Publications by authors named "Iscia Lopes-Cendes"

173 Publications

DRPLA: An unusual disease or an underestimated cause of ataxia in Brazil?

Parkinsonism Relat Disord 2021 Oct 11;92:67-71. Epub 2021 Oct 11.

Movement Disorders Unit, Hospital de Clínicas, Federal University of Paraná (UFPR), Curitiba, PR, Brazil.

Background: Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant spinocerebellar ataxia caused by pathological expansion of CAG trinucleotide repeats in the ATN1 gene. Most cases were described in patients from Japanese ancestry who presented with adult-onset progressive cerebellar ataxia associated with cognitive impairment, choreoathetosis and other movement disorders. DRPLA has been rarely described in Brazilian patients.

Methods: We performed a retrospective observational multicentric study including six different Neurology Centers in Brazil. All patients with genetically confirmed diagnosis of DRPLA had their medical records evaluated and clinical, genetic and neuroimaging features were analyzed.

Results: We describe of eight Brazilian patients (5 male, 3 female) from four nuclear families with genetically confirmed DRPLA. The most common neurological features included cerebellar ataxia (n = 7), dementia (n = 3), chorea (n = 2), psychiatric disturbances (n = 2), progressive myoclonic epilepsy (n = 2) and severe bulbar signs (n = 1). Progressive myoclonic epilepsy was observed in two juvenile-onset cases before 20-year. A large CAG trinucleotide length was observed in the two juvenile-onset cases and genetic anticipation was observed in all cases. Neuroimaging studies disclosed cerebellar atrophy (n = 6), as well as brainstem and cerebellar atrophy (n = 2) and leukoencephalopathy (n = 1).

Conclusion: The patients described herein reinforce that clinical features of DRPLA are highly influenced by age of onset, genetic anticipation and CAG repetition lengths. There is a large complex spectrum of neurological features associated with DRPLA, varying from pure cerebellar ataxia to dementia associated with other movement disorders (myoclonus, choreoathetosis). DRPLA is an unusual cause of cerebellar ataxia and neurodegeneration in Brazilian patients.
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http://dx.doi.org/10.1016/j.parkreldis.2021.10.004DOI Listing
October 2021

The Brazilian Initiative on Precision Medicine (BIPMed): fostering genomic data-sharing of underrepresented populations.

NPJ Genom Med 2020 Oct 2;5(1):42. Epub 2020 Oct 2.

Department of Medical Genetics and Genomic Medicine, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil.

The development of precision medicine strategies requires prior knowledge of the genetic background of the target population. However, despite the availability of data from admixed Americans within large reference population databases, we cannot use these data as a surrogate for that of the Brazilian population. This lack of transferability is mainly due to differences between ancestry proportions of Brazilian and other admixed American populations. To address the issue, a coalition of research centres created the Brazilian Initiative on Precision Medicine (BIPMed). In this study, we aim to characterise two datasets obtained from 358 individuals from the BIPMed using two different platforms: whole-exome sequencing (WES) and a single nucleotide polymorphism (SNP) array. We estimated allele frequencies and variant pathogenicity values from the two datasets and compared our results using the BIPMed dataset with other public databases. Here, we show that the BIPMed WES dataset contains variants not included in dbSNP, including 6480 variants that have alternative allele frequencies (AAFs) >1%. Furthermore, after merging BIPMed WES and SNP array data, we identified 809,589 variants (47.5%) not present within the 1000 Genomes dataset. Our results demonstrate that, through the incorporation of Brazilian individuals into public genomic databases, BIPMed not only was able to provide valuable knowledge needed for the implementation of precision medicine but may also enhance our understanding of human genome variability and the relationship between genetic variation and disease predisposition.
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http://dx.doi.org/10.1038/s41525-020-00149-6DOI Listing
October 2020

Multi-omic strategies applied to the study of pharmacoresistance in mesial temporal lobe epilepsy.

Epilepsia Open 2021 Sep 6. Epub 2021 Sep 6.

Departments of Translational Medicine, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil.

Mesial temporal lobe epilepsy (MTLE) is the most common type of focal epilepsy in adults, and hippocampal sclerosis (HS) is a frequent histopathological feature in patients with MTLE. Pharmacoresistance is present in at least one-third of patients with MTLE with HS (MTLE+HS). Several hypotheses have been proposed to explain the mechanisms of pharmacoresistance in epilepsy, including the effect of genetic and molecular factors. In recent years, the increased knowledge generated by high-throughput omic technologies has significantly improved the power of molecular genetic studies to discover new mechanisms leading to disease and response to treatment. In this review, we present and discuss the contribution of different omic modalities to understand the basic mechanisms determining pharmacoresistance in patients with MTLE+HS. We provide an overview and a critical discussion of the findings, limitations, new approaches, and future directions of these studies to improve the understanding of pharmacoresistance in MTLE+HS. However, it is important to point out that, as with other complex traits, pharmacoresistance to anti-seizure medications is likely a multifactorial condition in which gene-gene and gene-environment interactions play an important role. Thus, studies using multidimensional approaches are more likely to unravel these intricate biological processes.
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http://dx.doi.org/10.1002/epi4.12536DOI Listing
September 2021

Multidimensional Approach Assessing the Role of Interleukin 1 Beta in Mesial Temporal Lobe Epilepsy.

Front Neurol 2021 5;12:690847. Epub 2021 Aug 5.

Department of Translational Medicine, University of Campinas, Campinas, Brazil.

We aimed to investigate the role of interleukin-1 beta (IL-1β) in the mechanisms underlying mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE+HS). We assessed a cohort of 194 patients with MTLE+HS and 199 healthy controls. Patients were divided into those with positive and negative antecedent febrile seizures (FS). We used a multidimensional approach, including (i) genetic association with single nucleotide polymorphisms (SNPs) in the gene; (ii) quantification of the transcript in the hippocampal tissue of patients with refractory seizures; and (iii) quantification of the IL-1β protein in the plasma. We found a genetic association signal for two SNPs, rs2708928 and rs3730364C in the gene, regardless of the presence of FS (adjusted = 9.62e-11 and 5.14e-07, respectively). We found no difference between transcript levels when comparing sclerotic hippocampal tissue from patients with MTLE+HS, without FS, and hippocampi from autopsy controls ( > 0.05). Nevertheless, we found increased IL-1β in the plasma of patients with MTLE+HS with FS compared with controls ( = 0.0195). Our results support the hypothesis of a genetic association between MTLE+HS and the gene.
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http://dx.doi.org/10.3389/fneur.2021.690847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375265PMC
August 2021

Inflammatory and neurotrophic factor plasma levels are related to epilepsy independently of etiology.

Epilepsia 2021 Oct 31;62(10):2385-2394. Epub 2021 Jul 31.

University of Campinas, Campinas, Brazil.

Objective: Inflammation plays an essential role in epilepsy. Studies indicate that cytokines and neurotrophic factors can act in neuroexcitability and epileptogenesis. We aimed to investigate the association between plasma inflammatory and neurotrophic markers, seizure frequency, and chronic epilepsy subtypes.

Methods: We studied 446 patients with epilepsy and 166 healthy controls. We classified patients according to etiology and seizure frequency. We measured plasma levels of interleukin-1 (IL-1), IL-2, IL-4, IL-6, IL-10, IL-17, interferon-γ (IFNγ), tumor necrosis factor α (TNFα), soluble TNF receptor 1 (sTNFr1), sTNFr2, brain-derived neurotrophic factor (BDNF), neurotrophic factor 3 (NT3), NT4/5, ciliary neurotrophic factor (CNTF), nerve growth factor (NGF), and glial cell line-derived neurotrophic factor (GDNF) by enzyme-linked immunosorbent assay or cytometric bead array.

Results: The plasma levels of BDNF, NT3, NGF, and sTNFr2 were higher, whereas IL-2, IL-4, IL-6, IL-10, IL-17, IFNγ, TNFα, CNTF, and sTNFr1 were lower in patients than controls. IL1, GDNF, and NT4/5 were similar between groups. These markers did not correlate with age, sex, and epilepsy duration. The molecule sTNFr2 was the best marker to discriminate patients from controls (area under the curve = .857), also differing between patients with frequent and infrequent seizures.

Significance: This large cohort confirmed that patients with epilepsy have abnormal levels of plasma inflammatory and neurotrophic markers independent of the underlying etiology. Plasma level of sTNFr2 was related to seizure frequency and discriminated people with or without epilepsy with good accuracy, making it a potential biomarker for epilepsy and seizure burden.
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http://dx.doi.org/10.1111/epi.17023DOI Listing
October 2021

Slowly progressive behavioral frontotemporal dementia syndrome in a family co-segregating the C9orf72 expansion and a Synaptophysin mutation.

Alzheimers Dement 2021 Jul 26. Epub 2021 Jul 26.

Department of Neurology, University of Campinas (UNICAMP), Campinas, SP, Brazil.

Introduction: Synaptophysin, already related to X-linked intellectual disability, is expressed mainly in the central nervous system. Studies in humans indicate that the downregulation of synaptophysin could be involved in the development of dementia. Our study presents the first familial case of behavioral variant frontotemporal dementia associated with the co-occurrence of the repeat expansion in C9orf72 and a pathogenic variant in the SYP gene.

Methods: Exome sequencing and repeat-primed PCR for C9orf72 were performed for two siblings with clinical and imaging findings suggestive of slowly progressive behavioral frontotemporal dementia.

Results: We found that both siblings have the hexanucleotide expansion in C9orf72 and a null variant in the SYP gene. The most affected sibling presents the putative variant in a hemizygous state. With milder symptoms, his sister has the same pathogenic variant in heterozygosis, compatible with X-linked inheritance.

Discussion: Our results strengthened previous suggestive evidence that the phenotypes associated with C9orf72 repeat expansion are variable and probably influenced by additional genetic modifiers. We hypothesized that the pathogenic variant in the SYP gene might have modified the typical phenotype associated with the C9orf72 mutation.
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http://dx.doi.org/10.1002/alz.12409DOI Listing
July 2021

Association Analysis of Candidate Variants in Admixed Brazilian Patients With Genetic Generalized Epilepsies.

Front Genet 2021 8;12:672304. Epub 2021 Jul 8.

Department of Translational Medicine, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil.

Genetic generalized epilepsies (GGEs) include well-established epilepsy syndromes with generalized onset seizures: childhood absence epilepsy, juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), myoclonic absence epilepsy, epilepsy with eyelid myoclonia (Jeavons syndrome), generalized tonic-clonic seizures, and generalized tonic-clonic seizures alone. Genome-wide association studies (GWASs) and exome sequencing have identified 48 single-nucleotide polymorphisms (SNPs) associated with GGE. However, these studies were mainly based on non-admixed, European, and Asian populations. Thus, it remains unclear whether these results apply to patients of other origins. This study aims to evaluate whether these previous results could be replicated in a cohort of admixed Brazilian patients with GGE. We obtained SNP-array data from 87 patients with GGE, compared with 340 controls from the BIPMed public dataset. We could directly access genotypes of 17 candidate SNPs, available in the SNP array, and the remaining 31 SNPs were imputed using the BEAGLE v5.1 software. We performed an association test by logistic regression analysis, including the first five principal components as covariates. Furthermore, to expand the analysis of the candidate regions, we also interrogated 14,047 SNPs that flank the candidate SNPs (1 Mb). The statistical power was evaluated in terms of odds ratio and minor allele frequency (MAF) by the genpwr package. Differences in SNP frequencies between Brazilian and Europeans, sub-Saharan African, and Native Americans were evaluated by a two-proportion Z-test. We identified nine flanking SNPs, located on eight candidate regions, which presented association signals that passed the Bonferroni correction (rs12726617; rs9428842; rs1915992; rs1464634; rs6459526; rs2510087; rs9551042; rs9888879; and rs8133217; -values <3.55e). In addition, the two-proportion Z-test indicates that the lack of association of the remaining candidate SNPs could be due to different genomic backgrounds observed in admixed Brazilians. This is the first time that candidate SNPs for GGE are analyzed in an admixed Brazilian population, and we could successfully replicate the association signals in eight candidate regions. In addition, our results provide new insights on how we can account for population structure to improve risk stratification estimation in admixed individuals.
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http://dx.doi.org/10.3389/fgene.2021.672304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297412PMC
July 2021

Toward a better definition of focal cortical dysplasia: An iterative histopathological and genetic agreement trial.

Epilepsia 2021 06 5;62(6):1416-1428. Epub 2021 May 5.

Department of Neuropathology, Institute of Neurology, University College London, London, UK.

Objective: Focal cortical dysplasia (FCD) is a major cause of difficult-to-treat epilepsy in children and young adults, and the diagnosis is currently based on microscopic review of surgical brain tissue using the International League Against Epilepsy classification scheme of 2011. We developed an iterative histopathological agreement trial with genetic testing to identify areas of diagnostic challenges in this widely used classification scheme.

Methods: Four web-based digital pathology trials were completed by 20 neuropathologists from 15 countries using a consecutive series of 196 surgical tissue blocks obtained from 22 epilepsy patients at a single center. Five independent genetic laboratories performed screening or validation sequencing of FCD-relevant genes in paired brain and blood samples from the same 22 epilepsy patients.

Results: Histopathology agreement based solely on hematoxylin and eosin stainings was low in Round 1, and gradually increased by adding a panel of immunostainings in Round 2 and the Delphi consensus method in Round 3. Interobserver agreement was good in Round 4 (kappa = .65), when the results of genetic tests were disclosed, namely, MTOR, AKT3, and SLC35A2 brain somatic mutations in five cases and germline mutations in DEPDC5 and NPRL3 in two cases.

Significance: The diagnoses of FCD 1 and 3 subtypes remained most challenging and were often difficult to differentiate from a normal homotypic or heterotypic cortical architecture. Immunohistochemistry was helpful, however, to confirm the diagnosis of FCD or no lesion. We observed a genotype-phenotype association for brain somatic mutations in SLC35A2 in two cases with mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy. Our results suggest that the current FCD classification should recognize a panel of immunohistochemical stainings for a better histopathological workup and definition of FCD subtypes. We also propose adding the level of genetic findings to obtain a comprehensive, reliable, and integrative genotype-phenotype diagnosis in the near future.
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http://dx.doi.org/10.1111/epi.16899DOI Listing
June 2021

Exploring a Region on Chromosome 8p23.1 Displaying Positive Selection Signals in Brazilian Admixed Populations: Additional Insights Into Predisposition to Obesity and Related Disorders.

Front Genet 2021 25;12:636542. Epub 2021 Mar 25.

Department of Medical Genetics and Genomic Medicine, Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), University of Campinas - UNICAMP, Campinas, Brazil.

We recently reported a deviation of local ancestry on the chromosome (ch) 8p23.1, which led to positive selection signals in a Brazilian population sample. The deviation suggested that the genetic variability of candidate genes located on ch 8p23.1 may have been evolutionarily advantageous in the early stages of the admixture process. In the present work, we aim to extend the previous work by studying additional Brazilian admixed individuals and examining DNA sequencing data from the ch 8p23.1 candidate region. Thus, we inferred the local ancestry of 125 exomes from individuals born in five towns within the Southeast region of Brazil (São Paulo, Campinas, Barretos, and Ribeirão Preto located in the state of São Paulo and Belo Horizonte, the capital of the state of Minas Gerais), and compared to data from two public Brazilian reference genomic databases, BIPMed and ABraOM, and with information from the 1000 Genomes Project phase 3 and gnomAD databases. Our results revealed that ancestry is similar among individuals born in the five Brazilian towns assessed; however, an increased proportion of sub-Saharan African ancestry was observed in individuals from Belo Horizonte. In addition, individuals from the five towns considered, as well as those from the ABRAOM dataset, had the same overrepresentation of Native-American ancestry on the ch 8p23.1 locus that was previously reported for the BIPMed reference sample. Sequencing analysis of ch 8p23.1 revealed the presence of 442 non-synonymous variants, including frameshift, inframe deletion, start loss, stop gain, stop loss, and splicing site variants, which occurred in 24 genes. Among these genes, 13 were associated with obesity, type II diabetes, lipid levels, and waist circumference (, , , , , , , , , , , , and ). These results strengthen the hypothesis that a set of variants located on ch 8p23.1 that result from positive selection during early admixture events may influence obesity-related disease predisposition in admixed individuals of the Brazilian population. Furthermore, we present evidence that the exploration of local ancestry deviation in admixed individuals may provide information with the potential to be translated into health care improvement.
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http://dx.doi.org/10.3389/fgene.2021.636542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027303PMC
March 2021

Genetic variability in COVID-19-related genes in the Brazilian population.

Hum Genome Var 2021 2;8:15. Epub 2021 Apr 2.

Department of Translational Medicine, University of Campinas (UNICAMP), and The Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, SP Brazil.

SARS-CoV-2 utilizes the angiotensin-converting enzyme 2 (ACE2) receptor and transmembrane serine protease (TMPRSS2) to infect human lung cells. Previous studies have suggested that different host and genetic backgrounds might contribute to differences in the rate of SARS-CoV-2 infection or COVID-19 severity. Recent studies have also shown that variants in 15 genes related to type I interferon immunity to influenza virus might predispose patients toward life-threatening COVID-19 pneumonia. Other genes (, , and ) and alleles have also been implicated in the response to infection with SARS-CoV-2. Currently, Brazil has recorded the third-highest number of COVID-19 cases worldwide. We aimed to investigate the genetic variation present in COVID-19-related genes in the Brazilian population. We analyzed 27 candidate genes and alleles in 954 admixed Brazilian exomes. We used the information available in two public databases (http://www.bipmed.org and http://abraom.ib.usp.br/) and additional exomes from individuals born in southeast Brazil, the region of the country with the highest number of COVID-19 patients. Variant allele frequencies were compared with the 1000 Genomes Project phase 3 (1KGP) and gnomAD databases. We detected 395 nonsynonymous variants; of these, 325 were also found in the 1KGP and/or gnomAD. Six of these variants were previously reported to influence the rate of infection or clinical prognosis of COVID-19. The remaining 70 variants were identified exclusively in the Brazilian sample, with a mean allele frequency of 0.0025. In silico analysis revealed that seven of these variants are predicted to affect protein function. Furthermore, we identified alleles previously associated with the COVID-19 response at loci and . Our results showed genetic variability common to other populations and rare and ultrarare variants exclusively found in the Brazilian population. These findings might lead to differences in the rate of infection or response to infection by SARS-CoV-2 and should be further investigated in patients with this disease.
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http://dx.doi.org/10.1038/s41439-021-00146-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017521PMC
April 2021

Citral Effects on the Expression Profile of and Inflammatory Cytokines in Status Epilepticus-Induced Rats Using the Lithium-Pilocarpine Model.

J Med Food 2021 Sep 18;24(9):916-924. Epub 2021 Mar 18.

Department of Basic Sciences, Fluminense Federal University (ISNF-UFF), Nova Friburgo, Rio de Janeiro, Brazil.

Epilepsy is one of the most common neurological disorders. About one-third of people with epilepsy are refractory to available treatments. Studies suggest that mechanisms linked to the immune response and inflammatory process are related to seizure disorders. Citral is a monoterpene found in the essential oil of several plants, as in , used to make teas and has been the subject of numerous researches, from which it has been possible to demonstrate antiseizure and anti-inflammatory activities. In this study, the effects of citral on status epilepticus (SE) induced by the lithium-pilocarpine model in rats were investigated. Quantitative reverse transcription PCR (RT-qPCR) evaluated latency for seizure development, neuronal death in the hippocampus, and expression of the , tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), interleukin-1β ( IL-1β) and factor nuclear kappa B (NF-κB) genes. The results revealed that citral was able to increase latency until the first seizure, decrease neuronal death 2 h after SE and inhibit overexpression of proinflammatory genes.
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http://dx.doi.org/10.1089/jmf.2020.0073DOI Listing
September 2021

Multi-omics in mesial temporal lobe epilepsy with hippocampal sclerosis: Clues into the underlying mechanisms leading to disease.

Seizure 2021 Aug 4;90:34-50. Epub 2021 Mar 4.

Departments of Medical Genetics and Genomic Medicine, School of Medical Sciences, University of Campinas (UNICAMP), and the Brazilian Institute of Neuroscience and Neurotechnology, Campinas, SP, Brazil. Electronic address:

Mesial temporal lobe epilepsy (MTLE) is one of the most common types of focal epilepsy in the adult population. MTLE is frequently associated with a specific histopathological lesion in the medial temporal structures, namely hippocampal sclerosis (HS). A significant proportion of patients with MTLE+HS have severe epilepsy, which is often resistant to clinical treatment. For these patients, surgical resection of the epileptogenic lesion can be performed. Our understanding of the underlying mechanisms leading to MTLE+HS has improved significantly over the past few decades. In this review, we aim to present and discuss the most recent findings regarding the genetic determinants of MTLE+HS. Furthermore, we will address studies about transcriptomics, proteomics, metabolomics, and epigenomic signatures of the tissue that is surgically removed from patients with refractory MTLE+HS and animal models of the disorder. We expect to provide an overview and a critical discussion of the findings, limitations, new approaches, and future directions for multi-omics studies in MTLE+HS.
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http://dx.doi.org/10.1016/j.seizure.2021.03.002DOI Listing
August 2021

Neuroproteomics in Epilepsy: What Do We Know so Far?

Front Mol Neurosci 2020 7;13:604158. Epub 2021 Jan 7.

Department of Medical Genetics and Genomic Medicine, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil.

Epilepsies are chronic neurological diseases that affect approximately 2% of the world population. In addition to being one of the most frequent neurological disorders, treatment for patients with epilepsy remains a challenge, because a proportion of patients do not respond to the antiseizure medications that are currently available. This results in a severe economic and social burden for patients, families, and the healthcare system. A characteristic common to all forms of epilepsy is the occurrence of epileptic seizures that are caused by abnormal neuronal discharges, leading to a clinical manifestation that is dependent on the affected brain region. It is generally accepted that an imbalance between neuronal excitation and inhibition generates the synchronic electrical activity leading to seizures. However, it is still unclear how a normal neural circuit becomes susceptible to the generation of seizures or how epileptogenesis is induced. Herein, we review the results of recent proteomic studies applied to investigate the underlying mechanisms leading to epilepsies and how these findings may impact research and treatment for these disorders.
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http://dx.doi.org/10.3389/fnmol.2020.604158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817846PMC
January 2021

The impact of post-alignment processing procedures on whole-exome sequencing data.

Genet Mol Biol 2020 13;43(4):e20200047. Epub 2020 Nov 13.

Universidade Estadual de Campinas (UNICAMP), Faculdade de Ciências Médicas, Departamento de Genética Médica e Medicina Genômica, Campinas, SP, Brazil.

The use of post-alignment procedures has been suggested to prevent the identification of false-positives in massive DNA sequencing data. Insertions and deletions are most likely to be misinterpreted by variant calling algorithms. Using known genetic variants as references for post-processing pipelines can minimize mismatches. They allow reads to be correctly realigned and recalibrated, resulting in more parsimonious variant calling. In this work, we aim to investigate the impact of using different sets of common variants as references to facilitate variant calling from whole-exome sequencing data. We selected reference variants from common insertions and deletions available within the 1K Genomes project data and from databases from the Latin American Database of Genetic Variation (LatinGen). We used the Genome Analysis Toolkit to perform post-processing procedures like local realignment, quality recalibration procedures, and variant calling in whole exome samples. We identified an increased number of variants from the call set for all groups when no post-processing procedure was performed. We found that there was a higher concordance rate between variants called using 1K Genomes and LatinGen. Therefore, we believe that the increased number of rare variants identified in the analysis without realignment or quality recalibration indicated that they were likely false-positives.
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http://dx.doi.org/10.1590/1678-4685-GMB-2020-0047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783507PMC
November 2020

Is Ataxia an Underestimated Symptom of Huntington's Disease?

Front Neurol 2020 12;11:571843. Epub 2020 Nov 12.

Movement Disorders Unit, Neurology Service, Internal Medicine Department, Hospital de clínicas, Federal University of Paraná, Curitiba, Brazil.

Huntington's disease (HD) is a progressive disorder characterized by motor, cognitive and psychiatric features. Cerebellar ataxia is classically considered as uncommon in HD clinical spectrum. To determine the prevalence of cerebellar ataxia in patients with HD, both in the early and in the late stages of HD. Seventy-two individuals considered eligible were assessed by two trained doctors, applying the Scale for Assessment and Rating of Ataxia (SARA) and Brief Ataxia Rating Scale (BARS) for ataxia, the Unified Huntington's Disease Rating Scale (UHDRS) and also, Barthel Index (BI), in order to evaluate functional capacity. Fifty-one patients (70.8%) presented with clinical ataxia at the time of examination (mean time of disease was 9.1 years). Six (8.33%) patients presented with cerebellar ataxia as first symptom. When stratified according to time of disease, a decline in the presence of chorea ( = 0.032) and an increase in cognitive deficit ( = 0.023) were observed in the patients as the disease progressed. The presence of ataxia was associated with longer duration of illness and severity of illness (UHDRS) ( < 0.0001), and shorter Barthel (less functionality) ( = 0.001). Cerebellar involvement may play an important role in natural history of brain degeneration in HD. The presence of cerebellar ataxia in HD is relevant and it may occur even in early stages, and should be included as part of the motor features of the disease.
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http://dx.doi.org/10.3389/fneur.2020.571843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689004PMC
November 2020

Revisiting the clinical impact of variants in EFHC1 in patients with different phenotypes of genetic generalized epilepsy.

Epilepsy Behav 2020 11 29;112:107469. Epub 2020 Sep 29.

Department of Medical Genetics and Genomic Medicine, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil; The Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, SP, Brazil. Electronic address:

The most common form of genetic generalized epilepsy (GGE) is juvenile myoclonic epilepsy (JME), which accounts for 5 to 10% of all epilepsy cases. The gene EFHC1 has been implicated as a putative cause of JME. However, it remains debatable whether testing for EFHC1 mutations should be included in the diagnostic epilepsy gene panels. To investigate the clinical utility of EFHC1 testing, we studied 125 individuals: 100 with JME and 25 with other GGEs. We amplified and sequenced all EFHC1 coding exons. Then, we predicted the pathogenicity or benign impact of the variants using the analyses proposed by the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP). Mutation screening revealed 11 missense variants in 44 probands with JME (44%) and one of the seven individuals with generalized tonic-clonic seizures on awakening (14%). Six of the 11 variants (54%) were classified as 'benign,' and the remaining variants were considered variants of uncertain significance (VUS). There is currently a limitation to test for genes that predispose an individual to complex, nonmonogenic phenotypes. Thus, we show suggestive evidence that EFHC1 testing lacks a scientific foundation based on the disputed nature of the gene-disease relationship and should be currently limited to research purposes.
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http://dx.doi.org/10.1016/j.yebeh.2020.107469DOI Listing
November 2020

Multi-ancestry genetic study in 5,876 patients identifies an association between excitotoxic genes and early outcomes after acute ischemic stroke.

medRxiv 2020 Nov 3. Epub 2020 Nov 3.

During the first hours after stroke onset neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between NIH stroke scale (NIHSS) within six hours of stroke onset and NIHSS at 24h (ΔNIHSS). A total of 5,876 individuals from seven countries (Spain, Finland, Poland, United States, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of ΔNIHSS variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture than that of stroke risk. Seven loci (2p25.1, 2q31.2, 2q33.3, 4q34.3, 5q33.2, 6q26 and 7p21.1) were genome-wide significant and explained 2.1% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each loci. eQTL mapping and SMR indicate that (log Bayes Factor (LBF)=6.34) was driving the association for 2q33.3. Gene based analyses suggested that (LBF=5.26), which is predominantly expressed in brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated (LBF=5.30) and (LBF=5.70) for the 6q26 and 7p21.1 loci. Human brain single nuclei RNA-seq indicates that the gene expression of and is enriched in neurons. , a pre-synaptic protein, and , a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provides the first evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischemic stroke.

Research Into Context: No previous genome-wide association studies have investigated the genetic architecture of early outcomes after ischemic stroke. This is the first study that investigated genetic influences on early outcomes after ischemic stroke using a genome-wide approach, revealing seven genome-wide significant loci. A unique aspect of this genetic study is the inclusion of all of the major ethnicities by recruiting from participants throughout the world. Most genetic studies to date have been limited to populations of European ancestry. The findings provide the first evidence that genes implicating excitotoxicity contribute to human acute ischemic stroke, and demonstrates proof of principle that GWAS of acute ischemic stroke patients can reveal mechanisms involved in ischemic brain injury.
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http://dx.doi.org/10.1101/2020.10.29.20222257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654887PMC
November 2020

The Brazilian Initiative on Precision Medicine (BIPMed): fostering genomic data-sharing of underrepresented populations.

NPJ Genom Med 2020 2;5:42. Epub 2020 Oct 2.

Department of Medical Genetics and Genomic Medicine, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP Brazil.

The development of precision medicine strategies requires prior knowledge of the genetic background of the target population. However, despite the availability of data from admixed Americans within large reference population databases, we cannot use these data as a surrogate for that of the Brazilian population. This lack of transferability is mainly due to differences between ancestry proportions of Brazilian and other admixed American populations. To address the issue, a coalition of research centres created the Brazilian Initiative on Precision Medicine (BIPMed). In this study, we aim to characterise two datasets obtained from 358 individuals from the BIPMed using two different platforms: whole-exome sequencing (WES) and a single nucleotide polymorphism (SNP) array. We estimated allele frequencies and variant pathogenicity values from the two datasets and compared our results using the BIPMed dataset with other public databases. Here, we show that the BIPMed WES dataset contains variants not included in dbSNP, including 6480 variants that have alternative allele frequencies (AAFs) >1%. Furthermore, after merging BIPMed WES and SNP array data, we identified 809,589 variants (47.5%) not present within the 1000 Genomes dataset. Our results demonstrate that, through the incorporation of Brazilian individuals into public genomic databases, BIPMed not only was able to provide valuable knowledge needed for the implementation of precision medicine but may also enhance our understanding of human genome variability and the relationship between genetic variation and disease predisposition.
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http://dx.doi.org/10.1038/s41525-020-00149-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532430PMC
October 2020

Multi-omics analysis suggests enhanced epileptogenesis in the Cornu Ammonis 3 of the pilocarpine model of mesial temporal lobe epilepsy.

Hippocampus 2021 Feb 10;31(2):122-139. Epub 2020 Oct 10.

Department of Medical Genetics and Genomic Medicine, School of Medical Sciences. University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.

Mesial temporal lobe epilepsy (MTLE) is a chronic neurological disorder characterized by the occurrence of seizures, and histopathological abnormalities in the mesial temporal lobe structures, mainly hippocampal sclerosis (HS). We used a multi-omics approach to determine the profile of transcript and protein expression in the dorsal and ventral hippocampal dentate gyrus (DG) and Cornu Ammonis 3 (CA3) in an animal model of MTLE induced by pilocarpine. We performed label-free proteomics and RNAseq from laser-microdissected tissue isolated from pilocarpine-induced Wistar rats. We divided the DG and CA3 into dorsal and ventral areas and analyzed them separately. We performed a data integration analysis and evaluated enriched signaling pathways, as well as the integrated networks generated based on the gene ontology processes. Our results indicate differences in the transcriptomic and proteomic profiles among the DG and the CA3 subfields of the hippocampus. Moreover, our data suggest that epileptogenesis is enhanced in the CA3 region when compared to the DG, with most abnormalities in transcript and protein levels occurring in the CA3. Furthermore, our results show that the epileptogenesis in the pilocarpine model involves predominantly abnormal regulation of excitatory neuronal mechanisms mediated by N-methyl D-aspartate (NMDA) receptors, changes in the serotonin signaling, and neuronal activity controlled by calcium/calmodulin-dependent protein kinase (CaMK) regulation and leucine-rich repeat kinase 2 (LRRK2)/WNT signaling pathways.
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http://dx.doi.org/10.1002/hipo.23268DOI Listing
February 2021

Circulating Metabolites as Potential Biomarkers for Neurological Disorders-Metabolites in Neurological Disorders.

Metabolites 2020 Sep 29;10(10). Epub 2020 Sep 29.

Department of Medical Genetics and Genomic Medicine, School of Medical Sciences, University of Campinas (UNICAMP), Tessália Vieira de Camargo, 126 Cidade Universitária "Zeferino Vaz", Campinas SP 13083-887, Brazil.

There are, still, limitations to predicting the occurrence and prognosis of neurological disorders. Biomarkers are molecules that can change in different conditions, a feature that makes them potential tools to improve the diagnosis of disease, establish a prognosis, and monitor treatments. Metabolites can be used as biomarkers, and are small molecules derived from the metabolic process found in different biological media, such as tissue samples, cells, or biofluids. They can be identified using various strategies, targeted or untargeted experiments, and by different techniques, such as high-performance liquid chromatography, mass spectrometry, or nuclear magnetic resonance. In this review, we aim to discuss the current knowledge about metabolites as biomarkers for neurological disorders. We will present recent developments that show the need and the feasibility of identifying such biomarkers in different neurological disorders, as well as discuss relevant research findings in the field of metabolomics that are helping to unravel the mechanisms underlying neurological disorders. Although several relevant results have been reported in metabolomic studies in patients with neurological diseases, there is still a long way to go for the clinical use of metabolites as potential biomarkers in these disorders, and more research in the field is needed.
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http://dx.doi.org/10.3390/metabo10100389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601919PMC
September 2020

Placental transcriptome profile of women with sickle cell disease reveals differentially expressed genes involved in migration, trophoblast differentiation and inflammation.

Blood Cells Mol Dis 2020 09 8;84:102458. Epub 2020 Jun 8.

Center for Molecular Biology and Genetic Engineering (CBMEG), University of Campinas - UNICAMP, Campinas, SP 13083-875, Brazil. Electronic address:

Sickle cell disease (SCD) is a group of disorders whose common characteristic is the presence of hemoglobin (Hb) S in erythrocytes. The main consequence of this abnormality is vaso-occlusion, which can affect almost all organs including the placenta. This study aimed to evaluate the gene expression profile in placentas of women with SCD by means of total RNA sequencing. For this, we proposed a case-control study, with three groups of pregnant women: HbSS (n = 10), HbSC (n = 14) and HbAA (n = 21). The results showed differences in expression in a number of genes such as NOS2 (fold change, FC = 4.52), HLAG (FC = 5.56), ASCL2 (FC = 3.61), CXCL10 (FC = -3.66) and IL1R2 (FC = 3.92) for the HbSC group and S100A8 (FC = -3.82), CPXM2 (FC = 4.57), CXCL10 (FC = -4.59), CXCL11 (FC = -3.72) and CAMP (FC = -4.55) for the HbSS group. Differentially expressed genes are mainly associated with migration, trophoblast differentiation and inflammation. The causes leading to altered gene expression in placentas of sickle cell patients are not fully understood, but the presence of intravascular hemolysis and vaso-occlusion, with cycles of ischemia and reperfusion, may contribute to the emergence of an environment which can be very harmful for placental physiology, altering the nutrient supply and metabolic exchange for fetal growth.
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http://dx.doi.org/10.1016/j.bcmd.2020.102458DOI Listing
September 2020

Methodological differences can affect sequencing depth with a possible impact on the accuracy of genetic diagnosis.

Genet Mol Biol 2020 27;43(2):e20190270. Epub 2020 Apr 27.

Universidade Estadual de Campinas (UNICAMP), Faculdade de Ciências Médicas, Departamento de Genética Médica e Medicina Genômica, Campinas, SP, Brazil.

For a better interpretation of variants, evidence-based databases, such as ClinVar, compile data on the presumed relationships between variants and phenotypes. In this study, we aimed to analyze the pattern of sequencing depth in variants from whole-exome sequencing data in the 1000 Genomes project phase 3, focusing on the variants present in the ClinVar database that were predicted to affect protein-coding regions. We demonstrate that the distribution of the sequencing depth varies across different sequencing centers (pair-wise comparison, p < 0.001). Most importantly, we found that the distribution pattern of sequencing depth is specific to each facility, making it possible to correctly assign 96.9% of the samples to their sequencing center. Thus, indicating the presence of a systematic bias, related to the methods used in the different facilities, which generates significant variations in breadth and depth in whole-exome sequencing data in clinically relevant regions. Our results show that methodological differences, leading to significant heterogeneity in sequencing depth, may potentially influence the accuracy of genetic diagnosis. Furthermore, our findings highlight how it is still challenging to integrate results from different sequencing centers, which may also have an impact on genomic research.
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http://dx.doi.org/10.1590/1678-4685-GMB-2019-0270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198014PMC
April 2020

CAG repeats ≥ 34 in Ataxin-1 gene are associated with amyotrophic lateral sclerosis in a Brazilian cohort.

J Neurol Sci 2020 Jul 19;414:116842. Epub 2020 Apr 19.

Department of Neurology, School of Medicine, University of Campinas - UNICAMP, Rua Tessália Vieira de Camargo, 126, Cidade Universitária "Zeferino Vaz", 13083-887 Campinas, SP, Brazil.

Little is known about the genetic basis of amyotrophic lateral sclerosis (ALS) outside Europe and US. In this study, we investigated whether intermediate CAG expansions at ATXN1 were associated to ALS in the Brazilian population. To accomplish that, representative samples from 411 unrelated patients and 436 neurologically normal controls from 6 centers spread over the territory were genotyped to quantify ATXN1 expansions. We found that ATXN1 intermediate-length expansion (≥34 CAG repeats) are associated with the disease (odds ratio = 2.19, 95% CI = 1.081-4.441, p = .026). Most ATXN1-positive patients had classical phenotype, but some of them presented predominant lower motor neuron involvement. None of them had associated ataxia. Frontotemporal dementia was concomitantly found in 12.5% of patients carrying the intermediate ATXN1 expansion. Further studies are needed to validate these findings and to understand the pathophysiological mechanisms that connect ataxin-1 and ALS.
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http://dx.doi.org/10.1016/j.jns.2020.116842DOI Listing
July 2020

Epigenetics explained: a topic "primer" for the epilepsy community by the ILAE Genetics/Epigenetics Task Force.

Epileptic Disord 2020 Apr;22(2):127-141

Department of Physiology & Medical Physics and FutureNeuro SFI Research Centre Royal College of Surgeons in Ireland, Dublin, Ireland.

Epigenetics refers broadly to processes that influence medium to long-term gene expression by changing the readability and accessibility of the genetic code. The Neurobiology Commission of the International League Against Epilepsy (ILAE) recently convened a Task Force to explore and disseminate advances in epigenetics to better understand their role and intersection with genetics and the neurobiology of epilepsies and their co-morbidities, and to accelerate translation of these findings into the development of better therapies. Here, we provide a topic primer on epigenetics, explaining the key processes and findings to date in experimental and human epilepsy. We review the growing list of genes with epigenetic functions that have been linked with epilepsy in humans. We consider potential practical applications, including using epigenetic signals as biomarkers for tissue- and biofluid-based diagnostics and the prospects for developing epigenetic-based treatments for epilepsy. We include a glossary of terms, FAQs and other supports to facilitate a broad understanding of the topic for the non-expert. Last, we review the limitations, research gaps and the next challenges. In summary, epigenetic processes represent important mechanisms controlling the activity of genes, providing opportunities for insight into disease mechanisms, biomarkers and novel therapies for epilepsy.
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http://dx.doi.org/10.1684/epd.2020.1143DOI Listing
April 2020

Genome-wide association study identifies genetic factors that modify age at onset in Machado-Joseph disease.

Aging (Albany NY) 2020 03 23;12(6):4742-4756. Epub 2020 Mar 23.

Department of Human Genetics, McGill University, Montréal, Québec, Canada.

Machado-Joseph disease (MJD/SCA3) is the most common form of dominantly inherited ataxia worldwide. The disorder is caused by an expanded CAG repeat in the gene. Past studies have revealed that the length of the expansion partly explains the disease age at onset (AO) variability of MJD, which is confirmed in this study (Pearson's correlation coefficient R = 0.62). Using a total of 786 MJD patients from five different geographical origins, a genome-wide association study (GWAS) was conducted to identify additional AO modifying factors that could explain some of the residual AO variability. We identified nine suggestively associated loci ( < 1 × 10). These loci were enriched for genes involved in vesicle transport, olfactory signaling, and synaptic pathways. Furthermore, associations between AO and the and genes suggests that DNA repair mechanisms might be implicated in MJD pathogenesis. Our study demonstrates the existence of several additional genetic factors, along with CAG expansion, that may lead to a better understanding of the genotype-phenotype correlation in MJD.
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http://dx.doi.org/10.18632/aging.102825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138549PMC
March 2020

The genetic architecture of the human cerebral cortex.

Science 2020 03;367(6484)

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
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http://dx.doi.org/10.1126/science.aay6690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295264PMC
March 2020

Laser microdissection-based microproteomics of the hippocampus of a rat epilepsy model reveals regional differences in protein abundances.

Sci Rep 2020 03 10;10(1):4412. Epub 2020 Mar 10.

Department of Medical Genetics and Genomic Medicine, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil.

Mesial temporal lobe epilepsy (MTLE) is a chronic neurological disorder affecting almost 40% of adult patients with epilepsy. Hippocampal sclerosis (HS) is a common histopathological abnormality found in patients with MTLE. HS is characterised by extensive neuronal loss in different hippocampus sub-regions. In this study, we used laser microdissection-based microproteomics to determine the protein abundances in different regions and layers of the hippocampus dentate gyrus (DG) in an electric stimulation rodent model which displays classical HS damage similar to that found in patients with MTLE. Our results indicate that there are differences in the proteomic profiles of different layers (granule cell and molecular), as well as different regions, of the DG (ventral and dorsal). We have identified new signalling pathways and proteins present in specific layers and regions of the DG, such as PARK7, RACK1, and connexin 31/gap junction. We also found two major signalling pathways that are common to all layers and regions: inflammation and energy metabolism. Finally, our results highlight the utility of high-throughput microproteomics and spatial-limited isolation of tissues in the study of complex disorders to fully appreciate the large biological heterogeneity present in different cell populations within the central nervous system.
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http://dx.doi.org/10.1038/s41598-020-61401-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064578PMC
March 2020

The Machado-Joseph disease-associated form of ataxin-3 impacts dynamics of clathrin-coated pits.

Cell Biol Int 2020 May 11;44(5):1252-1259. Epub 2020 Feb 11.

Department of Pharmacology, University of Michigan Medical School, 2301 MSRB III, 1150 W. Medical Center Dr., Ann Arbor, Michigan, 48109, USA.

Expansion above a certain threshold in the polyglutamine (polyQ) tract of ataxin-3 is the main cause of neurodegeneration in Machado-Joseph disease. Ataxin-3 contains an N-terminal catalytic domain, called Josephin domain, and a highly aggregation-prone C-terminal domain containing the polyQ tract. Recent work has shown that protein aggregation inhibits clathrin-mediated endocytosis (CME). However, the effects of polyQ expansion in ataxin-3 on CME have not been investigated. We hypothesize that the expansion of the polyQ tract in ataxin-3 could impact CME. Here, we report that both the wild-type and the expanded ataxin-3 reduce transferrin internalization and expanded ataxin-3 impacts dynamics of clathrin-coated pits (CCPs) by reducing CCP nucleation and increasing short-lived abortive CCPs. Since endocytosis plays a central role in regulating receptor uptake and cargo release, our work highlights a potential mechanism linking protein aggregation to cellular dysregulation.
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http://dx.doi.org/10.1002/cbin.11312DOI Listing
May 2020

Using RNA Interference for Purinoceptor Knockdown In Vivo.

Methods Mol Biol 2020 ;2041:77-86

Departamento de Neurologia e Neurocirurgia, Disciplina de Neurociência, Universidade Federal de São Paulo-UNIFESP, São Paulo, Brazil.

RNA interference (RNAi) is a powerful post-transcriptional gene silencing (PTGS) induced by small double-stranded RNA (dsRNA). The method allows silencing of genes of interest by translation inhibition or by mRNA degradation. In this chapter, we provide a brief overview of the mechanisms involved in each step of gene silencing. A nonviral infusion of short siRNA into ventricular system of rats was used to study purinoceptor in the rat brain.
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http://dx.doi.org/10.1007/978-1-4939-9717-6_5DOI Listing
April 2020

Distribution of local ancestry and evidence of adaptation in admixed populations.

Sci Rep 2019 09 25;9(1):13900. Epub 2019 Sep 25.

Departament de Ciències Experimentals i de la Salut, Institute of Evolutionary Biology (CSIC-UPF), Universitat Pompeu Fabra, Barcelona, Spain.

Admixed American populations have different global proportions of European, Sub-Saharan African, and Native-American ancestry. However, individuals who display the same global ancestry could exhibit remarkable differences in the distribution of local ancestry blocks. We studied for the first time the distribution of local ancestry across the genome of 264 Brazilian admixed individuals, ascertained within the scope of the Brazilian Initiative on Precision Medicine. We found a decreased proportion of European ancestry together with an excess of Native-American ancestry on chromosome 8p23.1 and showed that this is due to haplotypes created by chromosomal inversion events. Furthermore, Brazilian non-inverted haplotypes were more similar to Native-American haplotypes than to European haplotypes, in contrast to what was found in other American admixed populations. We also identified signals of recent positive selection on chromosome 8p23.1, and one gene within this locus, PPP1R3B, is related to glycogenesis and has been associated with an increased risk of type 2 diabetes and obesity. These findings point to a selection event after admixture, which is still not entirely understood in recent admixture events.
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http://dx.doi.org/10.1038/s41598-019-50362-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761108PMC
September 2019
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