Proceedings of the National Academy of Sciences, 2006
Regulation of the levels of tyrosine phosphorylation is essential to maintain the functions of pr... more Regulation of the levels of tyrosine phosphorylation is essential to maintain the functions of proteins in different signaling pathways and other cellular systems, but how the steady-state levels of tyrosine phosphorylation are coordinated in different cellular systems to initiate complex cellular functions remains a formidable challenge. The receptor protein tyrosine phosphatase (RPTP)β/ζ is a transmembrane tyrosine phosphatase whose substrates include proteins important in intracellular and transmembrane protein-signaling pathways, cytoskeletal structure, cell–cell adhesion, endocytosis, and chromatin remodeling. Pleiotrophin (PTN the protein and Ptn the gene) is a ligand for RPTPβ/ζ; PTN inactivates RPTPβ/ζ, leaving unchecked the continued endogenous activity of tyrosine kinases that increase phosphorylation of the substrates of RPTPβ/ζ at sites dephosphorylated by RPTPβ/ζ in cells not stimulated by PTN. Thus, through the regulation of the tyrosine phosphatase activity of RPTPβ/ζ...
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) first discovered as the cons... more Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) first discovered as the constitutively active nucleophosmin-ALK oncoprotein in anaplastic large cell lymphomas (ALCL). Fulllength ALK has a critical role in normal development and differentiation. Activated full-length ALK also is found in different malignant cancers. Nevertheless, the ligand to activate ALK remained unknown until recently, when ALK was proposed to be the physiological receptor of the cytokine pleiotrophin (PTN, Ptn). However, earlier studies had demonstrated that receptor protein tyrosine phosphatase (RPTP) / is a physiological PTN receptor. We now demonstrate that phosphorylation of ALK in PTN-stimulated cells is mediated through the PTN/RPTP/ signaling pathway. ALK is phosphorylated independently of a direct interaction of PTN with ALK. The data thus support a unique model of ALK activation. In cells not stimulated by PTN, RPTP/ dephosphorylates ALK at the site(s) in ALK that is undergoing autophosphorylation through autoactivation. In contrast, when RPTP/ is inactivated in PTN-stimulated cells, the sites that are autophosphorylated in ALK no longer can be dephosphorylated by RPTP/; thus, autoactivation and tyrosine phosphorylation of ALK rapidly increase. The data indicate that the PTN/RPTP/ signaling pathway is a critical regulator of the steady state levels of tyrosine phosphorylation and activation of ALK; the data support the conclusion that ALK phosphorylation and activation in PTNstimulated cells are increased through a unique "alternative mechanism of RTK activation."
The present study deals with the localization and development of S-100 protein-like immunoreactiv... more The present study deals with the localization and development of S-100 protein-like immunoreactivity in the retina, ciliary body and iris of human fetuses. In the retina, numerous astrocytes, densely distributed in the nerve-fiber layer and ganglion-cell layer, were stained strongly with the S-100 antiserum. The first immunoreactive astrocytes occurred at the posterior pole of the retina and spread gradually outward and toward the ora serrata with increasing age. Miiller cells were not immunoreactive for S-100 during development, except in the retina of the latest fetus examined. S-100 immunoreactivity was also found in the nonpigmented ciliary epithelium and posterior epithelium of the iris, both of which are developed from the inner wall of the optic cup. On the other hand, the pigmented epithelium extending from retina to iris, derived from the outer layer of the optic cup, was free of S-100 immunoreactivity.
Convolutional neural networks (CNNs) have found applications in many image processing tasks, such... more Convolutional neural networks (CNNs) have found applications in many image processing tasks, such as feature extraction, image classification, and object recognition. It has also been shown that the inverse of CNNs, so-called deconvolutional neural networks, can be used for inverse problems such as plasma tomography. In essence, plasma tomography consists in reconstructing the 2D plasma profile on a poloidal cross-section of a fusion device, based on line-integrated measurements from multiple radiation detectors. Since the reconstruction process is computationally intensive, a deconvolutional neural network trained to produce the same results will yield a significant computational speedup, at the expense of a small error which can be assessed using different metrics. In this work, we discuss the design principles behind such networks, including the use of multiple layers, how they can be stacked, and how their dimensions can be tuned according to the number of detectors and the desired tomographic resolution for a given fusion device. We describe the application of such networks at JET and COMPASS, where at JET we use the bolometer system, and at COMPASS we use the soft X-ray diagnostic based on photodiode arrays.
Different microRNAs (miRNAs), including miR-29 family, may play a role in the development of hear... more Different microRNAs (miRNAs), including miR-29 family, may play a role in the development of heart failure (HF), but the underlying molecular mechanisms in HF pathogenesis remain unclear. We aimed at characterizing mice deficient in miR-29 in order to address the functional relevance of this family of miRNAs in the cardiovascular system and its contribution to heart disease. In this work, we show that mice deficient in miR-29a/b1 develop vascular remodeling and systemic hypertension, as well as HF with preserved ejection fraction (HFpEF) characterized by myocardial fibrosis, diastolic dysfunction, and pulmonary congestion, and die prematurely. We also found evidence that the absence of miR-29 triggers the up-regulation of its target, the master metabolic regulator PGC1α, which in turn generates profound alterations in mitochondrial biogenesis, leading to a pathological accumulation of small mitochondria in mutant animals that contribute to cardiac disease. Notably, we demonstrate that systemic hypertension and HFpEF caused by miR-29 deficiency can be rescued by PGC1α haploinsufficiency, which reduces cardiac mitochondrial accumulation and extends longevity of miR-29-mutant mice. In addition, PGC1α is overexpressed in hearts from patients with HF. Collectively, our findings demonstrate the in vivo role of miR-29 in cardiovascular homeostasis and unveil a novel miR-29/PGC1α regulatory circuitry of functional relevance for cell metabolism under normal and pathological conditions.
Background and objectives: Anchorage is one of the most challenging sides in orthodontics. The us... more Background and objectives: Anchorage is one of the most challenging sides in orthodontics. The use of biological modulators that inhibit osteoclasts could be a solution to address these problems and provide new adjunctive approaches. The aim of this study was to assess the effectiveness of recombinant osteoprotegerin fusion protein (OPG-Fc) in orthodontic anchorage. Materials and methods: Two groups of male Sprague-Dawley rats were utilized. The animals in the experimental group received twice-weekly injections with high dose of OPG-Fc (5.0 mg/kg) in mesial and distal mucosa of the first molars, and those in the control group received no drugs. Right first maxillary molars were mesialized using a calibrated nickel-titanium spring connected to an anterior mini-screw. Tooth movement was measured by two blinded observers using scanned and magnified stone casts. Receptor activator of nuclear factor κB (RANK), run-related transcription factor 2 (Runx2), type I collagen, vimentin, matrix metalloproteinases 2 and 9, S100 protein and the putative mechanoproteins acid-sensing ion channel (ASIC2) and transient receptor potential vainilloid 4 (TRPV4) were evaluated using immunohistochemistry. Results: OPG-Fc group showed an important decreased in mesial molar movement with only 52%, 31%, and 22% of the total mesial molar movement compared with control group at Days 7, 14, and 21, respectively (P < 0.001). RANK ligand and Runx2 positive cells were severely reduced after OPG-Fc treatment. Periodontal ligament architecture, cell arrangement, and immunohistochemical patter for vimentin, type I collagen and the mechanoproteins TRPV4 and ASIC2 were altered by tooth movement and all these parameters altered by the applied treatment. Conclusions: OPG-Fc effectively inhibits osteoclastogenesis resulting in improved bone quantity and orthodontic anchorage. Based on present results, OPG-Fc could have clinical utility in preventing undesired tooth movements. the bone remodeling occurring after the application of mechanical forces (1). Therefore, drugs influencing bony cells biology, may affect the results of orthodontic treatment (2), as it has been shown
Neurotrophins play a critical role in the development of the mammalian ovary, oogenesis and folli... more Neurotrophins play a critical role in the development of the mammalian ovary, oogenesis and folliculogenesis. In this study we investigated the cell localization of the two main receptors for nerve growth factor (NGF), TrkA and p75 NTR , in the cow and pig ovary, using immunohistochemistry. Specific immunoreactivity for TrkA and p75 NTR was detected in the ovary of both species, but the pattern and intensity of immunostaining were marginally different between them. The follicular cells regularly expressed immunoreactivity for both receptors. Immunoreactivity was also detected in the oocytes, independently of the maturational stage of the follicles, with the exception of primordial and primary follicles of the pig which did not display p75 NTR. Taken together, these results suggest a possible direct role of NGF on oocytes expressing TrkA and p75 NTR , in addition to the well-known roles in other ovary functions. The practical relevance of these data remains to be clarified.
In addition to their well‐known roles within the nervous system, the neurotrophins and their rece... more In addition to their well‐known roles within the nervous system, the neurotrophins and their receptors regulate some functions in the reproductive system. In this study we used combined morphological and immunohistochemical techniques to investigate the presence and cellular localization in the rat testicle of the two receptors of nerve growth factor (NGF), i.e. TrkA and p75NTR. Furthermore, to evaluate whether increased plasma levels of NGF affect the ageing process, 4‐methylcathechol (4‐MC), an inductor of NGF synthesis, was administered. Both TrkA and p75NTR were expressed in rat testicles, but the pattern and intensity of immunoreaction were marginally different between them. In adult rats TrkA was expressed in spermatozoa and spermatids, and p75 was expressed in spermatogonia. In newborn rats TrkA immunoreactivity was found in the Leydig cells, whereas p75 was detected in a cellular layer that surrounds the seminiferous tubules. In adult treated animals the immunoreaction for T...
In recent years, data have accumulated suggesting that the role of neurotrophins and Trk receptor... more In recent years, data have accumulated suggesting that the role of neurotrophins and Trk receptors may not be limited to the nervous system, and the presence of these substances has been detected in a variety of vertebrate and invertebrate non-nervous tissues. This study was designed to map the expression of immunoreactivity (IR) for Trk-like proteins in alevins of the teleost Dicentrarchus labrax, with particular emphasis on nonnervous structures. We used antibodies against specific epitopes of the intracellular domain of these proteins, a region that is highly conserved in phylogeny. Trk-like IR was seen in segregate cell populations of the nervous system, and non-nervous tissues. In the central nervous system TrkA-like and TrkC-like IR was abundant, whereas TrkB-like IR was restricted to a low number of brain areas. Expression of Trk-like protein IR was observed in the peripheral nervous system and sensory organs, with the exception of the lateral line organ. Outside the nervous system, TrkA-like IR was mainly found in different epithelia, TrkB-like IR in the endocrine and digestive system, and TrkC-like IR in the cardiovascular and immune systems. The gills showed IR for all three Trk-like proteins, whereas they were absent from the gonads. Furthermore, scattered cells positive for Trk-like proteins were found in most of the investigated tissues. The distribution of Trk-like IR in this teleost is compared with that of mammals and birds, which it often paralleled, and the possible role of neurotrophins and Trk-like receptor proteins in different non-neuronal tissues is discussed.
Neurotrophins are involved in the development and maintenance of some neuronal populations, actin... more Neurotrophins are involved in the development and maintenance of some neuronal populations, acting through tyrosine protein kinase (Trk) receptors, TrkA, TrkB and TrkC. In addition, recent studies have demonstrated the occurrence of Trk receptors in a wide variety of adult and embryonic non-neuronal tissues in vertebrates, including kidney. Nevertheless no data are available on Trk proteins distribution in teleost kidney. The present study, by using an immunoperoxidase technique, analyses Trk receptor protein distribution in the kidney of three species of freshwater and saltwater teleost. TrkA-like immunoreactivity was the only one detected in all examined species, while TrkB-like immunoreactivity was completely absent and TrkC-like immunoreactivity was detected only in goldfish. The TrkA immunoreactive cells were mainly localised in the collecting duct system, as this system was the only one to also display TrkC. Such data could provide new clues to Trk in fish and aid assessment of the role of Trk protein receptors during vertebrate evolution.
Age-dependent changes in the innervation of the pigeon (Columba livia, L.) bursa of Fabricius, fr... more Age-dependent changes in the innervation of the pigeon (Columba livia, L.) bursa of Fabricius, from hatching to 120 days of age, were studied by fluorescencehistochemical and neurochemical methods for demonstrating noradrenergic and acetylcholinesterase (AChE)reactive nerve fibres respectively. The distribution of both nerve fibre types was largely perivascular. Furthermore, a few isolated nerve fiber profiles were observed beneath the bursal epithelium, in the interfollicular septa and in the follicular cortex. No nerve fibre profiles reaching the medulla of the lymphoid follicles were observed. In addition to nerve fibres, AChE reactive neuron-like cells were encountered within the capsule and inter follicular septa. AChE reactivity was also found in dendritic-like cells localized in the cortical and cortico-medullary border. No changes in the density of perivascular noradrenergic innervation were noticeable during the ages studied, whereas the density of AChE-reactive fibres supplying vessels reached the adult pattern at 30 days, and then remained unvaried. The density of non-perivascular nerve fiber profiles, specially the AChE reactive type, increased until 30 days, remained unchanged until 75 days and then increased with aging (90-120 days). The interrelationship between the autonomic nervous system and the immune system is discussed.
The Sensory Innervation of the Human Pharynx: Searching for Mechanoreceptors
The Anatomical Record, 2013
ABSTRACTThe coordinate neural regulation of the upper airways muscles is basic to control airway ... more ABSTRACTThe coordinate neural regulation of the upper airways muscles is basic to control airway size and resistance. The superior constrictor pharyngeal muscle (SCPM) forms the main part of the lateral and posterior walls of the pharynx and typically is devoid of muscle spindles, the main type of proprioceptor. Because proprioception arising from SCPM is potentially important in the physiology of the upper airways, we have investigated if there are mechanical sensory nerve endings substitute for the muscle spindles. Samples of human pharynx were analyzed using immunohistochemistry associated to general axonic and Schwann cells markers (NSE, PGP 9.5, RT‐97, and S100P), intrafusal muscle fiber markers, and putative mechanical sense proteins (TRPV4 and ASIC2). Different kinds of sensory corpuscles were observed in the pharynx walls (Pacini‐like corpuscles, Ruffini‐like corpuscles, spiral‐wharves nerve structures, and others) which are supplied by sensory nerves and express putative me...
La función de los mecanorreceptores de las articulaciones y músculos se considera asociada a la p... more La función de los mecanorreceptores de las articulaciones y músculos se considera asociada a la propiocepción. Sin embargo, existen evidencias de que la propiocepción no sólo depende del morfotipo de mecanorreceptor presente en dichos tejidos sino también de las propiedades de las neuronas sensitivas primarias y las fibras sensitivas asociadas a ellos, así como de su proyección sobre el asta posterior de la médula espinal. Este artículo resume las bases morfológicas de la propiocepción a nivel del sistema nervioso periférico, analizando: a) las neuronas sensitivas primarias propioceptivas; b) los tipos de fibras nerviosas sensitivas que llegan a los propioceptores; c) la inervación sensitiva de articulaciones y músculos; d) los morfotipos de mecanorreceptores asociados a la propiocepción; e) los datos recientes obtenidos a partir de animales deficientes en factores clave para el desarrollo del sistema propioceptor.
Aims: To report a case of wet age-related macular degeneration (wet-AMD) refractory to intravitre... more Aims: To report a case of wet age-related macular degeneration (wet-AMD) refractory to intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy in a patient who showed visual and anatomical improvement and stabilization after starting a subcutaneous treatment course with adalimumab, an anti-tumor necrosis factor-alpha (TNF-α) drug, for concomitant Crohn's disease. Methods: Observational case report of a female patient. Ophthalmological evaluation was performed by slit lamp and ophthalmoscopy (posterior pole and anterior segment). Best-corrected visual acuity (BCVA) was determined, and imaging was performed by fluorescein angiography, indocyanine green angiography, and optical coherence tomography (OCT). Intravitreal therapies used and treatment with anti-TNF-α were recorded. Results: A 64-year-old woman with wet-AMD was treated with fourteen intravitreal injections of ranibizumab (0.5 mg) for a period of 40 months with intervals of 1-6 months. She initially showe...
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