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101.
102.
Palmitoyl-protein thioesterase 1 deficiency in Drosophila melanogaster causes accumulation of abnormal storage material and reduced life span
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Hickey AJ Chotkowski HL Singh N Ault JG Korey CA MacDonald ME Glaser RL 《Genetics》2006,172(4):2379-2390
Human neuronal ceroid lipofuscinoses (NCLs) are a group of genetic neurodegenerative diseases characterized by progressive death of neurons in the central nervous system (CNS) and accumulation of abnormal lysosomal storage material. Infantile NCL (INCL), the most severe form of NCL, is caused by mutations in the Ppt1 gene, which encodes the lysosomal enzyme palmitoyl-protein thioesterase 1 (Ppt1). We generated mutations in the Ppt1 ortholog of Drosophila melanogaster to characterize phenotypes caused by Ppt1 deficiency in flies. Ppt1-deficient flies accumulate abnormal autofluorescent storage material predominantly in the adult CNS and have a life span 30% shorter than wild type, phenotypes that generally recapitulate disease-associated phenotypes common to all forms of NCL. In contrast, some phenotypes of Ppt1-deficient flies differed from those observed in human INCL. Storage material in flies appeared as highly laminar spherical deposits in cells of the brain and as curvilinear profiles in cells of the thoracic ganglion. This contrasts with the granular deposits characteristic of human INCL. In addition, the reduced life span of Ppt1-deficient flies is not caused by progressive death of CNS neurons. No changes in brain morphology or increases in apoptotic cell death of CNS neurons were detected in Ppt1-deficient flies, even at advanced ages. Thus, Ppt1-deficient flies accumulate abnormal storage material and have a shortened life span without evidence of concomitant neurodegeneration. 相似文献
103.
Boyd HF Flynn ST Hickey DM Ife RJ Jones M Leach CA Macphee CH Milliner KJ Rawlings DA Slingsby BP Smith SA Stansfield IG Tew DG Theobald CJ 《Bioorganic & medicinal chemistry letters》2000,10(4):395-398
Starting from two weakly active hits from high throughput screening, a novel series of 2-(alkylthio)-pyrimidin-4-ones with high potency and selectivity for lipoprotein-associated phospholipase A2 has been designed. In contrast to previously known inhibitors, these have been shown to act by a non-covalent and substrate competitive mechanism. 相似文献
104.
Deane JA Abeynaike LD Norman MU Wee JL Kitching AR Kubes P Hickey MJ 《Journal of immunology (Baltimore, Md. : 1950)》2012,188(5):2179-2188
Regulatory T cells (Tregs) must express appropriate skin-homing adhesion molecules to exert suppressive effects on dermal inflammation. However, the mechanisms whereby they control local inflammation remain unclear. In this study we used confocal intravital microscopy in wild-type and Foxp3-GFP mice to examine adhesion of effector T cells and Tregs in dermal venules. These experiments examined a two-challenge model of contact sensitivity (CS) in which Treg abundance in the skin progressively increases during the course of the response. Adhesion of CD4(+) T cells increased during CS, peaking 8-24 h after an initial hapten challenge, and within 4 h of a second challenge. At these time points, 40% of adherent CD4(+) T cells were Foxp3(+) Tregs. CD4(+) T cell adhesion was highly dependent on ICAM-1, and consistent with this finding, anti-ICAM-1 prevented Treg adhesion. Skin TGF-β levels were elevated in skin during both challenges, in parallel with Treg adhesion. In the two-challenge CS model, inhibition of ICAM-1 eliminated Treg adhesion, an effect associated with a significant increase in neutrophil adhesion. Similarly, total CD4(+) T cell depletion caused an increase in adhesion of CD8(+) T cells. Because Treg adhesion was restricted by both of these treatments, these experiments suggest that adherent Tregs can control adhesion of proinflammatory leukocytes in vivo. Moreover, the critical role of ICAM-1 in Treg adhesion provides a potential explanation for the exacerbation of inflammation reported in some studies of ICAM-1-deficient mice. 相似文献
105.
Jena R. Hickey John P. Carroll Nathan P. Nibbelink 《International journal of primatology》2012,33(2):381-400
To conserve areas and species threatened by immediate landscape change requires that we make planning decisions for large
areas in the absence of adequate data. Here we study the utility of broad-scale landscape metrics as predictors of species
occurrence, especially for remote areas where there is a need to make the most of limited spatial and biological data. Bonobos
(Pan paniscus) are endangered great apes endemic to lowland forests of the Democratic Republic of Congo. They are threatened by bushmeat
hunting that is exacerbated by habitat fragmentation through slash-and-burn agriculture and timber harvest. We developed four
landscape metrics —edge density (ED), COHESION, CONTAGION, and class area (CA)— that may serve as surrogates for measuring
accessibility of areas to hunting in order to predict relative bonobo-habitat suitability. We calculated the metrics for the
Maringa-Lopori-Wamba (MLW) landscape and evaluated them for utility in predicting bonobo-nest occupancy based on 2009 field
data. Cross-validations showed that all four metrics performed similarly. However, forest ED was arguably the best predictor,
with an overall classification accuracy of 72.1% in which 85% of known nest blocks (N = 124) were classified correctly. We demonstrated that for a relatively intact landscape and a mobile forest-dwelling species
that is fairly tolerant of forest openings, forest fragmentation can still be an important predictor of species occurrence.
We suggest that ED can be helpful when mapping bonobo habitat in MLW and can aid landscape-planning and conservation efforts.
Our approach may be applied to other edge-sensitive species, especially where high-resolution data are deficient. 相似文献
106.
Travis Meuten Ariel Hickey Katherine Franklin Brian Grossi Jeremy Tobias Donna R Newman Samuel H Jennings Maria Correa Philip L Sannes 《Respiratory research》2012,13(1):62
Background
Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial pneumonia causing a loss of respiratory surface area due to a proliferative fibrotic response involving hyperplastic, hypertrophic, and metaplastic epithelium, cystic honeycomb change, septal expansion, and variable inflammation. Wnt (wingless) signaling glycoproteins are known to be involved in lung development and tissue repair, and are up-regulated in patients with IPF. Based on previous qRT-PCR data showing increased Wnt7B in lungs of IPF patients, a systematic, quantitative examination of its tissue site distribution was undertaken.Methods
Tissue samples from the Lung Tissue Research Consortium (LTRC) of 39 patients diagnosed with mild to severe IPF/usual interstitial pneumonia (UIP) and 19 normal patients were examined for the immunolocalization of Wnt7B.Results
In normal lung, moderate Wnt7B reactivity was confined to airway epithelium, smooth muscle of airways and vasculature, and macrophages. IPF lung showed strong Wnt7B reactivity in fibroblastic foci, dysplastic airway and alveolar epithelium, and in highly discrete subepithelial, basement membrane-associated regions. All reactive sites were sized and counted relative to specific microscopic regions. Those in the subepithelial sites were found in significantly greater numbers and larger relative area compared with the others. No reactive sites were present in normal patient controls.Conclusions
The results demonstrate Wnt7B to be expressed at high concentrations in regions of active hyperplasia, metaplasia, and fibrotic change in IPF patients. In this context and its previously established biologic activities, Wnt7B would be expected to be of potential importance in the pathogenesis of IPF. 相似文献107.
Jeffry L. Dean A. Kathleen McClendon Theresa E. Hickey Lisa M. Butler Wayne D. Tilley Agnieszka K. Witkiewicz Erik S. Knudsen 《Cell cycle (Georgetown, Tex.)》2012,11(14):2756-2761
To model the heterogeneity of breast cancer as observed in the clinic, we employed an ex vivo model of breast tumor tissue. This methodology maintained the histological integrity of the tumor tissue in unselected breast cancers, and importantly, the explants retained key molecular markers that are currently used to guide breast cancer treatment (e.g., ER and Her2 status). The primary tumors displayed the expected wide range of positivity for the proliferation marker Ki67, and a strong positive correlation between the Ki67 indices of the primary and corresponding explanted tumor tissues was observed. Collectively, these findings indicate that multiple facets of tumor pathophysiology are recapitulated in this ex vivo model. To interrogate the potential of this preclinical model to inform determinants of therapeutic response, we investigated the cytostatic response to the CDK4/6 inhibitor, PD-0332991. This inhibitor was highly effective at suppressing proliferation in approximately 85% of cases, irrespective of ER or HER2 status. However, 15% of cases were completely resistant to PD-0332991. Marker analyses in both the primary tumor tissue and the corresponding explant revealed that cases resistant to CDK4/6 inhibition lacked the RB-tumor suppressor. These studies provide important insights into the spectrum of breast tumors that could be treated with CDK4/6 inhibitors, and defines functional determinants of response analogous to those identified through neoadjuvant studies. 相似文献
108.
Is the failing heart out of fuel or a worn engine running rich? A study of mitochondria in old spontaneously hypertensive rats 总被引:1,自引:0,他引:1
Jüllig M Hickey AJ Chai CC Skea GL Middleditch MJ Costa S Choong SY Philips AR Cooper GJ 《Proteomics》2008,8(12):2556-2572
Hypertension now affects about 600 million people worldwide and is a leading cause of death in the Western world. The spontaneously hypertensive rat (SHR), provides a useful model to investigate hypertensive heart failure (HF). The SHR model replicates the clinical progression of hypertension in humans, wherein early development of hypertension is followed by a long stable period of compensated cardiac hypertrophy that slowly progresses to HF. Although the hypertensive failing heart generally shows increased substrate preference towards glucose and impaired mitochondrial function, the cause-and-effect relationship between these characteristics is incompletely understood. To explore these pathogenic processes, we compared cardiac mitochondrial proteomes of 20-month-old SHR and Wistar-Kyoto controls by iTRAQ-labelling combined with multidimensional LC/MS/MS. Of 137 high-scoring proteins identified, 79 differed between groups. Changes were apparent in several metabolic pathways, chaperone and antioxidant systems, and multiple subunits of the oxidative phosphorylation complexes were increased (complexes I, III and IV) or decreased (complexes II and V) in SHR heart mitochondria. Respiration assays on skinned fibres and isolated mitochondria showed markedly lower respiratory capacity on succinate. Enzyme activity assays often also showed mismatches between increased protein expression and activities suggesting elevated protein expression may be compensatory in the face of pathological stress. 相似文献
109.
Soral crypsis: protective mimicry of a coccid on an Indian fern 总被引:1,自引:0,他引:1
Herbivory with crypsis is not well documented in ferns. The present record of cryptic coloration of coccid Saissetia filicum Boisduval (Homoptera: Coccidae) to the sori of a fern species Asplenium nidus L. (Aspleniaceae) is unique. Predatory beetles (Jauravia sp., Coleoptera: Coccinellidae) that feed on the coccids, are suggested to be selective pressure for the development of the present homopteran soral crypsis. A higher rate of effective predation is noticed in the vegetative leaves than the fertile leaves. Aggressive ants were found harvesting honeydew secretions from the coccids and defending the trophobionts as well as the host fern from their natural enemies. In addition, a possible three-way mutualistic relationship among the coccids, its host fern and the tending ant is suggested. Differential numbers of coccids on vegetative and fertile leaves is correlated with their phenol content and degree of predation by beetles. Such coloration mimicry by the coccids may enable them to obtain the necessary blend of sorus of the host fern needed to evade beetle detection and attack. 相似文献
110.
Hickey H 《Biotechnology journal》2008,3(8):973-974
Computer game for protein folding Recombinant protein folding and misfolding in Escherichia coli Recent biotech patents on protein folding Protein location in the cell causes cancer Chemical engineer reveals the secret ingredient of the perfect sandwich Chemogenomics and open access to large-scale drug discovery data US drug patent expirations for August 2008 相似文献