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1.
Proc Natl Acad Sci U S A ; 116(39): 19464-19473, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31488723

RESUMO

Histone H3 lysine 9 methylation (H3K9me) is essential for cellular homeostasis; however, its contribution to development is not well established. Here, we demonstrate that the H3K9me2 demethylase PHF2 is essential for neural progenitor proliferation in vitro and for early neurogenesis in the chicken spinal cord. Using genome-wide analyses and biochemical assays we show that PHF2 controls the expression of critical cell cycle progression genes, particularly those related to DNA replication, by keeping low levels of H3K9me3 at promoters. Accordingly, PHF2 depletion induces R-loop accumulation that leads to extensive DNA damage and cell cycle arrest. These data reveal a role of PHF2 as a guarantor of genome stability that allows proper expansion of neural progenitors during development.

2.
Sci Rep ; 9(1): 9538, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31267011

RESUMO

Compensated pathogenic deviations (CPDs) are sequence variants that are pathogenic in humans but neutral in other species. In recent years, our molecular understanding of CPDs has advanced substantially. For example, it is known that their impact on human proteins is generally milder than that of average pathogenic mutations and that their impact is suppressed in non-human carriers by compensatory mutations. However, prior studies have ignored the evolutionarily relevant relationship between molecular impact and organismal phenotype. Here, we explore this topic using CPDs from FVIII and FIX and data concerning carriers' hemophilia severity. We find that, regardless of their molecular impact, these mutations can be associated with either mild or severe disease phenotypes. Only a weak relationship is found between protein stability changes and severity. We also characterize the population variability of hemostasis proteins, which constitute the genetic background of FVIII and FIX, using data from the 1000 Genome project. We observe that genetic background can vary substantially between individuals in terms of both the amount and nature of genetic variants. Finally, we discuss how these results highlight the need to include new terms in present models of protein evolution to explain the origin of CPDs.

3.
Hum Mutat ; 40(9): 1546-1556, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31294896

RESUMO

Testing for variation in BRCA1 and BRCA2 (commonly referred to as BRCA1/2), has emerged as a standard clinical practice and is helping countless women better understand and manage their heritable risk of breast and ovarian cancer. Yet the increased rate of BRCA1/2 testing has led to an increasing number of Variants of Uncertain Significance (VUS), and the rate of VUS discovery currently outpaces the rate of clinical variant interpretation. Computational prediction is a key component of the variant interpretation pipeline. In the CAGI5 ENIGMA Challenge, six prediction teams submitted predictions on 326 newly-interpreted variants from the ENIGMA Consortium. By evaluating these predictions against the new interpretations, we have gained a number of insights on the state of the art of variant prediction and specific steps to further advance this state of the art.

4.
Hum Mutat ; 40(9): 1593-1611, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31112341

RESUMO

BRCA1 and BRCA2 (BRCA1/2) germline variants disrupting the DNA protective role of these genes increase the risk of hereditary breast and ovarian cancers. Correct identification of these variants then becomes clinically relevant, because it may increase the survival rates of the carriers. Unfortunately, we are still unable to systematically predict the impact of BRCA1/2 variants. In this article, we present a family of in silico predictors that address this problem, using a gene-specific approach. For each protein, we have developed two tools, aimed at predicting the impact of a variant at two different levels: Functional and clinical. Testing their performance in different datasets shows that specific information compensates the small number of predictive features and the reduced training sets employed to develop our models. When applied to the variants of the BRCA1/2 (ENIGMA) challenge in the fifth Critical Assessment of Genome Interpretation (CAGI 5) we find that these methods, particularly those predicting the functional impact of variants, have a good performance, identifying the large compositional bias towards neutral variants in the CAGI sample. This performance is further improved when incorporating to our prediction protocol estimates of the impact on splicing of the target variant.

5.
Int J Mol Sci ; 20(7)2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30934865

RESUMO

One of the known potential effects of disease-causing amino acid substitutions in proteins is to modulate protein-protein interactions (PPIs). To interpret such variants at the molecular level and to obtain useful information for prediction purposes, it is important to determine whether they are located at protein-protein interfaces, which are composed of two main regions, core and rim, with different evolutionary conservation and physicochemical properties. Here we have performed a structural, energetics and computational analysis of interactions between proteins hosting mutations related to diseases detected in newborn screening. Interface residues were classified as core or rim, showing that the core residues contribute the most to the binding free energy of the PPI. Disease-causing variants are more likely to occur at the interface core region rather than at the interface rim (p < 0.0001). In contrast, neutral variants are more often found at the interface rim or at the non-interacting surface rather than at the interface core region. We also found that arginine, tryptophan, and tyrosine are over-represented among mutated residues leading to disease. These results can enhance our understanding of disease at molecular level and thus contribute towards personalized medicine by helping clinicians to provide adequate diagnosis and treatments.


Assuntos
Biologia Computacional/métodos , Doença/genética , Mutação/genética , Proteínas/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Humanos , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/genética , Simulação de Acoplamento Molecular , Proteínas Mutantes/química , Triagem Neonatal , Ligação Proteica , Subunidades Proteicas/química , Globinas beta/química
6.
FASEB J ; 33(6): 7168-7179, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30848931

RESUMO

Polymerase γ catalytic subunit (POLG) gene encodes the enzyme responsible for mitochondrial DNA (mtDNA) synthesis. Mutations affecting POLG are the most prevalent cause of mitochondrial disease because of defective mtDNA replication and lead to a wide spectrum of clinical phenotypes characterized by mtDNA deletions or depletion. Enhancing mitochondrial deoxyribonucleoside triphosphate (dNTP) synthesis effectively rescues mtDNA depletion in different models of defective mtDNA maintenance due to dNTP insufficiency. In this study, we studied mtDNA copy number recovery rates following ethidium bromide-forced depletion in quiescent fibroblasts from patients harboring mutations in different domains of POLG. Whereas control cells spontaneously recovered initial mtDNA levels, POLG-deficient cells experienced a more severe depletion and could not repopulate mtDNA. However, activation of deoxyribonucleoside (dN) salvage by supplementation with dNs plus erythro-9-(2-hydroxy-3-nonyl) adenine (inhibitor of deoxyadenosine degradation) led to increased mitochondrial dNTP pools and promoted mtDNA repopulation in all tested POLG-mutant cells independently of their specific genetic defect. The treatment did not compromise POLG fidelity because no increase in multiple deletions or point mutations was detected. Our study suggests that physiologic dNTP concentration limits the mtDNA replication rate. We thus propose that increasing mitochondrial dNTP availability could be of therapeutic interest for POLG deficiency and other conditions in which mtDNA maintenance is challenged.-Blázquez-Bermejo, C., Carreño-Gago, L., Molina-Granada, D., Aguirre, J., Ramón, J., Torres-Torronteras, J., Cabrera-Pérez, R., Martín, M. Á., Domínguez-González, C., de la Cruz, X., Lombès, A., García-Arumí, E., Martí, R., Cámara, Y. Increased dNTP pools rescue mtDNA depletion in human POLG-deficient fibroblasts.

7.
Neuropsychopharmacology ; 44(5): 890-897, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30568281

RESUMO

Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders in childhood and persists into adulthood in 40-65% of cases. Given the polygenic and heterogeneous architecture of the disorder and the limited overlap between genetic studies, there is a growing interest in epigenetic mechanisms, such as microRNAs, that modulate gene expression and may contribute to the phenotype. We attempted to clarify the role of microRNAs in ADHD at a molecular level through the first genome-wide integrative study of microRNA and mRNA profiles in peripheral blood mononuclear cells of medication-naive individuals with ADHD and healthy controls. We identified 79 microRNAs showing aberrant expression levels in 56 ADHD cases and 69 controls, with three of them, miR-26b-5p, miR-185-5p, and miR-191-5p, being highly predictive for diagnostic status in an independent dataset of 44 ADHD cases and 46 controls. Investigation of downstream microRNA-mediated mechanisms underlying the disorder, which was focused on differentially expressed, experimentally validated target genes of the three highly predictive microRNAs, provided evidence for aberrant myo-inositol signaling in ADHD and indicated an enrichment of genes involved in neurological disease and psychological disorders. Our comprehensive study design reveals novel microRNA-mRNA expression profiles aberrant in ADHD, provides novel insights into microRNA-mediated mechanisms contributing to the disorder, and highlights promising candidate peripheral biomarkers.

8.
Orphanet J Rare Dis ; 13(1): 125, 2018 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-30041674

RESUMO

BACKGROUND: Cellular cobalamin defects are a locus and allelic heterogeneous disorder. The gold standard for coming to genetic diagnoses of cobalamin defects has for some time been gene-by-gene Sanger sequencing of individual DNA fragments. Enzymatic and cellular methods are employed before such sequencing to help in the selection of the gene defects to be sought, but this is time-consuming and laborious. Furthermore some cases remain undiagnosed because no biochemical methods have been available to test for cobalamin absorption and transport defects. RESULTS: This paper reports the use of massive parallel sequencing of DNA (exome analysis) for the accurate and rapid genetic diagnosis of cobalamin-related defects in a cohort of affected patients. The method was first validated in an initial cohort with different cobalamin defects. Mendelian segregation, the frequency of mutations, and the comprehensive structural and functional analysis of gene variants, identified disease-causing mutations in 12 genes involved in the absorption and synthesis of active cofactors of vitamin B12 (22 cases), and in the non-cobalamin metabolism-related genes ACSF3 (in four biochemically misdiagnosed patients) and SUCLA2 (in one patient with an unusual presentation). We have identified thirteen new variants all classified as pathogenic according to the ACGM recommendation but four were classified as variant likely pathogenic in MUT and SUCLA2. Functional and structural analysis provided evidences to classify them as pathogenic variants. CONCLUSIONS: The present findings suggest that the technology used is sufficiently sensitive and specific, and the results it provides sufficiently reproducible, to recommend its use as a second-tier test after the biochemical detection of cobalamin disorder markers in the first days of life. However, for accurate diagnoses to be made, biochemical and functional tests that allow comprehensive clinical phenotyping are also needed.

10.
Nucleic Acids Res ; 46(7): 3351-3365, 2018 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-29438503

RESUMO

During neurogenesis, dynamic developmental cues, transcription factors and histone modifying enzymes regulate the gene expression programs by modulating the activity of neural-specific enhancers. How transient developmental signals coordinate transcription factor recruitment to enhancers and to which extent chromatin modifiers contribute to enhancer activity is starting to be uncovered. Here, we take advantage of neural stem cells as a model to unravel the mechanisms underlying neural enhancer activation in response to the TGFß signaling. Genome-wide experiments demonstrate that the proneural factor ASCL1 assists SMAD3 in the binding to a subset of enhancers. Once located at the enhancers, SMAD3 recruits the histone demethylase JMJD3 and the remodeling factor CHD8, creating the appropriate chromatin landscape to allow enhancer transcription and posterior gene activation. Finally, to analyze the phenotypical traits owed to cis-regulatory regions, we use CRISPR-Cas9 technology to demonstrate that the TGFß-responsive Neurog2 enhancer is essential for proper neuronal polarization.

11.
J Clin Immunol ; 37(8): 781-789, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28942469

RESUMO

The complement system is an important effector arm of innate immunity and plays a crucial role in the defense against common pathogens. But effective defense and maintenance of homeostasis requires a careful balance between complement activation and regulation. Factor I (FI) is one of the most important regulators of the complement system. Complete FI deficiency is a rare autosomal recessive disorder typically resulting in severe, recurrent infection by encapsulated bacteria. In the present study, we describe two patients from unrelated families with complete FI deficiency diagnosed at very different ages: Patient 1 is a 60-year-old man who had experienced several severe infections (pneumonia, meningitis, sepsis) since childhood, one of which caused significant and permanent neurologic sequelae. In contrast, patient 2 was diagnosed at the age of 4 years after a single infectious episode (otitis media) and through detection of a flat beta2 peak on serum protein electrophoresis. This early diagnosis of FI deficiency enabled prompt implementation of a therapeutic intervention consisting of vaccination with encapsulated bacteria and prophylactic antibiotics. The two patients had novel homozygous mutations in the CFI gene (p.Gly162Asp and p.His380Arg) that disrupted protein function. Interestingly, p.His380Arg is the first mutation described affecting a residue of the highly conserved FI catalytic triad (His380, Asp429, and Ser525). This study illustrates the importance of early versus late diagnosis of FI deficiency and, in general, highlights the clinical relevance of prompt detection of complement system deficiencies.


Assuntos
Vacinas Bacterianas/imunologia , Complemento C3/deficiência , Fator I do Complemento/genética , Doenças Genéticas Inatas/diagnóstico , Infecção/diagnóstico , Meningites Bacterianas/diagnóstico , Mutação/genética , Antibioticoprofilaxia , Pré-Escolar , Complemento C3/genética , Diagnóstico Tardio , Diagnóstico Precoce , Família , Doenças Genéticas Inatas/genética , Homozigoto , Humanos , Imunidade Inata , Infecção/genética , Masculino , Meningites Bacterianas/genética , Meningites Bacterianas/prevenção & controle , Pessoa de Meia-Idade , Linhagem , Vacinação
12.
BMC Genomics ; 18(Suppl 5): 569, 2017 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-28812538

RESUMO

BACKGROUND: Strict guidelines delimit the use of computational information in the clinical setting, due to the still moderate accuracy of in silico tools. These guidelines indicate that several tools should always be used and that full coincidence between them is required if we want to consider their results as supporting evidence in medical decision processes. Application of this simple rule certainly decreases the error rate of in silico pathogenicity assignments. However, when predictors disagree this rule results in the rejection of potentially valuable information for a number of variants. In this work, we focus on these variants of the protein sequence and develop specific predictors to help improve the success rate of their annotation. RESULTS: We have used a set of 59,442 protein sequence variants (15,723 pathological and 43,719 neutral) from 228 proteins to identify those cases for which pathogenicity predictors disagree. We have repeated this process for all the possible combinations of five known methods (SIFT, PolyPhen-2, PON-P2, CADD and MutationTaster2). For each resulting subset we have trained a specific pathogenicity predictor. We find that these specific predictors are able to discriminate between neutral and pathogenic variants, with a success rate different from random. They tend to outperform the constitutive methods but this trend decreases as the performance of the constitutive predictor improves (e.g. with PON-P2 and PolyPhen-2). We also find that specific methods outperform standard consensus methods (Condel and CAROL). CONCLUSION: Focusing development efforts on the case of variants for which known methods disagree we may obtain pathogenicity predictors with improved performances. Although we have not yet reached the success rate that allows the use of this computational evidence in a clinical setting, the simplicity of the approach indicates that more advanced methods may reach this goal in a close future.


Assuntos
Biologia Computacional/métodos , Simulação por Computador , Variação Genética , Análise de Sequência de Proteína/métodos , Virulência/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Proteínas/genética
13.
Int J Cancer ; 141(7): 1365-1380, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28577310

RESUMO

In a proportion of patients presenting mismatch repair (MMR)-deficient tumors, no germline MMR mutations are identified, the so-called Lynch-like syndrome (LLS). Recently, MMR-deficient tumors have been associated with germline mutations in POLE and MUTYH or double somatic MMR events. Our aim was to elucidate the molecular basis of MSH2-deficient LS-suspected cases using a comprehensive analysis of colorectal cancer (CRC)-associated genes at germline and somatic level. Fifty-eight probands harboring MSH2-deficient tumors were included. Germline mutational analysis of MSH2 (including EPCAM deletions) and MSH6 was performed. Pathogenicity of MSH2 variants was assessed by RNA analysis and multifactorial likelihood calculations. MSH2 cDNA and methylation of MSH2 and MSH6 promoters were studied. Matched blood and tumor DNA were analyzed using a customized next generation sequencing panel. Thirty-five individuals were carriers of pathogenic or probably pathogenic variants in MSH2 and EPCAM. Five patients harbored 4 different MSH2 variants of unknown significance (VUS) and one had 2 novel MSH6 promoter VUS. Pathogenicity assessment allowed the reclassification of the 4 MSH2 VUS and 6 probably pathogenic variants as pathogenic mutations, enabling a total of 40 LS diagnostics. Predicted pathogenic germline variants in BUB1, SETD2, FAN1 and MUTYH were identified in 5 cases. Three patients had double somatic hits in MSH2 or MSH6, and another 2 had somatic alterations in other MMR genes and/or proofreading polymerases. In conclusion, our comprehensive strategy combining germline and somatic mutational status of CRC-associated genes by means of a subexome panel allows the elucidation of up to 86% of MSH2-deficient suspected LS tumors.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Proteínas de Ligação a DNA/genética , Mutação em Linhagem Germinativa , Proteína 2 Homóloga a MutS/deficiência , Proteína 2 Homóloga a MutS/genética , DNA Glicosilases/genética , Metilação de DNA , Análise Mutacional de DNA , Proteínas de Ligação a DNA/deficiência , Molécula de Adesão da Célula Epitelial/genética , Exodesoxirribonucleases/genética , Sequenciamento de Nucleotídeos em Larga Escala , Histona-Lisina N-Metiltransferase/genética , Humanos , Perda de Heterozigosidade , Regiões Promotoras Genéticas/genética , Proteínas Serina-Treonina Quinases/genética
14.
Fam Cancer ; 16(4): 501-507, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28365877

RESUMO

The clinical spectrum of germline mismatch repair (MMR) gene variants continues increasing, encompassing Lynch syndrome, Constitutional MMR Deficiency (CMMRD), and the recently reported MSH3-associated polyposis. Genetic diagnosis of these hereditary cancer syndromes is often hampered by the presence of variants of unknown significance (VUS) and overlapping phenotypes. Two PMS2 VUS, c.2149G>A (p.V717M) and c.2444C>T (p.S815L), were identified in trans in one individual diagnosed with early-onset colorectal cancer (CRC) who belonged to a family fulfilling clinical criteria for hereditary cancer. Clinico-pathological data, multifactorial likelihood calculations and functional analyses were used to refine their clinical significance. Likelihood analysis based on cosegregation and tumor data classified the c.2444C>T variant as pathogenic, which was supported by impaired MMR activity associated with diminished protein expression in functional assays. Conversely, the c.2149G>A variant displayed MMR proficiency and protein stability. These results, in addition to the conserved PMS2 expression in normal tissues and the absence of germline microsatellite instability (gMSI) in the biallelic carrier ruled out a CMMRD diagnosis. The use of comprehensive strategies, including functional and clinico-pathological information, is mandatory to improve the clinical interpretation of naturally occurring MMR variants. This is critical for appropriate clinical management of cancer syndromes associated to MMR gene mutations.


Assuntos
Neoplasias Colorretais/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Mutação de Sentido Incorreto , Idade de Início , Estudos de Casos e Controles , Reparo de Erro de Pareamento de DNA , Feminino , Frequência do Gene , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Humanos , Masculino , Instabilidade de Microssatélites , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Linhagem
15.
Nucleic Acids Res ; 45(W1): W222-W228, 2017 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-28453649

RESUMO

We present here a full update of the PMut predictor, active since 2005 and with a large acceptance in the field of predicting Mendelian pathological mutations. PMut internal engine has been renewed, and converted into a fully featured standalone training and prediction engine that not only powers PMut web portal, but that can generate custom predictors with alternative training sets or validation schemas. PMut Web portal allows the user to perform pathology predictions, to access a complete repository of pre-calculated predictions, and to generate and validate new predictors. The default predictor performs with good quality scores (MCC values of 0.61 on 10-fold cross validation, and 0.42 on a blind test with SwissVar 2016 mutations). The PMut portal is freely accessible at http://mmb.irbbarcelona.org/PMut. A complete help and tutorial is available at http://mmb.irbbarcelona.org/PMut/help.

16.
Nucleic Acids Res ; 45(7): 3800-3811, 2017 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-28100697

RESUMO

A precise immune response is essential for cellular homeostasis and animal survival. The paramount importance of its control is reflected by the fact that its non-specific activation leads to inflammatory events that ultimately contribute to the appearance of many chronic diseases. However, the molecular mechanisms preventing non-specific activation and allowing a quick response upon signal activation are not yet fully understood. In this paper we uncover a new function of PHF8 blocking signal independent activation of immune gene promoters. Affinity purifications coupled with mass spectrometry analysis identified SIN3A and HDAC1 corepressors as new PHF8 interacting partners. Further molecular analysis demonstrated that prior to interferon gamma (IFNγ) stimulation, PHF8 is bound to a subset of IFNγ-responsive promoters. Through the association with HDAC1 and SIN3A, PHF8 keeps the promoters in a silent state, maintaining low levels of H4K20me1. Upon IFNγ treatment, PHF8 is phosphorylated by ERK2 and evicted from the promoters, correlating with an increase in H4K20me1 and transcriptional activation. Our data strongly indicate that in addition to its well-characterized function as a coactivator, PHF8 safeguards transcription to allow an accurate immune response.


Assuntos
Histona Desmetilases/metabolismo , Interferon gama/farmacologia , Fatores de Transcrição/metabolismo , Ativação Transcricional , Linhagem Celular , Cromatina/metabolismo , Inativação Gênica , Histona Desacetilase 1/metabolismo , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Regiões Promotoras Genéticas , Proteínas Repressoras/metabolismo
17.
Biochim Biophys Acta Mol Basis Dis ; 1863(1): 182-187, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27613247

RESUMO

Leber's hereditary optic neuropathy (LHON) is a mitochondrial genetic disease characterized by bilateral acute or subacute progressive central visual loss. Most cases of LHON syndrome are caused by point mutations in the MT-ND1, MT-ND4, and MT-ND6 genes. Here, we report a novel homoplasmic mutation in the MT-ND1 gene (m.3634A>G, p.Ser110Gly) in a patient with the classical clinical features of LHON syndrome. Several observations support the idea that the mutation is pathogenic and involved in the clinical phenotype of the patient: 1) The mutation affected a highly conserved amino acid, 2) A pathogenic mutation in the same amino acid (m.3635G>A, p.Ser110Asn) was previously reported in a patient with LHON syndrome, 3) The mutation is not recorded in the Mitomap or Human Mitochondrial Genome Database, 4) In silico predictors classified the mutation as "probably damaging", and 5) Cybrids carrying the mutation showed decreased Complex I enzyme activity, lower cell proliferation, and decreased mitochondrial membrane potential relative to control cybrids.

18.
Eur J Oral Sci ; 124(6): 559-565, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27748971

RESUMO

Patients with cardiac implantable electrical devices should take special precautions when exposed to electromagnetic fields. Proximity to equipment used in clinical dentistry may cause interference. This study evaluated in vitro the risks associated with different types/makes of cardiac devices and types of dental equipment. Six electronic dental tools were tested on three implantable cardioverter defibrillators and three pacemakers made by different manufacturers. Overall, the risk of interference with the pacemakers was 37% lower than with the implantable cardioverter defibrillators. Regarding the types/makes of cardiac devices analysed, that from Boston Scientific had a five-fold greater risk of interference than did that from Biotronik [prevalence ratio (PR) = 5.58]; there was no difference between that from Biotronik and that from Medtronic. Among the dental equipment, the electric pulp tester had the greatest risk of inducing interference and therefore this device was used as the benchmark. The electronic apex locator (PR = 0.29), Periotest M (PR = 0.47), and the ultrasonic dental scaler (PR = 0.59) were less likely to induce interference than the electric pulp tester. The risk was lowest with the electronic apex locator. Pacemakers presented a lower risk of light to moderate interference (PR = 0.63). However, the risk of severe electromagnetic interference was 3.5 times higher with pacemakers than with implantable cardioverter defibrillators (PR = 3.47).


Assuntos
Equipamentos Odontológicos , Campos Eletromagnéticos , Marca-Passo Artificial , Desfibriladores Implantáveis , Eletricidade , Falha de Equipamento , Humanos
19.
Hum Mutat ; 37(10): 1013-24, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27397615

RESUMO

The usage of next-generation sequencing with biomedical/clinical purposes has fuelled the demand for tools that assess the functional impact of sequence variants. For single amino acid variants, general methods (GM), based on biophysics/evolutionary principles and trained by pooling variants from many proteins, are already available. Until now, their accuracy range (∼80%) has limited their usage in clinical applications. In parallel, a series of studies indicate that protein-specific predictors (PSP), using only information from the protein of interest, could frequently surpass the performance of GM. However, two reasons suggest that this may not always be the case: the existence of a performance threshold affecting both GM and PSP, and the effect of training data scarcity. Here, we characterize the relationship between the two approaches deriving 82 PSP and comparing them with several GM (PolyPhen-2, SIFT, PON-P2, MutationTaster2, CADD). We find a complementary relationship between PSP and GM, with no approach always outperforming the other. However, the relationship varies between two limiting situations, for example, PSP are frequently outperformed by PON-P2, the best GM; however, the opposite happens when we compare PSP and SIFT. Finally, we explore how the observed complementarity could lead to increased success rates in pathogenicity prediction.


Assuntos
Substituição de Aminoácidos , Biologia Computacional/métodos , Proteínas/genética , Algoritmos , Humanos , Software
20.
Open Biol ; 6(4): 150227, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27248655

RESUMO

The function of EZH2 as a transcription repressor is well characterized. However, its role during vertebrate development is still poorly understood, particularly in neurogenesis. Here, we uncover the role of EZH2 in controlling the integrity of the neural tube and allowing proper progenitor proliferation. We demonstrate that knocking down the EZH2 in chick embryo neural tubes unexpectedly disrupts the neuroepithelium (NE) structure, correlating with alteration of the Rho pathway, and reduces neural progenitor proliferation. Moreover, we use transcriptional profiling and functional assays to show that EZH2-mediated repression of p21(WAF1/CIP1) contributes to both processes. Accordingly, overexpression of cytoplasmic p21(WAF1/CIP1) induces NE structural alterations and p21(WAF1/CIP1) suppression rescues proliferation defects and partially compensates for the structural alterations and the Rho activity. Overall, our findings describe a new role of EZH2 in controlling the NE integrity in the neural tube to allow proper progenitor proliferation.


Assuntos
Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Células Neuroepiteliais/citologia , Células Neuroepiteliais/metabolismo , Proteínas Repressoras/metabolismo , Animais , Polaridade Celular , Proliferação de Células , Embrião de Galinha , Inibidor de Quinase Dependente de Ciclina p21/genética , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Tubo Neural/citologia , Tubo Neural/metabolismo , Regiões Promotoras Genéticas/genética
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