17 research outputs found
The role of p53 and ASPP2 in neurodegenerative disease
No full textTwo cellular processes of central importance to cancer and neurodegeneration are apoptosis and cellular senescence. Both are a means of cellular suicide that are utilized in time- and context-dependent manners and have important evolutionary purposes. However, they are also the drivers of many deleterious processes underlying cancer and neurodegeneration. Many of the cellular responses to aging and age-related diseases, including apoptosis and senescence, converge on the tumor suppressor pathway, p53. Here I examine the molecular basis for loss of cell polarity and accelerated cell death mediated by apoptosis stimulating protein of p53 2 (ASPP2) in neurodegeneration. In this study we find that ASPP2 mediates STAT1Linduced apoptosis. Lipopolysaccharide (LPS) induces ASPP2 mRNA expression in vitro. Also, LPS induces nuclear ASPP2 in vivo at the blood-cerebral spinal fluid-barrier (BCSFB), the brain's barrier to inflammation. Consistent with ASPP2's role as a gatekeeper to inflammation, ASPP2 mutant mouse brains possess enhanced neuroinflammation. Elevated ASPP2 expression is also observed in mouse models and human neuroinflammatory disease tissue in astrocytes. The identification of ASPP2 as a novel transcriptional target of STAT1 and the observed increase in ASPP2 expression in both mouse and human neuroinflammatory disorders, suggests that the identified STAT1/ASPP2 pathway may connect tumor suppression and cell polarity to neuroinflammation. Additionally, I investigate the regulation of cellular senescence by p53 isoforms as a means to enhance neuroprotection of astrocytes in chronic neurodegenerative diseases, Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Here we report that p53 isoforms, Δ133p53 and p53β, are endogenous regulators of cellular senescence in the central nervous system (CNS). Δ133p53 functions as a dominant-negative regulator of full-length (FL)Lp53 and represses senescence, while p53β as a co-activator of FLLp53, promotes senescence. In neurodegenerative disease brain tissue, FLL53 and p53β are upregulated while Δ133p53 is downregulated. We demonstrate that Δ133p53 and p53β directly regulate astrocyte senescence, including the release of key neurotoxic proL inflammatory cytokines such as ILL6 and ILL1β. Also, we show that the p53 isoform switch that occurs during aging and neurodegeneration promotes neuronal toxicity using coL culture experiments with human iPSC-derived motor neurons and human astrocytes. We also demonstrate that astrocyte senescence can be rescued through overexpression of Δ133p53, revealing a promising therapeutic approach to delay or inhibit the progression of neurodegeneration
STAT1-induced ASPP2 transcription identifies a link between neuroinflammation, cell polarity, and tumor suppression.
No full textInflammation and loss of cell polarity play pivotal roles in neurodegeneration and cancer. A central question in both diseases is how the loss of cell polarity is sensed by cell death machinery. Here, we identify apoptosis-stimulating protein of p53 with signature sequences of ankyrin repeat-, SH3 domain-, and proline-rich region-containing protein 2 (ASPP2), a haploinsufficient tumor suppressor, activator of p53, and regulator of cell polarity, as a transcriptional target of signal transducer and activator of transcription 1 (STAT1). LPS induces ASPP2 expression in murine macrophage and microglial cell lines, a human monocyte cell line, and primary human astrocytes in vitro. LPS and IFNs induce ASPP2 transcription through an NF-κB RELA/p65-independent but STAT1-dependent pathway. In an LPS-induced maternal inflammation mouse model, LPS induces nuclear ASPP2 in vivo at the blood-cerebral spinal fluid barrier (the brain's barrier to inflammation), and ASPP2 mediates LPS-induced apoptosis. Consistent with the role of ASPP2 as a gatekeeper to inflammation, ASPP2-deficient brains possess enhanced neuroinflammation. Elevated ASPP2 expression is also observed in mouse models and human neuroinflammatory disease tissue, where ASPP2 was detected in GFAP-expressing reactive astrocytes that coexpress STAT1. Because the ability of ASPP2 to maintain cellular polarity is vital to CNS development, our findings suggest that the identified STAT1/ASPP2 pathway may connect tumor suppression and cell polarity to neuroinflammation
A Son of Two Countries : The education of a refugee from Nyarubuye
No full textA Son of Two Countries is a story of struggle for education. Born in 1946 in Rwanda under Belgian colonial rule, the author recounts his early education in Rwanda and later as a refugee in Tanzania. He was naturalized as a Tanzanian citizen in 1980 while doing his undergraduate studies at the University of Dar es Salaam. As he struggled to get education, the author was also grappling with his refugee status, with all the challenges that it entailed. The book gives insights into the contradictions of colonial and post-colonial education, as well as the author's reflections on education in Tanzania, given his long experience in the education sector in that country. Finally, we get some glimpses into the dual identity of the author as a Tanzanian citizen of Rwandan origin and how this shaped his relationship with the two countries he calls home. As he aptly puts it, 'Rwanda gave me my heart; Tanzania gave me my brain. I find it difficult to choose between my heart and my brain'
Le Forestier du Buisson-Sainte-Marguerite; croquis généalogiques depuis le XVe siècle.
No full textMode of access: Internet.With autograph of author
Tumor heterogeneity: does it matter?
No full textIntroduction: It has long been recognized that tumors are composed of a mosaic of cells and numerous methods have been developed to detect tumor heterogeneity, including in situ hybridization, multi-regional sampling, cytological assays, and whole genome and single cell sequencing. Using these methods, heterogeneity has been observed at the genetic, epigenetic, and phenotypic level in numerous cancers. With the advent of deep sequencing technology, we now appreciate a greater complexity of distinct genotypes and phenotypes that drive the biological behavior of cancer. Despite decades of progress in detecting tumor heterogeneity, the question remains: to what extent does it matter?Areas covered: This review explores the evidence for and against the importance of tumor heterogeneity in three main areas: prognostication, development of targeted therapeutics and tumor resistance; summarizing current understanding before evaluating ongoing experimental and clinical developments.Expert opinion: Theoretical understanding and in vitro detection of intratumour heterogeneity promises much but is yet to translate into meaningful clinical benefit. However, the recent emergence of a host of technological innovations and upcoming clinical trials may soon change the landscape of this field
On the edge of a digital pathology transformation: Views from a cellular pathology laboratory focus group
No full textIntroduction:Digital pathology has the potential to revolutionize the way clinical diagnoses are made while improving safety and quality. With a few notable exceptions in the UK, few National Health Service (NHS) departments have deployed digital pathology platforms. Thus, in the next few years, many departments are anticipated to undergo the transition to digital pathology. In this period of transition, capturing attitudes and experiences can elucidate issues to be addressed and foster collaboration between NHS Trusts. This study aims to qualitatively ascertain the benefits and challenges of transitioning to digital pathology from the perspectives of pathologists and biomedical scientists in a department about to undergo the transition from diagnostic reporting via traditional microscopy to digital pathology. Methods:A focus group discussion was held in the setting of a large NHS teaching hospital's cellular pathology department which was on the brink of transitioning to digital pathology. A set of open questions were developed and posed to a group of pathologists and biomedical scientists in a focus group setting. Notes of the discussion were made along with an audio recording with permission. The discussion was subsequently turned into a series of topic headings and analyzed using content analysis. Results:Identified benefits of digital pathology included enhanced collaboration, teaching, cost savings, research, growth of specialty, multidisciplinary teams, and patient-centered care. Barriers to transitioning to digital pathology included standardization, validation, national implementation, storage and backups, training, logistical implementation, cost-effectiveness, privacy, and legality. Conclusion:Many benefits of digital pathology were identified, but key barriers need to be addressed in order to fully implement digital pathology on a trust and national level
Solver-agnostic multi-fidelity coupling framework for the partitioned simulation of fluidstructure interactions
No full textFluid-structure interactions (FSI) are multi-physical phenomena where the dynamics of a fluid flow and the dynamics of a moving/deforming structure influence one another simultaneously. The accurate modelling, simulation and analysis of FSI is crucial for many engineering applications. However, high-fidelity FSI simulations are currently too computationally expensive for industrial purposes. The industry is in need of more efficient software to perform accurate FSI analyses at reduced computational cost. The complexity of developing such software is acknowledged and accounted for by preserving software modularity. Using black-box mono-physics solvers in a partitioned framework is one step towards ensuring software modularity. Partitioned procedures require a coupling algorithm to iteratively reduce errors related to the partitioning of the physical domains. Implementing coupling algorithms directly into each solver results in duplicitous work. Instead all algorithms related to coupling procedures should be centralised into a single unit. To this end a solver-agnostic framework is developed for the partitioned simulation of strongly-coupled fluid-structure interactions. This framework is named CASMIR (Coupling Algorithms for Strongly-Coupled Multi-physics Interaction Research).Future Fast Aeroelastic Simulation TechnologiesAerospace Engineering | Aerodynamics and Wind Energ
ASPP2 controls epithelial plasticity and inhibits metastasis through β-catenin-dependent regulation of ZEB1.
No full textEpithelial to mesenchymal transition (EMT), and the reverse mesenchymal to epithelial transition (MET), are known examples of epithelial plasticity that are important in kidney development and cancer metastasis. Here we identify ASPP2, a haploinsufficient tumour suppressor, p53 activator and PAR3 binding partner, as a molecular switch of MET and EMT. ASPP2 contributes to MET in mouse kidney in vivo. Mechanistically, ASPP2 induces MET through its PAR3-binding amino-terminus, independently of p53 binding. ASPP2 prevents β-catenin from transactivating ZEB1, directly by forming an ASPP2-β-catenin-E-cadherin ternary complex and indirectly by inhibiting β-catenin's N-terminal phosphorylation to stabilize the β-catenin-E-cadherin complex. ASPP2 limits the pro-invasive property of oncogenic RAS and inhibits tumour metastasis in vivo. Reduced ASPP2 expression results in EMT, and is associated with poor survival in hepatocellular carcinoma and breast cancer patients. Hence, ASPP2 is a key regulator of epithelial plasticity that connects cell polarity to the suppression of WNT signalling, EMT and tumour metastasis
Christian power against pagan power as depicted in Masław by Józef Ignacy Kraszewski
No full textCelem niniejszego artykułu jest przedstawienie w jaki sposób Józef Ignacy Kraszewski zaprezentowal zwalczające się siły - chrześcijańskie i pogańskie - w swej powieści historycznej Masław, której fabuła nawiązuje do wydarzeń reakcji pogańskiej XI wieku. Autor zwraca szczególną uwagę na przywódców obu stron - księcia Kazimierza I Odnowiciela oraz tytułowego namiestnika, prawdziwe motywacje obu stron i to jak Józef Ignacy pojmował prezentowane tu chrześcijaństwo i pogaństwo. W tekście jest także mowa o innych powieściach z cyklu Kraszewskiego Dzieje Polski, które w jakiś sposób nawiązują do omawianego tematu oraz o źródłach historiograficznych, które Józef Ignacy wykorzystywał w swej pracy (kroniki Anonima zwanego Gallem, Wincentego Kadłubka i Jana Długosza).The aim of this paper is to present how Józef Ignacy Kraszewski depicted two opposing sides of the medieval event known as the pagan reaction in his historical novel Masław. Author analyzes the images of the leaders - noble prince Casmir the Restorer, who leads christian knighthood and treacherous usurper, Miecław vel Masław, who stands for the rebellious pagans. The paper is examining the true motives of each leader and his followers and tries to answer the question what - according to Kraszewski's belief presented in analzyed novel - was christianity and what was paganism. The main source for the analysis comes from Masław and other Kraszewski's novels, which also belong to his monumental cycle Dzieje Polski (The History of Poland). Author also tries to demonstrate the source material used by Kraszewski and compare it to Józef Ignacy's final work
CLIPPERS: a case report with radiology, three serial biopsies and a literature review
No full textChronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare central nervous system inflammatory disorder primarily affecting the brainstem and cerebellum. We report a case of CLIPPERS in a 45-year-old man presenting with left facial numbness and dizziness. Imaging studies were conducted repeatedly over an 8-year follow-up period. Given diagnostic uncertainty in the early stages of the disease, three serial biopsies were obtained, which together with the clinical and radiological findings, led to the diagnosis. This case highlights the diagnostic challenges regarding the rare entity of CLIPPERS and discusses the main differential diagnoses that are necessary to consider. Additionally, some of the atypical features of this case, including the presenting finding of a large, solidly enhancing lesion on radiological imaging and prominent plasma cells on pathology, contribute to expanding the spectrum of appearances for CLIPPERS
