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Anna Vardi, Kostas Stamatopoulos and Anastasia Hadzidimitriou Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells critically dependent on microenvironmental stimulation for their survival ...doi:10.18632/oncotarget.22277 pmid:29245889 pmcid:PMC5725080 fatcat:bemznjs635getinubmp5oy3dra
The present study examines the effects of early emotional experiences on children's regulation or strategic control of attention in the presence of interpersonal hostility. Abused children's reactions to the unfolding of a realistic interpersonal emotional situation were measured through multiple methods including autonomic nervous system changes and overt behavioral performance. Although physically abused and non-physically abused 4-year-old children did not differ in terms of their baselinedoi:10.1111/j.1467-8624.2005.00890.x pmid:16149995 fatcat:bshgzp7n2jddvorwkqtw56lpgi
more »... vels of arousal, marked differences in physically abused children's regulatory responses to background anger emerged. These data suggest that the emergence of anger leads to increases in anticipatory monitoring of the environment among children with histories of abuse. Results are discussed in terms of risk factors in the development of psychopathology.
The study of the huge diversity of immune receptors, often referred to as immune repertoire profiling, is a prerequisite for diagnosis, prognostication and monitoring of hematological disorders. In the era of high-throughput sequencing (HTS), the abundance of immunogenetic data has revealed unprecedented opportunities for the thorough profiling of T-cell receptors (TR) and B-cell receptors (BcR). However, the volume of the data to be analyzed mandates for efficient and ease-to-use immunedoi:10.1186/s12859-018-2144-z pmid:29669518 pmcid:PMC5907363 fatcat:giqdpgrf7zbopmotimnvzp6rfe
more »... ire profiling software applications. Results: This work introduces Immune Repertoire Profiler (IRProfiler), a novel software pipeline that delivers a number of core receptor repertoire quantification and comparison functionalities on high-throughput TR and BcR sequencing data. Adopting 5 alternative clonotype definitions, IRProfiler implements a series of algorithms for 1) data filtering, 2) calculation of clonotype diversity and expression, 3) calculation of gene usage for the V and J subgroups, 4) detection of shared and exclusive clonotypes among multiple repertoires, and 5) comparison of gene usage for V and J subgroups among multiple repertoires. IRProfiler has been implemented as a toolbox of the Galaxy bioinformatics platform, comprising 6 tools. Theoretical and experimental evaluation has shown that the tools of IRProfiler are able to scale well with respect to the size of input dataset(s). IRProfiler has been utilized by a number of recently published studies concerning hematological disorders. Conclusion: IRProfiler is made freely available via 3 distribution channels, including the Galaxy Tool Shed. Despite being a new entry in a crowded ecosystem of immune repertoire profiling software, IRProfiler founds its added value on its support for alternative clonotype definitions in conjunction with a combination of properties stemming from its user-centric design, namely ease-of-use, ease-of-access, exploitability of the output data, and analysis flexibility.
One alternative is to use data from multiple sources to ensure that the results returned by different corpora agree (e.g., Cooper et al. 2019; Jarić et al. 2019; Vardi et al. 2021 ), a process that can ... al. 2016) , the effect of nature documentaries on public interest toward featured species (Fernández-Bellon & Kane 2020), and seasonal dynamics of public interest in nature (Mittermeier et al. 2019; Vardi ...doi:10.1111/cobi.13706 pmid:33749027 fatcat:nhywhihjtja55dpxbky2sayfpq
Although the etiology of chronic lymphocytic leukemia (CLL), the most common type of adult leukemia, is still unclear, strong evidence implicates antigen involvement in disease ontogeny and evolution. Primary and 3D structure analysis has been utilised in order to discover indications of antigenic pressure. The latter has been mostly based on the 3D models of the clonotypic B cell receptor immunoglobulin (BcR IG) amino acid sequences. Therefore, their accuracy is directly dependent on thedoi:10.1186/s12859-018-2381-1 fatcat:7mnozo63kbbffhyw2m2exuhfau
more »... y of the model construction algorithms and the specific methods used to compare the ensuing models. Thus far, reliable and robust methods that can group the IG 3D models based on their structural characteristics are missing. Results: Here we propose a novel method for clustering a set of proteins based on their 3D structure focusing on 3D structures of BcR IG from a large series of patients with CLL. The method combines techniques from the areas of bioinformatics, 3D object recognition and machine learning. The clustering procedure is based on the extraction of 3D descriptors, encoding various properties of the local and global geometrical structure of the proteins. The descriptors are extracted from aligned pairs of proteins. A combination of individual 3D descriptors is also used as an additional method. The comparison of the automatically generated clusters to manual annotation by experts shows an increased accuracy when using the 3D descriptors compared to plain bioinformatics-based comparison. The accuracy is increased even more when using the combination of 3D descriptors. Conclusions: The experimental results verify that the use of 3D descriptors commonly used for 3D object recognition can be effectively applied to distinguishing structural differences of proteins. The proposed approach can be applied to provide hints for the existence of structural groups in a large set of unannotated BcR IG protein files in both CLL and, by logical extension, other contexts where it is relevant to characterize BcR IG structural similarity. The method does not present any limitations in application and can be extended to other types of proteins.
Regulator of G-protein signaling 7 (RGS7) is predominately present in the nervous system and is essential for neuronal signaling involving G-proteins. Prior studies in cultured cells showed that RGS7 is regulated via proteasomal degradation, however no protein is known to facilitate proteasomal degradation of RGS7 and it has not been shown whether this regulation affects G-protein signaling in neurons. Here we used a knockout mouse model with conditional deletion of arginyltransferase (Ate1) indoi:10.1038/s41598-021-88628-3 pmid:33931669 pmcid:PMC8087773 fatcat:3ojj5o3x6vc6nmufq4b5q4ftaq
more »... the nervous system and found that in retinal ON bipolar cells, where RGS7 modulates a G-protein to signal light increments, deletion of Ate1 raised the level of RGS7. Electroretinographs revealed that lack of Ate1 leads to increased light-evoked response sensitivities of ON-bipolar cells, as well as their downstream neurons. In cultured mouse embryonic fibroblasts (MEF), RGS7 was rapidly degraded via proteasome pathway and this degradation was abolished in Ate1 knockout MEF. Our results indicate that Ate1 regulates RGS7 protein level by facilitating proteasomal degradation of RGS7 and thus affects G-protein signaling in neurons.
Journal of Pathology
Great interest has been shown in understanding the pathology of Gaucher disease (GD), due to the recently discovered genetic relationship with Parkinson's disease. For such studies, suitable animal models of GD are required. Chemical induction of GD by inhibition of acid β-glucosidase (GCase) using the irreversible inhibitor, conduritol B-epoxide (CBE), is particularly attractive, although few systematic studies examining the effect of CBE on development of symptoms associated with neurologicaldoi:10.1002/path.4751 pmid:27234572 fatcat:lklqbjuos5etrp6qxf3hixv5wa
more »... forms of GD have been performed. We now demonstrate a correlation between the amount of CBE injected into mice and levels of accumulation of the GD substrates, glucosylceramide and glucosylsphingosine, and show that disease pathology, indicated by altered levels of pathological markers, depends on both levels of accumulated lipids and the time at which their accumulation begins. Gene array analysis shows a remarkable similarity in the gene expression profiles of CBE-treated mice and a genetic GD mouse model, the Gba flox/flox ;nestin-Cre mouse, with 120 of the 144 genes up-regulated in CBE-treated mice also up-regulated in Gba flox/flox ;nestin-Cre mice. We also demonstrate that various aspects of neuropathology and some behavioral abnormalities can be arrested upon cessation of CBE treatment during a specific time window. Together, our data demonstrate that injection of mice with CBE provides a rapid and relatively easy way to induce symptoms typical of neuronal forms of GD. This is particularly useful when examining the role of specific biochemical pathways in GD pathology, since CBE can be injected into mice defective in components of putative pathological pathways, alleviating the need for time-consuming crossing of mice. Accepted Article different ages, and demonstrate that pathology is very similar to the two genetic models discussed above. Moreover, characterization of mice injected with CBE provides novel mechanistic insight into disease pathology. We suggest that the CBE model, even though it has inherent limitations, as do all mouse models, is nevertheless a useful and rapid means to induce nGD. In addition, we demonstrate that cessation of CBE treatment can arrest some but not all symptoms of nGD, and discuss how this experimental approach could be used to test the efficacy of potential therapies. Materials and methods Mice From postnatal days 8 or 15, C57BL/6 mice (Harlan Laboratories, Israel) were injected intra-peritoneally (IP) daily with 25, 37.5, 50 or 100 mg CBE (Calbiochem Millipore, Darmstadt, Germany) per kg body weight, or with PBS. Gba flox/flox mice were crossed with Gba flox/WT ;nestin-Cre mice to generate Gba flox/flox ;nestin-Cre mice and Gba flox/WT ;nestin-Cre mice, which served as healthy controls. Genotyping was performed by polymerase chain reaction. Mice with a mixed genetic background (C57BL6/J and CBA with further backcrossings with C57BL6/J; Jackson Laboratories, USA) were also injected with CBE; this mouse expresses Thy1-YFP-H in some cortical neurons (18). Mice were maintained in the experimental animal center of the Weizmann Institute of Science. All animal experiments were approved by the Weizmann Institute Institutional Animal Care and Use Committee. The use of K14-lnl/lnl mice is documented in the Supporting Information. GCase activity assays and sphingolipid analysis GCase activity assay was performed as described, as was sphingolipid analysis by liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) (8); for more details, see the Supporting Information. This article is protected by copyright. All rights reserved. Accepted Article RNA extraction and quantitative PCR RNA extraction and quantitative PCR were performed as described (9). A detailed description, along with the primers used for PCR, is given in the Supporting Information. Immunohistochemistry MAC2 staining was performed as described (7) and a detailed description, along with the methods used for GFAP and fluoro-Jade C staining, is given in the Supporting Information. Microarray analysis Starting from postnatal day 8, C57BL/6 mice were injected IP daily for 10 days with 25 mg CBE per kg body weight or with PBS. Microarray analysis was performed as documented in the Supporting Information. Behavioral experiments Behavioral tests were performed (23, 24) as documented in the Supporting Information. Results The effect of different concentrations of CBE on nGD pathology and comparison to Gba flox/flox ;nestin-Cre mice While previous studies have used a wide variety of CBE concentrations, ranging from 7.5 to 300 mg/kg body weight (Table 1) , little effort has been made to systematically compare the effects of CBE on development of nGD symptoms, and to determine how this correlates with levels of GlcCer and GlcSph accumulation. We injected C57BL/6 mice every day, starting on day 8, with different concentrations of CBE and measured the body weights of the mice and their life-spans. As might be predicted, the highest CBE concentration (100 mg/kg body weight) had the most dramatic effect, with C57BL/6 mice beginning to lose weight by This article is protected by copyright. All rights reserved.
Supplementary material, approximately 2.96 KB.doi:10.6084/m9.figshare.7103492 fatcat:nvqxucnvyrfjnlbbxakw4grhpy
The Mediator complex controls transcription of most eukaryotic genes with individual subunits required for the control of particular gene regulons in response to various perturbations. In this study, we reveal the roles of the plant Mediator subunits MED16, MED14, and MED2 in regulating transcription in response to the phytohormone abscisic acid (ABA) and we determine which cis elements are under their control. Using synthetic promoter reporters we established an effective system for testingdoi:10.3389/fpls.2021.649720 pmid:33777083 pmcid:PMC7991908 fatcat:qsjrfsybirei5fkisgaccu5wlu
more »... ationships between subunits and specific cis-acting motifs in protoplasts. Our results demonstrate that MED16, MED14, and MED2 are required for the full transcriptional activation by ABA of promoters containing both the ABRE (ABA-responsive element) and DRE (drought-responsive element). Using synthetic promoter motif concatamers, we showed that ABA-responsive activation of the ABRE but not the DRE motif was dependent on these three Mediator subunits. Furthermore, the three subunits were required for the control of water loss from leaves but played no role in ABA-dependent growth inhibition, highlighting specificity in their functions. Our results identify new roles for three Mediator subunits, provide a direct demonstration of their function and highlight that our experimental approach can be utilized to identify the function of subunits of plant transcriptional regulators.
class of PRRs with various Distinct Innate Immunity Pathways to Activation and Tolerance in Subgroups of Chronic Lymphocytic Leukemia with Distinct Immunoglobulin Receptors Stavroula Ntoufa, 1, 2 Anna ... Vardi, 2 Nikos Papakonstantinou, 2 Achilles Anagnostopoulos, 2 Vassiliki Aleporou-Marinou, 1 Chrysoula Belessi, 3 Paolo Ghia, 4, 5, 6, 7 Federico Caligaris-Cappio, 4, 5, 6, 7 Marta Muzio ...doi:10.2119/molmed.2011.00480 pmid:22437326 pmcid:PMC3521790 fatcat:w3mb6getfna7vdjdtonb3gwq2u
Cerebral metastases are a common cause of death in patients with melanoma. Systemic drug treatment of these metastases is rarely effective, and where possible surgical resection and/or stereotactic radiosurgery (SRS) are the preferred treatment options. Treatment with adjuvant whole brain radiotherapy (WBRT) following neurosurgery and/or SRS is controversial. Proponents of WBRT report prolongation of intracranial control with reduced neurological events and better palliation. Opponents statedoi:10.1186/1471-2407-11-142 pmid:21496312 pmcid:PMC3107806 fatcat:aduzaacyxrcmpjo23hzlkcrdpy
more »... anoma is radioresistant; that WBRT yields no survival benefit and may impair neurocognitive function. These opinions are based largely on studies in other tumour types in which assessment of neurocognitive function has been incomplete. Methods/Design: This trial is an international, prospective multi-centre, open-label, phase III randomised controlled trial comparing WBRT to observation following local treatment of intracranial melanoma metastases with surgery and/or SRS. Patients aged 18 years or older with 1-3 brain metastases excised and/or stereotactically irradiated and an ECOG status of 0-2 are eligible. Patients with leptomeningeal disease, or who have had previous WBRT or localised treatment for brain metastases are ineligible. WBRT prescription is at least 30 Gy in 10 fractions commenced within 8 weeks of surgery and/or SRS. Randomisation is stratified by the number of cerebral metastases, presence or absence of extracranial disease, treatment centre, sex, radiotherapy dose and patient age. The primary endpoint is the proportion of patients with distant intracranial failure as determined by MRI assessment at 12 months. Secondary end points include: survival, quality of life, performance status and neurocognitive function.
Evangelia, Minga, Anna Vardi, Evangelia Stalika, Anastasia Hadzidimitriou, and Kostas Stamatopoulos are with the Institute of Applied Biosciences (INAB), Center for Research and Technology Hellas Athanasios ... Vardi, Evangelia Stalika, Anastasia Hadzidimitriou, Kostas Stamatopoulos, Nicos Maglaveras, Sr Member, IEEE, and Ioanna Chouvarda, Member, IEEE I 978-1-4799-3163-7/13/$31.00 ©2013 IEEE redundancies, semantic ...doi:10.1109/bibe.2013.6701690 dblp:conf/bibe/MingaGVSHSMC13 fatcat:ju2kixoqbneq5nly6sly3ih72a
Dhillon, Corrinne Renton, Anna Dodd, Haibo Zhang, Philip Beale, Stephen Clarke Data analysis and interpretation: Janette L. Vardy, Haryana M. Dhillon, Gregory R. Pond, Sean B. ... Tannock Administrative support: Corrinne Renton, Anna Dodd Provision of study materials or patients: Philip Beale, Stephen Clarke Collection and assembly of data: Janette L. Vardy, Haryana M. ...doi:10.1200/jco.2015.63.0905 pmid:26527785 pmcid:PMC5683012 fatcat:6xspznilujetlnkfjd3kwk4rwm
BackgroundMutation in S-phase cyclin A-associated protein rin the endoplasmic reticulum (SCAPER) have been found across ethnicities and have been shown to cause variable penetrance of an array of pathological traits, including intellectual disability, retinitis pigmentosa and ciliopathies.MethodsHuman clinical phenotyping, surgical testicular sperm extraction and testicular tissue staining. Generation and analysis of short spindle 3 (ssp3) (SCAPER orthologue) Drosophila CAS9-knockout lines. Indoi:10.1136/jmedgenet-2020-106946 pmid:32527956 fatcat:7ghopndf6fgjlajf6ycpfal3qe
more »... itro microtubule (MT) binding assayed by total internal reflection fluorescence microscopy.ResultsWe show that patients homozygous for a SCAPER mutation lack SCAPER expression in spermatogonia (SPG) and are azoospermic due to early defects in spermatogenesis, leading to the complete absence of meiotic cells. Interestingly, Drosophila null mutants for the ubiquitously expressed ssp3 gene are viable and female fertile but male sterile. We further show that male sterility in ssp3 null mutants is due to failure in both chromosome segregation and cytokinesis. In cells undergoing male meiosis, the MTs emanating from the centrosomes do not appear to interact properly with the chromosomes, which remain dispersed within dividing spermatocytes (SPCs). In addition, mutant SPCs are unable to assemble a normal central spindle and undergo cytokinesis. Consistent with these results, an in vitro assay demonstrated that both SCAPER and Ssp3 directly bind MTs.ConclusionsOur results show that SCAPER null mutations block the entry into meiosis of SPG, causing azoospermia. Null mutations in ssp3 specifically disrupt MT dynamics during male meiosis, leading to sterility. Moreover, both SCAPER and Ssp3 bind MTs in vitro. These results raise the intriguing possibility of a common feature between human and Drosophila meiosis.
shared facilities for technical support, Xiaoan Ruan and the GIS Genome Sequencing Team for help with the SOLiD and Solexa high-throughput sequencing, Rory Johnson for design of the custom microarray, Anna ...doi:10.1038/srep09737 pmid:26024509 pmcid:PMC4448690 fatcat:uvbaqeadefbk5hdpxqxlwoxc6y
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