54 research outputs found
Analysis of histone posttranslational modifications in the control of chromatin plasticity observed at estrogen-responsive sites in human breast cancer cells
No full textIt is well established that histone posttranslational modifications mediate the control of gene expression played by chromatin. Such modifications are commonly reversible and many alternatives are open to drive transcription of inducible genes. Estrogens govern growth and survival of hormone-sensitive cells by inducing expression of genes important for cell cycle progression and apoptosis. Transcription of estrogen-responsive genes is triggered by the lysine-specific demethylase 1 (LSD1)-dependent demethylation of dimethylated lysine 9 in histone H3 (H3K9me2) that accompanies to local generation of oxygen reactive species (ROS). Production of ROS modifies guanines in neighbor DNA with consequent recruitment of base-excision repair (BER) enzymes and formation of breaks that support creation of bridges between sites that, although distant on linear DNA, establish strategic contacts useful for productive transcription
LSD1: more than demethylation of histone lysine residues
No full textLysine-specific histone demethylase 1 (LSD1) represents the first example of an identified nuclear protein with histone demethylase activity. In particular, it plays a special role in the epigenetic regulation of gene expression, as it removes methyl groups from mono- and dimethylated lysine 4 and/or lysine 9 on histone H3 (H3K4me1/2 and H3K9me1/2), behaving as a repressor or activator of gene expression, respectively. Moreover, it has been recently found to demethylate monomethylated and dimethylated lysine 20 in histone H4 and to contribute to the balance of several other methylated lysine residues in histone H3 (i.e., H3K27, H3K36, and H3K79). Furthermore, in recent years, a plethora of nonhistone proteins have been detected as targets of LSD1 activity, suggesting that this demethylase is a fundamental player in the regulation of multiple pathways triggered in several cellular processes, including cancer progression. In this review, we analyze the molecular mechanism by which LSD1 displays its dual effect on gene expression (related to the specific lysine target), placing final emphasis on the use of pharmacological inhibitors of its activity in future clinical studies to fight cancer
Nuclear receptor-induced transcription is driven by spatially and timely restricted waves of ROS. The role of Akt, IKKα, and DNA damage repair enzymes
No full textGene expression is governed by chromatin mainly through posttranslational modifications at the N-terminal tails of nucleosomal histone proteins. According to the histone code theory, peculiar sets of such modifications (marks) give rise to reproducible final effects on transcription and, very recently, a further level of complexity has been highlighted in binary switches between specific marks at adjacent residues. In particular, disappearance of dimethyl-lysine 9 in histone H3 is faced by phosphorylation of the following serine during activation of gene expression. Demethylation of lysine 9 by the lysine-specific demethylase 1 (LSD1) is a pre-requisite for addition of the phosphoryl mark to serine 10 and an essential step in the transcriptional control by estrogens. It generates a local burst of oxygen reactive species (ROS) that induce oxidation of nearby nucleotides and recruitment of repair enzymes with a consequent formation of single or double stranded nicks on DNA that modify chromatin flexibility in order to allow correct assembly of the transcriptional machinery. We describe here the molecular mechanism by which members of the family of nuclear receptors prevent the potential damage to DNA during transcription of target genes elicited by the use of ROS to shape chromatin. The mechanism is based on the presence of phosphorylated serine 10 in histone H3 to prevent unbalanced DNA oxidation waves. We also discuss the opportunities raised by the use of voluntary derangement of this servo system to induce selective death in hormone-responsive transformed cells
Retinoic acid impairs estrogen signaling in breast cancer cells by interfering with activation of LSD1 via PKA
No full textMore than 70% of breast cancers in women require estrogens for cell proliferation and survival. 17β-estradiol (E2) effect on mammary target cells is almost exclusively mediated by its binding to the estrogen receptor-α (ERα) that joins chromatin where it assembles active transcription complexes. The proliferative and pro-survival action of estrogens is antagonized in most cases by retinoic acid (RA), even though the cognate retinoic acid receptor-α (RARα) cooperates with ERα on promoters of estrogen-responsive genes. We have examined at the molecular level the crosstalk between these nuclear receptors from the point of view of their control of cell growth and show here that RA reverts estrogen-stimulated transcription of the pivotal anti-apoptotic bcl-2 gene by preventing demethylation of dimethyl lysine 9 in histone H3 (HeK9me2). As we previously reported, this is obtained by means of E2-triggered activation of the lysine-specific demethylase 1 (LSD1), an enzyme that manages chromatin plasticity in order to allow specific movements of chromosomal regions within the nucleus. We find that E2 fuels LSD1 by inducing migration of the catalytic subunit of protein kinase A (PKA) into the nucleus, where it targets estrogen-responsive loci. RA rescues LSD1-dependent disappearance of H3K9me2 at bcl-2 regulatory regions upon the prevention of PKA assembly to the same sites
Communication between cells: exosomes as a delivery system in prostate cancer
No full textAbstract Despite the considerable efforts in screening and diagnostic protocols, prostate cancer still represents the second leading cause of cancer-related death in men. Many patients with localized disease and low risk of recurrence have a favourable outcome. In a substantial proportion of patients, however, the disease progresses and becomes aggressive. The mechanisms that promote prostate cancer progression remain still debated. Many findings point to the role of cross-communication between prostate tumor cells and their surrounding microenvironment during the disease progression. Such a connection fosters survival, proliferation, angiogenesis, metastatic spreading and drug-resistance of prostate cancer. Recent years have seen a profound interest in understanding the way by which prostate cancer cells communicate with the surrounding cells in the microenvironment. In this regard, direct cell-to-cell contacts and soluble factors have been identified. Increasing evidence indicates that PC cells communicate with the surrounding cells through the release of extracellular vesicles, mainly the exosomes. By directly acting in stromal or prostate cancer epithelial cells, exosomes represent a critical intercellular communication system. By querying the public database ( https://pubmed.ncbi.nlm.nih.gov ) for the past 10 years, we have found more than four hundred papers. Among them, we have extrapolated the most relevant about the role of exosomes in prostate cancer malignancy and progression. Emerging data concerning the use of these vesicles in diagnostic management and therapeutic guidance of PC patients are also presented. Graphical Abstract Video Abstrac
Middleware to Support Sensor Network Applications
No full textCurrent trends in computing include increases in both distribution and wireless connectivity, leading to highly dynamic, complex environments on top of which applications must be built. The task of designing and ensuring the correctness of applications in these environments is similarly becoming more complex. The unified goal of much of the research in distributed wireless systems is to provide higher-level abstractions of complex low-level concepts to application programmers, easing the design and implementation of applications. A new and growing class of applications for wireless sensor networks require similar complexity encapsulation. However, sensor networks have some unique characteristics, including dynamic availability of data sources and application quality of service requirements, that are not common to other types of applications. These unique features, combined with the inherent distribution of sensors, and limited energy and bandwidth resources, dictate the need for network functionality and the individual sensors to be controlled to best serve the application requirements. In this article, we describe different types of sensor network applications and discuss existing techniques for managing these types of networks. We also overview a variety of related middleware and argue that no existing approach provides all the management tools required by sensor network applications. To meet this need, we have developed a new middleware called MiLAN. MiLAN allows applications to specify a policy for managing the network and sensors, but the actual implementation of this policy is effected within MiLAN. We describe MiLAN and show its effectiveness through the design of a sensor-based personal health monitor
Estrogen Receptors in Epithelial-Mesenchymal Transition of Prostate Cancer.
No full textProstate cancer (PC) remains a widespread malignancy in men. Since the
androgen/androgen receptor (AR) axis is associated with the pathogenesis of prostate cancer,
suppression of AR-dependent signaling by androgen deprivation therapy (ADT) still represents the
primary intervention for this disease. Despite the initial response, prostate cancer frequently
develops resistance to ADT and progresses. As such, the disease becomes metastatic and few
therapeutic options are available at this stage. Although the majority of studies are focused on the
role of AR signaling, compelling evidence has shown that estrogens and their receptors control
prostate cancer initiation and progression through a still debated mechanism. Epithelial versus
mesenchymal transition (EMT) is involved in metastatic spread as well as drug-resistance of human
cancers, and many studies on the role of this process in prostate cancer progression have been
reported. We discuss here the findings on the role of estrogen/estrogen receptor (ER) axis in
epithelial versus mesenchymal transition of prostate cancer cells. The pending questions concerning
this issue are presented, together with the impact of the available data in clinical management of
prostate cancer patients
Imputation and increment of spatial resolution in geophysical multivariate data in onshore basin: an approach with self organizing maps.
No full textA técnica Mapas Auto-Organizáveis, em inglês Self-Organizing Maps (SOM) têm sido amplamente utilizada em segmentação e agrupamento de banco de dados complexos e multivariados, permitindo um melhor entendimento de relações não lineares entre as variáveis. Tal técnica computacional possibilita identificar assinaturas dentro dos mais diversos conjuntos de dados, sejam estes compostos por variáveis categóricas ou contínuas. Diversos autores têm abordado estudos de caso envolvendo o uso de SOM para criar valores sintéticos em regiões com dados faltantes. A escassez de trabalhos sobre incremento de resolução utilizando dados multivariados demonstram as dificuldades encontradas e a necessidade de mais estudos. Este trabalho visa imputar e incrementar resolução espacial em dados, a partir da técnica SOM possibilitando a obtenção de dados com maior resolução a baixo custo, principalmente para dados gravimétricos, cuja aquisição é menos comum e demanda rigor analítico e processual. A primeira abordagem está relacionada à imputação de dados em locais de difícil acesso, tais como a região Amazônica, onde foram utilizados dados de gravimetria terrestre e aérea, distúrbio da gravidade e o modelo GEMMA, que é uma estimativa da espessura da crosta. Os diferentes tamanhos de mapas aplicados nas análises por SOM mostraram alta correlação em valores absolutos entre os dados sintéticos e os dados originais. Em uma segunda abordagem, voltada ao incremento de resolução espacial, foram utilizados dados aerogamaespectrométricos compostos por células originalmente com 125m de resolução espacial. Para fins de comparações a variável tório foi degradada para células com resoluções espaciais de 500 e 1000m. As análises SOM foram desenvolvidas com todo o universo de variáveis gamaespectrométricas incluindo, além da variável tório degradada, os dados de contagem total, urânio e potássio. Os resultados mostraram o incremento da resolução do tório de 500m e 1000m, para a resolução de 125m, que apresentaram, respectivamente, R2= 0,98 e 0,94. As análises desenvolvidas demonstram validade à imputação e ao incremento de resolução pela técnica SOM. Os resultados sugerem possibilidades de desenvolvimento de incremento de resolução espacial de variáveis com baixa resolução em áreas compostas por outras variáveis de maior resolução espacial.The Self-Organizing Maps (SOM) technique has been widely used for segmentation and clustering of complex and multivariate databases, allowing a better understanding of nonlinear relationships between variables. Such computational technique makes it possible to identify signatures within the most diverse data sets, whether these are categorical or continuous variables. Several authors have approached case studies involving the use of SOM to create synthetic values in regions with missing data. The lack of work on resolution increment using multivariate data demonstrates the difficulties encountered and the need for further studies. This work aims to impute and increase spatial resolution in data, using the SOM technique, enabling the obtaining of higher resolution data at low cost, especially for gravimetric data, whose acquisition is less common and demands analytical and procedural rigor. The first approach is related to data imputation in hard to reach places, such as the Amazon region, where terrestrial and air gravity data, gravity disturbance and the GEMMA model, which is an estimate of crust thickness, were used. The different map sizes applied in the SOM analyzes showed a high correlation in absolute values between the synthetic data and the original data. In a second approach, focused on the increment of spatial resolution, aerogamapectrometric data composed by cells originally with 125m of spatial resolution were used. For comparison purposes the thorium variable was degraded for cells with spatial resolutions of 500 and 1000m. The SOM analyzes were developed with the whole universe of gamma-spectrometric variables including, besides the degraded thorium variable, the total count, uranium and potassium data. The results showed an increase in the thorium resolution of 500m and 1000m, for the resolution of 125m, which presented, respectively, R2 = 0,98 e 0,94. The developed analyzes demonstrate validity to the imputation and the increment of resolution by the SOM technique. The results suggest possibilities of developing spatial resolution increment of low-resolution variables in areas composed by other variables of higher spatial resolution
Tra mondo reale e mondi possibili: la progettazione partecipata come dispositivo formativo
No full textThe essay, moving within the dialectic between constructivism and realism , offers some ideas on participatory practices . Pedagogy, analyzing the relationship between man and the world, can gather in participatory processes possible devices that allow to stay inside the practical dimension of reality.
A particular area of analysis about the educational outcomes inherent in participatory practices is the "participatory planning ": a planning tool that includes the involvement of inhabitants of a territory in the processes of urban transformation and involves the introduction of dynamic and interactive pathways , founded on the comparison between professionals and ordinary citizens.
In the logic of participatory planning , the reorganization of space must go through a reshaping of relations , with the active involvement of all stakeholders and a rethinking of policy practices
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