49 research outputs found
Histoire des jardins anciens et modernes
Issued 1867 with title: Les jardins; histoire et description.Mode of access: Internet
The tyrosine phosphatase CD148 is an essential positive regulator of platelet activation and thrombosis
Platelets play a fundamental role in hemostasis and thrombosis. They are also involved in pathologic conditions resulting from blocked blood vessels, including myocardial infarction and ischemic stroke. Platelet adhesion, activation, and aggregation at sites of vascular injury are regulated by a diverse repertoire of tyrosine kinaseâlinked and G proteinâcoupled receptors. Src family kinases (SFKs) play a central role in initiating and propagating signaling from several platelet surface receptors; however, the underlying mechanism of how SFK activity is regulated in platelets remains unclear. CD148 is the only receptor-like protein tyrosine phosphatase identified in platelets to date. In the present study, we show that mutant mice lacking CD148 exhibited a bleeding tendency and defective arterial thrombosis. Basal SFK activity was found to be markedly reduced in CD148-deficient platelets, resulting in a global hyporesponsiveness to agonists that signal through SFKs, including collagen and fibrinogen. G proteinâcoupled receptor responses to thrombin and other agonists were also marginally reduced. These results highlight CD148 as a global regulator of platelet activation and a novel antithrombotic drug targe
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Phosphorothioate backbone modifications of nucleotide-based drugs are potent platelet activators
Nucleotide-based drug candidates such as antisense oligonucleotides, aptamers, immunoreceptor-activating nucleotides, or (anti)microRNAs hold great therapeutic promise for many human diseases. Phosphorothioate (PS) backbone modification of nucleotide-based drugs is common practice to protect these promising drug candidates from rapid degradation by plasma and intracellular nucleases. Effects of the changes in physicochemical properties associated with PS modification on platelets have not been elucidated so far. Here we report the unexpected binding of PS-modified oligonucleotides to platelets eliciting strong platelet activation, signaling, reactive oxygen species generation, adhesion, spreading, aggregation, and thrombus formation in vitro and in vivo. Mechanistically, the platelet-specific receptor glycoprotein VI (GPVI) mediates these platelet-activating effects. Notably, platelets from GPVI function-deficient patients do not exhibit binding of PS-modified oligonucleotides, and platelet activation is fully abolished. Our data demonstrate a novel, unexpected, PS backbone-dependent, platelet-activating effect of nucleotide-based drug candidates mediated by GPVI. This unforeseen effect should be considered in the ongoing development programs for the broad range of upcoming and promising DNA/RNA therapeutics
Anatomical Global Spatial Normalization
Anatomical global spatial normalization (aGSN) is presented as a method to scale high-resolution brain images to control for variability in brain size without altering the mean size of other brain structures. Two types of mean preserving scaling methods were investigated, âshape preservingâ and âshape standardizingâ. aGSN was tested by examining 56 brain structures from an adult brain atlas of 40 individuals (LPBA40) before and after normalization, with detailed analyses of cerebral hemispheres, all gyri collectively, cerebellum, brainstem, and left and right caudate, putamen, and hippocampus. Mean sizes of brain structures as measured by volume, distance, and area were preserved and variance reduced for both types of scale factors. An interesting finding was that scale factors derived from each of the ten brain structures were also mean preserving. However, variance was best reduced using whole brain hemispheres as the reference structure, and this reduction was related to its high average correlation with other brain structures. The fractional reduction in variance of structure volumes was directly related to Ï2, the square of the reference-to-structure correlation coefficient. The average reduction in variance in volumes by aGSN with whole brain hemispheres as the reference structure was approximately 32%. An analytical method was provided to directly convert between conventional and aGSN scale factors to support adaptation of aGSN to popular spatial normalization software packages
Phosphorothioate backbone modifications of nucleotide-based drugs are potent platelet activators
Com o diabo no corpo: os terrĂveis papagaios do Brasil colĂŽnia
Desde a Antiguidade, papagaios, periquitos e afins (Psittacidae) fascinaram os europeus por seu vivo colorido e uma notĂĄvel capacidade de interação com seres humanos. A descoberta do Novo Mundo nada faria alĂ©m de acrescentar novos elementos ao trĂĄfico de animais exĂłticos hĂĄ muito estabelecido pelos europeus com a Ăfrica e o Oriente. Sem possuir grandes mamĂferos, a AmĂ©rica tropical participaria desse comĂ©rcio com o que tinha de mais atrativo, essencialmente felinos, primatas e aves - em particular os papagaios, os quais eram embarcados em bom nĂșmero. Contudo, a julgar pelos documentos do Brasil colĂŽnia, esses volĂĄteis podiam inspirar muito pouca simpatia, pois nenhum outro animal - exceto as formigas - foi tantas vezes mencionado como praga para a agricultura. AlĂ©m disso, alguns psitĂĄcidas mostravam-se tĂŁo loquazes que inspiravam a sĂ©ria desconfiança de serem animais demonĂacos ou possessos, pois sĂł trĂȘs classes de entidades - anjos, homens e demĂŽnios - possuĂam o dom da palavra. Nos dias de hoje, vĂĄrios representantes dos Psittacidae ainda constituem uma ameaça para a agricultura, enquanto os indivĂduos muito faladores continuam despertando a suspeita de estarem possuĂdos pelo demĂŽnio. Transcendendo a mera curiosidade, essa crença exemplifica o quĂŁo intrincadas podem ser as relaçÔes do homem com o chamado âmundo naturalâ, revelando um universo mais amplo e multifacetado do que se poderia supor a princĂpio. Nesse sentido, a existĂȘncia de aves capazes de falar torna essa relação ainda mais complexa e evidencia que as dificuldades de estabelecer o limite entre o animal e o humano se estendem alĂ©m dos primatas e envolvem as mais inusitadas espĂ©cies zoolĂłgicas.Since ancient times, parrots and their allies (Psittacidae) have fascinated Europeans by their striking colors and notable ability to interact with human beings. The discovery of the New World added new species to the international exotic animal trade, which for many centuries had brought beasts to Europe from Africa and the Orient. Lacking large mammals, tropical America participated in this trade with its most appealing species, essentially felines, primates and birds - especially parrots - which were shipped in large numbers. It should be noted, however, that at times these birds were not well liked. In fact, according to documents from colonial Brazil, only the ants rank higher than parrots as the animals most often mentioned as agricultural pests. On the other hand, some of these birds were so chatty that people suspected them to be demonic or possessed animals, since only three classes of beings - angels, men and demons - have the ability to speak. Nowadays, several Psittacidae still constitute a threat to agriculture, and the suspicion that extremely talkative birds were demon possessed has also survived. More than a joke or a mere curiosity, this belief exemplifies how intricate manâs relationships with the ânatural worldâ may be. In this sense, the existence of birds that are able to speak adds a further twist to these relationships, demonstrating that the problem of establishing a boundary between the animal and the human does not only involve primates, but also includes some unusual zoological species