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Artykuły w czasopismach na temat "Global and distal suppressors"
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Malaney, Prerna, Miguel Gallardo, Marisa J. Hornbaker, Xiaorui Zhang, Todd Link, Vrutant Shah, Sanzhar Alybayev i in. "hnRNP K: A Regulator of Global Transcription and Translation That Drives Lymphomagenesis". Blood 132, Supplement 1 (29.11.2018): 1346. http://dx.doi.org/10.1182/blood-2018-99-116163.
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Abstract hnRNP K is an RNA binding protein that controls a multitude of cellular processes and is aberrantly expressed in cancers. We have previously shown that hnRNP K functions as a haploinsufficient tumor suppressor in AML patients with 9q deletions. However, overexpression of hnRNP K is the more commonly observed clinical phenomenon. We have recently discovered that hnRNP K overexpression in patients with diffuse large B-cell lymphoma correlates with dismal outcomes and directly resulted in the development of lymphomas in transgenic mice. To understand the mechanistic basis for the oncogenicity of hnRNP K overexpression and to identify therapeutic vulnerabilities, we performed RNA-sequencing, RNA immunoprecipitation following by sequencing (RIP-Seq), mass spectrometry, and polysome assays. We observed that hnRNP K regulates both global transcription and translational processes within the cell via modulation of 7SK and translation initiation proteins (such as the eIFs and PABP), respectively. Consequently, we hypothesized that aberrant hnRNP K expression primarily perturbs oncogenes with short half-lives. Mechanistically, we identified that hnRNP K binds to the RNA and regulates the expression of a plethora of critical oncogenes and tumor suppressors involved in hematologic malignancies such as c-Myc, RUNX1, and Cyclin D1. As proof of concept for clinical applications, we have demonstrated that hnRNP K-driven c-Myc overexpression renders tumors susceptible to bromodomain inhibition. Given that hnRNP K directs global transcription and translation, it is likely that hnRNP K overexpressing tumors will also be sensitive to transcriptional and translational inhibitors such as CDK9 inhibitors and omacetaxine mepesuccinate, respectively. However, since hnRNP K also regulates a plethora of additional cellular processes that extend far beyond mRNA and protein synthesis, there is a need to develop hnRNP K-specific inhibitors that will only target these activities. Thus, we have recently begun to identify small molecule compounds that can directly inhibit hnRNP K-RNA binding function on specific targets using an in vitro fluorescent binding assay. Using this assay, we are currently screening a library of 70,000 small molecule compounds to identify agents that can prevent hnRNP K-RNA interactions. In summary, we have established that hnRNP K is a bona fide oncogene that drives lymphomagenesis. Global analyses have revealed therapeutic vulnerabilities of hnRNP K overexpressing tumors. Furthermore, using our in vitro RNA binding assays, we anticipate identification of novel hnRNP K-specific inhibitors. Disclosures No relevant conflicts of interest to declare.
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Nahar, Rahul, Parham Ramezani-Rad, Sinisa Dovat, Maike Buchner, Thomas G. Graeber i Markus Muschen. "Mechanisms of Ikaros-Mediated Tumor Suppression". Blood 118, nr 21 (18.11.2011): 408. http://dx.doi.org/10.1182/blood.v118.21.408.408.
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Abstract Abstract 408 Background: The Ikaros (IKZF1) tumor suppressor is deleted in >80% of the cases of Ph+ ALL. While Ikaros cooperates with pre-B cell receptor signaling to induce cell cycle exit in Ph+ ALL (Trageser et al., J Exp Med, 2009), the mechanism of Ikaros-mediated tumor suppression is poorly understood. Here we report on a series of genetic experiments that show that Ikaros (i) interferes with key survival pathways downstream of the BCR-ABL1 kinase, (ii) inhibits leukemia cell proliferation through interaction with the pre-B cell receptor signaling pathway and (iii) activates the tumor suppressors p53, p21 and p27. Results: To elucidate the mechanism of Ikaros-dependent tumor suppression in BCR-ABL1-driven B cell lineage leukemia, we studied regulation of critical phosphorylation events downstream of the BCR-ABL1 kinase as a central mediators of survival and proliferation. Reconstitution of Ikaros expression in BCR-ABL1-transformed pre-B ALL cells resulted in rapid and global dephosphorylation comparable to the effect of Imatinib. A detailed analysis showed that Ikaros-induced dephosphorylation events affect activation of Stat5 (Y694), AKT (S473), ERK1/2 (T202 and Y204) and SRC (Y416). Interestingly, both Imatinib-treatment and reconstitution of pre-B cell receptor signaling using retroviral vectors for expression of the m heavy chain or the BLNK adapter molecule have the same effects as reconstitution of Ikaros. In fact, a comprehensive gene expression analysis demonstrated that Ikaros reconstitution resulted in similar gene expression changes as reconstitution of pre-B cell receptor signaling (m heavy chain or BLNK), reconstitution of PAX5, Cre-mediated deletion of Stat5 or Myc, or treatment with Imatinib. The signature of common gene expression changes shared between reconstitution of Ikaros, Pax5, m heavy chain, BLNK and inducible deletion of Stat5 or Myc and Imatinib-treatment involves known tumor suppressors including SPIB, BTG1, and BTG2. These findings suggest that reconstitution of tumor suppressive transcription factor (Ikaros, Pax5) converges with pre-B cell receptor-mediated tumor suppression. To better understand how pre-B cell receptor signaling and Ikaros intersect, we combined reconstitution of Ikaros with genetic deletion of either the (more proximal) SYK kinase or the (more distal) BLNK adapter molecule. While inducible Cre-mediated deletion of Syk had no effect on Ikaros-mediated tumor suppression, deletion of the BLNK adapter compromised the ability of Ikaros to function as tumor suppressor. These findings were confirmed in an in vivo transplantation experiment. While mice transplanted with Ikaros+ BLNK+ leukemia cells survived indefinitely, mice transplanted with Ikaros- BLNK+, Ikaros+ BLNK- or Ikaros- BLNK- leukemia cells died after 24 to 31 days post transplantation. While these findings provide genetic evidence for collaboration between the Ikaros and pre-B cell receptor tumor suppressor pathways, Ikaros and pre-B cell receptor signaling differ with respect to activation of classical tumor suppressor pathways. While reconstitution of pre-B cell receptor signaling failed to activate Arf, p53 or p27, protein levels of all these molecules were strongly upregulated by Ikaros. In agreement with these findings, reconstitution of pre-B cell receptor signaling had the same tumor suppressive effect in wildtype leukemia cells as in Arf−/−, p53−/− as well as p27−/− leukemia cells. Conversely, deletion of Arf and p53 significantly diminished the ability of Ikaros to function as tumor suppressor. Conclusion: Ikaros deletion represents a near-obligatory lesion in the pathogenesis of Ph+ ALL. Here we provide genetic evidence for three novel pathways of Ikaros-mediated tumor suppression. Like PAX5, Ikaros reconstitution results in multiple dephosphorylation events (Stat5, AKT, ERK1/2 and SRC are affected). In collaboration with the pre-B cell receptor and its downstream adapter molecule BLNK, Ikaros suppressed MYC and inhibits cell cycle progression. Induction of the Arf/p53 pathway represents a distinct function of Ikaros, which is not shared with the pre-B cell receptor signaling pathway. Disclosures: No relevant conflicts of interest to declare.
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How, Jing Yuan, Rebecca K. Stephens, Krystle Y. B. Lim, Patrick O. Humbert i Marc Kvansakul. "Structural basis of the human Scribble–Vangl2 association in health and disease". Biochemical Journal 478, nr 7 (6.04.2021): 1321–32. http://dx.doi.org/10.1042/bcj20200816.
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Scribble is a critical cell polarity regulator that has been shown to work as either an oncogene or tumor suppressor in a context dependent manner, and also impacts cell migration, tissue architecture and immunity. Mutations in Scribble lead to neural tube defects in mice and humans, which has been attributed to a loss of interaction with the planar cell polarity regulator Vangl2. We show that the Scribble PDZ domains 1, 2 and 3 are able to interact with the C-terminal PDZ binding motif of Vangl2 and have now determined crystal structures of these Scribble PDZ domains bound to the Vangl2 peptide. Mapping of mammalian neural tube defect mutations reveal that mutations located distal to the canonical PDZ domain ligand binding groove can not only ablate binding to Vangl2 but also disrupt binding to multiple other signaling regulators. Our findings suggest that PDZ-associated neural tube defect mutations in Scribble may not simply act in a Vangl2 dependent manner but as broad-spectrum loss of function mutants by disrupting the global Scribble-mediated interaction network.
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Georgescu, Maria-Magdalena. "TAMI-32. TEMPOROSPATIAL INVASION AND GENETIC EVOLUTION FROM INFRATENTORIAL TO SUPRATENTORIAL COMPARTMENT IN DIFFUSE MIDLINE GLIOMA". Neuro-Oncology 22, Supplement_2 (listopad 2020): ii220. http://dx.doi.org/10.1093/neuonc/noaa215.920.
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Abstract Diffuse midline gliomas (DMGs) are very aggressive pediatric brain tumors with dismal prognosis due to therapy-resistant tumor growth and invasion. We performed the first integrated histologic/genomic/proteomic analysis of 21 tumor foci from three pontine DMG cases with supratentorial dissemination. Histone H3.3 K27M was the driver mutation, usually at high variant allele fraction due to recurrent chromosome 1q copy number gain, in combination with germline variants in ATM, FANCM and MYCN genes. Both previously reported and novel recurrent copy number variations and somatic pathogenic mutations in chromatin remodeling, DNA damage response and PI3K/MAPK growth pathways were variably detected, either in multiple or isolated foci. Proteomic analysis showed global upregulation of histone H3, lack of K27 tri-methylation, and further impairment of polycomb repressive complex 2 by ASXL1 downregulation. Activation of oncogenic pathways resulted from combined upregulation of N-Myc, SOX2, p65/p50 NF-kB and STAT3 transcription factors, EGFR, FGFR2, PDGFRa/b and MET receptor tyrosine kinases, and downregulation of PHLPP1/2, PTEN and p16/INK4A tumor suppressors. Upregulation of SMAD4, PAI-1, CD44, and c-Src in multiple foci most likely contributed to invasiveness. This integrated comprehensive analysis allowed spatiotemporal modeling of tumor progression and identified two general pathways of supratentorial invasion, and a multitude of migratory subpopulations within the infratentorial compartment. It also delineated common signaling pathways and potential therapeutic targets, revealing an unsuspected activation of a multitude of oncogenic pathways that may explain the resistance of DMG to current therapies.
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Ono, B. I., R. Fujimoto, Y. Ohno, N. Maeda, Y. Tsuchiya, T. Usui i Y. Ishino-Arao. "UGA suppressors in Saccharomyces cerevisiae: allelism, action spectra and map positions." Genetics 118, nr 1 (1.01.1988): 41–47. http://dx.doi.org/10.1093/genetics/118.1.41.
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Abstract Sixty independent UGA suppressors of Saccharomyces cerevisiae have been studied. They are dominant and are divided into 16 groups (loci) by recombination. Suppressors representing these loci are divided into two classes by action spectra; four in class 1 (a broad action spectrum) and 12 in class 2 (a narrow action spectrum). Class 1 suppressors are less frequent in terms of not only total number but also number per locus than class 2 suppressors, indicating difference in either or both mutation frequency and selective pressure between suppressors of the two classes. Two of the class 1 suppressors, SUP152 and SUP161, do not recombine with SUP28 and SUP33, leucine-inserting UAA suppressors, respectively, indicating that they are mutations in genes coding for tRNA(Leu)UUA. Of the remaining two class 1 suppressors, SUP160 which causes lethality in the psi+ cytoplasm is mapped on chromosome XV very close to the centromere, and SUP165 on the right arm of chromosome XIV 44 cM distal to lys9. Of the class 2 suppressors, ten do not recombine with one or another of previously known UGA suppressors. The remaining two class 2 suppressors, SUP154 and SUP155, are mapped on the left and right arms of chromosome VII, respectively.
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Chattopadhyay, Gopinath, Jayantika Bhowmick, Kavyashree Manjunath, Shahbaz Ahmed, Parveen Goyal i Raghavan Varadarajan. "Mechanistic insights into global suppressors of protein folding defects". PLOS Genetics 18, nr 8 (29.08.2022): e1010334. http://dx.doi.org/10.1371/journal.pgen.1010334.
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Most amino acid substitutions in a protein either lead to partial loss of function or are near neutral. Several studies have shown the existence of second-site mutations that can rescue defects caused by diverse loss of function mutations. Such global suppressor mutations are key drivers of protein evolution. However, the mechanisms responsible for such suppression remain poorly understood. To address this, we characterized multiple suppressor mutations both in isolation and in combination with inactive mutants. We examined six global suppressors of the bacterial toxin CcdB, the known M182T global suppressor of TEM-1 β-lactamase, the N239Y global suppressor of p53-DBD and three suppressors of the SARS-CoV-2 spike Receptor Binding Domain. When coupled to inactive mutants, they promote increased in-vivo solubilities as well as regain-of-function phenotypes. In the case of CcdB, where novel suppressors were isolated, we determined the crystal structures of three such suppressors to obtain insight into the specific molecular interactions responsible for the observed effects. While most individual suppressors result in small stability enhancements relative to wildtype, which can be combined to yield significant stability increments, thermodynamic stabilisation is neither necessary nor sufficient for suppressor action. Instead, in diverse systems, we observe that individual global suppressors greatly enhance the foldability of buried site mutants, primarily through increase in refolding rate parameters measured in vitro. In the crowded intracellular environment, mutations that slow down folding likely facilitate off-pathway aggregation. We suggest that suppressor mutations that accelerate refolding can counteract this, enhancing the yield of properly folded, functional protein in vivo.
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Gowda, Chandrika, Chunhua Song, Sadie Steffens, Yali Ding, Bo Zhang, Feng Yue, Soumya Iyer i in. "CK2 Inhibitor CX4945 Shows Strong In Vivo Anti Leukemia Effect in AML Via Augmented Ikaros-Mediated Regulation of Global Epigenetic Landscape". Blood 134, Supplement_1 (13.11.2019): 2522. http://dx.doi.org/10.1182/blood-2019-131200.
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Over-expression of Casein Kinase II (CK2) pro-oncogenic kinase in Acute Myelogenous Leukemia (AML) is associated with poor prognosis. Inhibition of CK2 by siRNAs or with the specific inhibitor, CX-4945, shows strong cytotoxic effects. CK2 is a ubiquitous, constitutively active serine/ threonine kinase which has been implicated in leukemia progression via multiple mechanisms. One of the well-established mechanism is CK2 mediated phosphorylation and impairment of tumor suppressor function of Ikaros transcription factor. Impaired function of Ikaros has been associated with the development of leukemia including AML. In B-cell lymphoblastic leukemia, CK2 inhibition has been shown to exert a therapeutic effect via restoration and/or enhancement of the tumor suppressor activity of the Ikaros protein. The mechanism of therapeutic action of CK2 inhibition in AML is largely unknown and in vivo efficacy CK2 inhibitors in AML has never been established. Here we report anti-leukemia effect of CX-4945 in preclinical models of AML and demonstrate mechanism of action of CK2 inhibitor via restoration of Ikaros driven global regulation of epigenetic landscape. In order to study the effect of CK2 inhibition on Ikaros function in AML, we used U937 - a human myelomonocytic leukemia cell line with high baseline CK2 expression. U937 cells were treated with specific CK2 inhibitor, CX4945 for 72 hours. CK2 activity and Ikaros phosphorylation was measured using CK2 kinase assay and in vivo labeling - radio immunoblot assay. Results showed significant decrease in CK2 activity and Ikaros phosphorylation with no change in overall expression of the Ikaros protein. Expression analysis using RNA sequencing showed that treatment with CX-4945 caused significant upregulation of genes controlling immunity, and inflammation; and downregulation of genes involved in nucleic acid metabolism, RNA processing, and translation. Analysis of global genome-wide Ikaros occupancy using Chromatin Immunoprecipitation followed by next generation sequencing (ChIP-seq) of CX4945 treated U937 cells demonstrated that CX-4945 treatment significantly increased the number of Ikaros binding sites as well as increased peak strength while minimally re-distributing Ikaros' global genomic occupancy. While increased binding to the Promoter, Gene Body, and Gene Desert elements in CX-4945-treated cells was similar, the increase in Ikaros' DNA binding to enhancers was particularly pronounced. Further analysis showed that enhanced Ikaros DNA binding following treatment with CX-4945, directly induces formation of de novo enhancers. In order to test whether enhanced DNA binding of Ikaros is accompanied by augmented Ikaros function in the global epigenetic regulation of gene expression. We determined and compared chromatin accessibility of U937 cells before and after treatment with CX-4945, using ATAC-seq. Results indicate that Ikaros-induced de novo open chromatin at distal regulatory regions controls genes involved in the negative regulation of biological processes and cellular metabolism. Overall, these data demonstrate that, augmented Ikaros DNA-binding following CK2 inhibition resulted in 1) Ikaros' pioneering activity, 2) Ikaros' ability to induce the de novo formation of enhancers and super-enhancers, and 3) Ikaros' ability to induce the de novo formation of active enhancers and to activate poised enhancers. Together, these data uncover novel Ikaros functions in regulating the epigenetic landscape and identifies CK2 as a critical regulator of Ikaros activity. Next, we treated AML xenograft model of luciferase labelled U937 cells with CX4945 via oral gavage at dose 200mg/kg/day for 3 weeks and demonstrated significantly lower leukemia burden in treated group as measured by decreased bio-luminescence imaging. In summary, these results demonstrate for the first time that CK2 inhibitor, CX-4945 has strong anti-leukemia effect in AML preclinical models. One of the mechanisms by which CX4945 exert a therapeutic effect in AML involves enhancing Ikaros' function as regulator of global epigenomic landscape. These results provide strong mechanistic basis to develop novel targeted combination therapies using CK2 inhibitors for treatment of AML. Further studies evaluating combination therapies using patient derived xenograft (PDX) models of AML are underway. Disclosures Payne: Elf Zone, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
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Scholl, Amanda, Alexander Muselman i Dong-Er Zhang. "An Intronic Suppressor Element Regulates RUNX1 Alternative Polyadenylation". Blood 126, nr 23 (3.12.2015): 3578. http://dx.doi.org/10.1182/blood.v126.23.3578.3578.
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Abstract Polyadenylation is a post-transcriptional modification where the 3' end of an mRNA is cleaved and 250-300 adenines are added. It is predicted that 70-75% of human genes have more than one polyadenylation sequence (PAS) and are subject to alternative polyadenylation (APA). APA events affect the coding sequence of a gene when a proximal PAS is located within an intron, constitutive exon, or alternative exon. Gene expression is also affected if there are multiple PAS within the distal 3' untranslated region (UTR); proximal PAS usage shortens the 3'UTR, which can remove cis-regulatory regions such as miRNA and RNA-binding protein (RBP) sites. Furthermore, global changes in APA are linked to cellular state-proximal PAS usage is associated with immature developmental phases, cell proliferation, and cancerous phenotypes. Consequently, APA is a pertinent post-transcriptional modification that regulates gene expression and isoform generation across developmental stages and tissue types. Despite its significance, there are few APA studies in the hematology field, and those that exist have focused on global shifts in PAS usage. In this study, we uniquely focus on the APA mechanism of a single gene, RUNX1, and how this event can alter hematopoietic stem cell (HSC) homeostasis and hematopoiesis. There are three main isoforms of RUNX1 that differ in promoter and/or PAS usage. RUNX1b/c use different promoters, but have identical C-terminal regions. RUNX1a utilizes the same promoter as RUNX1b, but differs from both RUNX1b/c due to usage of a proximal PAS located in alternative exon 7a. RUNX1b/c are robustly expressed in most progenitor populations and differentiated blood cell lineages, whereas RUNX1a is restricted to human CD34+ HSCs. Functionally, RUNX1b/c promote HSC differentiation and lineage commitment, whereas RUNX1a expands HSCs and their engraftment potential, a property with therapeutic advantages but leukemic potential. Due to the difference in expression pattern and distinct functionality of RUNX1a compared to RUNX1b/c, it is relevant to study the APA event that dictates isoform generation. Elucidating this mechanism could provide valuable insight into the transient control of the HSC population for therapeutic benefit and illuminate new leukemogenic pathways. To study RUNX1 APA, we cloned alternative terminal exon 7a (RUNX1a) and constitutive exon 7b (RUNX1b/c) in between the two exons of a split GFP minigene reporter, along with 500 bp of their upstream and downstream flanking introns. We hypothesized that exon 7a would be skipped during processing of the minigene construct because the proximal PAS is rarely used in vivo. Conversely, exon 7b, the penultimate exon in RUNX1b/c, would be spliced in between the GFP exons, disrupting the GFP protein. These constructs were tested in KG-1a and U937 cells. Flow cytometry for GFP fluorescence supported our hypothesis as the exon 7a minigene produced a robust GFP signal and the exon 7b minigene produced no GFP signal. We confirmed that the GFP changes were due to the hypothesized mRNA processing events by performing RT-PCR using primers specific to the two GFP exons. These data show that important cis-regulatory elements that determine RUNX1 APA are located within exon 7a, 7b, and the cloned intronic regions. Next, we altered these minigenes by strategically making chimeric constructs that consist of either exon 7a or 7b with all combinations of upstream/downstream flanking introns. We discovered that replacing the intron upstream of exon 7a confers 2-5 fold greater splicing and polyadenylation of exon 7a, indicative of RUNX1a isoform generation. Therefore, a suppressor cis-element is located in this upstream intronic region. However, placing this intron upstream of exon 7b is not sufficient to reduce its inclusion between the GFP exons. Instead, both the upstream and downstream intronic regions flanking exon 7a are required. This suggests an RNA-looping mechanism that prevents splicing and usage of the exon 7a proximal PAS. Cleavage factor (CFIm) and Polypyrimidine-tract binding protein 1 (PTBP1) are RBPs involved in splicing and polyadenylation that alter mRNA processing by RNA-looping. We aim to narrow down the suppressor region upstream of exon 7a to identify a consensus sequence and the respective RBP that diminishes RUNX1 proximal PAS usage. This knowledge can be leveraged to enhance RUNX1a production and expand HSCs for therapeutic benefit. Disclosures No relevant conflicts of interest to declare.
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Maine, E. M., i J. Kimble. "Suppressors of glp-1, a gene required for cell communication during development in Caenorhabditis elegans, define a set of interacting genes." Genetics 135, nr 4 (1.12.1993): 1011–22. http://dx.doi.org/10.1093/genetics/135.4.1011.
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Abstract The glp-1 gene is essential for two cell interactions that control cell fate in Caenorhabditis elegans: induction of anterior pharynx in the embryo and induction of mitotic proliferation in the germ line. To identify other genes involved in these cell interactions, we have isolated suppressors of two temperature sensitive alleles of glp-1. Each of 14 recessive suppressors rescues both embryonic and germline glp-1(ts) defects. These suppressors are extragenic and define a set of six genes designated sog, for suppressor of glp-1. Suppression of glp-1 is the only obvious phenotype associated with sog mutations. Mutations in different sog genes show allele-specific intergenic noncomplementation, suggesting that the sog gene products may interact. In addition, we have analyzed a semidominant mutation that suppresses only the glp-1 germline phenotype and has a conditional feminized phenotype of its own. None of the suppressors rescues a glp-1 null mutation and therefore they do not bypass a requirement for glp-1. Distal tip cell function remains necessary for germline proliferation in suppressed animals. These suppressor mutations identify genes that may encode other components of the glp-1 mediated cell-signaling pathway or regulate glp-1 expression.
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Lissemore, J. L., P. D. Currie, C. M. Turk i E. M. Maine. "Intragenic dominant suppressors of glp-1, a gene essential for cell-signaling in Caenorhabditis elegans, support a role for cdc10/SWI6/ankyrin motifs in GLP-1 function." Genetics 135, nr 4 (1.12.1993): 1023–34. http://dx.doi.org/10.1093/genetics/135.4.1023.
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Abstract The glp-1 gene product mediates cell-cell interactions required for cell fate specification during development in Caenorhabditis elegans. To identify genes that interact with glp-1, we screened for dominant suppressors of two temperature-sensitive glp-1 alleles and recovered 18 mutations that suppress both germline and embryonic glp-1 phenotypes. These dominant suppressors are tightly linked to glp-1 and do not bypass the requirement for a distal tip cell, which is thought to be the source of a signal that is received and transduced by the GLP-1 protein. Using single-strand conformation polymorphism (SSCP) analysis and DNA sequencing, we found that at least 17 suppressors are second-site intragenic revertants. The suppressors, like the original glp-1(ts) mutations, are all located in the cdc10/SWI6/ankyrin domain of GLP-1. cdc10/SWI6/ankyrin motifs have been shown to mediate specific protein-protein interactions in other polypeptides. We propose that the glp-1(ts) mutations disrupt contact between GLP-1 and an as yet unidentified target protein(s) and that the dominant suppressor mutations restore appropriate protein-protein interactions.
Rozprawy doktorskie na temat "Global and distal suppressors"
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Chandra, Soumyanetra. "Probing Protein Sequence-Function Relationships using Deep Mutational Scanning". Thesis, 2021. https://etd.iisc.ac.in/handle/2005/5662.
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Deep Mutational Scanning (DMS) approaches help elucidate sequence-function-phenotype relationships in proteins, which ultimately improves our understanding of residue (or nucleotide)-specific contributions to protein function and organismal fitness. Such comprehensive knowledge finds use in reliable prediction of consequences of mutations, as well as in protein design and engineering. We have investigated the molecular mechanisms of how mutations at surface exposed sites, away from the active sites in a model protein, CcdB produce drastic defects on the protein’s activity and organismal phenotype. Subsequently, we have surveyed double mutant libraries of CcdB, using a DMS approach, to identify mutants that can suppress the inactive phenotypes of exposed non active-site mutants in CcdB. These studies provide insights into the generally overlooked mutations that alter the fraction of active protein expressed, without affecting the activity of the folded fraction. We next describe a facile DMS method to accurately estimate binding energetics of protein-protein interactions (PPIs) and have used this methodology to probe residue specific contributions to partner binding in an intrinsically disordered protein CcdA. We also developed a model based on the CcdA mutational landscape to predict mutational effects on binding affinities in other IDPs. Using the insights from the CcdA mutational study, we also describe how Aspartate Scanning can be used to predict interface residues and local secondary structures for the MazF6 interacting, intrinsically disordered domain of MazE6 protein. This rapid and inexpensive methodology is readily applicable to experimentally unexplored, protein-interacting, intrinsically disordered domains. Finally, we also investigate how mutations in the ccdA gene can affect the protein’s activity and phenotype of the bacterial cell harboring it, in its native operonic context, and found a surprisingly high sensitivity to mutations (including synonymous mutations) in a manner dependent on the codon usage in the genome.
Książki na temat "Global and distal suppressors"
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Ekman, Paul, i Eve Ekman. Is Global Compassion Achievable? Redaktorzy Emma M. Seppälä, Emiliana Simon-Thomas, Stephanie L. Brown, Monica C. Worline, C. Daryl Cameron i James R. Doty. Oxford University Press, 2017. http://dx.doi.org/10.1093/oxfordhb/9780190464684.013.4.
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Two distinctions are introduced that were not previously explicit in the literature on compassion, which might clarify what is being studied and encourage attention to forms of compassion that have been largely ignored. The first distinction is whether the target of the compassionate behavior is proximal (e.g., seeing someone fall down, badly scraping his or her knee) or distal (e.g., someone not directly observed who might be injured now or in the future). Proximal is immediate, remedial if possible for the suffering witnessed; distal prevents harm in the future from occurring. The second set of distinctions refers to whether the compassion is empathic, involves action, or is an aspiration.
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Donahue, Thomas J. Unfreedom for All. Oxford University Press, 2019. http://dx.doi.org/10.1093/oso/9780190051686.001.0001.
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It is often said that we live in global systems of injustice. But if so, what are they, and what are their moral consequences? This book offers a theory of global injustice—“Unfreedom for All.” The theory explores and defends the old adage that “No one is free while others are oppressed” by putting five questions: Why and when ought we to combat injustices done to distant others, and does this require joining in solidarity against them? Do we live under global systems of injustice? What counts as systematic injustice or oppression? Who if anyone is made unfree by such injustices? What harms do they do? Unfreedom for All shows that the “No one is free” creed either answers or results from each of these questions. It defends that creed by considering how systematic injustices—such as global severe poverty, male supremacy, or racial oppression—are perpetuated. The book argues that where your society does such an injustice, it systematically suppresses anyone’s resistance to the injustice—including yours. It uses authoritarian tactics against everyone, so you too are subject to arbitrary power. Hence you too are unfree. This holds just as true of systematic injustices done by global society, and this should be the main reason for joining in solidarity against injustice.
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The World Market for Lightning Arresters, Voltage Limiters, and Surge Suppressors for Voltage Exceeding 1,000 Volts: A 2004 Global Trade Perspective. Icon Group International, Inc., 2005.
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Parker, Philip M. The World Market for Lightning Arresters, Voltage Limiters, and Surge Suppressors for Voltage Exceeding 1,000 Volts: A 2007 Global Trade Perspective. ICON Group International, Inc., 2006.
Znajdź pełny tekst źródłaCzęści książek na temat "Global and distal suppressors"
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Gosselin, Richard A., i David O. Oloruntoba. "Trauma of the Distal Femur, Knee, Tibia, and Fibula". W Global Orthopedics, 219–35. Cham: Springer International Publishing, 2019. http://dx.doi.org/10.1007/978-3-030-13290-3_23.
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Coudé-Gaussen, Geneviéve. "Local, Proximal and Distal Saharan Dusts: Characterization and Contribution to the Sedimentation". W Paleoclimatology and Paleometeorology: Modern and Past Patterns of Global Atmospheric Transport, 339–58. Dordrecht: Springer Netherlands, 1989. http://dx.doi.org/10.1007/978-94-009-0995-3_14.
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Mahapatra, Elizabeth, Salini Das, Souvick Biswas, Archismaan Ghosh, Debomita Sengupta, Madhumita Roy i Sutapa Mukherjee. "Insights of Cisplatin Resistance in Cervical Cancer: A Decision Making for Cellular Survival". W Cervical Cancer - A Global Public Health Treatise [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.98489.
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The clinical scenario of acquired cisplatin resistance is considered as a major impediment in cervical cancer treatment. Bulky drug-DNA adducts formed by cisplatin elicits DNA damage response (DDR) which either subsequently induces apoptosis in the cervical cancer cells or enables them to adapt with drug assault by invigorating pro-survival molecular cascades. When HPV infected cervical cancer cells encounter cisplatin, a complex molecular interaction between deregulated tumor suppressors, DNA damage-repair enzymes, and prosurvival molecules get initiated. Ambiguous molecular triggers allow cancer cells to cull apoptosis by opting for a survival fate. Overriding of the apoptotic cues by the pro-survival cues renders a cisplatin resistant phenotype in the tumor microenvironment. The present review undrapes the impact of deregulated signaling nexus formed due to crosstalk of the key molecules related to cell survival and apoptosis in orchestrating platinum resistance in cervical cancer.
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"Palm Oil as a Case Study of Distal Land Connections". W Rethinking Global Land Use in an Urban Era. The MIT Press, 2014. http://dx.doi.org/10.7551/mitpress/10011.003.0014.
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Wicke, Birka. "Palm Oil as a Case Study of Distal Land Connections". W Rethinking Global Land Use in an Urban Era, 163–80. The MIT Press, 2014. http://dx.doi.org/10.7551/mitpress/9780262026901.003.0009.
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Anaf, Julia, Fran Baum i Matt Fisher. "Global Health and Equity Burden of Commercial Determinants of Health". W The Commercial Determinants of Health, 17—C3.P79. Oxford University PressNew York, 2022. http://dx.doi.org/10.1093/oso/9780197578742.003.0003.
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Abstract In order to understand the extent to which commercial determinants of health impact on the health of populations globally, the evidence of their proximal and distal influences must be considered. In addition to disease burden, the commercial determinants of health often have important influences on health equity. Collective opposition to tax increases, public ownership of essential amenities, or minimum environment or labor standards all lead to greater health inequity and poorer health outcomes. Such effects are often overlooked in research and scholarship on commercial determinants yet may constitute a significant proportion of overall harm. It is imperative that there be agreement on the extent to which these broader effects should be considered as those in the field seek to measure the distal effects of commercial activity throughout the world. This chapter summarizes what is known about the effects of large commercial actors on health and health equity.
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Nigudkar, Advaita Satish, i Jagruti Rajan Wandrekar. "Living Within, Subverting, or Rewriting the Script". W Global Perspectives on the LGBT Community and Non-Discrimination, 84–109. IGI Global, 2022. http://dx.doi.org/10.4018/978-1-6684-2428-5.ch004.
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Discrimination towards the LGBTQIA+ community has an impact on mental health that is described using the minority stress theory by Meyer. The authors are mental health professionals in India who hypothesize that in India, families are the dominant source of minority stress. They explain how in India's collectivistic framework, families are cis-hetero-patriarchal and contribute to distal stress through direct and indirect violence and proximal stress through forcing concealment, internalized homo and trans-negativity, perceived rejection, and internalized guilt. LGBTQIA+ individuals in India use three pathways to manage minority stress: living within the script (i.e., heterosexual marriages and dual lives), subverting the script (i.e., trying to fit queer relationships in a societally acceptable framework), or rewriting the script (i.e., choosing to live alone, having families of choice, and practising non-traditional relationship structures). Legal provisions that aid and inhibit these are discussed. Ways to build community resilience are suggested.
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Villafuerte, Santiago Rodríguez, Sebastián Olaya, Luis Geovanny Mochas, Edison Endara i Bruna Cerbino. "Prognosis of patients with intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma undergoing liver transplantation". W GLOBAL HEALTH TRENDS AND PERSPECTIVES IN HEALTH SCIENCES. Seven Editora, 2023. http://dx.doi.org/10.56238/globalhealthprespesc-035.
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Cholangiocarcinoma (CC) is the most common of tumors of the biliary tree, according to its location is classified as intrahepatic, perihilar, and distal. Intrahepatic CC (ICC) constitutes about 5-10% of all CC. Although rare, its incidence has been increasing in several parts of the world. The mixed tumor hepatocellular carcinoma/cholangiocarcinoma (HCC-CC), which is also rare, presents histological findings of both hepatocellular carcinoma (HCC) and iCC in the same nodule. Patients with a presumptive diagnosis of HCC on imaging tests undergo liver transplantation when, in fact, they have iCC or HCC-CC. A consensus meeting of the 2014 European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Disease (AASLD) contraindicated liver transplantation (LT) in patients with iCC or HCC-CC. However, recent studies suggest that careful selection of patients with very early iCC have similar survival rates to patients transplanted by HCC, suggesting that early iCC patients should be considered for liver transplantation. Similar results were obtained in patients with HCC-CC; however, it would seem that the cutoff could be extended to 5 cm considering other post-LT variables
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Anaz, Aisha Al, Ravi Teja Chitturi Suryaprakash, Kate Shearston i Omar Kujan. "Growth Factors and Cancer". W Molecular Targets and Cancer Therapeutics (Part 1), 187–241. BENTHAM SCIENCE PUBLISHERS, 2023. http://dx.doi.org/10.2174/9789815080384123010008.
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Cancer causes major patient morbidity and mortality and is a critical health concern worldwide. The recent GLOBOCAN 2019 factsheet recorded nearly 19.2 million new cancer cases, 9.9 million cancer deaths and 50.55 million people suffering from different kinds of cancer globally within 5 years after diagnosis. Growth factors (GF) are a group of proteins that can affect cellular processes, including differentiation, division, intravasation, extravasation and dissemination. The circulating tumor cells in the bloodstream can populate distant tissues and organs and believe to be the primary cause of metastasis. Extravasation is a crucial phase in the metastasis process, in which tumor cells leave the bloodstream and enter the host tissue. The progress of metastasis is triggered by the tendency of cancer cells to disseminate to target organs from the site of the primary tumor. Despite extensive basic scientific and clinical investigations, cancer is still a major clinical and public health problem. The development of cancer can be influenced by genetics, environmental factors, gene-environment interaction, lifestyle, age and a number of other factors. The harnessing and enhancement of the body’s own cytotoxic cells to prevent basement membrane rupture and the intervening dissemination processes can provide useful insight into the development of cancer. The mutation in oncogenes and tumour suppressor genes, and chromosomal aberration is a cornerstones of the molecular basis of cancer. The basement Membrane (BM) acts as a cell invasion shield, thus identification of processes that underlie in breaching of BM can contribute to understanding the disease pathogenesis. TGF-β is known for its dual function; it requires inhibition in the advanced stage however, the growth inhibitory properties are displayed in the early stages of tumorigenesis. Therefore, inhibition of TGF-β signalling in the CD8+ T cell compartment may be necessary for tumor immunity to be restored. Quantitation of tumour cell dissemination is important and plays significant role in elucidating mechanisms of cancer and strategies for therapeutic intervention.
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Hagino, Hiroshi, i Akiko Kondo. "Common fractures in older adults". W Oxford Textbook of Geriatric Medicine, 533–38. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780198701590.003.0069.
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Among elderly individuals worldwide, the incidence of fractures is highest in the vertebrae, followed by the hips and distal forearms. There is a wide variation in global hip fracture incidence rates, with the rates in women approximately twice those in men. These rates are low in people under 70 years old, and increase exponentially with age thereafter. There are large geographic and secular changes in incidence of most common fragility fractures, for reasons that are not fully understood. Morbidity and mortality increases are associated with all fragility fractures, although to varying degrees depending on the site of the fracture. The mean decline in quality of life is greater in patients with hip fractures, than those with vertebral or distal forearm fractures.
Streszczenia konferencji na temat "Global and distal suppressors"
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Kumagai, Ayane, Yoshinobu Obata, Yinlai Jiang, Hiroshi Yokoi i Shunta Togo. "Evaluation of the precision grasping ability by artificial finger based on the morphology of distal phalanx". W 2020 IEEE 2nd Global Conference on Life Sciences and Technologies (LifeTech). IEEE, 2020. http://dx.doi.org/10.1109/lifetech48969.2020.1570616957.
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Marx, Kenneth A., John Sharko, Georges G. Grinstein, Shannon Odelberg i Hans-Georg Simon. "Evidence for Proximal to Distal Appendage Amputation Site Effects from Global Gene Expression Correlations Found in Newt Microarrays". W 2007 IEEE 7th International Symposium on BioInformatics and BioEngineering. IEEE, 2007. http://dx.doi.org/10.1109/bibe.2007.4375555.
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Soares, Maria Carolina, Paulo Victor Sgobbi de Souza, Igor Braga Farias, Paulo de Lima Serrano, Bruno de Mattos Lombardi Badia, Marco Antônio Troccoli Chieia, Wladimir Bocca Vieira de Rezende Pinto i Acary Souza Bulle Oliveira. "Juvenile-onset amyotrophic lateral sclerosis due to homozygous COQ7 variants". W XIV Congresso Paulista de Neurologia. Zeppelini Editorial e Comunicação, 2023. http://dx.doi.org/10.5327/1516-3180.141s1.402.
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Coenzyme Q10 (CoQ10) biosynthesis defects may lead to primary CoQ10 deficiency. This rare inherited metabolic disorder has been associated with a heterogeneous genetic basis, including rare pathogenic variants in the COQ7 gene. CoQ10 deficiency leads to dysfunction of mitochondrial energy, resulting in several distinct neuromuscular phenotypes, such as myopathy, axonal and demyelinating chronic polyneuropathy and hereditary motor neuronopathy. Herein, we present the first clinical association of COQ7 pathogenic variants with Juvenile Amyotrophic Lateral Sclerosis. A 38-year-old Brazilian man started at age 11 years with a slowly progressive history of distal lower extremity weakness that evolved to the proximal segment, distal extremities of upper limbs and speech disorders. His parents were first degree cousins. His father and brother had similar motor symptoms. Neurological examination disclosed dysarthria, lower limb and distal-dominant quadriparesis, global amyotrophy with dominant distal involvement, and brisk tendon reflexes in the lower limbs. Neuroimaging studies were unremarkable, as well as cerebrospinal fluid analysis. Needle electromyography disclosed diffuse chronic denervation involving cervical, thoracic, and lumbosacral myotomes, and acute denervation (positive sharp waves and fibrillation) in the four limbs; preserved sensory neuroconduction studies. Broad next-generation sequencing-based gene panel testing disclosed the homozygous pathogenic variant c.1A>G in the COQ7 gene. This description expands the pathophysiological basis associated with JALS. COQ7 variants should be included in the differential diagnosis of juvenile-onset motor neuron disease.
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Athayde, Natália Merten, Wladimir Bocca Vieira de Rezende Pinto, Paulo Victor Sgobbi de Souza, Acary Souza Bulle Oliveira i Alzira Alves de Siqueira Carvalho. "Expansion of the phenotype in ALS19". W XIII Congresso Paulista de Neurologia. Zeppelini Editorial e Comunicação, 2021. http://dx.doi.org/10.5327/1516-3180.455.
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Context: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects the upper and lower motor neurons. Most cases are sporadic, being 5-10% familial. Currently, more than 20 genes are described as causing familial ALS, with C9ORF72 and SOD1 the most common. Case report: Woman, 42 years old, with progressive weakness in her left foot for 3 years evolving with difficulty walking. No family history. Neurological exam(NE): asymmetric stepagge gait. Asymmetric proximal, distal and axial muscle weakness and distal atrophy. Hyperactive reflexes. EMG: pre-ganglionic lesion in lower limbs with active denervation. Brain MRI: high signal intensity on left corticospinal tract. ALS genetic panel: c.3878G> A, heterozygois in ErbB4(OMIM* 600543). CASE 2: Female, 55 years old, with parkinsonism for 2 years, evolving with muscle weakness, myalgia, dysphonia and dysphagia. After 7 months, respiratory failure and death. Family history: ALS and atypical parkinsonism. NE: Global amyotrophy, facial hypomimia, dropped head, fasciculations on the tongue. Bradykinesia. Plastic hypertonia in the 4 limbs. Proximal and distal weakness. Babinski sign on the right. Oculomotor apraxia. Dysarthrophonia. EMG: pre-ganglionic lesion in the 4 limbs. Brain MRI: global cortical atrophy with temporal predominance. Exome: pathogenic variant, in heterozygosis c. 2428G>A in ErbB4. Conclusion: There are only 3 cases reported in the literature associated to pathogenic variants in this gene. We suggest an expansion of the clinical phenotype for ALS19.
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Liddle, Kate D., Meir Marmor, Hyun Kyu Han, Marshall Fong, Thomas Chu, Viva Tai, Kathleen Mulligan, Jenni M. Buckley i Amir Matityahu. "Predicting the Strength of Volar Screw Purchase in the Distal Radius: Comparison Between DEXA and a New “Smart” Surgical Tool". W ASME 2010 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2010. http://dx.doi.org/10.1115/sbc2010-19086.
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The distal radius is a common site of fracture with volar plates and screws as the current clinical practice for fracture fixation [1]. Local measurements of bone quality at the sites of screw insertion aid in providing the most stable fixation with the least amount of hardware, minimizing the risk of construct failure and irritation to soft tissue [2, 3]. The clinical standard for pre-operative bone mineral density (BMD) assessment uses dual x-ray absorptiometry (DEXA). However, DEXA scans provide global BMD values and cannot accurately predict variations in BMD within a given anatomical site [4]. Furthermore, patients frequently present without a pre-operative DEXA scan, so intra-operative assessment would be ideal. We developed a simple sensor system that would be appropriate for assessing local BMD intra-operatively. The system consists of a “smart” Weber clamp instrumented with a single uniaxial strain gage that provides real-time feedback regarding the local BMD.
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Lemos, Ana Flavia Andrade, Maria Clara Foloni, Rebeca Aranha Barbosa Sousa, Yasmim Nadime José Frigo, Tarcísio Nunes Alvarenga, Patrick Emanuell Mesquita Sousa Santos, Gilberto Bento Magioni Junior i in. "Multifocal motor neuropathy atypical presentation: case report". W XIV Congresso Paulista de Neurologia. Zeppelini Editorial e Comunicação, 2023. http://dx.doi.org/10.5327/1516-3180.141s1.594.
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Case report: Woman, 34 years old, with paresis that started four years ago during pregnancy, predominantly distal in the lower limbs and progression to the upper limbs. No involvement of cranial nerves and sensitivity. Initially considered a diagnosis of Myasthenia Gravis and clinical gain was observed with the use of pyridostigmine. After a few months, the patient’s symptoms recurred with asymmetric flaccid tetraparesis, predominantly in the lower limbs, associated with global areflexia and oral immunosuppressive therapy was initiated, with improvement. Electroneuromyography with normal sensory nerve conduction studies, but reductions in amplitudes in proximal compound muscle action potentials, with markedly reduced persistence in F-wave studies of the four limbs. Diffuse neurogenic changes were observed on exertion and activities such as positive sharp waves, fibrillation, fasciculations and myokymia at rest. Repetitive nerve stimulation at 3Hz without changes. A hypothesis of multifocal motor neuropathy (MMN) was then made. Treatment with intravenous immunoglobulin was performed, with significant recovery of symptoms. Discussion: MMN is a rare disease (prevalence of 0.6 per 100,000 individuals), with a predominance in men and a mean age of onset around 40 years. The differential diagnosis includes motor neuron disease and other demyelinating neuropathies. It is immune-mediated by antianglioside antibodies (anti-GM1), but they are not identified in all patients and may be present in other neuropathies. It is defined by muscle weakness predominantly distal, asymmetrical, predominantly in the upper limbs, slowly progressive, associated with reduced deep reflexes in the affected regions. The main electrophysiological characteristic is the presence of motor nerve conduction blocks (CB) outside the usual sites of compression. Conclusion: The finding that CB presents in patients with MMN suggests that nerve conduction should be extensively studied in every patient with a lowermotor-neuron syndrome to identify patients who might respond favorably to immunomodulating treatment.
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Shimomura, Takahiro, i Motoyoshi Yamanaka. "Depositional Processes of the Cenomanian-Turonian Reworked Carbonates in the Eastern Abu Dhabi, UAE". W Abu Dhabi International Petroleum Exhibition & Conference. SPE, 2021. http://dx.doi.org/10.2118/208191-ms.
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Abstract There are a limited number of studies and exploration cases for a "reworked carbonate" in Abu Dhabi, although these sediments are composed from some large oil and gas fields around the world (e.g. Poza Rica oil field in Mexico and Ruby gas field in Indonesia). In this study, we focused on Cenomanian-Turonian carbonates and considered the depositional processes of a "reworked carbonate" in the eastern part of Abu Dhabi. To understand the stacking pattern and/or depositional process of the Cenomanian-Turonian carbonate, we conducted a well-well correlation for total 16 wells, based on the core observations, wireline logs correlation (GR, Neutron, Density, Resistivity and Sonic), carbon and oxygen isotope analysis and trace elements analysis. Sampling was conducted for 8 wells and samples were taken approximately every 5 ft. In addition, to predict the spatiotemporal expansion of the reworked deposit, a 3D seismic interpretation was conducted. The result of the well-well correlation reveals that the depositional process and the stacking pattern of the Cenomanian-Turonian shoals around eastern Abu Dhabi are well consistent with the depositional model that proposed by Razin et al., 2010, and the reworked deposits are developed around the distal environment. 3D seismic interpretation represents that these reworked sediments were input from the north-west side and spread to the south-east like as a submarine-fan. Considering the core observation result, cohesive debris flow deposits are dominated at the depositional up-dip side and dilute flow deposits are dominated in the depositional down-dip side. In addition, an obvious erosional surface can be recognized in seismic sections and it truncates the top shoal sediments. The result of both, a combination of localized up-rift and global eustatic sea level fall in the early-middle Turonian triggered the regional erosion which is recognized as the middle Turonian unconformity. The result of this study suggests that the shoal sediments were eroded and reworked to a more distal environment at the early-middle Turonian.
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Toloi, Marcella Canato, Thiago Ivan Vilchez Santillan, Kassia Braga Canzian, Isabela de Almeida Stella, Déborah Inayara Mendes Tenorio de Albuquerque, Taina Fatima Ramos Gonçalves i Herval Ribeiro Soares Neto. "Lower limb weakness: a challenge diagnosis". W XIV Congresso Paulista de Neurologia. Zeppelini Editorial e Comunicação, 2023. http://dx.doi.org/10.5327/1516-3180.141s1.713.
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A 46-year-old male patient started a condition of lower back pain radiating to the lower limbs in 2016. He underwent lumbar arthrodesis surgery between L5-S1 due to a herniated disc and reports that after the surgery, his clinical condition improved, remaining asymptomatic over four years. In 2020, he started to experience hypoesthesia in the calf and dorsal region of his right foot, with progressive worsening throughout the year, with a tripping sensation associated with a numbness and decreased distal strength of the right lower limb, with subsequent difficulty in climbing stairs over the next year. He continued to follow up with orthopedics and began following up with neurosurgery, which did not identify a clear etiology for his clinical condition. In 2021, the patient was already complaining of worsening weakness in the right foot with foot drop and a decrease in trophism of the entire right lower limb. The patient denies sphincter alterations or sexual dysfunction throughout the course of the disease. In March 2022, the patient began using unilateral support due to falls and returned to the neurosurgery outpatient clinic with a referral to clinical neurology. He denies recent worsening of strength. In October 2022, during a consultation with neurology, treatment with prednisone 20 mg/day was started without improvement in the clinical condition, and during a followup visit in January 2023, the need for diagnostic elucidation led to the patient being hospitalized at the Hospital do Servidor Publico Estadual for etiological investigation. On neurological examination, the patient presented alterations in the right lower limb, with grade IV proximal strength and II distal strength of this limb, including plantar and dorsiflexion flexion, associated with global hypotrophy of the limb up to the gluteal region, with normoactive deep tendon reflexes and plantar reflex in flexion. With regard to sensitivity, the patient presented hypoesthesia in the lateral region of the right leg and the sole of the right foot, worse distally in the topography of L4 L5-S1, with preserved artresthesia and palesthesia. No other alterations were present on the somatic examination, except for a right-hand scraping gait with a component of proximal weakness. In complementary investigation, no signs of spinal cord compression lesions were found on magnetic resonance imaging, no inflammatory signs were found in cerebrospinal fluid results, and no systemic involvement was found in chest and abdominal computed tomography exams, except for asymptomatic hepatosplenomegaly. Electroneuromyography (ENMG) revealed motor impairment with preserved sensory parameters, leading to a preganglionic pattern of impairment, in addition to recent denervation findings with fibrillations and positive sharp waves, which were also visualized in the contralateral lower limb in a lesser degree of involvement. Despite the hypoesthesia on the physical exam, no sensory alterations were demonstrated on ENMG, which may be justified by the previous spinal surgery. Due to findings on the neurological and complementary exams, with impairment only in the right lower limb, substantial atrophy, and weakness with ENMG findings, the hypothesis of flail leg syndrome, a variant of amyotrophic lateral sclerosis (ALS) with lower limbs onset, was raised. Flail leg syndrome is a rare variant (6%) of atypical forms of amyotrophic lateral sclerosis, predominantly affecting males between 55–65 years of age. Its manifestation includes asymmetric and progressive distal onset weakness and wasting with restricted involvement of the lower limbs for at least 12 to 24 months. ENMG shows fibrillations and positive sharp waves, with little evidence of fasciculations. It has a significantly better prognosis in terms of median and 5-year survival rates compared to bulbar and limb onset ALS, due to its slower progression to other locations. FLS ir rare, but it should be considered as an alternative diagnosis when there is limited impairment of lower limbs after at least one year of clinical observation.
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Magalhães, Paolla Giovanna Rossito de, Marina Buldrini Filogonio Seraidarian, Bernardo Tardin Caetano, Barbara Oliveira Paixão, Tassila Oliveira Nery de Freitas, Daniel Vasconcelos de Pinho Tavares, Gabriella Braga da Cunha Silva i in. "Case Report: Reversible Cerebral Vasoconstriction Syndrome in a cancer patient using ZoladexTM". W XIII Congresso Paulista de Neurologia. Zeppelini Editorial e Comunicação, 2021. http://dx.doi.org/10.5327/1516-3180.142.
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Context: The Reversible Cerebral Vasoconstriction Syndrome (SVCR) is characterized by rapid and reversible vasoconstriction and segmental dilation of cerebral arteries, usually preceded by thunderclap headache. The involvement of second and third-order branches of the cerebral arteries is the most commom finding in a cerebral angiography. This report is about a SVCR case with atypical involvement, significantly compromising extracranial vessels and raising the hypothesis of association between the use of hormonal blocker gosserelin acetate (ZoladexTM) with SVCR. Case report: Female, 39 years old, with breast cancer and bone metastasis using ZoladexTM that presented with a sudden headache and vomiting, progressing to global afasia and paresis in the right upper limb. Magnetic resonance identified hyperacute intraparenchymal hematoma in left frontoparietal convexity and subarachnoid haemorrhage. Cerebral angiography showed irregularities in the distal branches (M3 and M4) of the middle cerebral arteries, as well as in the superficial temporal artery, characterized by focal strictures. Conclusion: Studies show that hormonal fluctuations in the postpartum period can trigger SVCR due to the drop in estrogen and progesterone (gonadotropins). During postpartum, the stimulus of breastfeeding increases prolactin levels leading to GnRH suppression, which decreases the level of gonadotropins. ZoladexTM is a GnRH analogue and its chronic administration results in suppression of these hormones - similar to the postpartum period. Therefore, there may be an association of hormonal blockers with SVCR.
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Silva, Evelliny Gomes, Arthur Cesário de Holanda, Vitor Maia Arca, Daniel Alves Oliveira, Anna Paula Paranhos Miranda Covaleski, Letícia Klabinske Marques Monteiro i Eduardo Sousa de Melo. "“Wake-up” onset of pharyngocervicobrachial variant of Guillain-Barré syndrome: a case report". W XIV Congresso Paulista de Neurologia. Zeppelini Editorial e Comunicação, 2023. http://dx.doi.org/10.5327/1516-3180.141s1.565.
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Guillain-Barré syndrome (GBS) is the most common cause of acute flaccid paralysis in the world. There are variants. Of the cranial forms, the following stand out: the classic form, facial diplegia with distal paresthesias, pharyngo-cervico-brachial form, polyneuritis cranialis, Miller-Fisher syndrome and Bickerstaff encephalitis. This study aimed to report the case of a 73-year-old male patient, diabetic, former smoker and alcoholic, who presented at the Neurology outpatient clinic of a tertiary hospital in Pernambuco, after emergency care and 19 days of symptoms, reported as sudden cervical weakness, dysarthrophonia, dysphagia and weakness in the right hemiface, three weeks after vaccination (influenza and triple viral) and flu syndrome. He had dyspnea since the onset of the condition, with no progression or fluctuating complaints. The neurological examination showed multiple cranial nerve syndrome (right peripheral pattern facial palsy, reduced elevation of the soft palate and cervical extension paresis) associated with global hypo/arreflexia. Complementary exams showed, in addition to leukocytosis and signs of bronchopathy on chest tomography, cerebrospinal fluid with 00 cells and 48 proteins and electroneuromyography with predominantly sensitive axonal polyneuropathy, decrease in bilateral facial motor amplitude, needle with myopathic pattern. Brain magnetic resonance imaging without alterations. With the possibility of cranial polyradiculoneuritis and a history of dyspnea raised, he was admitted to the intensive care unit to monitor his breathing pattern and dysautonomia. He received antibiotic therapy for seven days due to pneumonia and pulse therapy with IVIG (2 g/kg for five days). He maintained progressive improvement of symptoms. He was discharged with a multidisciplinary outpatient follow-up scheduled. It is concluded, therefore, that the recognition of GBS and variant forms is necessary.
Raporty organizacyjne na temat "Global and distal suppressors"
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Chejanovsky, Nor, i Suzanne M. Thiem. Isolation of Baculoviruses with Expanded Spectrum of Action against Lepidopteran Pests. United States Department of Agriculture, grudzień 2002. http://dx.doi.org/10.32747/2002.7586457.bard.
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Our long-term goal is to learn to control (expand and restrict) the host range of baculoviruses. In this project our aim was to expand the host range of the prototype baculovirus Autographa cali/arnica nuclear polyhedrosis virus (AcMNPV) towards American and Israeli pests. To achieve this objective we studied AcMNPV infection in the non-permissive hosts L. dispar and s. littoralis (Ld652Y and SL2 cells, respectively) as a model system and the major barriers to viral replication. We isolated recombinant baculoviruses with expanded infectivity towards L. dispar and S. littoralis and tested their infectivity towards other Lepidopteran pests. The restricted host range displayed by baculoviruses constitutes an obstacle to their further implementation in the control of diverse Lepidopteran pests, increasing the development costs. Our work points out that cellular defenses are major role blocks to AcMNPV replication in non- and semi-permissive hosts. Therefore a major determinant ofbaculovirus host range is the ability of the virus to effectively counter cellular defenses of host cells. This is exemplified by our findings showing tliat expressing the viral gene Ldhrf-l overcomes global translation arrest in AcMNPV -infected Ld652Y cells. Our data suggests that Ld652Y cells have two anti-viral defense pathways, because they are subject to global translation arrest when infected with AcMNPV carrying a baculovirus apoptotic suppressor (e.g., wild type AcMNPV carryingp35, or recombinant AcMNPV carrying Opiap, Cpiap. or p49 genes) but apoptose when infected with AcMNPV-Iacking a functional apoptotic suppressor. We have yet to elucidate how hrf-l precludes the translation arrest mechanism(s) in AcMNPV-infected Ld652Y cells. Ribosomal profiles of AcMNPV infected Ld652Y cells suggested that translation initiation is a major control point, but we were unable to rule-out a contribution from a block in translation elongation. Phosphorylation of eIF-2a did not appear to playa role in AcMNPV -induced translation arrest. Mutagenesis studies ofhrf-l suggest that a highly acidic domain plays a role in precluding translation arrest. Our findings indicate that translation arrest may be linked to apoptosis either through common sensors of virus infection or as a consequence of late events in the virus life-cycle that occur only if apoptosis is suppressed. ~ AcMNPV replicates poorly in SL2 cells and induces apoptosis. Our studies in AcMNPV - infected SL2ceils led us to conclude that the steady-state levels of lEI (product of the iel gene, major AcMNPV -transactivator and multifunctional protein) relative to those of the immediate early viral protein lEO, playa critical role in regulating the viral infection. By increasing the IEl\IEO ratio we achieved AcMNPV replication in S. littoralis and we were able to isolate recombinant AcMNPV s that replicated efficiently in S. lifforalis cells and larvae. Our data that indicated that AcMNPV - infection may be regulated by an interaction between IE 1 and lED (of previously unknown function). Indeed, we showed that IE 1 associates with lED by using protein "pull down" and immunoprecipitation approaches High steady state levels of "functional" IE 1 resulted in increased expression of the apoptosis suppressor p35 facilitating AcMNPV -replication in SL2 cells. Finally, we determined that lED accelerates the viral infection in AcMNPV -permissive cells. Our results show that expressing viral genes that are able to overcome the insect-pest defense system enable to expand baculovirus host range. Scientifically, this project highlights the need to further study the anti-viral defenses of invertebrates not only to maximi~e the possibilities for manipulating baculovirus genomes, but to better understand the evolutionary underpinnings of the immune systems of vertebrates towards virus infection.
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Breiman, Adina, Jan Dvorak, Abraham Korol i Eduard Akhunov. Population Genomics and Association Mapping of Disease Resistance Genes in Israeli Populations of Wild Relatives of Wheat, Triticum dicoccoides and Aegilops speltoides. United States Department of Agriculture, grudzień 2011. http://dx.doi.org/10.32747/2011.7697121.bard.
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Wheat is the most widely grown crop on earth, together with rice it is second to maize in total global tonnage. One of the emerging threats to wheat is stripe (yellow) rust, especially in North Africa, West and Central Asia and North America. The most efficient way to control plant diseases is to introduce disease resistant genes. However, the pathogens can overcome rapidly the effectiveness of these genes when they are wildly used. Therefore, there is a constant need to find new resistance genes to replace the non-effective genes. The resistance gene pool in the cultivated wheat is depleted and there is a need to find new genes in the wild relative of wheat. Wild emmer (Triticum dicoccoides) the progenitor of the cultivated wheat can serve as valuable gene pool for breeding for disease resistance. Transferring of novel genes into elite cultivars is highly facilitated by the availability of information of their chromosomal location. Therefore, our goals in this study was to find stripe rust resistant and susceptible genotypes in Israeli T. dicoccoides population, genotype them using state of the art genotyping methods and to find association between genetic markers and stripe rust resistance. We have screened 129 accessions from our collection of wild emmer wheat for resistance to three isolates of stripe rust. About 30% of the accessions were resistant to one or more isolates, 50% susceptible, and the rest displayed intermediate response. The accessions were genotyped with Illumina'sInfinium assay which consists of 9K single nucleotide polymorphism (SNP) markers. About 13% (1179) of the SNPs were polymorphic in the wild emmer population. Cluster analysis based on SNP diversity has shown that there are two main groups in the wild population. A big cluster probably belongs to the Horanum ssp. and a small cluster of the Judaicum ssp. In order to avoid population structure bias, the Judaicum spp. was removed from the association analysis. In the remaining group of genotypes, linkage disequilibrium (LD) measured along the chromosomes decayed rapidly within one centimorgan. This is the first time when such analysis is conducted on a genome wide level in wild emmer. Such a rapid decay in LD level, quite unexpected for a selfer, was not observed in cultivated wheat collection. It indicates that wild emmer populations are highly suitable for association studies yielding a better resolution than association studies in cultivated wheat or genetic mapping in bi-parental populations. Significant association was found between an SNP marker located in the distal region of chromosome arm 1BL and resistance to one of the isolates. This region is not known in the literature to bear a stripe rust resistance gene. Therefore, there may be a new stripe rust resistance gene in this locus. With the current fast increase of wheat genome sequence data, genome wide association analysis becomes a feasible task and efficient strategy for searching novel genes in wild emmer wheat. In this study, we have shown that the wild emmer gene pool is a valuable source for new stripe rust resistance genes that can protect the cultivated wheat.