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61.
Tom?Ashmore Lee?D.?Roberts Andrea?J.?Morash Aleksandra?O.?Kotwica John?Finnerty James?A.?West Steven?A.?Murfitt Bernadette?O.?Fernandez Cristina?Branco Andrew?S.?Cowburn Kieran?Clarke Randall?S.?Johnson Martin?Feelisch Julian?L.?Griffin Andrew?J.?MurrayEmail author 《BMC biology》2015,13(1):110
Background
Insulin sensitivity in skeletal muscle is associated with metabolic flexibility, including a high capacity to increase fatty acid (FA) oxidation in response to increased lipid supply. Lipid overload, however, can result in incomplete FA oxidation and accumulation of potentially harmful intermediates where mitochondrial tricarboxylic acid cycle capacity cannot keep pace with rates of β-oxidation. Enhancement of muscle FA oxidation in combination with mitochondrial biogenesis is therefore emerging as a strategy to treat metabolic disease. Dietary inorganic nitrate was recently shown to reverse aspects of the metabolic syndrome in rodents by as yet incompletely defined mechanisms.Results
Herein, we report that nitrate enhances skeletal muscle FA oxidation in rodents in a dose-dependent manner. We show that nitrate induces FA oxidation through a soluble guanylate cyclase (sGC)/cGMP-mediated PPARβ/δ- and PPARα-dependent mechanism. Enhanced PPARβ/δ and PPARα expression and DNA binding induces expression of FA oxidation enzymes, increasing muscle carnitine and lowering tissue malonyl-CoA concentrations, thereby supporting intra-mitochondrial pathways of FA oxidation and enhancing mitochondrial respiration. At higher doses, nitrate induces mitochondrial biogenesis, further increasing FA oxidation and lowering long-chain FA concentrations. Meanwhile, nitrate did not affect mitochondrial FA oxidation in PPARα?/? mice. In C2C12 myotubes, nitrate increased expression of the PPARα targets Cpt1b, Acadl, Hadh and Ucp3, and enhanced oxidative phosphorylation rates with palmitoyl-carnitine; however, these changes in gene expression and respiration were prevented by inhibition of either sGC or protein kinase G. Elevation of cGMP, via the inhibition of phosphodiesterase 5 by sildenafil, also increased expression of Cpt1b, Acadl and Ucp3, as well as CPT1B protein levels, and further enhanced the effect of nitrate supplementation.Conclusions
Nitrate may therefore be effective in the treatment of metabolic disease by inducing FA oxidation in muscle.62.
Esperanza Diaz Beatriz Poblador-Pou Luis-Andrés Gimeno-Feliu Amaia Calderón-Larra?aga Bernadette N. Kumar Alexandra Prados-Torres 《PloS one》2015,10(12)
Introduction
As the flows of immigrant populations increase worldwide, their heterogeneity becomes apparent with respect to the differences in the prevalence of chronic physical and mental disease. Multimorbidity provides a new framework in understanding chronic diseases holistically as the consequence of environmental, social, and personal risks that contribute to increased vulnerability to a wide variety of illnesses. There is a lack of studies on multimorbidity among immigrants compared to native-born populations.Methodology
This nationwide multi-register study in Norway enabled us i) to study the associations between multimorbidity and immigrant origin, accounting for other known risk factors for multimorbidity such as gender, age and socioeconomic levels using logistic regression analyses, and ii) to identify patterns of multimorbidity in Norway for immigrants and Norwegian-born by means of exploratory factor analysis technique.Results
Multimorbidity rates were lower for immigrants compared to Norwegian-born individuals, with unadjusted odds ratios (OR) and 95% confidence intervals 0.38 (0.37–0.39) for Eastern Europe, 0.58 (0.57–0.59) for Asia, Africa and Latin America, and 0.67 (0.66–0.68) for Western Europe and North America. Results remained significant after adjusting for socioeconomic factors. Similar multimorbidity disease patterns were observed among Norwegian-born and immigrants, in particular between Norwegian-born and those from Western European and North American countries. However, the complexity of patterns that emerged for the other immigrant groups was greater. Despite differences observed in the development of patterns with age, such as ischemic heart disease among immigrant women, we were unable to detect the systematic development of the multimorbidity patterns among immigrants at younger ages.Conclusions
Our study confirms that migrants have lower multimorbidity levels compared to Norwegian-born. The greater complexity of multimorbidity patterns for some immigrant groups requires further investigation. Health care policies and practice will require a holistic approach for specific population groups in order to meet their health needs and to curb and prevent diseases. 相似文献63.
Paul R. Torgerson José E. Hagan Federico Costa Juan Calcagno Michael Kane Martha S. Martinez-Silveira Marga G. A. Goris Claudia Stein Albert I. Ko Bernadette Abela-Ridder 《PLoS neglected tropical diseases》2015,9(10)
Background
Leptospirosis, a spirochaetal zoonosis, occurs in diverse epidemiological settings and affects vulnerable populations, such as rural subsistence farmers and urban slum dwellers. Although leptospirosis can cause life-threatening disease, there is no global burden of disease estimate in terms of Disability Adjusted Life Years (DALYs) available.Methodology/Principal Findings
We utilised the results of a parallel publication that reported global estimates of morbidity and mortality due to leptospirosis. We estimated Years of Life Lost (YLLs) from age and gender stratified mortality rates. Years of Life with Disability (YLDs) were developed from a simple disease model indicating likely sequelae. DALYs were estimated from the sum of YLLs and YLDs. The study suggested that globally approximately 2·90 million DALYs are lost per annum (UIs 1·25–4·54 million) from the approximately annual 1·03 million cases reported previously. Males are predominantly affected with an estimated 2·33 million DALYs (UIs 0·98–3·69) or approximately 80% of the total burden. For comparison, this is over 70% of the global burden of cholera estimated by GBD 2010. Tropical regions of South and South-east Asia, Western Pacific, Central and South America, and Africa had the highest estimated leptospirosis disease burden.Conclusions/Significance
Leptospirosis imparts a significant health burden worldwide, which approach or exceed those encountered for a number of other zoonotic and neglected tropical diseases. The study findings indicate that highest burden estimates occur in resource-poor tropical countries, which include regions of Africa where the burden of leptospirosis has been under-appreciated and possibly misallocated to other febrile illnesses such as malaria. 相似文献64.
Bernadette A.S. J?ger Charlotte Finkenzeller Carolin Bock Leonie Majunke Julia K. Jueckstock Ulrich Andergassen Julia K. Neugebauer Aurelia Pestka Thomas W.P. Friedl Udo Jeschke Wolfgang Janni Sophie F. Doisneau-Sixou Brigitte K. Rack 《Translational oncology》2015,8(6):509-516
BACKGROUND: We evaluated both estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status on disseminated tumor cells (DTCs) in the bone marrow of 54 patients with early breast cancer and compared these with the corresponding primary tumor (PT). MATERIALS AND METHODS: Bone marrow aspirates were obtained at the time of first surgery, and ER and HER2 status on DTCs was assessed simultaneously by immunocytochemistry using a triple fluorescence staining method. RESULTS: The median number of DTCs was 13 (range 1-95). The concordance rate between ER status on DTC and PT was 74%. Patients with an ER-positive PT were significantly more likely to have at least one ER-positive DTC (34 out of 42) than patients with an ER-negative PT (6 out of 12; P = .031). Thirty-nine (93%) of the 42 patients with ER-positive PT had at least one ER-negative DTC. The concordance rate between HER2 status on DTC and PT was 52%. The probability of having at least one HER2-positive DTC was not related to the HER2 status of the PT (P = 0.56). Twenty-two (46%) of the 48 patients with a HER2-negative PT had at least one HER2-positive DTC. All the six patients with a HER2-positive PT had at least one HER2-negative DTC. CONCLUSION: Taken together, our study confirms that ER and/or HER2 status may differ between DTC and PT. This discordance could be important for patients lacking ER or HER2 expression on the PT but showing ER-positive or HER2-positive DTC because they might benefit from an endocrine and/or HER2-targeted therapy. 相似文献
65.
66.
Jonathan Pettitt Lucas Philippe Debjani Sarkar Christopher Johnston Henrike Johanna Gothe Diane Massie Bernadette Connolly Berndt Müller 《Genetics》2014,197(4):1201-1211
The organization of genes into operons, clusters of genes that are co-transcribed to produce polycistronic pre-mRNAs, is a trait found in a wide range of eukaryotic groups, including multiple animal phyla. Operons are present in the class Chromadorea, one of the two main nematode classes, but their distribution in the other class, the Enoplea, is not known. We have surveyed the genomes of Trichinella spiralis, Trichuris muris, and Romanomermis culicivorax and identified the first putative operons in members of the Enoplea. Consistent with the mechanism of polycistronic RNA resolution in other nematodes, the mRNAs produced by genes downstream of the first gene in the T. spiralis and T. muris operons are trans-spliced to spliced leader RNAs, and we are able to detect polycistronic RNAs derived from these operons. Importantly, a putative intercistronic region from one of these potential enoplean operons confers polycistronic processing activity when expressed as part of a chimeric operon in Caenorhabditis elegans. We find that T. spiralis genes located in operons have an increased likelihood of having operonic C. elegans homologs. However, operon structure in terms of synteny and gene content is not tightly conserved between the two taxa, consistent with models of operon evolution. We have nevertheless identified putative operons conserved between Enoplea and Chromadorea. Our data suggest that operons and “spliced leader” (SL) trans-splicing predate the radiation of the nematode phylum, an inference which is supported by the phylogenetic profile of proteins known to be involved in nematode SL trans-splicing. 相似文献
67.
Chae PS Rasmussen SG Rana RR Gotfryd K Chandra R Goren MA Kruse AC Nurva S Loland CJ Pierre Y Drew D Popot JL Picot D Fox BG Guan L Gether U Byrne B Kobilka B Gellman SH 《Nature methods》2010,7(12):1003-1008
The understanding of integral membrane protein (IMP) structure and function is hampered by the difficulty of handling these proteins. Aqueous solubilization, necessary for many types of biophysical analysis, generally requires a detergent to shield the large lipophilic surfaces of native IMPs. Many proteins remain difficult to study owing to a lack of suitable detergents. We introduce a class of amphiphiles, each built around a central quaternary carbon atom derived from neopentyl glycol, with hydrophilic groups derived from maltose. Representatives of this maltose-neopentyl glycol (MNG) amphiphile family show favorable behavior relative to conventional detergents, as manifested in multiple membrane protein systems, leading to enhanced structural stability and successful crystallization. MNG amphiphiles are promising tools for membrane protein science because of the ease with which they may be prepared and the facility with which their structures may be varied. 相似文献
68.
Leyvraz C Charles RP Rubera I Guitard M Rotman S Breiden B Sandhoff K Hummler E 《The Journal of cell biology》2005,170(3):487-496
Serine proteases are proteolytic enzymes that are involved in the regulation of various physiological processes. We generated mice lacking the membrane-anchored channel-activating serine protease (CAP) 1 (also termed protease serine S1 family member 8 [Prss8] and prostasin) in skin, and these mice died within 60 h after birth. They presented a lower body weight and exhibited severe malformation of the stratum corneum (SC). This aberrant skin development was accompanied by an impaired skin barrier function, as evidenced by dehydration and skin permeability assay and transepidermal water loss measurements leading to rapid, fatal dehydration. Analysis of differentiation markers revealed no major alterations in CAP1/Prss8-deficient skin even though the epidermal deficiency of CAP1/Prss8 expression disturbs SC lipid composition, corneocyte morphogenesis, and the processing of profilaggrin. The examination of tight junction proteins revealed an absence of occludin, which did not prevent the diffusion of subcutaneously injected tracer (approximately 600 D) toward the skin surface. This study shows that CAP1/Prss8 expression in the epidermis is crucial for the epidermal permeability barrier and is, thereby, indispensable for postnatal survival. 相似文献
69.
Shyam K. Sharan Bernadette Holdener-Kenny David W. Threadgill Terry Magnuson 《Mammalian genome》1992,3(2):79-83
Sensitive methods for analysis of DNA from limited amounts of tissue are often difficult, error prone, and time consuming. Here, we describe a procedure for molecular analysis of individual early post-implantation mouse embryos by Southern analysis. The procedure involves embedding single embryos in agarose before lysing and deproteinizing in situ. The embedded DNA can be digested with restriction enzymes and analyzed by standard Southern-blotting procedures. The procedure is sensitive enough to detect single-copy sequences in embryos as early as day 6.5 of development. We have used the technique to genotype embryos homozygous for an embryonic lethal deletion. Normally, the lethal phenotype associated with such mutations is identified by a retrospective statistical analysis of abnormal embryos produced from a heterozygous cross as compared to those produced from a control cross. Now, if associated with a detectable DNA abnormality, the mutant embryo can be genotyped directly. We also report the use of this method for mapping cloned markers relative to deletion breakpoints. This approach can save considerable time since mapping would conventionally be done using restriction fragment length polymorphisms (RFLPs) detected in Mus musculus/Mus spretus interspecies hybrids. Using this procedure, we have been able to redefine the distal limits of the region of Chromosome (Chr) 7 containing a gene (eed) needed for development of the embryonic ectoderm. 相似文献
70.
P. Mark Hogarth Margaret L. Hibbs Lisa Bonadonna Bernadette M. Scott Ewa Witort Geoffrey A. Pietersz Ian F. C. McKenzie 《Immunogenetics》1987,26(3):161-168
A cDNA clone encoding the mouse Ly-17+ Fc receptor for IgG, isolated from a myelomonocytic cell line, was sequenced and expression of mRNA and the functional FcR investigated. The receptor is a 301 amino acid transmembrane glycoprotein with two homologous extracellular domains that are also homologous to members of the Ig superfamily. The receptor has four sites of N-linked glycosylation and a long 94 amino acid cytoplasmic tail. Northern analysis, immune complex binding, and serological studies demonstrate that the receptor encoded by the cDNA clone binds mouse IgG1/2b and rabbit IgG complexes. 相似文献