Papers by Orsalia Hazapis
Aging Cell
Cellular senescence constitutes a generally irreversible proliferation barrier, accompanied by ma... more Cellular senescence constitutes a generally irreversible proliferation barrier, accompanied by macromolecular damage and metabolic rewiring. Several senescence types have been identified based on the initiating stimulus, such as replicative (RS), stress‐induced (SIS) and oncogene‐induced senescence (OIS). These senescence subtypes are heterogeneous and often develop subset‐specific phenotypes. Reduced protein synthesis is considered a senescence hallmark, but whether this trait pertains to various senescence subtypes and if distinct molecular mechanisms are involved remain largely unknown. Here, we analyze large published or experimentally produced RNA‐seq and Ribo‐seq datasets to determine whether major translation‐regulating entities such as ribosome stalling, the presence of uORFs/dORFs and IRES elements may differentially contribute to translation deficiency in senescence subsets. We show that translation‐regulating mechanisms may not be directly relevant to RS, however uORFs ar...
Cell death and differentiation, Jan 10, 2014
Alterations in the functions of neuronal RNA-binding proteins (RBPs) can contribute to neurodegen... more Alterations in the functions of neuronal RNA-binding proteins (RBPs) can contribute to neurodegenerative diseases. However, neurons also express a set of widely distributed RBPs that may have developed specialized functions. Here, we show that the ubiquitous member of the otherwise neuronal Elavl/Hu family of RNA-binding proteins, Elavl1/HuR, has a neuroprotective role. Mice engineered to lack exclusively HuR in the hippocampal neurons of the central nervous system (CNS), maintain physiologic levels of neuronal Elavls and develop a partially diminished seizure response following strong glutamatergic excitation; however, they display an exacerbated neurodegenerative response subsequent to the initial excitotoxic event. This response was phenocopied in hippocampal cells devoid of ionotropic glutamate receptors in which the loss of HuR results in enhanced mitochondrial dysfunction, oxidative damage and programmed necrosis solely after glutamate challenge. The molecular dissection of Hu...
Mediterranean Journal of Rheumatology
Several previous studies from our laboratory have indicated that the salivary gland epithelia of ... more Several previous studies from our laboratory have indicated that the salivary gland epithelia of primary Sjögren's syndrome (SS) patients are not only the target of autoimmune immune responses, but also key instigators of the chronic salivary gland inflammatory infiltrates of patients. In particular, the comparative analysis of salivary gland tissue specimens and of in-vitro cultured non-neoplastic salivary gland epithelial cell lines (SGEC, of ductal type) from SS-patients and non-SS diseasecontrols, have unequivocally highlighted the presence of intrinsic activation in the ductal epithelia of SS-patients and of aberrant expression of inflammagenic molecules thereof, that correlate with the severity of local histopathologic changes, as well as of systemic manifestations of the disease. In the same context, we have recently shown that the ductal epithelia of SS-patients manifest cellautonomous activation of the AIM2 inflammasome owing to the presence of aberrant cytoplasmic accumulations of damaged DNA. These findings not only provide a mechanistic explanation for the intrinsic activation and inflammatory status of SS ductal epithelia, but may also point towards the putative instigating role of an exogenous or endogenous agent (i.e., a microorganism or an endogenous retrovirus, respectively). On this basis and to further explore the nature of epithelial cell-intrinsic activation in SS, the present proposal aims to investigate the expression of endogenous retroviral and/or non-human nucleic acid sequences of microbial origin in the ductal salivary gland epithelia of SS-patients, using metagenomic analysis of high throughput DNA and RNA genome sequencing data, which will be obtained from SGEC lines derived from SS-patients and disease-controls.
Nature Communications
The biological role of RNA-binding proteins in the secretory pathway is not well established. Her... more The biological role of RNA-binding proteins in the secretory pathway is not well established. Here, we describe that human HDLBP/Vigilin directly interacts with more than 80% of ER-localized mRNAs. PAR-CLIP analysis reveals that these transcripts represent high affinity HDLBP substrates and are specifically bound in their coding sequences (CDS), in contrast to CDS/3’UTR-bound cytosolic mRNAs. HDLBP crosslinks strongly to long CU-rich motifs, which frequently reside in CDS of ER-localized mRNAs and result in high affinity multivalent interactions. In addition to HDLBP-ncRNA interactome, quantification of HDLBP-proximal proteome confirms association with components of the translational apparatus and the signal recognition particle. Absence of HDLBP results in decreased translation efficiency of HDLBP target mRNAs, impaired protein synthesis and secretion in model cell lines, as well as decreased tumor growth in a lung cancer mouse model. These results highlight a general function for ...
Physiological Reviews
Cardiovascular diseases (CVDs) constitute the prime cause of global mortality, with an immense im... more Cardiovascular diseases (CVDs) constitute the prime cause of global mortality, with an immense impact on patient quality of life and disability. Clinical evidence has revealed a strong connection between cellular senescence and worse cardiac outcomes in the majority of CVDs concerning both ischemic and nonischemic cardiomyopathies. Cellular senescence is characterized by cell cycle arrest accompanied by alterations in several metabolic pathways, resulting in morphological and functional changes. Metabolic rewiring of senescent cells results in marked paracrine activity, through a unique secretome, often exerting deleterious effects on neighboring cells. Here, we recapitulate the hallmarks and key molecular pathways involved in cellular senescence in the cardiac context and summarize the different roles of senescence in the majority of CVDs. In the last few years, the possibility of eliminating senescent cells in various pathological conditions has been increasingly explored, giving ...
European Respiratory Journal
BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of the respirato... more BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of the respiratory system can progress to a multisystemic disease with aberrant inflammatory response. Cellular senescence promotes chronic inflammation, named senescence-associated secretory phenotype (SASP). We investigated whether coronavirus disease 2019 (COVID-19) is associated with cellular senescence and SASP.MethodsAutopsy lung tissue samples from 11 COVID-19 patients and 43 age-matched non-COVID-19 controls with similar comorbidities were analysed by immunohistochemistry for SARS-CoV-2, markers of senescence and key SASP cytokines. Virally induced senescence was functionally recapitulated in vitro, by infecting epithelial Vero-E6 cells and a three-dimensional alveosphere system of alveolar type 2 (AT2) cells with SARS-CoV-2 strains isolated from COVID-19 patients.ResultsSARS-CoV-2 was detected by immunocytochemistry and electron microscopy predominantly in AT2 cells. Infected AT2 cells expresse...
Cancers, 2021
Circular RNAs (circRNA) comprise a distinct class of non-coding RNAs that are abundantly expresse... more Circular RNAs (circRNA) comprise a distinct class of non-coding RNAs that are abundantly expressed in the cell. CircRNAs have the capacity to regulate gene expression by interacting with regulatory proteins and/or other classes of RNAs. While a vast number of circRNAs have been discovered, the majority still remains poorly characterized. Particularly, there is no detailed information on the identity and functional role of circRNAs that are transcribed from genes encoding components of the DNA damage response and repair (DDRR) network. In this article, we not only review the available published information on DDRR-related circRNAs, but also conduct a bioinformatic analysis on data obtained from public repositories to uncover deposited, yet uncharacterized circRNAs derived from components of the DDRR network. Finally, we interrogate for potential targets that are regulated by this class of molecules and look into potential functional implications.
Cancer Genomics - Proteomics, 2021
In this review, the fundamental basis of machine learning (ML) and data mining (DM) are summarize... more In this review, the fundamental basis of machine learning (ML) and data mining (DM) are summarized together with the techniques for distilling knowledge from state-of-theart omics experiments. This includes an introduction to the basic mathematical principles of unsupervised/supervised learning methods, dimensionality reduction techniques, deep neural networks architectures and the applications of these in bioinformatics. Several case studies under evaluation mainly involve next generation sequencing (NGS) experiments, like deciphering gene expression from total and single cell (scRNAseq) analysis; for the latter, a description of all recent artificial intelligence (AI) methods for the investigation of cell sub-types, biomarkers and imputation techniques are described. Other areas of interest where various ML schemes have been investigated are for providing information regarding transcription factors (TF) binding sites, chromatin organization patterns and RNA binding proteins (RBPs), while analyses on RNA sequence and structure as well as 3D dimensional protein structure predictions with the use of ML are described. Furthermore, we summarize the recent methods of using ML in clinical oncology, when taking into consideration the current omics data with pharmacogenomics to determine personalized 605 This article is freely accessible online.
Rationale: SARS-CoV-2 infection of the respiratory system can progress to a life threatening mult... more Rationale: SARS-CoV-2 infection of the respiratory system can progress to a life threatening multi-systemic disease, mediated via an excess of cytokines ("cytokine storm"), but the molecular mechanisms are poorly understood. Objectives: To investigate whether SARS-CoV-2 may induce cellular senescence in lung epithelial cells, leading to secretion of inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP). Methods: Autopsy lung tissue samples from eleven COVID-19 patients and sixty age-matched non-infected controls were analysed by immunohistochemistry for SARS-CoV-2 and markers of cellular senescence (SenTraGor, p16INK4A) and key SASP cytokines (interleukin-1β, interleukin-6). We also investigated whether SARS-CoV-2 infection of an epithelial cell line induces senescence and cytokine secretion. Measurements and Main Results: SARS-CoV-2 was detected by immunocytochemistry and electron microscopy predominantly in alveolar type-2 (AT2) cells, whi...
Cell Reports, 2020
Highlights d Attenuation by codon pair deoptimization is determined by suboptimal codon pairs d S... more Highlights d Attenuation by codon pair deoptimization is determined by suboptimal codon pairs d Suboptimal codon pairs reduce mRNA stability and throttle or abrogate translation d CpG dinucleotides are dispensable for attenuation by codon pair deoptimization d Codon pairs are important determinants of mRNA stability
2011 21st International Conference on Field Programmable Logic and Applications, 2011
ABSTRACT Simulation of biomolecular networks with thousands of reactions is becoming essential fo... more ABSTRACT Simulation of biomolecular networks with thousands of reactions is becoming essential for systems biology. We are presenting the design of a scalable System on Chip parallel architecture that implements Gillespie's First Reaction Method in reconfigurable FPGA hardware. Our SoC architecture can deliver performance (Mega-Reactions/sec) and throughput (M-Reaction cycles/sec) that is increasing linearly with the number of processors when simulating large biomolecular networks with up to m = 4096 reactions using a moderate size FPGA. We have synthesized and verified various SoC instances with up to N=8 Processing Elements for Xilinx Virtex 5 and Altera Cyclone III FPGAs, reaching clock frequencies up to 180 MHz and delivering simulation performance that is more than 2 order of magnitude higher than that of Intel Core 2 and i7 CPUs running at frequencies above 2GHz.
2012 19th IEEE International Conference on Electronics, Circuits, and Systems (ICECS 2012), 2012
ABSTRACT A soft IP core, expressed in parametric VHDL, has been developed and used to synthesize ... more ABSTRACT A soft IP core, expressed in parametric VHDL, has been developed and used to synthesize different multiprocessor Systems on Chip (SoCs) for the stochastic simulation of large-size biochemical reaction networks based on Gillespie's First Reaction Method (FRM). The SoCs can be configured to have up to N=8 Processing Elements and simulate efficiently in hardware biomolecular networks with up to m=16K reactions. The FPGA implementations of the SoCs are communicating with a host PC via the serial and Ethernet ports for control and data transmission respectively. When mapped to a Virtex-5 Xilinx FPGA the FRM SoCs can deliver simulation performance (in Mega-Reactions/sec) that may exceed by up to two orders of magnitude the performance of well known software simulators running on fast PCs.
ACM Transactions on Embedded Computing Systems, 2014
We present SysPy (System Python) a tool which exploits the strengths of the popular Python script... more We present SysPy (System Python) a tool which exploits the strengths of the popular Python scripting language to boost design productivity of embedded System on Chips for FPGAs. SysPy acts as a “glue” software between mature HDLs, ready-to-use VHDL components and programmable processor soft IP cores. SysPy can be used to: (i) automatically translate hardware components described in Python into synthesizable VHDL, (ii) capture top-level structural descriptions of processor-centric SoCs in Python, (iii) implement all the steps necessary to compile the user's C code for an instruction set processor core and generate processor specific Tcl scripts that import to the design project all the necessary HDL files of the processor's description and instantiate/connect the core to other blocks in a synthesizable top-level Python description. Moreover, we have developed a Hardware ion Layer (HAL) in Python which allows user applications running in a host PC to utilize effortlessly the S...
Genome research, Aug 8, 2017
The cellular response to genotoxic stress is mediated by a well-characterized network of DNA surv... more The cellular response to genotoxic stress is mediated by a well-characterized network of DNA surveillance pathways. The contribution of posttranscriptional gene regulatory networks to the DNA damage response (DDR) has not been extensively studied. Here, we systematically identified RNA-binding proteins differentially interacting with polyadenylated transcripts upon exposure of human breast carcinoma cells to ionizing radiation (IR). Interestingly, more than 260 proteins including many nucleolar proteins showed increased binding to poly(A) RNA in IR-exposed cells. The functional analysis of DDX54, a candidate genotoxic stress responsive RNA helicase, revealed that this protein is an immediate-to-early DDR regulator required for the splicing efficacy of its target IR-induced pre-mRNAs. Upon IR exposure, DDX54 acts by increased interaction with a well-defined class of pre-mRNAs which harbor introns with weak acceptor splice sites, as well as by protein-protein contacts within component...
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Papers by Orsalia Hazapis