased cell death in the Hoechst-positive (Hst(+)), low pyronin Y (PY)-staining (2N Hst(+)/PY(-)) G(0) population and in sorted small side-population (SSP) MM cells. These findings provide evidence that cytokinetically quiescent MM cells are highly susceptible to simultaneous Chk1 and MEK1/2 inhibition.

  9. Cerebral blood flow and red cell delivery in normal subjects and in multiple sclerosis

    Swank, R.L.; Roth, J.G.; Woody, D.C. Jr.

    1983-01-01

    Regional cerebral blood flow (rCBF) was determined in 77 normal females and 53 normal males of different ages and in 26 men and 45 women with multiple sclerosis by the inhalation of radioactive Xe133 method. In the normal subjects the CBF was relatively high in the teens and fell, at first rapidly and then slowly in both sexes with age. During adult life the flow in females was significantly higher than in males. The delivery of packed red cells (RCD) was determined by multiplying the CBF by the percentage concentration of red cells (HCT). The RCD for both sexes was nearly the same. In the patients with multiple sclerosis there occurred a progressive generalized decrease in CBF and in RCD with age which was significantly greater than observed in normal subjects. The rate of decrease in CBF and RCD correlated directly with the rate of progress of the disease

  10. Twelve-year survival after multiple recurrences and repeated metastasectomies for renal cell Carcinoma

    Wang Jue

    2011-11-01

    Full Text Available Abstract Background Metastatic renal cell carcinoma (RCC presents a therapeutic challenge for clinicians because of the unpredictable clinical course, resistance to chemotherapy or radiotherapy and the limited response to immunotherapy. Patients and Methods We report a case of a 62-year-old woman who underwent nephrectomy for T4N0 RCC, clear cell type, Fuhrman grade 3/4 in 1999. The patinet subsequently had multiple tumor recurrences. Results The patient underwent eight metastasectomies, including multiple partial left nephrectomies, right adrenalectomy, a complete left nephrectomy, and distal pancreatectomy. She remains well and tumor free 12 years after initial diagnosis. Conclusion Repeated resections after initial metastasectomy can be carried out safely and provide long-term survival in selected patients with recurrent metastasis from RCC. The findings from our case indicate that close follow-up for the early detection of recurrence and complete resection of metastases can improve the results after repeated resection.

  11. Gait initiation time is associated with the risk of multiple falls-A population-based study.

    Callisaya, Michele L; Blizzard, Leigh; Martin, Kara; Srikanth, Velandai K

    2016-09-01

    In a population-based study of older people to examine whether 1) overall gait initiation (GI) time or its components are associated with falls and 2) GI under dual-task is a stronger predictor of falls risk than under single-task. Participants aged 60-85 years were randomly selected from the electoral roll. GI was obtained with a force platform under both single and dual-task conditions. Falls were ascertained prospectively over a 12-month period. Log multinomial regression was used to examine the association between GI time (total and its components) and risk of single and multiple falls. Age, sex and physiological and cognitive falls risk factors were considered as confounders. The mean age of the sample (n=124) was 71.0 (SD 6.8) years and 58.9% (n=73) were male. Over 12 months 21.8% (n=27) of participants reported a single fall and 16.1% (n=20) reported multiple falls. Slower overall GI time under both single (RR all per 100ms 1.28, 95%CI 1.03, 1.58) and dual-task (RR 1.14, 95%CI 1.02, 1.27) was associated with increased risk of multiple, but not single falls (pfalls were also associated with slower time to first lateral movement under single-task (RR 1.90 95%CI 0.59, 1.51) and swing time under dual-task condition (RR 1.44 95%CI 1.08, 1.94). Slower GI time is associated with the risk of multiple falls independent of other risk factors, suggesting it could be used as part of a comprehensive falls assessment. Time to the first lateral movement under single-task may be the best measures of this risk. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Multiple Synchronous Central Giant Cell Granulomas of the Maxillofacial Region: A Case Report

    Kang, Min Seok; Kim, Hak Jin

    2010-01-01

    Multifocal central giant cell granulomas (CGCG) in the maxillofacial region are suggestive of systemic disease such as hyperparathyroidism or an inherited syndrome such as Noonan-like multiple giant cell lesion syndrome. Only 5 cases of multifocal CGCGs in the maxillofacial region without any concomitant systemic disease have currently been reported. We report here on an unusual case of 17-year-old man who presented with multifocal CGCGs of the bilateral posterior mandible and right maxilla and he was without any concomitant systemic disease

  13. Multiple Synchronous Central Giant Cell Granulomas of the Maxillofacial Region: A Case Report

    Kang, Min Seok; Kim, Hak Jin [Pusan National University Hospital, Busan (Korea, Republic of)

    2010-01-15

    Multifocal central giant cell granulomas (CGCG) in the maxillofacial region are suggestive of systemic disease such as hyperparathyroidism or an inherited syndrome such as Noonan-like multiple giant cell lesion syndrome. Only 5 cases of multifocal CGCGs in the maxillofacial region without any concomitant systemic disease have currently been reported. We report here on an unusual case of 17-year-old man who presented with multifocal CGCGs of the bilateral posterior mandible and right maxilla and he was without any concomitant systemic disease

  14. Merkel cell carcinoma with fingolimod treatment for multiple sclerosis: A case report.

    Mahajan, Kedar R; Ko, Jennifer S; Tetzlaff, Michael T; Hudgens, Courtney W; Billings, Steven D; Cohen, Jeffrey A

    2017-10-01

    Neoplasms and reactivation of latent viruses have been observed in individuals taking fingolimod. Merkel cell carcinoma (MCC), a rare neuroendocrine skin cancer, is associated with immunosuppression and can be triggered by the oncogenic Merkel cell polyoma virus (MCPyV). We report a case of a 61-year-old man with multiple sclerosis who developed MCPyV-positive MCC 4 years after starting fingolimod. This is the second report of MCC associated with MCPyV in an individual on fingolimod. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Multiple growths of epitaxial lift-off solar cells from a single InP substrate

    Lee, Kyusang; Shiu, Kuen-Ting; Zimmerman, Jeramy D.; Forrest, Stephen R.; Renshaw, Christopher K.

    2010-01-01

    We demonstrate multiple growths of flexible, thin-film indium tin oxide-InP Schottky-barrier solar cells on a single InP wafer via epitaxial lift-off (ELO). Layers that protect the InP parent wafer surface during the ELO process are subsequently removed by selective wet-chemical etching, with the active solar cell layers transferred to a thin, flexible plastic host substrate by cold welding at room temperature. The first- and second-growth solar cells exhibit no performance degradation under simulated Atmospheric Mass 1.5 Global (AM 1.5G) illumination, and have a power conversion efficiency of η p =14.4±0.4% and η p =14.8±0.2%, respectively. The current-voltage characteristics for the solar cells and atomic force microscope images of the substrate indicate that the parent wafer is undamaged, and is suitable for reuse after ELO and the protection-layer removal processes. X-ray photoelectron spectroscopy, reflection high-energy electron diffraction observation, and three-dimensional surface profiling show a surface that is comparable or improved to the original epiready wafer following ELO. Wafer reuse over multiple cycles suggests that high-efficiency; single-crystal thin-film solar cells may provide a practical path to low-cost solar-to-electrical energy conversion.

  16. Petiveria alliacea extracts uses multiple mechanisms to inhibit growth of human and mouse tumoral cells

    Kaur Punit

    2008-11-01

    Full Text Available Abstract Background There is ethnopharmacological evidence that Petiveria alliacea can have antitumor activity; however, the mechanism of its cytotoxic activity is not well understood. We assessed multiple in vitro biological activities of an ethyl acetate soluble plant fraction over several tumor cell lines. Methods Tumor cell lines were evaluated using the following tests: trypan blue exclusion test, MTT [3-(4,5-dimethylthiazol-2-yl-2,5-diphenyl tetrazolium bromide], flow cytometry, cytoskeleton organization analysis, cell cycle, mitochondria membrane depolarization, clonogenicity test, DNA fragmentation test and differential protein expression by HPLC-Chip/MS analysis. F4 fraction characterization was made by HPLC-MS. Results Petiveria alliacea fraction characterized by de-replication was found to alter actin cytoskeleton organization, induce G2 cell cycle arrest and cause apoptotic cell death in a mitochondria independent way. In addition, we found down regulation of cytoskeleton, chaperone, signal transduction proteins, and proteins involved in metabolic pathways. Finally up regulation of proteins involved in translation and intracellular degradation was also observed. Conclusion The results of this study indicate that Petiveria alliacea exerts multiple biological activities in vitro consistent with cytotoxicity. Further studies in animal models are needed but Petiveria alliacea appears to be a good candidate to be used as an antitumor agent.

  17. Inhibition of Ubc13-mediated Ubiquitination by GPS2 Regulates Multiple Stages of B Cell Development.

    Lentucci, Claudia; Belkina, Anna C; Cederquist, Carly T; Chan, Michelle; Johnson, Holly E; Prasad, Sherry; Lopacinski, Amanda; Nikolajczyk, Barbara S; Monti, Stefano; Snyder-Cappione, Jennifer; Tanasa, Bogdan; Cardamone, M Dafne; Perissi, Valentina

    2017-02-17

    Non-proteolytic ubiquitin signaling mediated by Lys 63 ubiquitin chains plays a critical role in multiple pathways that are key to the development and activation of immune cells. Our previous work indicates that GPS2 (G-protein Pathway Suppressor 2) is a multifunctional protein regulating TNFα signaling and lipid metabolism in the adipose tissue through modulation of Lys 63 ubiquitination events. However, the full extent of GPS2-mediated regulation of ubiquitination and the underlying molecular mechanisms are unknown. Here, we report that GPS2 is required for restricting the activation of TLR and BCR signaling pathways and the AKT/FOXO1 pathway in immune cells based on direct inhibition of Ubc13 enzymatic activity. Relevance of this regulatory strategy is confirmed in vivo by B cell-targeted deletion of GPS2, resulting in developmental defects at multiple stages of B cell differentiation. Together, these findings reveal that GPS2 genomic and non-genomic functions are critical for the development and cellular homeostasis of B cells. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. Petiveria alliacea extracts uses multiple mechanisms to inhibit growth of human and mouse tumoral cells.

    Urueña, Claudia; Cifuentes, Claudia; Castañeda, Diana; Arango, Amparo; Kaur, Punit; Asea, Alexzander; Fiorentino, Susana

    2008-11-18

    There is ethnopharmacological evidence that Petiveria alliacea can have antitumor activity; however, the mechanism of its cytotoxic activity is not well understood. We assessed multiple in vitro biological activities of an ethyl acetate soluble plant fraction over several tumor cell lines. Tumor cell lines were evaluated using the following tests: trypan blue exclusion test, MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide], flow cytometry, cytoskeleton organization analysis, cell cycle, mitochondria membrane depolarization, clonogenicity test, DNA fragmentation test and differential protein expression by HPLC-Chip/MS analysis. F4 fraction characterization was made by HPLC-MS. Petiveria alliacea fraction characterized by de-replication was found to alter actin cytoskeleton organization, induce G2 cell cycle arrest and cause apoptotic cell death in a mitochondria independent way. In addition, we found down regulation of cytoskeleton, chaperone, signal transduction proteins, and proteins involved in metabolic pathways. Finally up regulation of proteins involved in translation and intracellular degradation was also observed. The results of this study indicate that Petiveria alliacea exerts multiple biological activities in vitro consistent with cytotoxicity. Further studies in animal models are needed but Petiveria alliacea appears to be a good candidate to be used as an antitumor agent.

  19. Regulation of hTERT by BCR-ABL at multiple levels in K562 cells

    Chai, Juin Hsien; Zhang, Yong; Tan, Wei Han; Chng, Wee Joo; Li, Baojie; Wang, Xueying

    2011-01-01

    The cytogenetic characteristic of Chronic Myeloid Leukemia (CML) is the formation of the Philadelphia chromosome gene product, BCR-ABL. Given that BCR-ABL is the specific target of Gleevec in CML treatment, we investigated the regulation of the catalytic component of telomerase, hTERT, by BCR-ABL at multiple levels in K562 cells. Molecular techniques such as over expression, knockdown, real-time PCR, immunoprecipitation, western blotting, reporter assay, confocal microscopy, telomerase assays and microarray were used to suggest that hTERT expression and activity is modulated by BCR-ABL at multiple levels. Our results suggest that BCR-ABL plays an important role in regulating hTERT in K562 (BCR-ABL positive human leukemia) cells. When Gleevec inhibited the tyrosine kinase activity of BCR-ABL, phosphorylation of hTERT was downregulated, therefore suggesting a positive correlation between BCR-ABL and hTERT. Gleevec treatment inhibited hTERT at mRNA level and significantly reduced telomerase activity (TA) in K562 cells, but not in HL60 or Jurkat cells (BCR-ABL negative cells). We also demonstrated that the transcription factor STAT5a plays a critical role in hTERT gene regulation in K562 cells. Knockdown of STAT5a, but not STAT5b, resulted in a marked downregulation of hTERT mRNA level, TA and hTERT protein level in K562 cells. Furthermore, translocation of hTERT from nucleoli to nucleoplasm was observed in K562 cells induced by Gleevec. Our data reveal that BCR-ABL can regulate TA at multiple levels, including transcription, post-translational level, and proper localization. Thus, suppression of cell growth and induction of apoptosis by Gleevec treatment may be partially due to TA inhibition. Additionally, we have identified STAT5a as critical mediator of the hTERT gene expression in BCR-ABL positive CML cells, suggesting that targeting STAT5a may be a promising therapeutic strategy for BCR-ABL positive CML patients

  20. Genetic structure of Phytophthora infestans populations in China indicates multiple migration events.

    Guo, Liyun; Zhu, Xiao-Qiong; Hu, Chia-Hui; Ristaino, Jean Beagle

    2010-10-01

    One hundred isolates of Phytophthora infestans collected from 10 provinces in China between 1998 and 2004 were analyzed for mating type, metalaxyl resistance, mitochondrial DNA (mtDNA) haplotype, allozyme genotype, and restriction fragment length polymorphism (RFLP) with the RG-57 probe. In addition, herbarium samples collected in China, Russia, Australia, and other Asian countries were also typed for mtDNA haplotype. The Ia haplotype was found during the first outbreaks of the disease in China (1938 and 1940), Japan (1901, 1930, and 1931), India (1913), Peninsular Malaysia (1950), Nepal (1954), The Philippines (1910), Australia (1917), Russia (1917), and Latvia (1935). In contrast, the Ib haplotype was found after 1950 in China on both potato and tomato (1952, 1954, 1956, and 1982) and in India (1968 and 1974). Another migration of a genotype found in Siberia called SIB-1 (Glucose-6-phosphate isomerase [Gpi] 100/100, Peptidase [Pep] 100/100, IIa mtDNA haplotype) was identified using RFLP fingerprints among 72% of the isolates and was widely distributed in the north and south of China and has also been reported in Japan. A new genotype named CN-11 (Gpi 100/111, Pep 100/100, IIb mtDNA haplotype), found only in the south of China, and two additional genotypes (Gpi 100/100, Pep 100/100, Ia mtDNA haplotype) named CN-9 and CN-10 were identified. There were more diverse genotypes among isolates from Yunnan province than elsewhere. The SIB-1 (IIa) genotype is identical to those from Siberia, suggesting later migration of this genotype from either Russia or Japan into China. The widespread predominance of SIB-1 suggests that this genotype has enhanced fitness compared with other genotypes found. Movement of the pathogen into China via infected seed from several sources most likely accounts for the distribution of pathogen genotypes observed. MtDNA haplotype evidence and RFLP data suggest multiple migrations of the pathogen into China after the initial introduction of the

  1. Treatment of multiple unresectable basal cell carcinomas from Gorlin-Goltz syndrome: a case report.

    Ojevwe, Fidelis O; Ojevwe, Cindy D; Zacny, James P; Dudek, Arkadiusz Z; Lin, Amy; Kohlitz, Patrick

    2015-03-01

    Nevoid basal cell carcinoma syndrome (NBCCS), which is also known by other names, including Gorlin-Goltz syndrome and multiple basal-cell carcinoma (BCC) syndrome, is a rare multi-systemic disease inherited in a dominant autosomal manner with complete penetrance and variable expressivity. The main clinical manifestations include multiple BCCs, odontogenic keratocysts of the jaw, hyperkeratosis of the palms and soles, skeletal abnormalities, intracranial calcifications and facial deformities. A 31-year-old male diagnosed with Gorlin-Goltz syndrome with multiple unresectable facial BCCs was treated with the Hedgehog inhibitor vismodegib. After one month of therapy on vismodegib, there were significant reductions in the size of multiple BCCs on the patient's face. The patient remains on this therapy. Hedgehog pathway inhibition is an effective strategy to treat unresectable BCCs from Gorlin-Goltz syndrome. Although vismodegib shows some promising clinical results in the early phase of its use, there are concerns of possible resistance developing within months. Duration of therapy, role of maintenance treatment and drug modification to reduce resistance need to be explored in future case studies. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  2. Altered 67Ga citrate distribution in patients with multiple red blood cell transfusions

    Engelstad, B.; Luk, S.S.; Hattner, R.S.

    1982-01-01

    Gallium-67 citrate studies from four patients who received multiple red blood cell transfusions were reviewed. Increased kidney, bladder, or bone localization was associated with decreased liver and colon activity. The findings suggest altered distribution due to competition with iron for receptor binding. Identification of inflammatory disease in two patients was possible. However, the effect of transfusions on detection of inflammatory or neoplastic diseases requires further evaluation

  3. Involvement of multiple myeloma cell-derived exosomes in osteoclast differentiation

    Raimondi, Lavinia; De Luca, Angela; Amodio, Nicola; Manno, Mauro; Raccosta, Samuele; Taverna, Simona; Bellavia, Daniele; Naselli, Flores; Fontana, Simona; Schillaci, Odessa; Giardino, Roberto; Fini, Milena; Tassone, Pierfrancesco; Santoro, Alessandra; De Leo, Giacomo

    2015-01-01

    Bone disease is the most frequent complication in multiple myeloma (MM) resulting in osteolytic lesions, bone pain, hypercalcemia and renal failure. In MM bone disease the perfect balance between bone-resorbing osteoclasts (OCs) and bone-forming osteoblasts (OBs) activity is lost in favour of OCs, thus resulting in skeletal disorders. Since exosomes have been described for their functional role in cancer progression, we here investigate whether MM cell-derived exosomes may be involved in OCs ...

  4. Carrier population control and surface passivation in solar cells

    Cuevas, Andres; Wan, Yimao; Yan, Di; Samundsett, Christian; Allen, Thomas; Zhang, Xinyu; Cui, Jie; Bullock, James

    2018-01-01

    Controlling the concentration of charge carriers near the surface is essential for solar cells. It permits to form regions with selective conductivity for either electrons or holes and it also helps to reduce the rate at which they recombine

  5. small cell lung cancer in a Chinese population

    clinical significance in patients with non-small cell lung cancer (NSCLC) in Hubei province ... diagnosis, tumor stage, treatment, progression .... Table 4: Association between EGFR mutation, gender and histologic type in 138 NSCLC patients.

  6. Merging Mixture Components for Cell Population Identification in Flow Cytometry

    Greg Finak

    2009-01-01

    Full Text Available We present a framework for the identification of cell subpopulations in flow cytometry data based on merging mixture components using the flowClust methodology. We show that the cluster merging algorithm under our framework improves model fit and provides a better estimate of the number of distinct cell subpopulations than either Gaussian mixture models or flowClust, especially for complicated flow cytometry data distributions. Our framework allows the automated selection of the number of distinct cell subpopulations and we are able to identify cases where the algorithm fails, thus making it suitable for application in a high throughput FCM analysis pipeline. Furthermore, we demonstrate a method for summarizing complex merged cell subpopulations in a simple manner that integrates with the existing flowClust framework and enables downstream data analysis. We demonstrate the performance of our framework on simulated and real FCM data. The software is available in the flowMerge package through the Bioconductor project.

  7. Analysis of Vaginal Cell Populations during Experimental Vaginal Candidiasis

    Fidel, Paul L.; Luo, Wei; Steele, Chad; Chabain, Joseph; Baker, Marc; Wormley, Floyd

    1999-01-01

    Studies with an estrogen-dependent murine model of vaginal candidiasis suggest that local cell-mediated immunity (CMI) is more important than systemic CMI for protection against vaginitis. The present study, however, showed that, compared to uninfected mice, little to no change in the percentage or types of vaginal T cells occurred during a primary vaginal infection or during a secondary vaginal infection where partial protection was observed. Furthermore, depletion of polymorphonuclear leuko...

  8. In Silico Prediction Analysis of Idiotope-Driven T–B Cell Collaboration in Multiple Sclerosis

    Rune A. Høglund

    2017-10-01

    Full Text Available Memory B cells acting as antigen-presenting cells are believed to be important in multiple sclerosis (MS, but the antigen they present remains unknown. We hypothesized that B cells may activate CD4+ T cells in the central nervous system of MS patients by presenting idiotopes from their own immunoglobulin variable regions on human leukocyte antigen (HLA class II molecules. Here, we use bioinformatics prediction analysis of B cell immunoglobulin variable regions from 11 MS patients and 6 controls with other inflammatory neurological disorders (OINDs, to assess whether the prerequisites for such idiotope-driven T–B cell collaboration are present. Our findings indicate that idiotopes from the complementarity determining region (CDR 3 of MS patients on average have high predicted affinities for disease associated HLA-DRB1*15:01 molecules and are predicted to be endosomally processed by cathepsin S and L in positions that allows such HLA binding to occur. Additionally, complementarity determining region 3 sequences from cerebrospinal fluid (CSF B cells from MS patients contain on average more rare T cell-exposed motifs that could potentially escape tolerance and stimulate CD4+ T cells than CSF B cells from OIND patients. Many of these features were associated with preferential use of the IGHV4 gene family by CSF B cells from MS patients. This is the first study to combine high-throughput sequencing of patient immune repertoires with large-scale prediction analysis and provides key indicators for future in vitro and in vivo analyses.

  9. N-way FRET microscopy of multiple protein-protein interactions in live cells.

    Adam D Hoppe

    Full Text Available Fluorescence Resonance Energy Transfer (FRET microscopy has emerged as a powerful tool to visualize nanoscale protein-protein interactions while capturing their microscale organization and millisecond dynamics. Recently, FRET microscopy was extended to imaging of multiple donor-acceptor pairs, thereby enabling visualization of multiple biochemical events within a single living cell. These methods require numerous equations that must be defined on a case-by-case basis. Here, we present a universal multispectral microscopy method (N-Way FRET to enable quantitative imaging for any number of interacting and non-interacting FRET pairs. This approach redefines linear unmixing to incorporate the excitation and emission couplings created by FRET, which cannot be accounted for in conventional linear unmixing. Experiments on a three-fluorophore system using blue, yellow and red fluorescent proteins validate the method in living cells. In addition, we propose a simple linear algebra scheme for error propagation from input data to estimate the uncertainty in the computed FRET images. We demonstrate the strength of this approach by monitoring the oligomerization of three FP-tagged HIV Gag proteins whose tight association in the viral capsid is readily observed. Replacement of one FP-Gag molecule with a lipid raft-targeted FP allowed direct observation of Gag oligomerization with no association between FP-Gag and raft-targeted FP. The N-Way FRET method provides a new toolbox for capturing multiple molecular processes with high spatial and temporal resolution in living cells.

  10. Tackling Energy Loss for High-Efficiency Organic Solar Cells with Integrated Multiple Strategies.

    Zuo, Lijian; Shi, Xueliang; Jo, Sae Byeok; Liu, Yun; Lin, Fracis; Jen, Alex K-Y

    2018-04-01

    Limited by the various inherent energy losses from multiple channels, organic solar cells show inferior device performance compared to traditional inorganic photovoltaic techniques, such as silicon and CuInGaSe. To alleviate these fundamental limitations, an integrated multiple strategy is implemented including molecular design, interfacial engineering, optical manipulation, and tandem device construction into one cell. Considering the close correlation among these loss channels, a sophisticated quantification of energy-loss reduction is tracked along with each strategy in a perspective to reach rational overall optimum. A novel nonfullerene acceptor, 6TBA, is synthesized to resolve the thermalization and V OC loss, and another small bandgap nonfullerene acceptor, 4TIC, is used in the back sub-cell to alleviate transmission loss. Tandem architecture design significantly reduces the light absorption loss, and compensates carrier dynamics and thermalization loss. Interfacial engineering further reduces energy loss from carrier dynamics in the tandem architecture. As a result of this concerted effort, a very high power conversion efficiency (13.20%) is obtained. A detailed quantitative analysis on the energy losses confirms that the improved device performance stems from these multiple strategies. The results provide a rational way to explore the ultimate device performance through molecular design and device engineering. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma

    Drent, Esther; Groen, Richard W. J.; Noort, Willy A. Noort

    2016-01-01

    Adoptive transfer of chimeric antigen receptor-transduced T cells is a promising strategy for cancer immunotherapy. The CD38 molecule, with its high expression on multiple myeloma cells, appears a suitable target for antibody therapy. Prompted by this, we used three different CD38 antibody...... sequences to generate second-generation retroviral CD38- chimeric antigen receptor constructs with which we transduced T cells from healthy donors and multiple myeloma patients. We then evaluated the preclinical efficacy and safety of the transduced T cells. Irrespective of the donor and antibody sequence......, CD38-chimeric antigen receptor-transduced T cells proliferated, produced inflammatory cytokines and effectively lysed malignant cell lines and primary malignant cells from patients with acute myeloid leukemia and multi-drug resistant multiple myeloma in a cell-dose, and CD38-dependent manner, despite...

  12. Estimating average alcohol consumption in the population using multiple sources: the case of Spain.

    Sordo, Luis; Barrio, Gregorio; Bravo, María J; Villalbí, Joan R; Espelt, Albert; Neira, Montserrat; Regidor, Enrique

    2016-01-01

    National estimates on per capita alcohol consumption are provided regularly by various sources and may have validity problems, so corrections are needed for monitoring and assessment purposes. Our objectives were to compare different alcohol availability estimates for Spain, to build the best estimate (actual consumption), characterize its time trend during 2001-2011, and quantify the extent to which other estimates (coverage) approximated actual consumption. Estimates were: alcohol availability from the Spanish Tax Agency (Tax Agency availability), World Health Organization (WHO availability) and other international agencies, self-reported purchases from the Spanish Food Consumption Panel, and self-reported consumption from population surveys. Analyses included calculating: between-agency discrepancy in availability, multisource availability (correcting Tax Agency availability by underestimation of wine and cider), actual consumption (adjusting multisource availability by unrecorded alcohol consumption/purchases and alcohol losses), and coverage of selected estimates. Sensitivity analyses were undertaken. Time trends were characterized by joinpoint regression. Between-agency discrepancy in alcohol availability remained high in 2011, mainly because of wine and spirits, although some decrease was observed during the study period. The actual consumption was 9.5 l of pure alcohol/person-year in 2011, decreasing 2.3 % annually, mainly due to wine and spirits. 2011 coverage of WHO availability, Tax Agency availability, self-reported purchases, and self-reported consumption was 99.5, 99.5, 66.3, and 28.0 %, respectively, generally with downward trends (last three estimates, especially self-reported consumption). The multisource availability overestimated actual consumption by 12.3 %, mainly due to tourism imbalance. Spanish estimates of per capita alcohol consumption show considerable weaknesses. Using uncorrected estimates, especially self-reported consumption, for

  13. Evidence of multiple insecticide resistance mechanisms in Anopheles gambiae populations in Bangui, Central African Republic.

    Olé Sangba, Marina Lidwine; Sidick, Aboubakar; Govoetchan, Renaud; Dide-Agossou, Christian; Ossè, Razaki A; Akogbeto, Martin; Ndiath, Mamadou Ousmane

    2017-01-13

    Knowledge of insecticide resistance status in the main malaria vectors is an essential component of effective malaria vector control. This study presents the first evaluation of the status of insecticide resistance in Anopheles gambiae populations from Bangui, the Central African Republic. Anopheles mosquitoes were reared from larvae collected in seven districts of Bangui between September to November 2014. The World Health Organisation's bioassay susceptibility tests to lambda-cyhalothrin (0.05%), deltamethrin (0.05%), DDT (4%), malathion (5%), fenitrothion (1%) and bendiocarb (0.1%) were performed on adult females. Species and molecular forms as well as the presence of L1014F kdr and Ace-1 R mutations were assessed by PCR. Additional tests were conducted to assess metabolic resistance status. After 1 h exposure, a significant difference of knockdown effect was observed between districts in all insecticides tested except deltamethrin and malathion. The mortality rate (MR) of pyrethroids group ranging from 27% (CI: 19-37.5) in Petevo to 86% (CI: 77.6-92.1) in Gbanikola; while for DDT, MR ranged from 5% (CI: 1.6-11.3) in Centre-ville to 39% (CI: 29.4-49.3) in Ouango. For the organophosphate group a MR of 100% was observed in all districts except Gbanikola where a MR of 96% (CI: 90-98.9) was recorded. The mortality induced by bendiocarb was very heterogeneous, ranging from 75% (CI: 62.8-82.8) in Yapele to 99% (CI: 84.5-100) in Centre-ville. A high level of kdr-w (L1014F) frequency was observed in all districts ranging from 93 to 100%; however, no kdr-e (L1014S) and Ace-1 R mutation were found in all tested mosquitoes. Data of biochemical analysis showed significant overexpression activities of cytochrome P450, GST and esterases in Gbanikola and Yapele (χ 2  = 31.85, df = 2, P resistance to DDT and pyrethroids as well as precocious emergence of resistance to carbamates were detected among A. gambiae mosquitoes from Bangui, including target-site mutations

  14. Electric properties and carrier multiplication in breakdown sites in multi-crystalline silicon solar cells

    Schneemann, Matthias; Carius, Reinhard; Rau, Uwe [IEK5-Photovoltaics, Forschungszentrum Jülich, Jülich 52425 (Germany); Kirchartz, Thomas, E-mail: t.kirchartz@fz-juelich.de [IEK5-Photovoltaics, Forschungszentrum Jülich, Jülich 52425 (Germany); Faculty of Engineering and CENIDE, University of Duisburg-Essen, Carl-Benz-Str. 199, Duisburg 47057 (Germany)

    2015-05-28

    This paper studies the effective electrical size and carrier multiplication of breakdown sites in multi-crystalline silicon solar cells. The local series resistance limits the current of each breakdown site and is thereby linearizing the current-voltage characteristic. This fact allows the estimation of the effective electrical diameters to be as low as 100 nm. Using a laser beam induced current (LBIC) measurement with a high spatial resolution, we find carrier multiplication factors on the order of 30 (Zener-type breakdown) and 100 (avalanche breakdown) as new lower limits. Hence, we prove that also the so-called Zener-type breakdown is followed by avalanche multiplication. We explain that previous measurements of the carrier multiplication using thermography yield results higher than unity, only if the spatial defect density is high enough, and the illumination intensity is lower than what was used for the LBIC method. The individual series resistances of the breakdown sites limit the current through these breakdown sites. Therefore, the measured multiplication factors depend on the applied voltage as well as on the injected photocurrent. Both dependencies are successfully simulated using a series-resistance-limited diode model.

  15. Heterogeneity within populations of recombinant Chinese hamster ovary cells expressing human interferon-gamma.

    Coppen, S R; Newsam, R; Bull, A T; Baines, A J

    1995-04-20

    The Chinese hamster ovary (CHO) cell line has great commercial importance in the production of recombinant human proteins, especially those for therapeutic use. Much attention has been paid to CHO cell population physiology in order to define factors affecting product fidelity and yield. Such studies have revealed that recombinant proteins, including human interferon-gamma (IFN-gamma), can be heterogeneous both in glycosylation and in proteolytic processing. The type of heterogeneity observed depends on the growth physiology of the cell population, although the relationship between them is complex. In this article we report results of a cytological study of the CHO320 line which expresses recombinant human IFN-gamma. When grown in suspension culture, this cell line exhibited three types of heterogeneity: (1) heterogeneity of the production of IFN-gamma within the cell population, (2) heterogeneity of the number of nuclei and mitotic spindles in dividing cells, and (3) heterogeneity of cellular environment. The last of these arises from cell aggregates which form in suspension culture: Some cells are exposed to the culture medium; others are fully enclosed within the mass with little or no direct access to the medium. Thus, live cells producing IFN-gamma are heterogeneous in their environment, with variable access to O(2) and nutrients. Within the aggregates, it appears that live cells proliferate on a dead cell mass. The layer of live cells can be several cells deep. Specific cell-cell attachments are observed between the living cells in these aggregates. Two proteins, known to be required for the formation of certain types of intercellular junctions, spectrin and vinculin, have been localized to the regions of cell-cell contact. The aggregation of the cells appears to be an active process requiring protein synthesis. (c) 1995 John Wiley & Sons, Inc.

  16. B cell follicle-like structures in multiple sclerosis-with focus on the role of B cell activating factor

    Morten, Haugen; Frederiksen, Jette L; Vinter, Matilda Degn

    2014-01-01

    B lymphocytes play an important role in the pathogenesis of multiple sclerosis (MS). Follicle-like structures (FLS) have recently been found in the subarachnoid space in the leptomeninges in some patients with secondary progressive MS (SPMS). They contain proliferating B lymphocytes, plasma cells......, helper T lymphocytes and a network of follicular dendritic cells. FLS have been shown to correlate with increased cortical demyelination, neuronal loss, meningeal infiltration and central nervous system inflammation, as well as lower age at disease onset and progression to severe disability and death....... In this review, we will discuss the role of FLS in MS pathogenesis and disease course and the possible influence by B cell activating factor (BAFF) and C-X-C motif chemokine 13 (CXCL13)....

  17. Replication of Syngrapha falcifera Multiple-Nuclear Polyhedrosis Virus-D in Different Insect Cells

    Khalid Nessr Alhag, Sadeq; Xin, Peng Jian

    Six insect cell lines were tested for susceptibility to Syngrapha falcifera multiple nucleocapsid nucleopolyhedrovirus-D (SfaMNPV-D) infection by use of a typical endpoint assay procedure. Cell lines from Trichoplusia ni (Tn5B1-4), (L105-clone), Spodoptera litura (SL-ZSU-1), Spodoptera frugiperda (IPLB-SF-21), Pieris rapaeb (Pr-E-HNU9) and Helicoverpa zea (BCIRL-HZ-AM1) in 96-well tissue culture plates were infected with dilutions of extra cellular virus suspensions of (SfaMNPV-D). Each cell/virus combination was incubated at temperatures 27°C and wells were scored for positive infection at 2 to 4 day intervals. The resulting data were analyzed by Reed and Muench method, providing virus titers for each combination of virus, cell line. The results were categorized by accuracy and by rapidity of maximum titer. Virus titer of Tn5B-4 was higher than other cell lines TCID50 8.7x108, the lowest level detected in infected was in (Pr-E-HNU9) cells TCID50 2.4x108. No Virions or polyhedral inclusion bodies were detected in infected SL-ZSU-1 cells.

  18. Comparative proteomics analysis of Spodoptera frugiperda cells during Autographa californica multiple nucleopolyhedrovirus infection.

    Yu, Qian; Xiong, Youhua; Gao, Hang; Liu, Jianliang; Chen, Zhiqiang; Wang, Qin; Wen, Dongling

    2015-08-04

    Increasing evidence sugggest that in addition of balculovirus controling insect host, host cells also responds to balculovirus infection. However, compared to existing knowledge on virus gene, host cell responses are relatively poorly understood. In this study, Spodoptera frugiperda (Sf9) cells were infected with Autographa californica multiple nucleopolyhedrovirus (AcMNPV). The protein composition and protein changes of Spodoptera frugiperda (Sf9) cells of different infection stages were analysed by isobaric tag for relative and absolute quantification (iTRAQ) techniques. A total of 4004 Sf9 proteins were identified by iTRAQ and 413 proteins were found as more than 1.5-fold changes in abundance. The 413 proteins were categorised according to GO classification for insects and were categorised into: biological process, molecular function and cellular component. The determination of the protein changes in infected Sf9 cells would help to better understanding of host cell responses and facilitate better design of this virus-host cell interaction in pest insect control and other related fields.

  19. Cell cycle commitment in budding yeast emerges from the cooperation of multiple bistable switches

    Zhang, Tongli; Schmierer, Bernhard; Novák, Béla

    2011-01-01

    The start-transition (START) in the G1 phase marks the point in the cell cycle at which a yeast cell initiates a new round of cell division. Once made, this decision is irreversible and the cell is committed to progressing through the entire cell cycle, irrespective of arrest signals such as pheromone. How commitment emerges from the underlying molecular interaction network is poorly understood. Here, we perform a dynamical systems analysis of an established cell cycle model, which has never been analysed from a commitment perspective. We show that the irreversibility of the START transition and subsequent commitment can be consistently explained in terms of the interplay of multiple bistable molecular switches. By applying an existing mathematical model to a novel problem and by expanding the model in a self-consistent manner, we achieve several goals: we bring together a large number of experimental findings into a coherent theoretical framework; we increase the scope and the applicability of the original model; we give a systems level explanation of how the START transition and the cell cycle commitment arise from the dynamical features of the underlying molecular interaction network; and we make clear, experimentally testable predictions. PMID:22645649

  20. Discovery of Power-Law Growth in the Self-Renewal of Heterogeneous Glioma Stem Cell Populations.

    Michiya Sugimori

    glioma stem cell populations. That the data always fit a power-law suggests that: (i clone sizes follow continuous, non-random, and scale-free hierarchy; (ii precise biologic rules that reflect self-organizing emergent behaviors govern the generation of neurospheres. That the power-law behavior and the original GS heterogeneity are maintained over multiple passages indicates that these rules are invariant. These self-organizing mechanisms very likely underlie tumor heterogeneity during tumor growth. Discovery of this power-law behavior provides a mechanism that could be targeted in the development of new, more effective, anti-cancer agents.

  1. Endometrial Stromal Cells and Immune Cell Populations Within Lymph Nodes in a Nonhuman Primate Model of Endometriosis

    Fazleabas, A. T.; Braundmeier, A. G.; Markham, R.; Fraser, I. S.; Berbic, M.

    2011-01-01

    Mounting evidence suggests that immunological responses may be altered in endometriosis. The baboon (Papio anubis) is generally considered the best model of endometriosis pathogenesis. The objective of the current study was to investigate for the first time immunological changes within uterine and peritoneal draining lymph nodes in a nonhuman primate baboon model of endometriosis. Paraffin-embedded femoral lymph nodes were obtained from 22 normally cycling female baboons (induced endometriosis n = 11; control n = 11). Immunohistochemical staining was performed with antibodies for endometrial stromal cells, T cells, immature and mature dendritic cells, and B cells. Lymph nodes were evaluated using an automated cellular imaging system. Endometrial stromal cells were significantly increased in lymph nodes from animals with induced endometriosis, compared to control animals (P = .033). In animals with induced endometriosis, some lymph node immune cell populations including T cells, dendritic cells and B cells were increased, suggesting an efficient early response or peritoneal drainage. PMID:21617251

  2. Multiple origins of spontaneously arising micronuclei in HeLa cells: Direct evidence from long-term live cell imaging

    Rao Xiaotang; Zhang Yingyin; Yi Qiyi; Hou Heli; Xu Bo; Chu Liang; Huang Yun; Zhang Wenrui; Fenech, Michael; Shi Qinghua

    2008-01-01

    Although micronuclei (MNi) are extensively used to evaluate genotoxic effects and chromosome instability, the most basic issue regarding their origins has not been completely addressed due to limitations of traditional methods. Recently, long-term live cell imaging was developed to monitor the dynamics of single cell in a real-time and high-throughput manner. In the present study, this state-of-the-art technique was employed to examine spontaneous micronucleus (MN) formation in untreated HeLa cells. We demonstrate that spontaneous MNi are derived from incorrectly aligned chromosomes in metaphase (displaced chromosomes, DCs), lagging chromosomes (LCs) and broken chromosome bridges (CBs) in later mitotic stages, but not nuclear buds in S phase. However, most of bipolar mitoses with DCs (91.29%), LCs (73.11%) and broken CBs (88.93%) did not give rise to MNi. Our data also show directly, for the first time, that MNi could originate spontaneously from (1) MNi already presented in the mother cells; (2) nuclear fragments that appeared during mitosis with CB; and (3) chromosomes being extruded into a minicell which fused with one of the daughter cells later. Quantitatively, most of MNi originated from LCs (63.66%), DCs (10.97%) and broken CBs (9.25%). Taken together, these direct evidences show that there are multiple origins for spontaneously arising MNi in HeLa cells and each mechanism contributes to overall MN formation to different extents

  3. Multiple origins of spontaneously arising micronuclei in HeLa cells: Direct evidence from long-term live cell imaging

    Rao Xiaotang; Zhang Yingyin; Yi Qiyi; Hou Heli; Xu Bo; Chu Liang; Huang Yun; Zhang Wenrui [Laboratory of Molecular and Cell Genetics, Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027 (China); Fenech, Michael [CSIRO Human Nutrition, PO Box 10041, Adelaide BC, Adelaide, SA 5000 (Australia); Shi Qinghua [Laboratory of Molecular and Cell Genetics, Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027 (China)], E-mail: qshi@ustc.edu.cn

    2008-11-10

    Although micronuclei (MNi) are extensively used to evaluate genotoxic effects and chromosome instability, the most basic issue regarding their origins has not been completely addressed due to limitations of traditional methods. Recently, long-term live cell imaging was developed to monitor the dynamics of single cell in a real-time and high-throughput manner. In the present study, this state-of-the-art technique was employed to examine spontaneous micronucleus (MN) formation in untreated HeLa cells. We demonstrate that spontaneous MNi are derived from incorrectly aligned chromosomes in metaphase (displaced chromosomes, DCs), lagging chromosomes (LCs) and broken chromosome bridges (CBs) in later mitotic stages, but not nuclear buds in S phase. However, most of bipolar mitoses with DCs (91.29%), LCs (73.11%) and broken CBs (88.93%) did not give rise to MNi. Our data also show directly, for the first time, that MNi could originate spontaneously from (1) MNi already presented in the mother cells; (2) nuclear fragments that appeared during mitosis with CB; and (3) chromosomes being extruded into a minicell which fused with one of the daughter cells later. Quantitatively, most of MNi originated from LCs (63.66%), DCs (10.97%) and broken CBs (9.25%). Taken together, these direct evidences show that there are multiple origins for spontaneously arising MNi in HeLa cells and each mechanism contributes to overall MN formation to different extents.

  4. Analysis of Vaginal Cell Populations during Experimental Vaginal Candidiasis

    Fidel, Paul L.; Luo, Wei; Steele, Chad; Chabain, Joseph; Baker, Marc; Wormley, Floyd

    1999-01-01

    Studies with an estrogen-dependent murine model of vaginal candidiasis suggest that local cell-mediated immunity (CMI) is more important than systemic CMI for protection against vaginitis. The present study, however, showed that, compared to uninfected mice, little to no change in the percentage or types of vaginal T cells occurred during a primary vaginal infection or during a secondary vaginal infection where partial protection was observed. Furthermore, depletion of polymorphonuclear leukocytes (PMN) had no effect on infection in the presence or absence of pseudoestrus. These results indicate a lack of demonstrable effects by systemic CMI or PMN against vaginitis and suggest that if local T cells are important, they are functioning without showing significant increases in numbers within the vaginal mucosa during infection. PMID:10338532

  5. Cellular population dynamics control the robustness of the stem cell niche

    Adam L. MacLean

    2015-11-01

    Full Text Available Within populations of cells, fate decisions are controlled by an indeterminate combination of cell-intrinsic and cell-extrinsic factors. In the case of stem cells, the stem cell niche is believed to maintain ‘stemness’ through communication and interactions between the stem cells and one or more other cell-types that contribute to the niche conditions. To investigate the robustness of cell fate decisions in the stem cell hierarchy and the role that the niche plays, we introduce simple mathematical models of stem and progenitor cells, their progeny and their interplay in the niche. These models capture the fundamental processes of proliferation and differentiation and allow us to consider alternative possibilities regarding how niche-mediated signalling feedback regulates the niche dynamics. Generalised stability analysis of these stem cell niche systems enables us to describe the stability properties of each model. We find that although the number of feasible states depends on the model, their probabilities of stability in general do not: stem cell–niche models are stable across a wide range of parameters. We demonstrate that niche-mediated feedback increases the number of stable steady states, and show how distinct cell states have distinct branching characteristics. The ecological feedback and interactions mediated by the stem cell niche thus lend (surprisingly high levels of robustness to the stem and progenitor cell population dynamics. Furthermore, cell–cell interactions are sufficient for populations of stem cells and their progeny to achieve stability and maintain homeostasis. We show that the robustness of the niche – and hence of the stem cell pool in the niche – depends only weakly, if at all, on the complexity of the niche make-up: simple as well as complicated niche systems are capable of supporting robust and stable stem cell dynamics.

  6. In vitro expansion of the mammary stem/progenitor cell population by xanthosine treatment

    Choudhary Ratan K

    2012-06-01

    Full Text Available Abstract Background Mammary stem cells are critical for growth and maintenance of the mammary gland and therefore are of considerable interest for improving productivity and efficiency of dairy animals. Xanthosine treatment has been demonstrated to promote expansion of putative mammary stem cells in vivo, and hepatic and hair follicle stem cells in vitro. In the latter, xanthosine promoted the symmetrical division of hepatic and hair follicle stem cells. The objective of this study was to determine if treating primary cultures of bovine mammary epithelial cells (MEC with xanthosine increases the stem/progenitor cell population by promoting symmetrical division of mammary stem cells. Results In vitro treatment with xanthosine increased the population of MEC during the exponential phase of cell growth, reducing the doubling time from 86 h in control cultures to 60 h in xanthosine-treated cultures. The bromodeoxyuridine (BrdU labeling index and the proportion of MEC in S-phase both were increased by xanthosine treatment, indicating that increased cell accretion was due to increased cell proliferation. Analysis of daughter-pairs indicated that xanthosine promoted a shift from asymmetric to symmetric cell division. Moreover, the 30 % increase in symmetric cell division was concomitant with an increase in the proportion of MEC that were positive for a putative stem cell marker (FNDC3B and a trend toward increased telomerase activity. These results suggest that xanthosine treatment in vitro can increase cell proliferation, promote symmetric cell division and enhance stem/progenitor cell activity. Conclusions Xanthosine treatment increased the proliferation rate of bovine MEC in vitro. This was likely to be mediated by an increase in the proportion of stem/progenitor cells in the MEC population due to promotion of symmetrical stem cell division by xanthosine.

  7. B-cell activating factor in the pathophysiology of multiple myeloma: a target for therapy?

    Hengeveld, P J; Kersten, M J

    2015-01-01

    Multiple myeloma (MM) is a currently incurable malignancy of plasma cells. Malignant myeloma cells (MMCs) are heavily dependent upon the bone marrow (BM) microenvironment for their survival. One component of this tumor microenvironment, B-Cell Activating Factor (BAFF), has been implicated as a key player in this interaction. This review discusses the role of BAFF in the pathophysiology of MM, and the potential of BAFF-inhibitory therapy for the treatment of MM. Multiple studies have shown that BAFF functions as a survival factor for MMCs. Furthermore, MMCs express several BAFF-binding receptors. Of these, only Transmembrane Activator and CAML Interactor (TACI) correlates with the MMC's capability to ligate BAFF. Additionally, the level of expression of TACI correlates with the level of the MMC's BM dependency. Ligation of BAFF receptors on MMCs causes activation of the Nuclear Factor of κ-B (NF-κB) pathway, a crucial pathway for the pathogenesis of many B-cell malignancies. Serum BAFF levels are significantly elevated in MM patients when compared to healthy controls, and correlate inversely with overall survival. BAFF signaling is thus an interesting target for the treatment of MM. Several BAFF-inhibitory drugs are currently under evaluation for the treatment of MM. These include BAFF-monoclonal antibodies (tabalumab) and antibody-drug conjugates (GSK2857916)

  8. Efficient Generation of NKX6-1+ Pancreatic Progenitors from Multiple Human Pluripotent Stem Cell Lines

    M. Cristina Nostro

    2015-04-01

    Full Text Available Human pluripotent stem cells (hPSCs represent a renewable source of pancreatic beta cells for both basic research and therapeutic applications. Given this outstanding potential, significant efforts have been made to identify the signaling pathways that regulate pancreatic development in hPSC differentiation cultures. In this study, we demonstrate that the combination of epidermal growth factor (EGF and nicotinamide signaling induces the generation of NKX6-1+ progenitors from all hPSC lines tested. Furthermore, we show that the size of the NKX6-1+ population is regulated by the duration of treatment with retinoic acid, fibroblast growth factor 10 (FGF10, and inhibitors of bone morphogenetic protein (BMP and hedgehog signaling pathways. When transplanted into NOD scid gamma (NSG recipients, these progenitors differentiate to give rise to exocrine and endocrine cells, including monohormonal insulin+ cells. Together, these findings provide an efficient and reproducible strategy for generating highly enriched populations of hPSC-derived beta cell progenitors for studies aimed at further characterizing their developmental potential in vivo and deciphering the pathways that regulate their maturation in vitro.

  9. A Case of Cushing's Syndrome with Multiple Adrenocortical Adenomas Composed of Compact Cells and Clear Cells.

    Asakawa, Masahiro; Yoshimoto, Takanobu; Ota, Mitsutane; Numasawa, Mitsuyuki; Sasahara, Yuriko; Takeuchi, Takato; Nakano, Yujiro; Oohara, Norihiko; Murakami, Masanori; Bouchi, Ryotaro; Minami, Isao; Tsuchiya, Kyoichiro; Hashimoto, Koshi; Izumiyama, Hajime; Kawamura, Naoko; Kihara, Kazunori; Negi, Mariko; Akashi, Takumi; Eishi, Yoshinobu; Sasano, Hironobu; Ogawa, Yoshihiro

    2016-06-01

    A 58-year-old woman was referred to our hospital for Cushingoid features and diagnosed as adrenal Cushing's syndrome due to a right adrenocortical mass (60 × 55 mm). The mass was composed of three different tumors; the first one was homogeneously lipid-poor neoplasm measuring 20 × 13 mm located at the most dorsal region, the second one was heterogeneous and lipid-rich tumor containing multiple foci of calcification measuring 50 × 32 mm located at the central region, and the last one was heterogeneous harboring dilated and tortuous vessels and lipid-poor one measuring 35 × 18 mm at the most ventral region of the adrenal gland. A right adrenalectomy was subsequently performed by open surgery. Macroscopic and microscopic analyses revealed that all three tumors were adrenocortical adenomas; the first one represents a pigmented adrenocortical adenoma, the second one adrenocortical adenoma associated with degeneration, and the third one adrenocortical adenoma harboring extensive degeneration. Immunohistochemical analysis of the steroidogenic enzymes also revealed that all of the tumors had the capacity of synthesizing cortisol. This is a very rare case of Cushing's syndrome caused by multiple adrenocortical adenomas including a pigmented adenoma. Immunohistochemical analysis of steroidogenic enzymes contributed to understanding of steroidogenesis in each of these three different adrenocortical adenomas in this case.

  10. Synchronization of glycolytic oscillations in a yeast cell population

    Dano, S.; Hynne, F.; De Monte, Silvia

    2001-01-01

    The mechanism of active phase synchronization in a suspension of oscillatory yeast cells has remained a puzzle for almost half a century. The difficulty of the problem stems from the fact that the synchronization phenomenon involves the entire metabolic network of glycolysis and fermentation, and...

  11. MESENCHYMAL STEM CELLS AS A THERAPEUTIC STRATEGY FOR MULTIPLE SCLEROSIS: ISSUES AND PERSPECTIVES

    M. M. Zafranskaya

    2017-01-01

    Full Text Available The ability of mesenchymal stem cells (MSC to influence the regulatory/suppressive effect in the autoimmune process and promote remyelination allows to consider them a new method of multiple sclerosis (MS therapy, by means of modifying the disease activity. Genetic stability, proliferative potential, ability to migrate into the damaged tissue areas and agreed protocols for isolation and culture are the main advantages for successful autologous, as well as allogeneic MSC therapy. Preliminary results from clinical studies using MSC application in MS patients show efficiency and safety of this therapeutic approach. Nevertheless, successful dem