110 research outputs found
POZ-, AT-hook-, and Zinc Finger-containing Protein (PATZ) Interacts with Human Oncogene B Cell Lymphoma 6 (BCL6) and Is Required for Its Negative Autoregulation.
The PATZ1 gene encoding a POZ/AT-hook/Kruppel zinc finger (PATZ) transcription factor, is considered a cancer-related gene because of its loss or misexpression in human neoplasias. As for other POZ/domain and Kruppel zinc finger (POK) family members, the transcriptional activity of PATZ is due to the POZ-mediated oligomer formation, suggesting that it might be not a typical transactivator but an architectural transcription factor, thus functioning either as activator or as repressor depending on the presence of proteins able to interact with it. Therefore, to better elucidate PATZ function, we searched for its molecular partners. By yeast two-hybrid screenings, we found a specific interaction between PATZ and BCL6, a human oncogene that plays a key role in germinal center (GC) derived neoplasias. We demonstrate that PATZ and BCL6 interact in germinal center-derived B lymphoma cells, through the POZ domain of PATZ. Moreover, we show that PATZ is able to bind the BCL6 regulatory region, where BCL6 itself acts as a negative regulator, and to contribute to negatively modulate its activity. Consistently, disruption of one or both Patz1 alleles in mice causes focal expansion of thymus B cells, in which BCL6 is up-regulated. This phenotype was almost completely rescued by crossing Patz1(+/-) with Bcl6(+/-) mice, indicating a key role for Bcl6 expression in its development. Finally, a significant number of Patz1 knock-out mice (both heterozygous and homozygous) also develop BCL6-expressing lymphomas. Therefore, the disruption of one or both Patz1 alleles may favor lymphomagenesis by activating the BCL6 pathway
Acute otitis externa: Consensus definition, diagnostic criteria and core outcome set development.
OBJECTIVE: Evidence for the management of acute otitis externa (AOE) is limited, with unclear diagnostic criteria and variably reported outcome measures that may not reflect key stakeholder priorities. We aimed to develop 1) a definition, 2) diagnostic criteria and 3) a core outcome set (COS) for AOE. STUDY DESIGN: COS development according to Core Outcome Measures in Effectiveness Trials (COMET) methodology and parallel consensus selection of diagnostic criteria/definition. SETTING: Stakeholders from the United Kingdom. SUBJECTS AND METHODS: Comprehensive literature review identified candidate items for the COS, definition and diagnostic criteria. Nine individuals with past AOE generated further patient-centred candidate items. Candidate items were rated for importance by patient and professional (ENT doctors, general practitioners, microbiologists, nurses, audiologists) stakeholders in a three-round online Delphi exercise. Consensus items were grouped to form the COS, diagnostic criteria, and definition. RESULTS: Candidate COS items from patients (n = 28) and literature (n = 25) were deduplicated and amalgamated to a final candidate list (n = 46). Patients emphasised quality-of-life and the impact on daily activities/work. Via the Delphi process, stakeholders agreed on 31 candidate items. The final COS covered six outcomes: pain; disease severity; impact on quality-of-life and daily activities; patient satisfaction; treatment-related outcome; and microbiology. 14 candidate diagnostic criteria were identified, 8 reaching inclusion consensus. The final definition for AOE was 'diffuse inflammation of the ear canal skin of less than 6 weeks duration'. CONCLUSION: The development and adoption of a consensus definition, diagnostic criteria and a COS will help to standardise future research in AOE, facilitating meta-analysis. Consulting former patients throughout development highlighted deficiencies in the outcomes adopted previously, in particular concerning the impact of AOE on daily life
ANCA-associated vasculitis.
The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are a group of disorders involving severe, systemic, small-vessel vasculitis and are characterized by the development of autoantibodies to the neutrophil proteins leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). The three AAV subgroups, namely granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophilic GPA (EGPA), are defined according to clinical features. However, genetic and other clinical findings suggest that these clinical syndromes may be better classified as PR3-positive AAV (PR3-AAV), MPO-positive AAV (MPO-AAV) and, for EGPA, by the presence or absence of ANCA (ANCA+ or ANCA-, respectively). Although any tissue can be involved in AAV, the upper and lower respiratory tract and kidneys are most commonly and severely affected. AAVs have a complex and unique pathogenesis, with evidence for a loss of tolerance to neutrophil proteins, which leads to ANCA-mediated neutrophil activation, recruitment and injury, with effector T cells also involved. Without therapy, prognosis is poor but treatments, typically immunosuppressants, have improved survival, albeit with considerable morbidity from glucocorticoids and other immunosuppressive medications. Current challenges include improving the measures of disease activity and risk of relapse, uncertainty about optimal therapy duration and a need for targeted therapies with fewer adverse effects. Meeting these challenges requires a more detailed knowledge of the fundamental biology of AAV as well as cooperative international research and clinical trials with meaningful input from patients
Evolution of the avian β-defensin and cathelicidin genes
Background: β-defensins and cathelicidins are two families of cationic antimicrobial peptides (AMPs) with a broad range of antimicrobial activities that are key components of the innate immune system. Due to their important roles in host defense against rapidly evolving pathogens, the two gene families provide an ideal system for studying adaptive gene evolution. In this study we performed phylogenetic and selection analyses on β-defensins and cathelicidins from 53 avian species representing 32 orders to examine the evolutionary dynamics of these peptides in birds. Results and conclusions: Avian β-defensins are found in a gene cluster consisting of 13 subfamiles. Nine of these are conserved as one to one orthologs in all birds, while the others (AvBD1, AvBD3, AvBD7 and AvBD14) are more subject to gene duplication or pseudogenisation events in specific avian lineages. Avian cathelicidins are found in a gene cluster consisting of three subfamilies with species-specific duplications and gene loss. Evidence suggested that the propiece and mature peptide domains of avian cathelicidins are possibly co-evolving in such a way that the cationicity of the mature peptide is partially neutralised by the negative charge of the propiece prior to peptide secretion (further evidence obtained by repeating the analyses on primate cathelicidins). Negative selection (overall mean d
Adaptive-predictive control strategy for HVAC systems in smart buildings – A review
High share of energy consumption in buildings and subsequent increase in greenhouse gas emissions along with stricter legislations have motivated researchers to look for sustainable solutions in order to reduce energy consumption by using alternative renewable energy resources and improving the efficiency in this sector. Today, the smart building and socially resilient city concepts have been introduced where building automation technologies are implemented to manage and control the energy generation/consumption/storage. Building automation and control systems can be roughly classified into traditional and advanced control strategies. Traditional strategies are not a viable choice for more sophisticated features required in smart buildings. The main focus of this paper is to review advanced control strategies and their impact on buildings and technical systems with respect to energy/cost saving. These strategies should be predictive/responsive/adaptive against weather, user, grid and thermal mass. In this context, special attention is paid to model predictive control and adaptive control strategies. Although model predictive control is the most common type used in buildings, it is not well suited for systems consisting of uncertainties and unpredictable data. Thus, adaptive predictive control strategies are being developed to address these shortcomings. Despite great progress in this field, the quantified results of these strategies reported in literature showed a high level of inconsistency. This is due to the application of different control modes, various boundary conditions, hypotheses, fields of application, and type of energy consumption in different studies. Thus, this review assesses the implementations and configurations of advanced control solutions and highlights research gaps in this field that need further investigations
Parametric energy performance analysis and monitoring of buildings—HEART project platform case study
Building performance analysis changed the way in which buildings are designed and operated. The evaluation of different design and operation options is becoming more resource intensive than ever before. Although building dynamic simulation tools are potentially a suitable way for assessing energy performance of buildings accurately, they require adequate training and a careful evaluation of model input data. In Europe, the majority of buildings were constructed before 1990 and are in urgent need for a significant energy efficiency improvement, through deep renovation. In this respect, advanced renovation solutions are available, but costly and lengthy renovation processes and technical complexities hinder the achievement of a large scale impact. Energy refurbishment of buildings is an open challenge and essentially requires the adoption of a valid methodological approach to link design and operational performance analysis transparently, in order to address the potential gap between simulated and measured results. The HEART project, funded in the EU Horizon 2020 program, aims to address the increasing need for deep retrofit interventions and to develop systemic strategies leading to high performance and cost effective solutions. The research for the cloud platform used in the project is based on two fundamental tools: parametric simulation to produce a large spectrum of possible building energy performance outcomes (considering realistically the impact of the user behaviour and variable operating conditions from the very beginning), and model calibration employing simple, robust and scalable techniques. In this paper we present the preliminary development and testing of the computational processes that will be implemented in the cloud platform, employing the first pilot case study of HEART Project in Italy, currently under refurbishment
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