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Search Results: 1 - 10 of 71014 matches for " Maria Barcikowska "
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A Novel MAPT Mutation, G55R, in a Frontotemporal Dementia Patient Leads to Altered Tau Function
Abhinaya Iyer, Nichole E. LaPointe, Krzysztof Zielke, Mariusz Berdynski, Elmer Guzman, Anna Barczak, Ma?gorzata Chodakowska-?ebrowska, Maria Barcikowska, Stuart Feinstein, Cezary ?ekanowski
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0076409
Abstract: Over two dozen mutations in the gene encoding the microtubule associated protein tau cause a variety of neurodegenerative dementias known as tauopathies, including frontotemporal dementia (FTD), PSP, CBD and Pick's disease. The vast majority of these mutations map to the C-terminal region of tau possessing microtubule assembly and microtubule dynamics regulatory activities as well as the ability to promote pathological tau aggregation. Here, we describe a novel and non-conservative tau mutation (G55R) mapping to an alternatively spliced exon encoding part of the N-terminal region of the protein in a patient with the behavioral variant of FTD. Although less well understood than the C-terminal region of tau, the N-terminal region can influence both MT mediated effects as well as tau aggregation. The mutation changes an uncharged glycine to a basic arginine in the midst of a highly conserved and very acidic region. In vitro, 4-repeat G55R tau nucleates microtubule assembly more effectively than wild-type 4-repeat tau; surprisingly, this effect is tau isoform specific and is not observed in a 3-repeat G55R tau versus 3-repeat wild-type tau comparison. In contrast, the G55R mutation has no effect upon the abilities of tau to regulate MT growing and shortening dynamics or to aggregate. Additionally, the mutation has no effect upon kinesin translocation in a microtubule gliding assay. Together, (i) we have identified a novel tau mutation mapping to a mutation deficient region of the protein in a bvFTD patient, and (ii) the G55R mutation affects the ability of tau to nucleate microtubule assembly in vitro in a 4-repeat tau isoform specific manner. This altered capability could markedly affect in vivo microtubule function and neuronal cell biology. We consider G55R to be a candidate mutation for bvFTD since additional criteria required to establish causality are not yet available for assessment.
PIN1 gene variants in Alzheimer's disease
Aleksandra Maruszak, Krzysztof Safranow, Katarzyna Gustaw, Beata Kijanowska-Ha?adyna, Katarzyna Jakubowska, Maria Olszewska, Maria Styczyńska, Mariusz Berdyński, Andrzej Tysarowski, Dariusz Chlubek, Janusz Siedlecki, Maria Barcikowska, Cezary ?ekanowski
BMC Medical Genetics , 2009, DOI: 10.1186/1471-2350-10-115
Abstract: We performed analysis of coding and promoter regions of PIN1 in early- and late-onset AD and frontotemporal dementia (FTD) patients in comparison with healthy controls.Analysis of eighteen PIN1 common polymorphisms and their haplotypes in EOAD, LOAD and FTD individuals in comparison with the control group did not reveal their contribution to disease risk.In six unrelated familial AD patients four novel PIN1 sequence variants were detected. c.58+64C>T substitution that was identified in three patients, was located in an alternative exon. In silico analysis suggested that this variant highly increases a potential affinity for a splicing factor and introduces two intronic splicing enhancers. In the peripheral leukocytes of one living patient carrying the variant, a 2.82 fold decrease in PIN1 expression was observed.Our data does not support the role of PIN1 common polymorphisms as AD risk factor. However, we suggest that the identified rare sequence variants could be directly connected with AD pathology, influencing PIN1 splicing and/or expression.PIN1 is a ubiquitously expressed protein, belonging to the evolutionarily conserved peptidyl-prolyl isomerase (PPIase) family. PIN1 isomerizes p(Ser/Thr)-Pro motifs in the target proteins, which leads to the alteration of their structure, function, intracellular localization and/or stability [1]. Previous studies have demonstrated that PIN1 plays a crucial role in multiple cellular processes and, likewise, it has been implicated in pathogenesis of several diseases, including cancer, inflammation to neurodegenerative diseases [2-8].The gene encoding PIN1 maps to chromosome 19p13.2, a region associated with late-onset Alzheimer's disease (LOAD) [9]. Moreover, PIN1 is the only known gene whose knockout in mice can cause both Tau and Aβ-related pathologies in an age-dependent manner [4,10]. It was shown that PIN1-catalysed conformation change of pT668 could prevent amyloidogenic processing of APP [10]. Additionally, in a similar
Conformational Altered p53 as an Early Marker of Oxidative Stress in Alzheimer's Disease
Laura Buizza, Giovanna Cenini, Cristina Lanni, Giulia Ferrari-Toninelli, Chiara Prandelli, Stefano Govoni, Erica Buoso, Marco Racchi, Maria Barcikowska, Maria Styczynska, Aleksandra Szybinska, David Allan Butterfield, Maurizio Memo, Daniela Uberti
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0029789
Abstract: In order to study oxidative stress in peripheral cells of Alzheimer's disease (AD) patients, immortalized lymphocytes derived from two peculiar cohorts of patients, referring to early onset AD (EOSAD) and subjects harboured AD related mutation (ADmut), were used. Oxidative stress was evaluated measuring i) the typical oxidative markers, such as HNE Michel adducts, 3 Nitro-Tyrosine residues and protein carbonyl on protein extracts, ii) and the antioxidant capacity, following the enzymatic kinetic of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GRD). We found that the signs of oxidative stress, measured as oxidative marker levels, were evident only in ADmut but not in EOSAD patients. However, oxidative imbalance in EOSAD as well as ADmut lymphocytes was underlined by a reduced SOD activity and GRD activity in both pathological groups in comparison with cells derived from healthy subjects. Furthermore, a redox modulated p53 protein was found conformational altered in both EOSAD and ADmut B lymphocytes in comparison with control cells. This conformational altered p53 isoform, named “unfolded p53”, was recognized by the use of two specific conformational anti-p53 antibodies. Immunoprecipitation experiments, performed with the monoclonal antibodies PAb1620 (that recognizes p53wt) and PAb240 (that is direct towards unfolded p53), and followed by the immunoblotting with anti-4-hydroxynonenal (HNE) and anti- 3-nitrotyrosine (3NT) antibodies, showed a preferential increase of nitrated tyrosine residues in unfolded p53 isoform comparing to p53 wt protein, in both ADmut and EOSAD. In addition, a correlation between unfolded p53 and SOD activity was further found. Thus this study suggests that ROS/RNS contributed to change of p53 tertiary structure and that unfolded p53 can be considered as an early marker of oxidative imbalance in these patients.
A Patient with Posterior Cortical Atrophy Possesses a Novel Mutation in the Presenilin 1 Gene
Emilia J. Sitek, Ewa Naro?ańska, Beata Pep?ońska, S?awomir Filipek, Anna Barczak, Maria Styczyńska, Krzysztof Mlynarczyk, Bogna Brockhuis, Erik Portelius, Dorota Religa, Maria Barcikowska, Jaros?aw S?awek, Cezary ?ekanowski
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061074
Abstract: Posterior cortical atrophy is a dementia syndrome with symptoms of cortical visual dysfunction, associated with amyloid plaques and neurofibrillary tangles predominantly affecting visual association cortex. Most patients diagnosed with posterior cortical atrophy will finally develop a typical Alzheimer's disease. However, there are a variety of neuropathological processes, which could lead towards a clinical presentation of posterior cortical atrophy. Mutations in the presenilin 1 gene, affecting the function of γ-secretase, are the most common genetic cause of familial, early-onset Alzheimer's disease. Here we present a patient with a clinical diagnosis of posterior cortical atrophy who harbors a novel Presenilin 1 mutation (I211M). In silico analysis predicts that the mutation could influence the interaction between presenilin 1 and presenilin1 enhancer-2 protein, a protein partner within the γ-secretase complex. These findings along with published literature support the inclusion of posterior cortical atrophy on the Alzheimer's disease spectrum.
Replication of EPHA1 and CD33 associations with late-onset Alzheimer's disease: a multi-centre case-control study
Minerva M Carrasquillo, Olivia Belbin, Talisha A Hunter, Li Ma, Gina D Bisceglio, Fanggeng Zou, Julia E Crook, V Pankratz, Sigrid B Sando, Jan O Aasly, Maria Barcikowska, Zbigniew K Wszolek, Dennis W Dickson, Neill R Graff-Radford, Ronald C Petersen, Peter Passmore, Kevin Morgan, for the Alzheimer's Research UK (ARUK) consortium, Steven G Younkin
Molecular Neurodegeneration , 2011, DOI: 10.1186/1750-1326-6-54
Abstract: We found no significant evidence of series heterogeneity. Associations with LOAD were successfully replicated for EPHA1 (rs11767557; OR = 0.87, p = 5 × 10-4) and CD33 (rs3865444; OR = 0.92, p = 0.049), with odds ratios comparable to those previously reported. Although the two ARID5B variants (rs2588969 and rs494288) showed significant association with LOAD in meta-analysis of our dataset (p = 0.046 and 0.008, respectively), the associations did not survive adjustment for covariates (p = 0.30 and 0.11, respectively). We had insufficient evidence in our data to support the association of the CD2AP variant (rs9349407, p = 0.56).Our data overwhelmingly support the association of EPHA1 and CD33 variants with LOAD risk: addition of our data to the results previously reported (total n > 42,000) increased the strength of evidence for these variants, providing impressive p-values of 2.1 × 10-15 (EPHA1) and 1.8 × 10-13 (CD33).Following the identification of the APOE ε4 allele as a risk factor for late-onset Alzheimer's disease (LOAD) in 1993 [1], consistent replication of subsequently identified candidates was not achieved until 2009, when two genome-wide association studies (GWAS) [2,3] identified associations of variants in or near CLU, PICALM , and CR1 with LOAD, which were consistently replicated in multiple large, independent case-control studies [4-17]. Subsequently, a variant near BIN1 was reported [4] to achieve genome-wide significant association in a later GWAS published in 2010 that also replicated well in follow-up studies [14-19]. These results demonstrate the utility of the hypothesis-free GWAS approach for identifying loci that associate with LOAD and the necessity of pooling samples and data from multiple centers to obtain resources with sufficient statistical power (GWAS typically > 14,000, follow-up typically total > 28,000) to detect the modest ORs (e.g. 0.8/1.2) associated with these variants in GWAS and follow-up studies.Two recently published companion s
LRRTM3 Interacts with APP and BACE1 and Has Variants Associating with Late-Onset Alzheimer’s Disease (LOAD)
Sarah Lincoln, Mariet Allen, Claire L. Cox, Louise P. Walker, Kimberly Malphrus, Yushi Qiu, Thuy Nguyen, Christopher Rowley, Naomi Kouri, Julia Crook, V. Shane Pankratz, Samuel Younkin, Linda Younkin, Minerva Carrasquillo, Fanggeng Zou, Samer O. Abdul-Hay, Wolfdieter Springer, Sigrid B. Sando, Jan O. Aasly, Maria Barcikowska, Zbigniew K. Wszolek, Jada M. Lewis, Dennis Dickson, Neill R. Graff-Radford, Ronald C. Petersen, Elizabeth Eckman, Steven G. Younkin, Nilüfer Ertekin-Taner
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064164
Abstract: Leucine rich repeat transmembrane protein 3 (LRRTM3) is member of a synaptic protein family. LRRTM3 is a nested gene within α-T catenin (CTNNA3) and resides at the linkage peak for late-onset Alzheimer’s disease (LOAD) risk and plasma amyloid β (Aβ) levels. In-vitro knock-down of LRRTM3 was previously shown to decrease secreted Aβ, although the mechanism of this is unclear. In SH-SY5Y cells overexpressing APP and transiently transfected with LRRTM3 alone or with BACE1, we showed that LRRTM3 co-localizes with both APP and BACE1 in early endosomes, where BACE1 processing of APP occurs. Additionally, LRRTM3 co-localizes with APP in primary neuronal cultures from Tg2576 mice transduced with LRRTM3-expressing adeno-associated virus. Moreover, LRRTM3 co-immunoprecipitates with both endogenous APP and overexpressed BACE1, in HEK293T cells transfected with LRRTM3. SH-SY5Y cells with knock-down of LRRTM3 had lower BACE1 and higher CTNNA3 mRNA levels, but no change in APP. Brain mRNA levels of LRRTM3 showed significant correlations with BACE1, CTNNA3 and APP in ~400 humans, but not in LRRTM3 knock-out mice. Finally, we assessed 69 single nucleotide polymorphisms (SNPs) within and flanking LRRTM3 in 1,567 LOADs and 2,082 controls and identified 8 SNPs within a linkage disequilibrium block encompassing 5′UTR-Intron 1 of LRRTM3 that formed multilocus genotypes (MLG) with suggestive global association with LOAD risk (p = 0.06), and significant individual MLGs. These 8 SNPs were genotyped in an independent series (1,258 LOADs and 718 controls) and had significant global and individual MLG associations in the combined dataset (p = 0.02–0.05). Collectively, these results suggest that protein interactions between LRRTM3, APP and BACE1, as well as complex associations between mRNA levels of LRRTM3, CTNNA3, APP and BACE1 in humans might influence APP metabolism and ultimately risk of AD.
Glutathione S-transferase omega genes in Alzheimer and Parkinson disease risk, age-at-diagnosis and brain gene expression: an association study with mechanistic implications
Mariet Allen, Fanggeng Zou, High Chai, Curtis S Younkin, Richard Miles, Asha A Nair, Julia E Crook, V Pankratz, Minerva M Carrasquillo, Christopher N Rowley, Thuy Nguyen, Li Ma, Kimberly G Malphrus, Gina Bisceglio, Alexandra I Ortolaza, Ryan Palusak, Sumit Middha, Sooraj Maharjan, Constantin Georgescu, Debra Schultz, Fariborz Rakhshan, Christopher P Kolbert, Jin Jen, Sigrid B Sando, Jan O Aasly, Maria Barcikowska, Ryan J Uitti, Zbigniew K Wszolek, Owen A Ross, Ronald C Petersen, Neill R Graff-Radford, Dennis W Dickson, Steven G Younkin, Nilüfer Ertekin-Taner
Molecular Neurodegeneration , 2012, DOI: 10.1186/1750-1326-7-13
Abstract: We found that rs156697 minor allele associates with significantly increased risk (odds ratio = 1.14, p = 0.038) in the older ADs with age-at-diagnosis > 80 years. The minor allele of GSTO1 rs4925 associates with decreased risk in familial PD (odds ratio = 0.78, p = 0.034). There was no other association with disease risk or age-at-diagnosis. The minor alleles of both GSTO SNPs associate with lower brain levels of GSTO2 (p = 4.7 × 10-11-1.9 × 10-27), but not GSTO1. Pathway analysis of significant genes in our brain expression GWAS, identified significant enrichment for glutathione metabolism genes (p = 0.003).These results suggest that GSTO locus variants may lower brain GSTO2 levels and consequently confer AD risk in older age. Other glutathione metabolism genes should be assessed for their effects on AD and other chronic, neurologic diseases.Glutathione S-Transferase (GST) family of genes have been implicated in multiple neuropsychiatric [1-4] and neurodegenerative diseases [5-11]; where altered levels or function of these enzymes is thought to impact levels of oxidative stress and/or inflammation in a way that contributes to disease susceptibility. A linkage locus on chromosome 10q that has been implicated in both Alzheimer's (AD)[11-13] and Parkinson's disease (PD)[13] harbors two GST genes of the omega class: GSTO1 and GSTO2, which are approximately 75 kb apart.GSTOs have enzymatic activities as thioltransferases and dehydroascorbate reductases that promote antioxidant activity and can also function in metabolism of drugs and toxins[14]. Additionally, GSTO1 was shown to promote activation of the pro-inflammatory cytokine, interleukin-1β (IL-1β) by post-translational processing[15]. Given their location and function, they have been studied as candidate genes in AD and PD[5,6,9,11,14,16-18]. Li et al. compared hippocampal gene expression levels in 6 AD vs. 2 control brains and identified significantly lower GSTO1 levels in the AD hippocampi[5]. This group studied
In the Shadow of the Serbian Paramilitary Units: Narrative Patterns about the Role of Paramilitary Units in Former Yugoslav Conflict  [PDF]
Maria Vivod
Advances in Anthropology (AA) , 2013, DOI: 10.4236/aa.2013.31004
Abstract:
This article1 offers several basic data about Serbian paramilitary units employed in the armed conflict of the 1990’s during the decomposition of the former Yugoslavia, with the goal to depict the transformation of the representation of the paramilitary unit members and their leaders essentially through Serbian media. Once, at the beginning of the conflicts, represented as the saviors, protectors of the Serbian nation, ever present as main figures of the public life of the 90s—they have fallen into oblivion after a decade. Their most notorious leaders are either dead or in prison. After the fall of the Milo?evi? regime (2000) their involvement in war crimes, looting and genocide reached Serbia. From being divinized gradually they become diabolized. The contemporary events and happenings in Serbia are explained in the light of the past of these paramilitary units.
The Future Human Lifespan: A Study on Italian Population  [PDF]
Maria Russolillo
Applied Mathematics (AM) , 2014, DOI: 10.4236/am.2014.511158
Abstract:

In the latter part of the 20th century, continued improvements in living standards, health behaviors, and medical care reduced mortality and produced amazing advances in life expectancy. These trends, followed by all industrial nations, decidedly affect the financial position of an insurance company, interested in the construction of updated life tables. The approach to this problem is faced in this paper by using the Lee-Carter methodology. In particular, in the present work, we are interested in modeling and forecasting mortality and life expectancy on a period basis through the use of a stochastic forecasting method which uses time-series models to make long-term forecasts.

Radiation Induced Bystander Effect: From in Vitro Studies to Clinical Application  [PDF]
Maria Widel
International Journal of Medical Physics,Clinical Engineering and Radiation Oncology (IJMPCERO) , 2016, DOI: 10.4236/ijmpcero.2016.51001
Abstract: In the past 20 years, the classic paradigm in radiobiology recognizing DNA as the main target for the action of radiation has changed. The new paradigm assumes that both targeted and non-targeted effects of radiation determine the final outcome of irradiation. Radiotherapy is one of the main modality treatments of neoplastic diseases with intent to cure, or sometimes to palliate only, thus radiation-induced non-targeted effect, commonly referred to as the radiation-induced bystander effect (RIBE) may have a share in cancer treatment. RIBE is mediated by molecular signaling from radiation targeted cells to their non-irradiated neighbors, and comprises such phenomena as bystander effect, genomic instability, adaptive response and abscopal effect. Whereas first three phenomena may appear both in vitro and in vivo, an abscopal effect is closely related to partial body irradiation and is a systemic effect mediated by immunologic system which synergizes with radiotherapy. From the clinical point of view abscopal effect is particularly interesting due to both its possible valuable contribution to the treatment of metastases, and the potential harmful effects as induction of genetic instability and carcinogenesis. This review summarized the main results of investigations of non-targeted effects coming from in vitro monolayer cultures, 3-dimentional models of tissues, preclinical studies on rodents and clinically observed beneficial abscopal effects with particular emphasis on participation of immunotherapy in the creation of abscopal effects.
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