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  • 1
    Publication Date: 2012-04-25
    Description: Mutations leading to expansion of a poly-glutamine track in Huntingtin (Htt) cause Huntington's disease (HD). Signs of endoplasmic reticulum (ER) stress have been recently reported in animal models of HD, associated with the activation of the unfolded protein response (UPR). Here we have investigated the functional contribution of ER stress to HD by targeting the expression of two main UPR transcription factors, XBP1 and ATF4 (activating transcription factor 4), in full-length mutant Huntingtin (mHtt) transgenic mice. XBP1-deficient mice were more resistant to developing disease features, associated with improved neuronal survival and motor performance, and a drastic decrease in mHtt levels. The protective effects of XBP1 deficiency were associated with enhanced macroautophagy in both cellular and animal models of HD. In contrast, ATF4 deficiency did not alter mHtt levels. Although, XBP1 mRNA splicing was observed in the striatum of HD transgenic brains, no changes in the levels of classical ER stress markers were detected in symptomatic animals. At the mechanistic level, we observed that XBP1 deficiency led to augmented expression of Forkhead box O1 (FoxO1), a key transcription factor regulating autophagy in neurons. In agreement with this finding, ectopic expression of FoxO1 enhanced autophagy and mHtt clearance in vitro . Our results provide strong evidence supporting an involvement of XBP1 in HD pathogenesis probably due to an ER stress-independent mechanism involving the control of FoxO1 and autophagy levels.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
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  • 2
    Publication Date: 2012-10-01
    Description: The assemblage strontium anorthite, quartz, and kyanite was reacted with H 2 O+CaCl 2 solutions at 500 °C and pressures between 460 and ~1300 MPa using a hydrothermal diamond-anvil cell. Information on the kinetics was obtained in situ based on time-resolved synchrotron-radiation X-ray fluorescence analyses of the Sr concentration in the fluid. The reaction products (anorthite or zoisite) were studied using transmission electron microscopy to obtain information on the reaction mechanism and mineral-fluid partitioning of strontium. The time required for equilibration was primarily controlled by the reaction mechanism, but not discernibly affected by pressure or chloride concentration. Nucleation and growth of zoisite at the expense of strontium anorthite was much faster than the Sr-Ca exchange reaction of strontium anorthite to anorthite, and resulted in chemically homogeneous crystals. The anorthite had developed a high nanoporosity during the reaction, which is indicative of coupled dissolution-precipitation. A zoisite-fluid exchange coefficient \[ {K}_{D(\hbox{ Sr }-\hbox{ Ca })}^{\hbox{ zoisite }-\hbox{ fluid }}=\frac{{X}_{\hbox{ Sr }}^{\hbox{ zoisite }}}{{X}_{\hbox{ Ca }}^{\hbox{ zoisite }}}/\frac{{X}_{\hbox{ Sr }}^{\hbox{ fluid }}}{{X}_{\hbox{ Ca }}^{\hbox{ fluid }}}=0.42 \] was obtained for the Sr-Ca fractionation at 500 °C and ~1300 MPa. At low bulk Sr/Ca, this value is in very good agreement with literature data, which are based on zoisite syntheses from oxide and hydroxide mixtures in chloridic fluids at 600 °C, 2 GPa and analyses after quench. This suggests that the Ca-Sr ratios in fluid and zoisite were not affected by back reactions during quenching. The constrained anorthite-fluid Sr partition coefficient for 500 °C, 460 MPa is, likewise, consistent with literature data, but determination of mineral-fluid partition and exchange coefficients can be hampered by quench phases in nanopores if coupled dissolution-precipitation acted as reaction mechanism.
    Print ISSN: 0003-004X
    Electronic ISSN: 1945-3027
    Topics: Geosciences
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  • 3
    Publication Date: 2013-12-11
    Description: Analysis of genome sequences of 159 isolates of Plasmodium falciparum from Senegal yields an extraordinarily high proportion (26.85%) of protein-coding genes with the ratio of nonsynonymous to synonymous polymorphism greater than one. This proportion is much greater than observed in other organisms. Also unusual is that the site-frequency spectra of...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 4
    Publication Date: 2007-08-31
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Borden, J H -- Marland, G -- Schlamadinger, B -- Matthews, R -- Schulze, E D -- Wirth, C -- Heimann, M -- New York, N.Y. -- Science. 2000 Dec 8;290(5498):1895c-986c.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17742053" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2012-08-08
    Description: Through rapid genetic adaptation and natural selection, the Plasmodium falciparum parasite—the deadliest of those that cause malaria—is able to develop resistance to antimalarial drugs, thwarting present efforts to control it. Genome-wide association studies (GWAS) provide a critical hypothesis-generating tool for understanding how this occurs. However, in P. falciparum, the limited amount of linkage disequilibrium hinders the power of traditional array-based GWAS. Here, we demonstrate the feasibility and power improvements gained by using whole-genome sequencing for association studies. We analyzed data from 45 Senegalese parasites and identified genetic changes associated with the parasites’ in vitro response to 12 different antimalarials. To further increase statistical power, we adapted a common test for natural selection, XP-EHH (cross-population extended haplotype homozygosity), and used it to identify genomic regions associated with resistance to drugs. Using this sequence-based approach and the combination of association and selection-based tests, we detected several loci associated with drug resistance. These loci included the previously known signals at pfcrt, dhfr, and pfmdr1, as well as many genes not previously implicated in drug-resistance roles, including genes in the ubiquitination pathway. Based on the success of the analysis presented in this study, and on the demonstrated shortcomings of array-based approaches, we argue for a complete transition to sequence-based GWAS for small, low linkage-disequilibrium genomes like that of P. falciparum.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 6
    Publication Date: 2012-10-17
    Description: Malaria is a deadly disease that causes nearly one million deaths each year. To develop methods to control and eradicate malaria, it is important to understand the genetic basis of Plasmodium falciparum adaptations to antimalarial treatments and the human immune system while taking into account its demographic history. To study the demographic history and identify genes under selection more efficiently, we sequenced the complete genomes of 25 culture-adapted P. falciparum isolates from three sites in Senegal. We show that there is no significant population structure among these Senegal sampling sites. By fitting demographic models to the synonymous allele-frequency spectrum, we also estimated a major 60-fold population expansion of this parasite population ~20,000–40,000 years ago. Using inferred demographic history as a null model for coalescent simulation, we identified candidate genes under selection, including genes identified before, such as pfcrt and PfAMA1 , as well as new candidate genes. Interestingly, we also found selection against G/C to A/T changes that offsets the large mutational bias toward A/T, and two unusual patterns: similar synonymous and nonsynonymous allele-frequency spectra, and 18% of genes having a nonsynonymous-to-synonymous polymorphism ratio 〉1.
    Print ISSN: 0737-4038
    Electronic ISSN: 1537-1719
    Topics: Biology
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  • 7
    Publication Date: 2014-01-15
    Description: Drug resistance emerges in an ecological context where fitness costs restrict the diversity of escape pathways. These pathways are targets for drug discovery, and here we demonstrate that we can identify small-molecule inhibitors that differentially target resistant parasites. Combining wild-type and mutant-type inhibitors may prevent the emergence of competitively viable...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 8
    Publication Date: 2022-05-25
    Description: Author Posting. © American Geophysical Union, 2007. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 112 (2007): G02029, doi:10.1029/2006JG000380.
    Description: Wildfire is a common occurrence in ecosystems of northern high latitudes, and changes in the fire regime of this region have consequences for carbon feedbacks to the climate system. To improve our understanding of how wildfire influences carbon dynamics of this region, we used the process-based Terrestrial Ecosystem Model to simulate fire emissions and changes in carbon storage north of 45°N from the start of spatially explicit historically recorded fire records in the twentieth century through 2002, and evaluated the role of fire in the carbon dynamics of the region within the context of ecosystem responses to changes in atmospheric CO2 concentration and climate. Our analysis indicates that fire plays an important role in interannual and decadal scale variation of source/sink relationships of northern terrestrial ecosystems and also suggests that atmospheric CO2 may be important to consider in addition to changes in climate and fire disturbance. There are substantial uncertainties in the effects of fire on carbon storage in our simulations. These uncertainties are associated with sparse fire data for northern Eurasia, uncertainty in estimating carbon consumption, and difficulty in verifying assumptions about the representation of fires that occurred prior to the start of the historical fire record. To improve the ability to better predict how fire will influence carbon storage of this region in the future, new analyses of the retrospective role of fire in the carbon dynamics of northern high latitudes should address these uncertainties.
    Description: Funding for this study was provided by grants from the National Science Foundation Biocomplexity Program (ATM-0120468) and Office of Polar Programs (OPP-0531047 and OPP- 0327664); the National Aeronautics and Space Administration Land Cover Land Use Change Program (NAF-11142) and North America Carbon Program (NNG05GD25G); the Bonanza Creek LTER (Long-Term Ecological Research) Program (funded jointly by NSF grant DEB-0423442 and USDA Forest Service, Pacific Northwest Research Station grant PNW01- JV11261952-231); and the U.S. Geological Survey.
    Keywords: Fire emissions ; Ecosystem modeling ; Boreal carbon dynamics
    Repository Name: Woods Hole Open Access Server
    Type: Article
    Format: application/pdf
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  • 9
    Publication Date: 2022-05-26
    Description: Author Posting. © The Author(s), 2006. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Ecosystems 9 (2006): 1041-1050, doi:10.1007/s10021-005-0105-7.
    Description: Recent patterns and projections of climatic change have focused increased scientific and public attention on patterns of carbon (C) cycling and its controls, particularly the factors that determine whether an ecosystem is a net source or sink of atmospheric CO2. Net ecosystem production (NEP), a central concept in C-cycling research, has been used to represent two different concepts by C-cycling scientists. We propose that NEP be restricted to just one of its two original definitions—the imbalance between gross primary production (GPP) and ecosystem respiration (ER), and that a new term—net ecosystem carbon balance (NECB)—be applied to the net rate of C accumulation in (or loss from; negative sign) ecosystems. NECB differs from NEP when C fluxes other than C fixation and respiration occur or when inorganic C enters or leaves in dissolved form. These fluxes include leaching loss or lateral transfer of C from the ecosystem; emission of volatile organic C, methane, and carbon monoxide; and soot and CO2 from fire. C fluxes in addition to NEP are particularly important determinants of NECB over long time scales. However, even over short time scales, they are important in ecosystems such as streams, estuaries, wetlands, and cities. Recent technological advances have led to a diversity of approaches to measuring C fluxes at different temporal and spatial scales. These approaches frequently capture different components of NEP or NECB and can therefore be compared across scales only by carefully specifying the fluxes included in the measurements. By explicitly identifying the fluxes that comprise NECB and other components of the C cycle, such as net ecosystem exchange (NEE) and net biome production (NBP), we provide a less ambiguous framework for understanding and communicating recent changes in the global C cycle. Key words: Net ecosystem production, net ecosystem carbon balance, gross primary production, ecosystem respiration, autotrophic respiration, heterotrophic respiration, net ecosystem exchange, net biome production, net primary production.
    Keywords: Net ecosystem production ; Net ecosystem carbon balance ; Gross primary production ; Ecosystem respiration ; Autotrophic respiration ; Heterotrophic respiration ; Net ecosystem exchange ; Net biome production ; Net primary production
    Repository Name: Woods Hole Open Access Server
    Type: Preprint
    Format: 297623 bytes
    Format: application/pdf
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  • 10
    Publication Date: 2014-09-15
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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