The Experts below are selected from a list of 66 Experts worldwide ranked by ideXlab platform
Massimo Corbo - One of the best experts on this subject based on the ideXlab platform.
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Case Report Valproate Treatment in an ALS Patient Carrying a c.194G>A Spastin Mutation and SMN2 Homozygous Deletion
2016Co-Authors: Massimo Corbo, Carlo FerrareseAbstract:Copyright © 2014 Lucio Tremolizzo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Here we report the case of anALS patient found to carry both a novel heterozygous change (c.194G>A)within the spastin gene and a homozygous deletion of the SMN2 gene.The patient was started on valproic acid (VPA, 600mg/die per os) considering the capacity of this drug of increasing survival motor neuron through an epigenetic mechanism. Patient clinical course and molecular effects of VPA on skin fibroblasts obtained from the proband are described.This c.194G>A spastin mutation might expand the previously known borders of type 4 spastic paraplegia (SPG4) and we suggest the intriguing possibility that the absence of SMN2 might have acted as a contributory risk factor for starting lower motor neuron damage. Exploring the relationship Genocopy-phenocopy in selected ALS patients might represent an interesting strategy for understanding its clinical variability. 1
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valproate treatment in an als patient carrying a c 194g a spastin mutation and smn2 homozygous deletion
Case reports in neurological medicine, 2014Co-Authors: L Tremolizzo, G Sala, E Conti, Virginia Rodriguezmenendez, Antonella Fogli, Angela Michelucci, Paolo Simi, Silvana Penco, Christian Lunetta, Massimo CorboAbstract:Here we report the case of an ALS patient found to carry both a novel heterozygous change (c.194G>A) within the spastin gene and a homozygous deletion of the SMN2 gene. The patient was started on valproic acid (VPA, 600 mg/die per os) considering the capacity of this drug of increasing survival motor neuron through an epigenetic mechanism. Patient clinical course and molecular effects of VPA on skin fibroblasts obtained from the proband are described. This c.194G>A spastin mutation might expand the previously known borders of type 4 spastic paraplegia (SPG4) and we suggest the intriguing possibility that the absence of SMN2 might have acted as a contributory risk factor for starting lower motor neuron damage. Exploring the relationship Genocopy-phenocopy in selected ALS patients might represent an interesting strategy for understanding its clinical variability.
Pawel Olszewski - One of the best experts on this subject based on the ideXlab platform.
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genetic optimization and experimental verification of complex parallel pumping station with centrifugal pumps
Applied Energy, 2016Co-Authors: Pawel OlszewskiAbstract:Abstract While single pump design allows operation at high performance levels, multi-pumping systems are controlled to cover actual flow rate requirements, with less emphasis on power consumption. Widely accessible sensors and programmable controllers can improve this approach. This paper discusses the methodology for optimizing analysis of a complex pumping system with set of parallel centrifugal pumps. For this purpose, an experimental model pumping station, with four pumps in a parallel configuration, was designed and constructed. Auxiliary equipment allows control of each pump by three possible methods: (i) discharge valve, (ii) by-pass flow, and (iii) variable speed drive (VSD). For system performance optimization, three estimating strategies, that are functions of control input parameters at each pump were proposed: (i) minimization of power consumption, (ii) flow rate balancing and (iii) maximization of overall efficiency. A Uniquely developed (C++) genetic algorithm (GENOCOP) determined solutions and these were positively verified by measurements at the model experimental station. Results show the existence of multiple local extrema for all of estimating strategies. These solutions show it is possible to control a complex pumping station with various combinations of control parameters, giving similar results. This analysis demonstrates that the strategy of minimizing power consumption is the most energy efficient and proves the described methodology as a powerful tool for optimizing of complex pumping stations.
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genetic optimization of steam multi turbines system
Applied Thermal Engineering, 2014Co-Authors: Pawel OlszewskiAbstract:Abstract Optimization analysis of partially loaded cogeneration, multiple-stages steam turbines system was numerically investigated by using own-developed code (C++). The system can be controlled by following variables: fresh steam temperature, pressure, and flow rates through all stages in steam turbines. Five various strategies, four thermodynamics and one economical, which quantify system operation, were defined and discussed as an optimization functions. Mathematical model of steam turbines calculates steam properties according to the formulation proposed by the International Association for the Properties of Water and Steam. Genetic algorithm GENOCOP was implemented as a solving engine for non–linear problem with handling constrains. Using formulated methodology, example solution for partially loaded system, composed of five steam turbines (30 input variables) with different characteristics, was obtained for five strategies. The genetic algorithm found multiple solutions (various input parameters sets) giving similar overall results. In real application it allows for appropriate scheduling of machine operation that would affect equable time load of every system compounds. Also based on these results three strategies where chosen as the most complex: the first thermodynamic law energy and exergy efficiency maximization and total equivalent energy minimization. These strategies can be successfully used in optimization of real cogeneration applications.
Sanghyun Lee - One of the best experts on this subject based on the ideXlab platform.
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disruption of type iii interferon ifn genes ifnl2 and ifnl3 recapitulates loss of the type iii ifn receptor in the mucosal antiviral response
Journal of Virology, 2019Co-Authors: Stefan T Peterson, Elizabeth A Kennedy, Pamela H Brigleb, Gwen M Taylor, Kelly Urbanek, Traci L Bricker, Sanghyun LeeAbstract:Type III interferon (IFN), or IFN lambda (IFN-λ), is an essential component of the innate immune response to mucosal viral infections. In both the intestine and the lung, signaling via the IFN-λ receptor (IFNLR) controls clinically important viral pathogens, including influenza virus, norovirus, and rotavirus. While it is thought that IFN-λ cytokines are the exclusive ligands for signaling through IFNLR, it is not known whether genetic ablation of these cytokines phenotypically recapitulates disruption of the receptor. Here, we report the serendipitous establishment of Ifnl2- / - Ifnl3- / - mice, which lack all known functional murine IFN-λ cytokines. We demonstrate that, like Ifnlr1- / - mice lacking IFNLR signaling, these mice display defective control of murine norovirus, reovirus, and influenza virus and therefore Genocopy Ifnlr1- / - mice. Thus, for regulation of viral infections at mucosal sites of both the intestine and lung, signaling via IFNLR can be fully explained by the activity of known cytokines IFN-λ2 and IFN-λ3. Our results confirm the current understanding of ligand-receptor interactions for type III IFN signaling and highlight the importance of this pathway in regulation of mucosal viral pathogens.IMPORTANCE Type III interferons are potent antiviral cytokines important for regulation of viruses that infect at mucosal surfaces. Studies using mice lacking the Ifnlr1 gene encoding the type III interferon receptor have demonstrated that signaling through this receptor is critical for protection against influenza virus, norovirus, and reovirus. Using a genetic approach to disrupt murine type III interferon cytokine genes Ifnl2 and Ifnl3, we found that mice lacking these cytokines fully recapitulate the impaired control of viruses observed in mice lacking Ifnlr1 Our results support the idea of an exclusive role for known type III interferon cytokines in signaling via IFNLR to mediate antiviral effects at mucosal surfaces. These findings emphasize the importance of type III interferons in regulation of a variety of viral pathogens and provide important genetic evidence to support our understanding of the ligand-receptor interactions in this pathway.
Eric M J Bindels - One of the best experts on this subject based on the ideXlab platform.
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atypical 3q26 mecom rearrangements Genocopy inv 3 t 3 3 in acute myeloid leukemia
Blood, 2020Co-Authors: Sophie Ottema, Roger Muletlazaro, Berna H Beverloo, Claudia Erpelinck, Stanley Van Herk, Robert Van Der Helm, Marije Havermans, Tim Grob, Peter J M Valk, Eric M J BindelsAbstract:Acute myeloid leukemia (AML) with inv(3)/t(3;3)(q21q26) is a distinct World Health Organization recognized entity, characterized by its aggressive course and poor prognosis. In this subtype of AML, the translocation of a GATA2 enhancer (3q21) to MECOM (3q26) results in overexpression of the MECOM isoform EVI1 and monoallelic expression of GATA2 from the unaffected allele. The full-length MECOM transcript, MDS1-EVI1, is not expressed as the result of the 3q26 rearrangement. Besides the classical inv(3)/t(3;3), a number of other 3q26/MECOM rearrangements with poor treatment response have been reported in AML. Here, we demonstrate, in a group of 33 AML patients with atypical 3q26 rearrangements, MECOM involvement with EVI1 overexpression but no or low MDS1-EVI1 levels. Moreover, the 3q26 translocations in these AML patients often involve superenhancers of genes active in myeloid development (eg, CD164, PROM1, CDK6, or MYC). In >50% of these cases, allele-specific GATA2 expression was observed, either by copy-number loss or by an unexplained allelic imbalance. Altogether, atypical 3q26 recapitulate the main leukemic mechanism of inv(3)/t(3;3) AML, namely EVI1 overexpression driven by enhancer hijacking, absent MDS1-EVI1 expression and potential GATA2 involvement. Therefore, we conclude that both atypical 3q26/MECOM and inv(3)/t(3;3) can be classified as a single entity of 3q26-rearranged AMLs. Routine analyses determining MECOM rearrangements and EVI1 and MDS1-EVI1 expression are required to recognize 3q-rearranged AML cases.
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complex 3q26 evi1 rearrangements Genocopy inv 3 t 3 3 acute myeloid leukemias by enhancer hijacking evi1 overexpression absent mds1 evi1 and low gata2 expression
Blood, 2018Co-Authors: Sophie Ottema, Roger Muletlazaro, Berna H Beverloo, Marije Havermans, Tim Grob, Peter J M Valk, Eric M J Bindels, Claudia A J Erpelinckverschueren, Torsten Haferlach, Claudia HaferlachAbstract:Introduction Acute myeloid leukemia (AML) with inv(3)(q21q26) or t(3;3)(q21;q26) overexpress EVI1 and have a very poor prognosis. EVI1 is part of the MECOM (MDS1-EVI1-Combination) locus from which MDS1-EVI1 and EVI1 can be transcribed from two different promoters. Although EVI1 is expressed at high levels, MDS1-EVI1 is absent or expressed at very low levels in inv(3)/t(3;3)-AMLs. Aberrant EVI1 expression in these leukemias is driven by the long-distant GATA2 enhancer, translocated from 3q21 to EVI1 at 3q26 (Groschel et al, 2014). As a result of this GATA2 enhancer hijack by EVI1, GATA2 is switched off on the rearranged allele, resulting in mono-allelic and low GATA2 expression. We hypothesize that leukemic transformation of inv(3)/t(3;3)-AMLs is driven by EVI1 overexpression and by low GATA2 and that these leukemias are marked by the absence of MDS1-EVI1 expression. We previously reported about a group of AML patients that presented with complex rearrangements of 3q26 (refer to as variant-3q26-AML) with frequent MECOM involvement and very poor survival (Lugthart et al, 2010). Here we address the questions if these variant-3q26-AMLs 1) overexpress EVI1 by enhancer hijacking, 2) are marked by absent MDS1-EVI1 and 3) express low levels of GATA2. Accordingly, the variant-3q26-AMLs should be classified as inv(3)/t(3;3)-AMLs. Results We identified 37 variant-3q26-AMLs with MECOM rearrangement as determined by Fluorescent in-situ hybridization (FISH). RNA-seq of these AMLs revealed EVI1 overexpression but also demonstrated the absence of MDS1-EVI1 in 90% of patient samples. Applying 3q-capture DNA-seq, we found that in 2 cases the patient cells harboured a "hidden" inv(3)(q21q26) with involvement of the GATA2 enhancer. In 7 cases recurrent 3q26/EVI1 translocations were identified, e.g. t(2;3)(p21;q26), t(3;8)(q26;q24), t(3;7)(q26;q11), involving the THADA, MYC or CDK6 loci respectively as previously described. Interestingly, we identified new translocations to the EVI1 locus in 13 AMLs, including a t(3;6)(q26;q21) and a t(3;4)(q26;p15), involving the CD164, and PROM1 loci respectively. In these samples we find clearly skewed expression of these genes to one allele, suggestively caused by the rearrangement and enhancer hijacking. CD164 plays a key role in adhesion, proliferation and migration of CD34+ hematopoietic progenitor cells (Watt et al, 2000). PROM1 (CD133) is expressed in human hematopoietic stem and progenitor cells and is thought to be involved in maintaining stem cell properties by suppressing differentiation (Bauer et al, 2008). We argue that EVI1 overexpression in these variant-3q26-AMLs is driven by hijacking enhancers of genes that are normally active in myeloid progenitors. In most of the patients the translocation breakpoints are in between the promoters of MDS1 and EVI1, explaining absence of MDS1-EVI1 expression. In addition, analysis of SNP-array data of these patients (N=33) showed Copy Number Loss (CNL) of the MDS1 exon(s) and not the EVI1 exons in at least 5 cases. Together these data suggest the importance of MDS1-EVI1 loss in 3q26-AMLs. Furthermore we wondered whether low GATA2 expression is an important event in variant-3q26-AMLs. Similar to inv(3)/t(3;3)-AMLs (Groschel et al, 2014), RNA-seq revealed that the GATA2 expression was on average a two-fold lower in the variant-3q26-AMLs (N=37), compared to non-3q26 rearranged AMLs (N=114). Surprisingly, SNP-array analysis in 26 variant-3q26-AMLs revealed CNLs of GATA2 and/or its enhancer in 7 patients. Detailed SNP analysis in GATA2 exons by combined 3q-capture DNA-seq and RNA-seq uncovered another 7 cases with mono-allelic GATA2 expression or skewing to expression of one allele (allele_freq Conclusion Given their complex karyotype, variant-3q26-AMLs are often not recognised as 3q26/EVI1 AMLs. Although the exact mechanism remains elusive, the overall effect seems to be alike. EVI1 overexpression, potentially driven by enhancer hijacking of genes that are active in early myeloid progenitors, combined with absent MDS1-EVI1 and mono-allelic/low GATA2 expression results in AML with very poor survival. Given these data we believe variant-3q26-AMLs Genocopy inv(3)/t(3;3)-AMLs and should be classified as such. Disclosures Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
David M Kurnit - One of the best experts on this subject based on the ideXlab platform.
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situs inversus in the developing mouse proteins affected by the iv mutation Genocopy and the teratogen retinoic acid phenocopy
Molecular Reproduction and Development, 1991Co-Authors: Margaret L Van Keuren, W M Layton, Ruxandra A Iacob, David M KurnitAbstract:To decipher genes that are important in the determination of laterality, we compared two-dimensional protein gels from wild-type C57BL/6J mice and C57BL/6J mice that carried the iv mutation, which confers random determination of visceral situs. To span the time period(s) during which laterality determination occurs, we compared computer-analyzed two-dimensional protein gels from wild-type mouse embryos and iv/iv mouse embryos at 7.5, 8.0, and 8.5 days post-coitum. One polypeptide that was expressed only on day 8.0 of development and only in wild-type embryos represents a particular candidate for determination of laterality. Day 8.5 postcoitum represents the earliest time in murine development that laterality is manifest. Two-dimensional gels were compared from 8.5 day embryos that were C57BL/6J wild-type, C57BL/6J iv/iv, or C57BL/6J wild-type and exposed to the teratogen retinoic acid late on day 7. Reproducible alterations of protein synthesis were observed in both the iv Genocopy and retinoic acid phenocopy, yielding abnormal laterality determination. The intersection of these peptide changes identifies a protein likely to play a role in the determination of laterality.