391 research outputs found
Structural Determinants of Protein Kinase CK2 Regulation by Autoinhibitory Polymerization
No full textCK2 is a Ser/Thr protein kinase essential for cell viability whose activity is anomalously high in several cancers. CK2 is a validated target for cancer therapy with one small molecule inhibitor in phase I clinical trials. This enzyme is not regulated by mechanisms common to other protein kinases, and how its activity is controlled is still unclear. We present a new crystal structure of the CK2 holoenzyme that supports an autoinhibitory mechanism of regulation whereby the β-subunit plays an essential role in the formation of inactive polymeric assemblies. The derived structural model of (down)regulation by aggregation contributes to the interpretation of biochemical and functional data and paves the way for new strategies in the modulation of CK2 activity and for the design of non-ATP-competitive inhibitors targeting the interaction between the α catalytic and the β regulatory subunits
Structural and functional analysis of the flexible regions of the catalytic α-subunit of protein kinase CK2.
No full textCK2 is a Ser/Thr protein kinase essential for cell viability. Its activity is anomalously high in several solid (prostate, mammary gland, lung, kidney and head and neck) and haematological tumours (AML, CML and PML), creating conditions favouring the onset of cancer. Cancer cells become addicted to high levels of CK2 activity and therefore this kinase is a remarkable example of "non-oncogene addiction". CK2 is a validated target for cancer therapy with one inhibitor in phase I clinical trials. Several crystal structures of CK2 are available, many in complex with ATP-competitive inhibitors, showing the presence of regions with remarkable flexibility. We present the structural characterisation of these regions by means of seven new crystal structures, in the apo form and in complex with inhibitors. We confirm previous findings about the unique flexibility of the CK2alpha catalytic subunit in the hinge/alphaD region, the p-loop and the beta4beta5 loop, and show here that there is no clear-cut correlation between the conformations of these flexible zones. Our findings challenge some of the current interpretations on the functional role of these regions and dispute the hypothesis that small ligands stabilize an inactive state. The mobility of the hinge/alphaD region in the human enzyme is unique among protein kinases, and this can be exploited for the development of more selective ATP-competitive inhibitors. The identification of different ligand binding modes to a secondary site can provide hints for the design of non-ATP-competitive inhibitors targeting the interaction between the alpha catalytic and the beta regulatory subunits
PPARα Signaling: A Candidate Target in Psychiatric Disorder Management
No full textPeroxisome proliferator-activator receptors (PPARs) regulate lipid and glucose metabolism, control inflammatory processes, and modulate several brain functions. Three PPAR isoforms have been identified, PPARα, PPARβ/δ, and PPARγ, which are expressed in different tissues and cell types. Hereinafter, we focus on PPARα involvement in the pathophysiology of neuropsychiatric and neurodegenerative disorders, which is underscored by PPARα localization in neuronal circuits involved in emotion modulation and stress response, and its role in neurodevelopment and neuroinflammation. A multiplicity of downstream pathways modulated by PPARα activation, including glutamatergic neurotransmission, upregulation of brain-derived neurotrophic factor, and neurosteroidogenic effects, encompass mechanisms underlying behavioral regulation. Modulation of dopamine neuronal firing in the ventral tegmental area likely contributes to PPARα effects in depression, anhedonia, and autism spectrum disorder (ASD). Based on robust preclinical evidence and the initial results of clinical studies, future clinical trials should assess the efficacy of PPARα agonists in the treatment of mood and neurodevelopmental disorders, such as depression, schizophrenia, and ASD
Filosofia pedagogica del canto consapevole
No full textSince 2021, Graziano D'Urso's research has evolved into an editorial and pedagogical project aimed at redefining singing as a complex and multidimensional phenomenon rather than mere technical skill. Through seven volumes, the author integrates musicology, artistic vocology, pedagogy, and law to outline a unified vision of the voice that encompasses an ontology of singing, an ethics of mediation in teaching, and an experiential synthesis of emotions, mind, and body
"Passer le temps". The Graziano Arici’s archive of photography
No full textL’Archivio Graziano Arici est une archive photographique d’un genre résolument singulier ; elle réunit des enjeux et ou assemble des finalités qui ne se rejoignent que partiellement. Archive courante des photographies de Graziano Arici (photographe né en 1949 à Venise, résidant actuellement à Arles, et toujours en activité), fonctionnant comme une base d’images permettant au photographe d’accumuler et de vendre ses productions, elle est aussi, dès le départ, conçue comme une forme-conservatoire destinée, dans son ensemble, par son auteur même, à représenter une époque, à rester comme un témoignage porté par un regard sur une époque. Par l’acquisition de fractions d’archives photographiques, la mise en place d’une politique de préservation des images, et par ses créations, son travail plastique, le photographe se fait tout à la fois héritier d’un domaine précaire, mais aussi son passeur. Dans ce cas particulier, en effet, le rassemblement qu’est l’archive photographique se trouve être, non seulement, un lieu d’origine, premier, mais également l’endroit et le moment d’une recomposition, d’un remontage de productions antérieures, donnant ainsi naissance à un art consommé de l’assemblage, dans un lieu devenu paradoxal.The Archive Graziano Arici is a definitely unique photograph Archive of its kind. It concentrates issues, or combine objectives which only partially meet. The standard Archive of Graziano Arici’s photograph (Arici is a photographer born in Venice, now living in Arles and still working) first acting as a picture-base which enables the photographer to gather together and sell his productions, is also, from the outset, designed as a conservation device, and by its author himself intended in its entirety to represent particular times and bear testimony to individual perceptions of those times ; by acquiring fractions of photograph archives, and setting up a picture-conservation policy, but through his own creation and plastic work as well, the photographer becomes heir to a fleeting world, and his go-between, too, giving birth to an art of assembling, and his archive becoming a paradoxical place
Passer le temps. Vies d'une archive photographique contemporaine : l'archivio Graziano Arici
No full textThe Archive Graziano Arici is a definitely unique photograph Archive of its kind. It concentrates issues, or combine objectives which only partially meet. The standard Archive of Graziano Arici’s photograph (Arici is a photographer born in Venice, now living in Arles and still working) first acting as a picture-base which enables the photographer to gather together and sell his productions, is also, from the outset, designed as a conservation device, and by its author himself intended in its entirety to represent particular times and bear testimony to individual perceptions of those times ; by acquiring fractions of photograph archives, and setting up a picture-conservation policy, but through his own creation and plastic work as well, the photographer becomes heir to a fleeting world, and his go-between, too, giving birth to an art of assembling, and his archive becoming a paradoxical place.L’Archivio Graziano Arici est une archive photographique d’un genre résolument singulier ; elle réunit des enjeux et ou assemble des finalités qui ne se rejoignent que partiellement. Archive courante des photographies de Graziano Arici (photographe né en 1949 à Venise, résidant actuellement à Arles, et toujours en activité), fonctionnant comme une base d’images permettant au photographe d’accumuler et de vendre ses productions, elle est aussi, dès le départ, conçue comme une forme-conservatoire destinée, dans son ensemble, par son auteur même, à représenter une époque, à rester comme un témoignage porté par un regard sur une époque. Par l’acquisition de fractions d’archives photographiques, la mise en place d’une politique de préservation des images, et par ses créations, son travail plastique, le photographe se fait tout à la fois héritier d’un domaine précaire, mais aussi son passeur. Dans ce cas particulier, en effet, le rassemblement qu’est l’archive photographique se trouve être, non seulement, un lieu d’origine, premier, mais également l’endroit et le moment d’une recomposition, d’un remontage de productions antérieures, donnant ainsi naissance à un art consommé de l’assemblage, dans un lieu devenu paradoxal
Riflessioni sulla traduzione verso l'italiano
No full textpp.69-80This article claims that the irnportant works on translation studies which have
been published in Italy in the last few years have not been paralleled by a higher
quality of the translations from French into Italian. The majority of such
translations, published by the most well-known Italian publishers, still display
many source-text interpretation errors. It is argued that the blame for the low
quality of translations from French into Italian is to be ascribed mainly to Italian
universities, where translating into Italian from a foreign language is crucially
considered as a very elementary activity. Thus considerably less irnportance is
attached to forma1 courses of translation into Italian by both teachers and
students as compared to courses focussing on second language acquisition. It is
further argued that teaching translation should mean mainly giving trainees the
tools to solve any new translation problem they may encounter in their careers -
what the author calls a "translating mentality", ie. a well-balanced and
homogeneous mix of translation theory and practice giving rise to the
translator's specific (and particular) methodological approach
Quantum Dot Cellular Automata Check Node Implementation for LDPC Decoders
No full textThe quantum dot Cellular Automata (QCA) is an emerging nanotechnology that has gained significant research interest in recent years. Extremely small feature sizes, ultralow power consumption, and high clock frequency make QCA a potentially attractive solution for implementing computing architectures at the nanoscale. To be considered as a suitable CMOS substitute, the QCA technology must be able to implement complex real-time applications with affordable complexity. Low density parity check (LDPC) decoding is one of such applications. The core of LDPC decoding lies in the check node (CN) processing element which executes actual decoding algorithm and contributes toward overall performance and complexity of the LDPC decoder. This study presents a novel QCA architecture for partial parallel, layered LDPC check node. The CN executes Normalized Min Sum decoding algorithm and is flexible to support CN degree dc up to 20. The CN is constructed using a VHDL behavioral model of QCA elementary circuits which provides a hierarchical bottom up approach to evaluate the logical behavior, area, and power dissipation of the whole design. Performance evaluations are reported for the two main implementations of QCA i.e. molecular and magneti
Integrating the RFID identification system for Charolaise breeding bulls with 3D imaging for virtual archive creation
No full textThe individual electronic identification (EID) of cattle based on RFID technology (134.2 kHz ISO standard 11784) will definitely enter into force in European countries as an official means of animal identification from July 2019. Integrating EID with 3D digital images of the animal would lead to the creation of a virtual archive of breeding animals for the evaluation and promotion of morphology associated with economic traits, strategic in beef cattle production. The genetically-encoded morphology of bulls and cows together with the expression in the phenotype were the main drivers of omic technologies of beef cattle production. The evaluation of bulls raised for reproduction is mainly based on the conformation and heritability of traits, which culminates in muscle mass and optimized carcass traits in the offspring destined to be slaughtered. A bottom-up approach by way of SWOT analysis of the current morphological and functional evaluation process for bulls revealed a technological gap. The innovation of the process through the use of smart technologies was tested in the field. The conventional 2D scoring system based on visual inspection by breed experts was carried out on a 3D model of the live animal, which was found to be a faithful reproduction of live animal morphology, thanks to the non significant variance (p > 0.05) of means of the somatic measures determined on the virtual 3D model and on the real bull. The four main groups composing the scoring system of bull morphology can easily be carried out on the 3D model. These are as follows: (1) Muscular condition; (2) Skeletal development; (3) Functional traits; (4) Breed traits. The 3D-Bull model derived from the Structure from Motion (SfM) algorithm displays a high tech profile for the evaluation of animal morphology in an upgraded system
The lysine-specific demethylase 1 is a novel substrate of protein kinase CK2
No full textProtein kinase CK2 is a pleiotropic serine/threonine kinase responsible for the generation of a substantial proportion of the human phosphoproteome. CK2 is generally found as a tetramer with two catalytic, alpha and alpha' and two non catalytic beta subunits. CK2 alpha C-terminal tail phosphotylation is regulated during the mitotic events and the absence of these phosphosites in alpha' suggests an isoform specialization. We used a proteomic approach to identify proteins specifically phosphorylated by a CK2 alpha phosphomimetic mutant, CK2 alpha T344ET360ES362ES370E (CK2 alpha 4E), in human neuroblastoma SKNBE cellular extract. One of these proteins is lysine-specific demethylase 1 (LSD1 or KDM1A), an important player of the epigenetic machinery. LSD1 is a FAD-dependent amine oxidase and promotes demethylation of lysine 4 and lysine 9 of mono- and di-methylated histone H3. We found that LSD1 is a new substrate and an interacting partner of protein kinase CK2. Three CK2 phosphosites, (Ser131, Ser137 and Ser166) in the N-terminal region of LSD1 have been identified. This domain is found in all chordates but not in more ancient organisms and it is not essential for LSD1 catalytic event while it could modulate the interaction with CK2 and with other partners in gene repressing and activating complexes. Our data support the view that the phosphorylation of the N-terminal domain by CK2 may represent a mechanism for regulating histone methylation, disclosing a new role for protein kinase CK2 in epigenetics. (C) 2014 Elsevier B.V. All rights reserved
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