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81.
Platelet formation is the consequence of caspase activation within megakaryocytes 总被引:21,自引:10,他引:21
De Botton S Sabri S Daugas E Zermati Y Guidotti JE Hermine O Kroemer G Vainchenker W Debili N 《Blood》2002,100(4):1310-1317
Platelets are formed from mature megakaryocytes (MKs) and arise from the development of long and thin cytoplasmic extensions called proplatelets. After platelet release, the senescent MKs (nucleus surrounded by some cytoplasm) undergo cell death by apoptosis. To explore the precise role of apoptosis in proplatelet formation, we grew human MKs from CD34(+) cells and assessed the possible role of caspases. Proteolytic maturation of procaspase-3 and procaspase-9 was detected by immunoblots in maturing MKs as well as in proplatelet-bearing MKs and senescent MKs. Cleavage of caspase substrates such as gelsolin or poly adenosine diphosphate (ADP)-ribose polymerase (PARP) was also detected. Interestingly, activated forms of caspase-3 were detected in maturing MKs, before proplatelet formation, with a punctuate cytoplasmic distribution, whereas a diffuse staining pattern was seen in senescent and apoptotic MKs. This localized activation of caspase-3 was associated with a mitochondrial membrane permeabilization as assessed by the release of cytochrome c, suggesting an activation of the intrinsic pathway. Moreover, these MKs with localized activated caspase-3 had no detectable DNA fragmentation. In contrast, when apoptosis was induced by staurosporine, diffuse caspase activation was seen; these MKs had signs of DNA fragmentation, and no proplatelet formation occurred. The pan-caspase inhibitor z-VAD.fmk as well as more specific inhibitors of caspase-3 and caspase-9 blocked proplatelet formation, whereas an inhibitor of calpeptin had no effect. Overexpression of Bcl-2 also inhibited proplatelet formation in maturing MKs. Thus, localized caspase activation is causal to proplatelet formation. We conclude that proplatelet formation is regulated by a caspase activation limited to only some cellular compartments. 相似文献
82.
Beta -Arrestin 1 down-regulation after insulin treatment is associated with supersensitization of beta 2 adrenergic receptor Galpha s signaling in 3T3-L1 adipocytes 总被引:1,自引:0,他引:1 下载免费PDF全文
Hupfeld CJ Dalle S Olefsky JM 《Proceedings of the National Academy of Sciences of the United States of America》2003,100(1):161-166
beta-Arrestin 1 is required for internalization and mitogen-activated protein (MAP) kinase activation by the beta2 adrenergic receptor (beta2AR). Our previous studies have shown that chronic insulin treatment down-regulates cellular beta-arrestin 1 levels, leading to a marked impairment in G protein-coupled receptor and insulin-like growth factor-1 receptor-mediated MAP kinase and mitogenic signaling. In this study, we show that chronic insulin-treated, beta-arrestin 1depleted 3T3-L1 adipocytes display (i) increased isoproterenol-induced cAMP generation (53 +/- 38% at 1.5 min, 25 +/- 19% at 5 min, 63 +/- 14% at 30 min, and 59 +/- 2% at 60 min), a Galpha(s)-associated pathway; (ii) impaired isoproterenol-induced beta2AR internalization (reduced by 98 +/- 4%), which is required for MAP kinase signaling, a Galpha(i)-associated pathway; and (iii) increased beta-arrestin 1 phosphorylation at Ser-412. Taken together, these findings represent a hitherto unknown mechanism (degradation and phosphorylation of beta-arrestin, whereby the activation of the insulin receptor, belonging to the family of receptor tyrosine kinases, causes supersensitization of Galpha(s)-associated signaling and inhibition of Galpha(i)-associated signaling by the beta2AR, a prototypical G protein-coupled receptor. 相似文献
83.
Origins and antiquity of X-linked triallelic color vision systems in New World monkeys 总被引:7,自引:0,他引:7 下载免费PDF全文
Stephane Boissinot Ying Tan Song-Kun Shyue Horacio Schneider Iracilda Sampaio Katherine Neiswanger David Hewett-Emmett Wen-Hsiung Li 《Proceedings of the National Academy of Sciences of the United States of America》1998,95(23):13749-13754
It is known that the squirrel monkey, marmoset, and other related New World (NW) monkeys possess three high-frequency alleles at the single X-linked photopigment locus, and that the spectral sensitivity peaks of these alleles are within those delimited by the human red and green pigment genes. The three alleles in the squirrel monkey and marmoset have been sequenced previously. In this study, the three alleles were found and sequenced in the saki monkey, capuchin, and tamarin. Although the capuchin and tamarin belong to the same family as the squirrel monkey and marmoset, the saki monkey belongs to a different family and is one of the species that is most divergent from the squirrel monkey and marmoset, suggesting the presence of the triallelic system in many NW monkeys. The nucleotide sequences of these alleles from the five species studied indicate that gene conversion occurs frequently and has partially or completely homogenized intronic and exonic regions of the alleles in each species, making it appear that a triallelic system arose independently in each of the five species studied. Nevertheless, a detailed analysis suggests that the triallelic system arose only once in the NW monkey lineage, from a middle wavelength (green) opsin gene, and that the amino acid differences at functionally critical sites among alleles have been maintained by natural selection in NW monkeys for >20 million years. Moreover, the two X-linked opsin genes of howler monkeys (a NW monkey genus) were evidently derived from the incorporation of a middle (green) and a long wavelength (red) allele into one chromosome; these two genes together with the (autosomal) blue opsin gene would immediately enable even a male monkey to have trichromatic vision. 相似文献
84.
Natalie Nanayakkara Sanjeeva Ranasinha Adelle Gadowski Stephane Heritier Jeff R. Flack Natalie Wischer Jencia Wong Sophia Zoungas 《Journal of diabetes and its complications》2018,32(3):279-290
Background
Type 2 diabetes (T2DM) is increasingly diagnosed in younger patients. The trajectory of complications in patients diagnosed at a younger or older age is not well understood. We examine the associations between age, age at diagnosis and diabetes duration and vascular complications in patients with T2DM.Methods
A cross-sectional study of pre-specified demographic and clinical data, from 3419 adults with T2DM participating in the Australian National Diabetes Audit (2015). Factors associated with diabetes complications were analysed using logistic regression.Results
Mean (± SD) current age was 62.9 ± 12.5 years, age at diagnosis was 49.4 ± 12.3 years and mean diabetes duration was 13.5 ± 9.4 years. Macrovascular complications were more prevalent in patients who were older at diabetes diagnosis whereas microvascular complications were more prevalent in patients who were younger at diabetes diagnosis. Age, age at diagnosis and diabetes duration were all independently associated with increased risk of macrovascular complications after adjustment for sex, smoking, BMI and microvascular complications (all p < 0.001). In contrast, only diabetes duration was independently associated with microvascular complications after adjustment for sex, smoking, BMI and macrovascular complications (p < 0.001).Conclusions
Age, age at diagnosis, and diabetes duration were all independently associated with macrovascular complications whereas only diabetes duration was independently associated with microvascular complications. 相似文献85.
Lelievre Benedicte Triau Stephane Codron Philippe Mariau Yoran Papin-Lefebvre Frederique Collin Alexandre Drevin Guillaume Le Roux Gael Briet Marie Boels David Letournel Franck 《Forensic Toxicology》2020,38(2):505-510
Forensic Toxicology - In developed countries, lead intoxication is decreasing in adults as sources of contamination were considerably reduced. Hence, cases of lead encephalopathy have become... 相似文献
86.
Mia C. Hikke Stine Braaen Stephane Villoing Kjartan Hodneland Corinne Geertsema Lisa Verhagen Petter Frost Just M. Vlak Espen Rimstad Gorben P. Pijlman 《Vaccine》2014
Salmonid alphavirus (SAV; also known as Salmon pancreas disease virus; family Togaviridae) causes pancreas disease and sleeping disease in Atlantic salmon and rainbow trout, respectively, and poses a major burden to the aquaculture industry. SAV infection in vivo is temperature-restricted and progeny virus is only produced at low temperatures (10–15 °C). Using engineered SAV replicons we show that viral RNA replication is not temperature-restricted suggesting that the viral structural proteins determine low-temperature dependency. The processing/trafficking of SAV glycoproteins E1 and E2 as a function of temperature was investigated via baculovirus vectors in Sf9 insect cells and by transfection of CHSE-214 fish cells with DNA constructs expressing E1 and E2. We identified SAV E2 as the temperature determinant by demonstrating that membrane trafficking and surface expression of E2 occurs only at low temperature and only in the presence of E1. Finally, a vaccination-challenge model in Atlantic salmon demonstrates the biological significance of our findings and shows that SAV replicon DNA vaccines encoding E2 elicit protective immunity only when E1 is co-expressed. This is the first study that identifies E2 as the critical determinant of SAV low-temperature dependent virion formation and defines the prerequisites for induction of a potent immune response in Atlantic salmon by DNA vaccination. 相似文献
87.
Harold M. Hudson Serigne N. Lô R. John Simes Andrew M. Tonkin Stephane Heritier 《Statistics in medicine》2014,33(10):1621-1645
Transform methods have proved effective for networks describing a progression of events. In semi‐Markov networks, we calculated the transform of time to a terminating event from corresponding transforms of intermediate steps. Saddlepoint inversion then provided survival and hazard functions, which integrated, and fully utilised, the network data. However, the presence of censored data introduces significant difficulties for these methods. Many participants in controlled trials commonly remain event‐free at study completion, a consequence of the limited period of follow‐up specified in the trial design. Transforms are not estimable using nonparametric methods in states with survival truncated by end‐of‐study censoring. We propose the use of parametric models specifying residual survival to next event. As a simple approach to extrapolation with competing alternative states, we imposed a proportional incidence (constant relative hazard) assumption beyond the range of study data. No proportional hazards assumptions are necessary for inferences concerning time to endpoint; indeed, estimation of survival and hazard functions can proceed in a single study arm. We demonstrate feasibility and efficiency of transform inversion in a large randomised controlled trial of cholesterol‐lowering therapy, the Long‐Term Intervention with Pravastatin in Ischaemic Disease study. Transform inversion integrates information available in components of multistate models: estimates of transition probabilities and empirical survival distributions. As a by‐product, it provides some ability to forecast survival and hazard functions forward, beyond the time horizon of available follow‐up. Functionals of survival and hazard functions provide inference, which proves sharper than that of log‐rank and related methods for survival comparisons ignoring intermediate events. Copyright © 2013 John Wiley & Sons, Ltd. 相似文献
88.
Yasser Khazaal Mathias van Singer Anne Chatton Sophia Achab Daniele Zullino Stephane Rothen Riaz Khan Joel Billieux Gabriel Thorens 《Journal of medical Internet research》2014,16(7)
Background
The number of medical studies performed through online surveys has increased dramatically in recent years. Despite their numerous advantages (eg, sample size, facilitated access to individuals presenting stigmatizing issues), selection bias may exist in online surveys. However, evidence on the representativeness of self-selected samples in online studies is patchy.Objective
Our objective was to explore the representativeness of a self-selected sample of online gamers using online players’ virtual characters (avatars).Methods
All avatars belonged to individuals playing World of Warcraft (WoW), currently the most widely used online game. Avatars’ characteristics were defined using various games’ scores, reported on the WoW’s official website, and two self-selected samples from previous studies were compared with a randomly selected sample of avatars.Results
We used scores linked to 1240 avatars (762 from the self-selected samples and 478 from the random sample). The two self-selected samples of avatars had higher scores on most of the assessed variables (except for guild membership and exploration). Furthermore, some guilds were overrepresented in the self-selected samples.Conclusions
Our results suggest that more proficient players or players more involved in the game may be more likely to participate in online surveys. Caution is needed in the interpretation of studies based on online surveys that used a self-selection recruitment procedure. Epidemiological evidence on the reduced representativeness of sample of online surveys is warranted. 相似文献89.
Validation of the HFA‐PEFF score for the diagnosis of heart failure with preserved ejection fraction
90.
Corsten MF Papageorgiou A Verhesen W Carai P Lindow M Obad S Summer G Coort SL Hazebroek M van Leeuwen R Gijbels MJ Wijnands E Biessen EA De Winther MP Stassen FR Carmeliet P Kauppinen S Schroen B Heymans S 《Circulation research》2012,111(4):415-425
Rationale: Viral myocarditis results from an adverse immune response to cardiotropic viruses, which causes irreversible myocyte destruction and heart failure in previously healthy people. The involvement of microRNAs and their usefulness as therapeutic targets in this process are unknown. Objective: To identify microRNAs involved in viral myocarditis pathogenesis and susceptibility. Methods and Results: Cardiac microRNAs were profiled in both human myocarditis and in Coxsackievirus B3-injected mice, comparing myocarditis-susceptible with nonsusceptible mouse strains longitudinally. MicroRNA responses diverged depending on the susceptibility to myocarditis after viral infection in mice. MicroRNA-155, -146b, and -21 were consistently and strongly upregulated during acute myocarditis in both humans and susceptible mice. We found that microRNA-155 expression during myocarditis was localized primarily in infiltrating macrophages and T lymphocytes. Inhibition of microRNA-155 by a systemically delivered LNA-anti-miR attenuated cardiac infiltration by monocyte-macrophages, decreased T lymphocyte activation, and reduced myocardial damage during acute myocarditis in mice. These changes were accompanied by the derepression of the direct microRNA-155 target PU.1 in cardiac inflammatory cells. Beyond the acute phase, microRNA-155 inhibition reduced mortality and improved cardiac function during 7 weeks of follow-up. Conclusions: Our data show that cardiac microRNA dysregulation is a characteristic of both human and mouse viral myocarditis. The inflammatory microRNA-155 is upregulated during acute myocarditis, contributes to the adverse inflammatory response to viral infection of the heart, and is a potential therapeutic target for viral myocarditis. 相似文献