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NF1 loss induces senescence during human melanocyte differentiation in an iPSC‐based model 下载免费PDF全文
Lionel Larribere Huizi Wu Daniel Novak Marta Galach Mathias Bernhardt Elias Orouji Kasia Weina Nathalie Knappe Christos Sachpekidis Ludmila Umansky Philipp Beckhove Viktor Umansky Sofie De Schepper Dieter Kaufmann Robert Ballotti Corine Bertolotto Jochen Utikal 《Pigment cell & melanoma research》2015,28(4):407-416
Neurofibromatosis type 1 (NF1) is a frequent genetic disease leading to the development of Schwann cell‐derived neurofibromas or melanocytic lesions called café‐au‐lait macules (CALMs). The molecular mechanisms involved in CALMs formation remain largely unknown. In this report, we show for the first time pathophysiological mechanisms of abnormal melanocyte differentiation in a human NF1+/?‐induced pluripotent stem cell (iPSC)‐based model. We demonstrate that NF1 patient‐derived fibroblasts can be successfully reprogrammed in NF1+/? iPSCs with active RAS signaling and that NF1 loss induces senescence during melanocyte differentiation as well as in patient's‐derived CALMs, revealing a new role for NF1 in the melanocyte lineage. 相似文献
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Paul N Newton Michael D Green Dallas C Mildenhall Aline Plançon Henry Nettey Leonard Nyadong Dana M Hostetler Isabel Swamidoss Glenn A Harris Kristen Powell Ans E Timmermans Abdinasir A Amin Stephen K Opuni Serge Barbereau Claude Faurant Ray CW Soong Kevin Faure Jonarthan Thevanayagam Peter Fernandes Harparkash Kaur Brian Angus Kasia Stepniewska Philippe J Guerin Facundo M Fernández 《Malaria journal》2011,10(1):1-22
Background
The most common pesticide products for controlling malaria-transmitting mosquitoes combine two distinct modes of action: 1) conventional insecticidal activity which kills mosquitoes exposed to the pesticide and 2) deterrence of mosquitoes away from protected humans. While deterrence enhances personal or household protection of long-lasting insecticidal nets and indoor residual sprays, it may also attenuate or even reverse communal protection if it diverts mosquitoes to non-users rather than killing them outright.Methods
A process-explicit model of malaria transmission is described which captures the sequential interaction between deterrent and toxic actions of vector control pesticides and accounts for the distinctive impacts of toxic activities which kill mosquitoes before or after they have fed upon the occupant of a covered house or sleeping space.Results
Increasing deterrency increases personal protection but consistently reduces communal protection because deterrent sub-lethal exposure inevitably reduces the proportion subsequently exposed to higher lethal doses. If the high coverage targets of the World Health Organization are achieved, purely toxic products with no deterrence are predicted to generally provide superior protection to non-users and even users, especially where vectors feed exclusively on humans and a substantial amount of transmission occurs outdoors. Remarkably, this is even the case if that product confers no personal protection and only kills mosquitoes after they have fed.Conclusions
Products with purely mosquito-toxic profiles may, therefore, be preferable for programmes with universal coverage targets, rather than those with equivalent toxicity but which also have higher deterrence. However, if purely mosquito-toxic products confer little personal protection because they do not deter mosquitoes and only kill them after they have fed, then they will require aggressive "catch up" campaigns, with behaviour change communication strategies that emphasize the communal nature of protection, to achieve high coverage rapidly. 相似文献106.
Raddassi K Kent SC Yang J Bourcier K Bradshaw EM Seyfert-Margolis V Nepom GT Kwok WW Hafler DA 《Journal of immunology (Baltimore, Md. : 1950)》2011,187(2):1039-1046
Multiple sclerosis (MS) is an autoimmune disease characterized by infiltration of pathogenic immune cells in the CNS resulting in destruction of the myelin sheath and surrounding axons. We and others have previously measured the frequency of human myelin-reactive T cells in peripheral blood. Using T cell cloning techniques, a modest increase in the frequency of myelin-reactive T cells in patients as compared with control subjects was observed. In this study, we investigated whether myelin oligodendrocyte glycoprotein (MOG)-specific T cells could be detected and their frequency was measured using DRB1*0401/MOG(97-109(107E-S)) tetramers in MS subjects and healthy controls expressing HLA class II DRB1*0401. We defined the optimal culture conditions for expansion of MOG-reactive T cells upon MOG peptide stimulation of PMBCs. MOG(97-109)-reactive CD4(+) T cells, isolated with DRB1*0401/MOG(97-109) tetramers, and after a short-term culture of PMBCs with MOG(97-109) peptides, were detected more frequently from patients with MS as compared with healthy controls. T cell clones from single cell cloning of DRB1*0401/MOG(97-109(107E-S)) tetramer(+) cells confirmed that these T cell clones were responsive to both the native and the substituted MOG peptide. These data indicate that autoantigen-specific T cells can be detected and enumerated from the blood of subjects using class II tetramers, and the frequency of MOG(97-109)-reactive T cells is greater in patients with MS as compared with healthy controls. 相似文献
107.
SA Funke D Bartnik JM Glück K Piorkowska K Wiesehan U Weber B Gulyas C Halldin A Pfeifer C Spenger A Muhs D Willbold 《PloS one》2012,7(7):e41457
Alzheimer's disease (AD) is a devastating disease affecting predominantly the aging population. One of the characteristic pathological hallmarks of AD are neuritic plaques, consisting of amyloid-β peptide (Aβ). While there has been some advancement in diagnostic classification of AD patients according to their clinical severity, no fully reliable method for pre-symptomatic diagnosis of AD is available. To enable such early diagnosis, which will allow the initiation of treatments early in the disease progress, neuroimaging tools are under development, making use of Aβ-binding ligands that can visualize amyloid plaques in the living brain. Here we investigate the properties of a newly designed series of D-enantiomeric peptides which are derivatives of ACI-80, formerly called D1, which was developed to specifically bind aggregated Aβ1-42. We describe ACI-80 derivatives with increased stability and Aβ binding properties, which were characterized using surface plasmon resonance and enzyme-linked immunosorbent assays. The specific interactions of the lead compounds with amyloid plaques were validated by ex vivo immunochemistry in transgenic mouse models of AD. The novel compounds showed increased binding affinity and are promising candidates for further development into in vivo imaging compounds. 相似文献
108.
Mathematical models have made considerable contributions to our understanding of HIV dynamics. Introducing time delays to HIV models usually brings challenges to both mathematical analysis of the models and comparison of model predictions with patient data. In this paper, we incorporate two delays, one the time needed for infected cells to produce virions after viral entry and the other the time needed for the adaptive immune response to emerge to control viral replication, into an HIV-1 model. We begin model analysis with proving the positivity and boundedness of the solutions, local stability of the infection-free and infected steady states, and uniform persistence of the system. By developing a few Lyapunov functionals, we obtain conditions ensuring global stability of the steady states. We also fit the model including two delays to viral load data from 10 patients during primary HIV-1 infection and estimate parameter values. Although the delay model provides better fits to patient data (achieving a smaller error between data and modeling prediction) than the one without delays, we could not determine which one is better from the statistical standpoint. This highlights the need of more data sets for model verification and selection when we incorporate time delays into mathematical models to study virus dynamics. 相似文献
109.
Huyen T.T. Phan Kasia Rybak Eiko Furuki Susan Breen Peter S. Solomon Richard P. Oliver Kar‐Chun Tan 《The Plant journal : for cell and molecular biology》2016,87(4):343-354
Fungal effector–host sensitivity gene interactions play a key role in determining the outcome of septoria nodorum blotch disease (SNB) caused by Parastagonospora nodorum on wheat. The pathosystem is complex and mediated by interaction of multiple fungal necrotrophic effector–host sensitivity gene systems. Three effector sensitivity gene systems are well characterized in this pathosystem; SnToxA–Tsn1, SnTox1–Snn1 and SnTox3–Snn3. We tested a wheat mapping population that segregated for Snn1 and Snn3 with SN15, an aggressive P. nodorum isolate that produces SnToxA, SnTox1 and SnTox3, to study the inheritance of sensitivity to SnTox1 and SnTox3 and disease susceptibility. Interval quantitative trait locus (QTL) mapping showed that the SnTox1–Snn1 interaction was paramount in SNB development on both seedlings and adult plants. No effect of the SnTox3–Snn3 interaction was observed under SN15 infection. The SnTox3–Snn3 interaction was however, detected in a strain of SN15 in which SnTox1 had been deleted (tox1–6). Gene expression analysis indicates increased SnTox3 expression in tox1–6 compared with SN15. This indicates that the failure to detect the SnTox3–Snn3 interaction in SN15 is due – at least in part – to suppressed expression of SnTox3 mediated by SnTox1. Furthermore, infection of the mapping population with a strain deleted in SnToxA, SnTox1 and SnTox3 (toxa13) unmasked a significant SNB QTL on 2DS where the SnTox2 effector sensitivity gene, Snn2, is located. This QTL was not observed in SN15 and tox1–6 infections and thus suggesting that SnToxA and/or SnTox3 were epistatic. Additional QTLs responding to SNB and effectors sensitivity were detected on 2AS1 and 3AL. 相似文献
110.
Jake Dunning Foday Sahr Amanda Rojek Fiona Gannon Gail Carson Baimba Idriss Thomas Massaquoi Regina Gandi Sebatu Joseph Hassan K. Osman Timothy J. G. Brooks Andrew J. H. Simpson Ian Goodfellow Lucy Thorne Armando Arias Laura Merson Lyndsey Castle Rebecca Howell-Jones Raul Pardinaz-Solis Benjamin Hope-Gill Mauricio Ferri Jennifer Grove Mark Kowalski Kasia Stepniewska Trudie Lang John Whitehead Piero Olliaro Mohammed Samai Peter W. Horby for the RAPIDE-TKM trial team 《PLoS medicine》2016,13(4)
BackgroundTKM-130803, a small interfering RNA lipid nanoparticle product, has been developed for the treatment of Ebola virus disease (EVD), but its efficacy and safety in humans has not been evaluated.ConclusionsAdministration of TKM-130803 at a dose of 0.3 mg/kg/d by intravenous infusion to adult patients with severe EVD was not shown to improve survival when compared to historic controls.