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981.
Kohli MA Lucae S Saemann PG Schmidt MV Demirkan A Hek K Czamara D Alexander M Salyakina D Ripke S Hoehn D Specht M Menke A Hennings J Heck A Wolf C Ising M Schreiber S Czisch M Müller MB Uhr M Bettecken T Becker A Schramm J Rietschel M Maier W Bradley B Ressler KJ Nöthen MM Cichon S Craig IW Breen G Lewis CM Hofman A Tiemeier H van Duijn CM Holsboer F Müller-Myhsok B Binder EB 《Neuron》2011,70(2):252-265
Major depression (MD) is one of the most prevalent psychiatric disorders and a leading cause of loss in work productivity. A combination of genetic and environmental risk factors probably contributes to MD. We present data from a genome-wide association study revealing a neuron-specific neutral amino acid transporter (SLC6A15) as a susceptibility gene for MD. Risk allele carrier status in humans and chronic stress in mice were associated with a downregulation of the expression of this gene in the hippocampus, a brain region implicated in the pathophysiology of?MD. The same polymorphisms also showed associations with alterations in hippocampal volume and neuronal integrity. Thus, decreased SLC6A15 expression, due to genetic or environmental factors, might alter neuronal circuits related to the susceptibility for MD. Our convergent data from human genetics, expression studies, brain imaging, and animal models suggest a pathophysiological mechanism for MD that may be accessible to drug targeting. 相似文献
982.
Jason T. Hoverman Christopher J. Davis Earl E. Werner David K. Skelly Rick A. Relyea Kerry L. Yurewicz 《Ecography》2011,34(6):1049-1058
A fundamental goal of ecology is to understand the factors that influence community structure and, consequently, generate heterogeneity in species richness across habitats. While niche‐assembly (e.g. species‐sorting) and dispersal‐assembly mechanisms are widely recognized as factors structuring communities, there remains substantial debate concerning the relative importance of each of these mechanisms. Using freshwater snails as a model system, we explore how abiotic and biotic factors interact with dispersal to structure local communities and generate regional patterns in species richness. Our data set consisted of 24 snail species from 43 ponds and lakes surveyed for seven years on the Univ. of Michigan's E. S. George Reserve and Pinckney State Recreation Area near Ann Arbor, Michigan. We found that heterogeneity in habitat conditions mediated species‐sorting mechanism to drive patterns in snail species richness across sites. In particular, physical environmental variables (i.e. habitat area, hydroperiod, and canopy cover), pH, and fish presence accounted for the majority of variation in the species richness across sites. We also found evidence of Gleasonian structure (i.e. significant species turnover with stochastic species loss) in the metacommunity. Turnover in snail species distributions was driven by the replacement of several pulmonate species with prosobranch species at the pond permanence transition. Turnover appeared to be driven by physiological constraints associated with differences in respiration mode between the snail orders and shell characteristics that deter molluscivorous fish. In contrast to these niche‐assembly mechanisms, there was no evidence that dispersal‐assembly mechanisms were structuring the communities. This suggests that niche‐assembly mechanisms are more important than dispersal‐assembly mechanisms for structuring local snail communities. 相似文献
983.
Shao L Hewitt MC Wang F Malcolm SC Ma J Campbell JE Campbell UC Engel SR Spicer NA Hardy LW Schreiber R Spear KL Varney MA 《Bioorganic & medicinal chemistry letters》2011,21(5):1434-1437
Novel chiral cyclohexylaryl amines were developed with potent reuptake inhibition against the serotonin, norepinephrine and dopamine transporters and activity at 10 and 30 mpk PO in the mouse tail suspension test. Prototype compound 31 (SERT, NET, DAT IC50 ? 1, 21, 28 nM) was highly brain penetrant, had minimal CYP and hERG inhibition, and represents a previously undisclosed architecture with potential for treatment of major depressive disorder. 相似文献
984.
Xu F Peng G Phan T Dilip U Chen JL Chernov-Rogan T Zhang X Grindstaff K Annamalai T Koller K Gallop MA Wustrow DJ 《Bioorganic & medicinal chemistry letters》2011,21(21):6582-6585
Structure-activity studies have led to a discovery of 3-(4-pyridyl)methyl ether derivative 9d that has 25- to 50-fold greater functional potency than R-baclofen at human and rodent GABA(B) receptors in vitro. Mouse hypothermia studies confirm that this compound crosses the blood-brain barrier and is approximately 50-fold more potent after systemic administration. 相似文献
985.
Shao L Wang F Malcolm SC Ma J Hewitt MC Campbell UC Bush LR Spicer NA Engel SR Saraswat LD Hardy LW Koch P Schreiber R Spear KL Varney MA 《Bioorganic & medicinal chemistry》2011,19(1):663-676
The present work describes a series of novel chiral amines that potently inhibit the in vitro reuptake of serotonin, norepinephrine and dopamine (triple reuptake inhibitors) and were active in vivo in a mouse model predictive of antidepressant like activity. The detailed synthesis and in vitro activity and ADME profile of compounds is described, which represent a previously undisclosed triple reuptake inhibitor chemotype. 相似文献
986.
Aukema JE Leung B Kovacs K Chivers C Britton KO Englin J Frankel SJ Haight RG Holmes TP Liebhold AM McCullough DG Von Holle B 《PloS one》2011,6(9):e24587
Reliable estimates of the impacts and costs of biological invasions are critical to developing credible management, trade and regulatory policies. Worldwide, forests and urban trees provide important ecosystem services as well as economic and social benefits, but are threatened by non-native insects. More than 450 non-native forest insects are established in the United States but estimates of broad-scale economic impacts associated with these species are largely unavailable. We developed a novel modeling approach that maximizes the use of available data, accounts for multiple sources of uncertainty, and provides cost estimates for three major feeding guilds of non-native forest insects. For each guild, we calculated the economic damages for five cost categories and we estimated the probability of future introductions of damaging pests. We found that costs are largely borne by homeowners and municipal governments. Wood- and phloem-boring insects are anticipated to cause the largest economic impacts by annually inducing nearly $1.7 billion in local government expenditures and approximately $830 million in lost residential property values. Given observations of new species, there is a 32% chance that another highly destructive borer species will invade the U.S. in the next 10 years. Our damage estimates provide a crucial but previously missing component of cost-benefit analyses to evaluate policies and management options intended to reduce species introductions. The modeling approach we developed is highly flexible and could be similarly employed to estimate damages in other countries or natural resource sectors. 相似文献
987.
Kerry PS Ayllon J Taylor MA Hass C Lewis A García-Sastre A Randall RE Hale BG Russell RJ 《PloS one》2011,6(3):e17946
Influenza A virus NS1 protein is a multifunctional virulence factor consisting of an RNA binding domain (RBD), a short linker, an effector domain (ED), and a C-terminal 'tail'. Although poorly understood, NS1 multimerization may autoregulate its actions. While RBD dimerization seems functionally conserved, two possible apo ED dimers have been proposed (helix-helix and strand-strand). Here, we analyze all available RBD, ED, and full-length NS1 structures, including four novel crystal structures obtained using EDs from divergent human and avian viruses, as well as two forms of a monomeric ED mutant. The data reveal the helix-helix interface as the only strictly conserved ED homodimeric contact. Furthermore, a mutant NS1 unable to form the helix-helix dimer is compromised in its ability to bind dsRNA efficiently, implying that ED multimerization influences RBD activity. Our bioinformatical work also suggests that the helix-helix interface is variable and transient, thereby allowing two ED monomers to twist relative to one another and possibly separate. In this regard, we found a mAb that recognizes NS1 via a residue completely buried within the ED helix-helix interface, and which may help highlight potential different conformational populations of NS1 (putatively termed 'helix-closed' and 'helix-open') in virus-infected cells. 'Helix-closed' conformations appear to enhance dsRNA binding, and 'helix-open' conformations allow otherwise inaccessible interactions with host factors. Our data support a new model of NS1 regulation in which the RBD remains dimeric throughout infection, while the ED switches between several quaternary states in order to expand its functional space. Such a concept may be applicable to other small multifunctional proteins. 相似文献
988.
Nitrate paradigm does not hold up for sugarcane 总被引:1,自引:0,他引:1
Robinson N Brackin R Vinall K Soper F Holst J Gamage H Paungfoo-Lonhienne C Rennenberg H Lakshmanan P Schmidt S 《PloS one》2011,6(4):e19045
Modern agriculture is based on the notion that nitrate is the main source of nitrogen (N) for crops, but nitrate is also the most mobile form of N and easily lost from soil. Efficient acquisition of nitrate by crops is therefore a prerequisite for avoiding off-site N pollution. Sugarcane is considered the most suitable tropical crop for biofuel production, but surprisingly high N fertilizer applications in main producer countries raise doubt about the sustainability of production and are at odds with a carbon-based crop. Examining reasons for the inefficient use of N fertilizer, we hypothesized that sugarcane resembles other giant tropical grasses which inhibit the production of nitrate in soil and differ from related grain crops with a confirmed ability to use nitrate. The results of our study support the hypothesis that N-replete sugarcane and ancestral species in the Andropogoneae supertribe strongly prefer ammonium over nitrate. Sugarcane differs from grain crops, sorghum and maize, which acquired both N sources equally well, while giant grass, Erianthus, displayed an intermediate ability to use nitrate. We conclude that discrimination against nitrate and a low capacity to store nitrate in shoots prevents commercial sugarcane varieties from taking advantage of the high nitrate concentrations in fertilized soils in the first three months of the growing season, leaving nitrate vulnerable to loss. Our study addresses a major caveat of sugarcane production and affords a strong basis for improvement through breeding cultivars with enhanced capacity to use nitrate as well as through agronomic measures that reduce nitrification in soil. 相似文献
989.
The continuity of duplex DNA is generally considered a prerequisite for chromosome continuity. However, as previously shown in yeast as well as human cells, the introduction of a double-strand break (DSB) does not generate a chromosome break (CRB) in yeast or human cells. The transition from DSB to CRB was found to be under limited control by the tethering function of the RAD50/MRE11/XRS2 (MRX) complex. Using a system for differential fluorescent marking of both sides of an endonuclease-induced DSB in single cells, we found that nearly all DSBs are converted to CRBs in cells lacking both exonuclease 1 (EXO1) activity and MRX complex. Thus, it appears that some feature of exonuclease processing or resection at a DSB is critical for maintaining broken chromosome ends in close proximity. In addition, we discovered a thermal sensitive (cold) component to CRB formation in an MRX mutant that has implications for chromosome end mobility and/or end-processing. 相似文献
990.
Two of the major limitations to effective management of coral reef ecosystems are a lack of information on the spatial distribution of marine species and a paucity of data on the interacting environmental variables that drive distributional patterns. Advances in marine remote sensing, together with the novel integration of landscape ecology and advanced niche modelling techniques provide an unprecedented opportunity to reliably model and map marine species distributions across many kilometres of coral reef ecosystems. We developed a multi-scale approach using three-dimensional seafloor morphology and across-shelf location to predict spatial distributions for five common Caribbean fish species. Seascape topography was quantified from high resolution bathymetry at five spatial scales (5–300 m radii) surrounding fish survey sites. Model performance and map accuracy was assessed for two high performing machine-learning algorithms: Boosted Regression Trees (BRT) and Maximum Entropy Species Distribution Modelling (MaxEnt). The three most important predictors were geographical location across the shelf, followed by a measure of topographic complexity. Predictor contribution differed among species, yet rarely changed across spatial scales. BRT provided ‘outstanding’ model predictions (AUC = >0.9) for three of five fish species. MaxEnt provided ‘outstanding’ model predictions for two of five species, with the remaining three models considered ‘excellent’ (AUC = 0.8–0.9). In contrast, MaxEnt spatial predictions were markedly more accurate (92% map accuracy) than BRT (68% map accuracy). We demonstrate that reliable spatial predictions for a range of key fish species can be achieved by modelling the interaction between the geographical location across the shelf and the topographic heterogeneity of seafloor structure. This multi-scale, analytic approach is an important new cost-effective tool to accurately delineate essential fish habitat and support conservation prioritization in marine protected area design, zoning in marine spatial planning, and ecosystem-based fisheries management. 相似文献