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81.
Martin Friedrichsen Pernille Poulsen J?rgen Wojtaszewski Peter Riis Hansen Allan Vaag Henrik Berg Rasmussen 《PloS one》2013,8(2)
Context and Aims
Carboxylesterase 1 (CES1) appears to play an important role in the control of the metabolism of triglycerides and cholesterol in adipocytes and other cell types including hepatocytes. Therefore, it is relevant to gain insights into the genetic versus non-genetic mechanisms involved in the control of CES1 mRNA expression. Here, we investigated CES1 mRNA expression level in adipose tissue and its association with measures of adiposity and metabolic function in a population of elderly twins. Furthermore, the heritability of CES1 mRNA expression level in adipose tissue and the effect of CES1 gene duplication were assessed.Methodology
A total of 295 monozygotic and dizygotic twin subjects (62–83 years) with (n = 48) or without (n = 247) type 2 diabetes mellitus were enrolled in the study. They were subjected to a standard oral glucose tolerance test and excision of abdominal subcutaneous fat biopsies during the fasting state. Levels of CES1 mRNA and copy number of the gene were assessed by quantitative PCR.Results
CES1 mRNA expression level in adipose tissue was positively associated with body-mass index (P<0.001), homeostasis model assessment-insulin resistance (P = 0.003) and level of fasting glucose (P = 0.002), insulin (P = 0.006), and triglycerides (P = 0.003). The heritability for the expression of CES1 mRNA in adipose tissue was high. CES1 gene duplication was positively associated with insulin sensitivity (P = 0.05) as well as glucose tolerance (P = 0.03) and negatively associated with homeostasis model assessment-insulin resistance (P = 0.02). Duplication of CES1 was not linked to mRNA level of this gene (P = 0.63).Conclusion
CES1 mRNA in adipose tissue appears to be under strong genetic control and was associated with measures of metabolic function raising the possibility of a potential role of this enzyme in the development of type 2 diabetes mellitus. Further studies are needed to understand the potential effect of CES1 gene duplication on adipocyte and whole-body metabolic functions. 相似文献82.
83.
Martin R. Jakobsen Kieran Cashin Michael Roche Jasminka Sterjovski Anne Ellett Katharina Borm Jacqueline Flynn Christian Erikstrup Maelenn Gouillou Lachlan R. Gray Nitin K. Saksena Bin Wang Damian F. J. Purcell Per Kallestrup Rutendo Zinyama-Gutsire Exnevia Gomo Henrik Ullum Lars ?stergaard Benhur Lee Paul A. Ramsland Melissa J. Churchill Paul R. Gorry 《PloS one》2013,8(6)
HIV-1 subtype C (C-HIV) is responsible for most HIV-1 cases worldwide. Although the pathogenesis of C-HIV is thought to predominantly involve CCR5-restricted (R5) strains, we do not have a firm understanding of how frequently CXCR4-using (X4 and R5X4) variants emerge in subjects with progressive C-HIV infection. Nor do we completely understand the molecular determinants of coreceptor switching by C-HIV variants. Here, we characterized a panel of HIV-1 envelope glycoproteins (Envs) (n = 300) cloned sequentially from plasma of 21 antiretroviral therapy (ART)-naïve subjects who experienced progression from chronic to advanced stages of C-HIV infection, and show that CXCR4-using C-HIV variants emerged in only one individual. Mutagenesis studies and structural models suggest that the evolution of R5 to X4 variants in this subject principally involved acquisition of an “Ile-Gly” insertion in the gp120 V3 loop and replacement of the V3 “Gly-Pro-Gly” crown with a “Gly-Arg-Gly” motif, but that the accumulation of additional gp120 “scaffold” mutations was required for these V3 loop changes to confer functional effects. In this context, either of the V3 loop changes could confer possible transitional R5X4 phenotypes, but when present together they completely abolished CCR5 usage and conferred the X4 phenotype. Our results show that the emergence of CXCR4-using strains is rare in this cohort of untreated individuals with advanced C-HIV infection. In the subject where X4 variants did emerge, alterations in the gp120 V3 loop were necessary but not sufficient to confer CXCR4 usage. 相似文献
84.
Jenny K. Gustafsson Nazanin Navabi Ana M. Rodriguez-Pi?eiro Ala H. A. Alomran Pushpa Premaratne Harvey R. Fernandez Debashish Banerjee Henrik Sj?vall Gunnar C. Hansson Sara K. Lindén 《PloS one》2013,8(12)
Citrobacter rodentium is an attaching and effacing pathogen used as a murine model for enteropathogenic Escherichia coli. The mucus layers are a complex matrix of molecules, and mucus swelling, hydration and permeability are affected by many factors, including ion composition. Here, we used the C. rodentium model to investigate mucus dynamics during infection. By measuring the mucus layer thickness in tissue explants during infection, we demonstrated that the thickness changes dynamically during the course of infection and that its thickest stage coincides with the start of a decrease of bacterial density at day 14 after infection. Although quantitative PCR analysis demonstrated that mucin mRNA increases during early infection, the increased mucus layer thickness late in infection was not explained by increased mRNA levels. Proteomic analysis of mucus did not demonstrate the appearance of additional mucins, but revealed an increased number of proteins involved in defense responses. Ussing chamber-based electrical measurements demonstrated that ion secretion was dynamically altered during the infection phases. Furthermore, the bicarbonate ion channel Bestrophin-2 mRNA nominally increased, whereas the Cftr mRNA decreased during the late infection clearance phase. Microscopy of Muc2 immunostained tissues suggested that the inner striated mucus layer present in the healthy colon was scarce during the time point of most severe infection (10 days post infection), but then expanded, albeit with a less structured appearance, during the expulsion phase. Together with previously published literature, the data implies a model for clearance where a change in secretion allows reformation of the mucus layer, displacing the pathogen to the outer mucus layer, where it is then outcompeted by the returning commensal flora. In conclusion, mucus and ion secretion are dynamically altered during the C. rodentium infection cycle. 相似文献
85.
Corey Bragg Sam McKechnie Jamie Newman David Fletcher Henrik Moller Darren Scott 《New Zealand journal of zoology.》2013,40(3):275-289
Abstract Sooty shearwater (Puffinus griesus, titi) abundance, harvest levels and chick mass were monitored repeatedly on Putauhinu Island, south‐west of Rakiura (Stewart Island) between 1997 and 2005. Putauhinu is the second largest of the Titi Islands and has a relatively high density of chicks distributed over most of the island, so it supports what is likely the second‐largest population of sooty shearwaters in the Rakiura region (after Taukihepa, Big South Cape Island). Rakiura Maori harvested chicks from five “manu” (family birding areas) that covered 56% of the 128.4 ha of breeding colony of the island. Chick density was lower on the unharvested area in the interior of the island than on harvested areas. Burrow entrance density was higher where there was more ground cover (mainly fern) vegetation, but these areas had lower burrow occupancy, so overall chick density was similar at different levels of ground cover. Twenty‐six harvesters present on Putauhinu in 2005 took 31 280 chicks in total, equivalent to 8.4% (95% CI = 6.6–12%) of the available chicks on the entire island. Seasonal variation in total chicks harvested (CV 15–22%) was not related to chick abundance or mass. Refuges, including impenetrable patches of vegetated ground within manu, the unharvested centre of the island, and even nearby unharvested islands, will ameliorate localised impacts of harvest if density‐dependent immigration is operating. 相似文献
86.
Abstract On Tiritiri, a small predator-free island in northern New Zealand, kiore (Rattus exulans) were live and snap trapped in grassland and forest. In both habitats, kiore abundance peaked in late summer/autumn. The increase followed a 3 month breeding season during which females produced two to three litters, each averaging 7 young. During the population decline in autumn and winter, animals lost weight. Few bred in the breeding season of their birth and none lived to breed in a second breeding season, so the population consisted of distinct age cohorts. These patterns may relate to a highly seasonal food supply. Kiore elsewhere in New Zealand show seasonal breeding, but the length of breeding, sexual maturation, and litter size vary. Other studies of kiore in the Pacific show less marked seasonal fluctuations, longer breeding seasons, and smaller litters. We propose a model to explain the variation in rodent demography in New Zealand. The model is based on the seasonal availability of food, along with the modifying influences of predation and dispersal. 相似文献
87.
Hedayat Zakizadeh Henrik Lütken Sridevy Sriskandarajah Margrethe Serek Renate Müller 《Plant cell reports》2013,32(2):195-205
Key message
The P SAG12 -ipt gene was transferred to miniature rose, as the first woody species, resulting in increased ethylene resistance due to specific up-regulation of the ipt gene under senescence promoting conditions.Abstract
Transgenic plants of Rosa hybrida ‘Linda’ were obtained via transformation with Agrobacterium tumefaciens strain harboring the binary vector pSG529(+) containing the P SAG12 -ipt construct. A. tumefaciens strains AGL1, GV3850 and LBA4404 (containing P35S-INTGUS gene) were used for transformation of embryogenic callus, but transgenic shoots were obtained only when AGL1 was applied. The highest transformation frequency was 10 % and it was achieved when half MS medium was used for the dilution of overnight culture of Agrobacterium. Southern blot confirmed integration of 1–6 copies of the nptII gene into the rose genome in the tested lines. Four transgenic lines were obtained which were morphologically true-to-type and indistinguishable from Wt shoots while they were in in vitro cultures. Adventitious root induction was more difficult in transgenic shoots compared to the Wt shoots, however, one of the transgenic lines (line 6) was rooted and subsequently analyzed phenotypically. The ipt expression levels were determined in this line after exposure to exogenous ethylene (3.5 μl l?1) and/or darkness. Darkness resulted in twofold up-regulation of ipt expression, whereas darkness combined with ethylene caused eightfold up-regulation in line 6 compared to Wt plants. The transgenic line had significantly higher content of chlorophyll at the end of the treatment period compared to Wt plants. 相似文献88.
Stéphanie B. N. Serre Henrik B. Krarup Jens Bukh Judith M. Gottwein 《Journal of virology》2013,87(23):12776-12793
Alpha interferon (IFN-α) is an essential component of innate antiviral immunity and of treatment regimens for chronic hepatitis C virus (HCV) infection. Resistance to IFN might be important for HCV persistence and failure of IFN-based therapies. Evidence for HCV genetic correlates of IFN resistance is limited. Experimental studies were hampered by lack of HCV culture systems. Using genotype (strain) 1a(H77) and 3a(S52) Core-NS2 JFH1-based recombinants, we aimed at identifying viral correlates of IFN-α resistance in vitro. Long-term culture with IFN-α2b in Huh7.5 cells resulted in viral spread with acquisition of putative escape mutations in HCV structural and nonstructural proteins. Reverse genetic studies showed that primarily amino acid changes I348T in 1a(H77) E1 and F345V/V414A in 3a(S52) E1/E2 increased viral fitness. Single-cycle assays revealed that I348T and F345V/V414A enhanced viral entry and release, respectively. In assays allowing viral spread, these mutations conferred a level of IFN-α resistance exceeding the observed fitness effect. The identified mutations acted in a subtype-specific manner but were not found in genotype 1a and 3a patients, who failed IFN-α therapy. Studies with HCV recombinants with different degrees of culture adaptation confirmed the correlation between viral fitness and IFN-α resistance. In conclusion, in vitro escape experiments led to identification of HCV envelope mutations resulting in increased viral fitness and conferring IFN-α resistance. While we established a close link between viral fitness and IFN-α resistance, identified mutations acted via different mechanisms and appeared to be relatively specific to the infecting virus, possibly explaining difficulties in identifying signature mutations for IFN resistance. 相似文献
89.
Majid Haddad Momeni Christina M. Payne Henrik Hansson Nils Egil Mikkelsen Jesper Svedberg ?ke Engstr?m Mats Sandgren Gregg T. Beckham Jerry St?hlberg 《The Journal of biological chemistry》2013,288(8):5861-5872
Root rot fungi of the Heterobasidion annosum complex are the most damaging pathogens in temperate forests, and the recently sequenced Heterobasidion irregulare genome revealed over 280 carbohydrate-active enzymes. Here, H. irregulare was grown on biomass, and the most abundant protein in the culture filtrate was identified as the only family 7 glycoside hydrolase in the genome, which consists of a single catalytic domain, lacking a linker and carbohydrate-binding module. The enzyme, HirCel7A, was characterized biochemically to determine the optimal conditions for activity. HirCel7A was crystallized and the structure, refined at 1.7 Å resolution, confirms that HirCel7A is a cellobiohydrolase rather than an endoglucanase, with a cellulose-binding tunnel that is more closed than Phanerochaete chrysosporium Cel7D and more open than Hypocrea jecorina Cel7A, suggesting intermediate enzyme properties. Molecular simulations were conducted to ascertain differences in enzyme-ligand interactions, ligand solvation, and loop flexibility between the family 7 glycoside hydrolase cellobiohydrolases from H. irregulare, H. jecorina, and P. chrysosporium. The structural comparisons and simulations suggest significant differences in enzyme-ligand interactions at the tunnel entrance in the −7 to −4 binding sites and suggest that a tyrosine residue at the tunnel entrance of HirCel7A may serve as an additional ligand-binding site. Additionally, the loops over the active site in H. jecorina Cel7A are more closed than loops in the other two enzymes, which has implications for the degree of processivity, endo-initiation, and substrate dissociation. Overall, this study highlights molecular level features important to understanding this biologically and industrially important family of glycoside hydrolases. 相似文献
90.