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Enrique Armijo Claudio Soto Brian R. Davis 《Cellular and molecular life sciences : CMLS》2014,71(14):2641-2649
Since HIV/AIDS was first recognized in 1981, an urgent need has existed for the development of novel therapeutic strategies to treat the disease. Due to the current antiretroviral therapy not being curative, human stem cell-based therapeutic intervention has emerged as an approach for its treatment. Genetically modified hematopoietic stem cells (HSCs) possess the potential to self-renew, reconstitute the immune system with HIV-resistant cells, and thus control, or even eliminate, viral replication. However, HSCs may be difficult to isolate in sufficient number from HIV-infected individuals for transplantation and/or re-infusion of autologous HSCs preparations would also include some contaminating HIV-infected cells. Furthermore, since genetic modification of HSCs is not completely efficient, the risk of providing unprotected immune cells to become new targets for HIV to infect could contribute to continued immune system failure. Therefore, induced pluripotent stem cells (iPSCs) should be considered a new potential source of cells to be engineered for HIV resistance and subsequently differentiated into clonal anti-HIV HSCs or hematopoietic progeny for transplant. In this article, we provide an overview of the current possible cellular therapies for treating HIV/AIDS. 相似文献
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Sergio Claudio Saccà Alberto Izzotti 《Cellular and molecular life sciences : CMLS》2014,71(12):2197-2218
Primary open-angle glaucoma is a multifactorial disease that affects the retinal ganglion cells, but currently its therapy is to lower the eye pressure. This indicates a definite involvement of the trabecular meshwork, key region in the pathogenesis of glaucoma. This is the first target of glaucoma, and its functional complexity is a real challenge to search. Its functions are those to allow the outflow of aqueous humor and not the reflux. This article describes the morphological and functional changes that happen in anterior chamber. The “primus movens” is oxidative stress that affects trabecular meshwork, particularly its endothelial cells. In these develops a real mitochondriopaty. This leads to functional impotence, the trabecular meshwork altering both motility and cytoarchitecture. Its cells die by apoptosis, losing barrier functions and altering the aqueous humor outflow. All the morphological alterations occur that can be observed under a microscope. Intraocular pressure rises and the malfunctioning trabecular meshwork endotelial cells express proteins that completely alter the aqueous humor. This is a liquid whose functional proteomics complies with the conditions of the trabecular meshwork. Indeed, in glaucoma, it is possible detect the presence of proteins which testify to what occurs in the anterior chamber. There are six classes of proteins which confirm the vascular endothelium nature of the anterior chamber and are the result of the morphofunctional trabecular meshwork decay. It is possible that, all or in part, these proteins can be used as a signal to the posterior pole. 相似文献
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Tartaglia M Pennacchio LA Zhao C Yadav KK Fodale V Sarkozy A Pandit B Oishi K Martinelli S Schackwitz W Ustaszewska A Martin J Bristow J Carta C Lepri F Neri C Vasta I Gibson K Curry CJ Siguero JP Digilio MC Zampino G Dallapiccola B Bar-Sagi D Gelb BD 《Nature genetics》2007,39(1):75-79
Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies. Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome-associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development. 相似文献
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Theory predicts and observations confirm that low-mass stars (like the Sun) in their early life grow by accreting gas from the surrounding material. But for stars approximately 10 times more massive than the Sun (approximately 10M(o)), the powerful stellar radiation is expected to inhibit accretion and thus limit the growth of their mass. Clearly, stars with masses >10M(o) exist, so there must be a way for them to form. The problem may be solved by non-spherical accretion, which allows some of the stellar photons to escape along the symmetry axis where the density is lower. The recent detection of rotating disks and toroids around very young massive stars has lent support to the idea that high-mass ( > 8M(o)) stars could form in this way. Here we report observations of an ammonia line towards a high-mass star forming region. We conclude that the gas is falling inwards towards a very young star of approximately 20M(o), in line with theoretical predictions of non-spherical accretion. 相似文献
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P Dutta G Courties Y Wei F Leuschner R Gorbatov CS Robbins Y Iwamoto B Thompson AL Carlson T Heidt MD Majmudar F Lasitschka M Etzrodt P Waterman MT Waring AT Chicoine AM van der Laan HW Niessen JJ Piek BB Rubin J Butany JR Stone HA Katus SA Murphy DA Morrow MS Sabatine C Vinegoni MA Moskowitz MJ Pittet P Libby CP Lin FK Swirski R Weissleder M Nahrendorf 《Nature》2012,487(7407):325-329
During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaques in the arterial wall and cause their rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischaemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, Apoe-/- mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. Seeking the source of surplus monocytes in plaques, we found that myocardial infarction liberated haematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signalling. The progenitors then seeded the spleen, yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression. 相似文献
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Scuoppo C Miething C Lindqvist L Reyes J Ruse C Appelmann I Yoon S Krasnitz A Teruya-Feldstein J Pappin D Pelletier J Lowe SW 《Nature》2012,487(7406):244-248
Tumour suppressor genes encode a broad class of molecules whose mutational attenuation contributes to malignant progression. In the canonical situation, the tumour suppressor is completely inactivated through a two-hit process involving a point mutation in one allele and chromosomal deletion of the other. Here, to identify tumour suppressor genes in lymphoma, we screen a short hairpin RNA library targeting genes deleted in human lymphomas. We functionally identify those genes whose suppression promotes tumorigenesis in a mouse lymphoma model. Of the nine tumour suppressors we identified, eight correspond to genes occurring in three physically linked 'clusters', suggesting that the common occurrence of large chromosomal deletions in human tumours reflects selective pressure to attenuate multiple genes. Among the new tumour suppressors are adenosylmethionine decarboxylase 1 (AMD1) and eukaryotic translation initiation factor 5A (eIF5A), two genes associated with hypusine, a unique amino acid produced as a product of polyamine metabolism through a highly conserved pathway. Through a secondary screen surveying the impact of all polyamine enzymes on tumorigenesis, we establish the polyamine-hypusine axis as a new tumour suppressor network regulating apoptosis. Unexpectedly, heterozygous deletions encompassing AMD1 and eIF5A often occur together in human lymphomas and co-suppression of both genes promotes lymphomagenesis in mice. Thus, some tumour suppressor functions can be disabled through a two-step process targeting different genes acting in the same pathway. 相似文献
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P systems have been used many times to face with computationally difficult problems, such as NP-complete decision problems and NP-hard optimization problems. In this paper we focus our attention on another computationally intractable problem: factorization. In particular, we first propose a simple method to encode binary numbers using multisets. Then, we describe three families of P systems: the first two allow to add and to multiply two binary encoded numbers, respectively, and the third solves the factorization problem. 相似文献
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1. Introduction The Analytic Hierarchy Process (AHP) for decision-making uses objective mathematics to process the inescapably subjective and personal preferences of an individual or a group in making a decision. With the AHP, we construct hierarchies that have a first level of strategic or politic criteria, then expand each one of these criteria into more specific subcriteria until reach the terminal criteria, the behavior indicators. Later, makes judgments or performs measurements on pai… 相似文献