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81.
Michael W.J. Cleeter Kai-Yin Chau Caroline Gluck Atul Mehta Derralynn A. Hughes Michael Duchen Nicholas William Wood John Hardy J. Mark Cooper Anthony Henry Schapira 《Neurochemistry international》2013
Mutations of the gene for glucocerebrosidase 1 (GBA) cause Gaucher disease (GD), an autosomal recessive lysosomal storage disorder. Individuals with homozygous or heterozygous (carrier) mutations of GBA have a significantly increased risk for the development of Parkinson’s disease (PD), with clinical and pathological features that mirror the sporadic disease. The mechanisms whereby GBA mutations induce dopaminergic cell death and Lewy body formation are unknown. There is evidence of mitochondrial dysfunction and oxidative stress in PD and so we have investigated the impact of glucocerebrosidase (GCase) inhibition on these parameters to determine if there may be a relationship of GBA loss-of-function mutations to the known pathogenetic pathways in PD. We have used exposure to a specific inhibitor (conduritol-β-epoxide, CβE) of GCase activity in a human dopaminergic cell line to identify the biochemical abnormalities that follow GCase inhibition. We show that GCase inhibition leads to decreased ADP phosphorylation, reduced mitochondrial membrane potential and increased free radical formation and damage, together with accumulation of alpha-synuclein. Taken together, inhibition of GCase by CβE induces abnormalities in mitochondrial function and oxidative stress in our cell culture model. We suggest that GBA mutations and reduced GCase activity may increase the risk for PD by inducing these same abnormalities in PD brain. 相似文献
82.
Laura L. Yates Carsten Schnatwinkel Lee Hazelwood Lauren Chessum Anju Paudyal Helen Hilton M. Rosario Romero Jonathan Wilde Debora Bogani Jeremy Sanderson Caroline Formstone Jennifer N. Murdoch Lee A. Niswander Andy Greenfield Charlotte H. Dean 《Developmental biology》2013,373(2):267-280
During lung development, proper epithelial cell arrangements are critical for the formation of an arborized network of tubes. Each tube requires a lumen, the diameter of which must be tightly regulated to enable optimal lung function. Lung branching and lumen morphogenesis require close epithelial cell–cell contacts that are maintained as a result of adherens junctions, tight junctions and by intact apical–basal (A/B) polarity. However, the molecular mechanisms that maintain epithelial cohesion and lumen diameter in the mammalian lung are unknown. Here we show that Scribble, a protein implicated in planar cell polarity (PCP) signalling, is necessary for normal lung morphogenesis. Lungs of the Scrib mouse mutant Circletail (Crc) are abnormally shaped with fewer airways, and these airways often lack a visible, ‘open’ lumen. Mechanistically we show that Scrib genetically interacts with the core PCP gene Vangl2 in the developing lung and that the distribution of PCP pathway proteins and Rho mediated cytoskeletal modification is perturbed in ScribCrc/Crc lungs. However A/B polarity, which is disrupted in Drosophila Scrib mutants, is largely unaffected. Notably, we find that Scrib mediates functions not attributed to other PCP proteins in the lung. Specifically, Scrib localises to both adherens and tight junctions of lung epithelia and knockdown of Scrib in lung explants and organotypic cultures leads to reduced cohesion of lung epithelial cells. Live imaging of Scrib knockdown lungs shows that Scrib does not affect bud bifurcation, as previously shown for the PCP protein Celsr1, but is required to maintain epithelial cohesion. To understand the mechanism leading to reduced cell–cell association, we show that Scrib associates with β-catenin in embryonic lung and the sub-cellular distribution of adherens and tight junction proteins is perturbed in mutant lung epithelia. Our data reveal that Scrib is required for normal lung epithelial organisation and lumen morphogenesis by maintaining cell–cell contacts. Thus we reveal novel and important roles for Scrib in lung development operating via the PCP pathway, and in regulating junctional complexes and cell cohesion. 相似文献
83.
84.
Mathieu Weitten Jean-Patrice Robin Hugues Oudart Paul Pévet Caroline Habold 《Hormones and behavior》2013
Animals have to adapt to seasonal variations in food resources and temperature. Hibernation is one of the most efficient means used by animals to cope with harsh winter conditions, wherein survival is achieved through a significant decrease in energy expenditure. The hibernation period is constituted by a succession of torpor bouts (hypometabolism and decrease in body temperature) and periodic arousals (eumetabolism and euthermia). Some species feed during these periodic arousals, and thus show different metabolic adaptations to fat-storing species that fast throughout the hibernation period. Our study aims to define these metabolic adaptations, including hormone (insulin, glucagon, leptin, adiponectin, GLP-1, GiP) and metabolite (glucose, free fatty acids, triglycerides, urea) profiles together with body composition adjustments. Syrian hamsters were exposed to varied photoperiod and temperature conditions mimicking different phases of the hibernation cycle: a long photoperiod at 20 °C (LP20 group), a short photoperiod at 20 °C (SP20 group), and a short photoperiod at 8 °C (SP8). SP8 animals were sampled either at the beginning of a torpor bout (Torpor group) or at the beginning of a periodic arousal (Arousal group). We show that fat store mobilization in hamsters during torpor bouts is associated with decreased circulating levels of glucagon, insulin, leptin, and an increase in adiponectin. Refeeding during periodic arousals results in a decreased free fatty acid plasma concentration and an increase in glycemia and plasma incretin concentrations. Reduced incretin and increased adiponectin levels are therefore in accordance with the changes in nutrient availability and feeding behavior observed during the hibernation cycle of Syrian hamsters. 相似文献
85.
86.
Constance Delaby Vincent Oustric Caroline Schmitt Francoise Muzeau Anne-Marie Robreau Philippe Letteron Eric Couchi Angel Yu Saïd Lyoumi Jean-Charles Deybach Herve Puy Zoubida Karim Carole Beaumont Bernard Grandchamp Peter Demant Laurent Gouya 《Mammalian genome》2013,24(11-12):427-438
Disorders of iron metabolism are among the most common acquired and constitutive diseases. Hemochromatosis has a solid genetic basis and in Northern European populations it is usually associated with homozygosity for the C282Y mutation in the HFE protein. However, the penetrance of this mutation is incomplete and the clinical presentation is highly variable. The rare and common variants identified so far as genetic modifiers of HFE-related hemochromatosis are unable to account for the phenotypic heterogeneity of this disorder. There are wide variations in the basal iron status of common inbred mouse strains, and this diversity may reflect the genetic background of the phenotypic diversity under pathological conditions. We therefore examined the genetic basis of iron homeostasis using quantitative trait loci mapping applied to the HcB-15 recombinant congenic strains for tissue and serum iron indices. Two highly significant QTL containing either the N374S Mon1a mutation or the Ferroportin locus were found to be major determinants in spleen and liver iron loading. Interestingly, when considering possible epistatic interactions, the effects of Mon1a on macrophage iron export are conditioned by the genotype at the Slc40a1 locus. Only mice that are C57BL/10ScSnA homozygous at both loci display a lower spleen iron burden. Furthermore, the liver-iron lowering effect of the N374S Mon1a mutation is observed only in mice that display a nonsense mutation in the Ceruloplasmin (Cp) gene. This study highlights the existence of genetic interactions between Cp, Mon1a, and the Slc40a1 locus in iron metabolism, suggesting that epistasis may be a crucial determinant of the variable biological and clinical presentations in iron disorders. 相似文献
87.
Kayigan Wilson d’Almeida Dominique Pateron Gérald Kierzek Bertrand Renaud Caroline Semaille Pierre de Truchis Fran?ois Simon Judith Leblanc France Lert Stéphane Le Vu Anne-Claude Crémieux 《PloS one》2013,8(4)
Objective
We assessed the EDs’ characteristics associated with the offer and acceptance rates of a nontargeted HIV rapid-test screening in 29 Emergency Departments (EDs) in the metropolitan Paris region (11.7 million inhabitants), where half of France’s new HIV cases are diagnosed annually.Methods
EDs nurses offered testing to all patients 18–64-year-old, able to provide consent, either with or without supplemental staff (hybrid staff model or indigenous staff model). The EDS’ characteristics collected included structural characteristics (location, type, size), daily workload (patients’ number and severity, length of stay in hours), staff’s participation (training, support to the intervention, leadership), type of week day (weekends vs weekdays) and time (in days). Associations between these variables and the staff model, the offer and acceptance rates were studied using multilevel modeling.Results
Indigenous staff model was more frequent in EDs with a lower daily patient flow and a higher staff support score to the intervention. In indigenous-model EDs, the offer rate was associated with the patient flow (OR = 0.838, 95% CI = 0.773–0.908), was lower during weekends (OR = 0.623, 95% CI = 0.581–0.667) and decreased over time (OR = 0.978, 95% CI = 0.975–0.981). Similar results were found in hybrid-model EDs. Acceptance was poorly associated with EDs characteristics in indigenous-model EDs while in hybrid-model EDs it was lower during weekends (OR = 0.713, 95% CI = 0.623–0.816) and increased after the first positive test (OR = 1.526, 95% CI = 1.142–2.038).The EDs’ characteristics explained respectively 38.5% and 15% of the total variance in the offer rate across indigenous model-EDs and hybrid model-EDs vs 12% and 1% for the acceptance rate.Conclusion
Our findings suggest the need for taking into account EDs’ characteristics while considering the implementation of an ED-based HIV screening program. Strategies allowing the optimization of human resources’ utilization such as HIV targeted screening in the EDs might be privileged. 相似文献88.
Shaina L. Byrne Peter D. Buckett Jonghan Kim Flora Luo Jack Sanford Juxing Chen Caroline Enns Marianne Wessling-Resnick 《PloS one》2013,8(7)
Previous studies have shown that the small molecule iron transport inhibitor ferristatin (NSC30611) acts by down-regulating transferrin receptor-1 (TfR1) via receptor degradation. In this investigation, we show that another small molecule, ferristatin II (NSC8679), acts in a similar manner to degrade the receptor through a nystatin-sensitive lipid raft pathway. Structural domains of the receptor necessary for interactions with the clathrin pathway do not appear to be necessary for ferristatin II induced degradation of TfR1. While TfR1 constitutively traffics through clathrin-mediated endocytosis, with or without ligand, the presence of Tf blocked ferristatin II induced degradation of TfR1. This effect of Tf was lost in a ligand binding receptor mutant G647A TfR1, suggesting that Tf binding to its receptor interferes with the drug’s activity. Rats treated with ferristatin II have lower TfR1 in liver. These effects are associated with reduced intestinal 59Fe uptake, lower serum iron and transferrin saturation, but no change in liver non-heme iron stores. The observed hypoferremia promoted by degradation of TfR1 by ferristatin II appears to be due to induced hepcidin gene expression. 相似文献
89.
Evguenia Krastinova Remonie Seng Patrick Yeni Jean-Paul Viard Daniel Vittecoq Caroline Lascoux-Combe Erwan Fourn Golriz Pahlavan Jean Fran?ois Delfraissy Laurence Meyer for the ANRS PRIMO COPANA Cohorts 《PloS one》2013,8(8)
Objective
Guidelines for initiating HIV treatment are regularly revised. We explored how physicians in France have applied these evolving guidelines for ART initiation over the last decade in two different situations: chronic (CHI) and primary HIV-1 infection (PHI), since specific recommendations for PHI are also provided in France.Methods
Data came from the ANRS PRIMO (1267 patients enrolled during PHI in 1996–2010) and COPANA (800 subjects enrolled at HIV diagnosis in 2004–2008) cohorts. We defined as guidelines-inconsistent during PHI and CHI, patients meeting criteria for ART initiation and not treated in the following month and during the next 6 months, respectively.Results
ART initiation during PHI dramatically decreased from 91% of patients in 1996–99 to 22% in 2007 and increased to 60% in 2010, following changes in recommendations. In 2007, however, after the CD4 count threshold was raised to 350 cells/mm3 in 2006, only 55% of the patients with CD4≤350 were treated and 66% in 2008. During CHI, ART was more frequently initiated in patients who met the criteria at entry (96%) than during follow-up: 83% when recommendation to treat was 200 and 73% when it was 350 cells/mm3. Independent risk factors for not being treated during CHI despite meeting the criteria were lower viral load, lower educational level, and poorer living conditions.Conclusion
HIV ART initiation guidelines are largely followed by practitioners in France. What can still be improved, however, is time to treat when CD4 cell counts reach the threshold to treat. Risk factors for lack of timely treatment highlight the need to understand better how patients’ living conditions and physicians’ perceptions influence the decision to initiate treatment. 相似文献90.
Jiankang Liu DeMarc A. Hickson Solomon K. Musani Sameera A. Talegawkar Teresa C. Carithers Katherine L. Tucker Caroline S. Fox Herman A. Taylor 《Obesity (Silver Spring, Md.)》2013,21(3):644-651