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1.
Nat Commun ; 12(1): 2075, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824302

RESUMO

Variable number tandem repeats (VNTRs) account for significant genetic variation in many organisms. In humans, VNTRs have been implicated in both Mendelian and complex disorders, but are largely ignored by genomic pipelines due to the complexity of genotyping and the computational expense. We describe adVNTR-NN, a method that uses shallow neural networks to genotype a VNTR in 18 seconds on 55X whole genome data, while maintaining high accuracy. We use adVNTR-NN to genotype 10,264 VNTRs in 652 GTEx individuals. Associating VNTR length with gene expression in 46 tissues, we identify 163 "eVNTRs". Of the 22 eVNTRs in blood where independent data is available, 21 (95%) are replicated in terms of significance and direction of association. 49% of the eVNTR loci show a strong and likely causal impact on the expression of genes and 80% have maximum effect size at least 0.3. The impacted genes are involved in diseases including Alzheimer's, obesity and familial cancers, highlighting the importance of VNTRs for understanding the genetic basis of complex diseases.

2.
Int J Pharm ; 577: 119037, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31953081

RESUMO

Spinal Cord Injury (SCI) is one of the leading causes of physical disability. In this study, spherical PLGA nanoparticles (NPs) containing ChABC enzyme were manufactured and fully characterized for SCI therapy. The NPs were used in the rat's contused spinal cord to assess the functional improvement and scar digestion. Twenty-three adult male Wistar rats (275 ± 25 g) were assigned into four groups of control, sham, blank-treated particle, and ChABC-treated particle. Throughout the survey, the BBB scores were obtained for all the groups. Finally, the injured sections of animals were dissected, and histological studies were conducted using Luxol fast blue and Bielschowsky. The biocompatibility and non-toxicity effects of the NPs on olfactory ensheathing cells (OECs) were confirmed by the MTT test. The flow-cytometry revealed the purity of cultured OECs with p75+/GFAP+ at around 87.9 ± 2.4%. Animals in the control and the blank-treated groups exhibited significantly lower BBB scores compared with the ChABC-treated particle group. Histological results confirmed the induced contusion models in the injured site. Myelin was observed in the treated groups, especially when the ChABC-loaded nanoparticles were utilized. The immunohistochemistry results indicated the scar glial degradation in animals treated by the ChABC-loaded particles. According to this study, the loaded particles can potentially serve as a suitable candidate for spinal cord repair, functional recovery and axonal regeneration.

3.
Nat Commun ; 10(1): 392, 2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30674876

RESUMO

Focal oncogene amplification and rearrangements drive tumor growth and evolution in multiple cancer types. We present AmpliconArchitect (AA), a tool to reconstruct the fine structure of focally amplified regions using whole genome sequencing (WGS) and validate it extensively on multiple simulated and real datasets, across a wide range of coverage and copy numbers. Analysis of AA-reconstructed amplicons in a pan-cancer dataset reveals many novel properties of copy number amplifications in cancer. These findings support a model in which focal amplifications arise due to the formation and replication of extrachromosomal DNA. Applying AA to 68 viral-mediated cancer samples, we identify a large fraction of amplicons with specific structural signatures suggestive of hybrid, human-viral extrachromosomal DNA. AA reconstruction, integrated with metaphase fluorescence in situ hybridization (FISH) and PacBio sequencing on the cell-line UPCI:SCC090 confirm the extrachromosomal origin and fine structure of a Forkhead box E1 (FOXE1)-containing hybrid amplicon.


Assuntos
Amplificação de Genes , Neoplasias/genética , Algoritmos , Linhagem Celular , Linhagem Celular Tumoral , Duplicação Cromossômica , Cromossomos Humanos/genética , Computadores Moleculares , Fatores de Transcrição Forkhead/genética , Genes Virais , Humanos , Hibridização in Situ Fluorescente
4.
Mol Neurobiol ; 56(1): 307-318, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29549645

RESUMO

A neurological disorder is any disorder or abnormality in the nervous system. Among different neurological disorders, Alzheimer's disease (AD) is recognized as the sixth leading cause of death globally. Considerable research has been conducted to find pioneer treatments for this devastating disorder among which cell therapy has attracted remarkable attentions over the last decade. Up to now, targeted differentiation into specific desirable cell types has remained a major obstacle to clinical application of cell therapy. Also, potential risks including uncontrolled growth of stem cells could be disastrous. In our novel protocol, we used basal forebrain cholinergic progenitor cells (BFCN) derived from human chorion-derived mesenchymal stem cells (hC-MSCs) which made it possible to obtain high-quality population of cholinergic neurons and in vivo in much shorter time period than previous established methods. Remarkably, the transplanted progenitors fully differentiated to cholinergic neurons which in turn integrated in higher cortical networks of host brains, resulting in significant improvement in cognitive assessments. This method may have profound implications in cell therapies for any other neurodegenerative disorders. Graphical Abstract ᅟ.


Assuntos
Neurônios Colinérgicos/transplante , Córion/citologia , Doenças do Sistema Nervoso/terapia , Transplante de Células-Tronco , Células-Tronco/citologia , Doença de Alzheimer/patologia , Doença de Alzheimer/terapia , Animais , Diferenciação Celular , Neurônios Colinérgicos/citologia , Cognição , Modelos Animais de Doenças , Humanos , Masculino , Prosencéfalo/citologia , Ratos Wistar , Recuperação de Função Fisiológica
5.
Mol Neurobiol ; 56(1): 319-320, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29700773

RESUMO

The original version of this article unfortunately contained mistake in the affiliation. Affiliation 1 should be read as "Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran". The original article has been corrected.

6.
Genome Res ; 28(11): 1709-1719, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30352806

RESUMO

Whole-genome sequencing is increasingly used to identify Mendelian variants in clinical pipelines. These pipelines focus on single-nucleotide variants (SNVs) and also structural variants, while ignoring more complex repeat sequence variants. Here, we consider the problem of genotyping Variable Number Tandem Repeats (VNTRs), composed of inexact tandem duplications of short (6-100 bp) repeating units. VNTRs span 3% of the human genome, are frequently present in coding regions, and have been implicated in multiple Mendelian disorders. Although existing tools recognize VNTR carrying sequence, genotyping VNTRs (determining repeat unit count and sequence variation) from whole-genome sequencing reads remains challenging. We describe a method, adVNTR, that uses hidden Markov models to model each VNTR, count repeat units, and detect sequence variation. adVNTR models can be developed for short-read (Illumina) and single-molecule (Pacific Biosciences [PacBio]) whole-genome and whole-exome sequencing, and show good results on multiple simulated and real data sets.


Assuntos
Técnicas de Genotipagem/métodos , Repetições Minissatélites , Genoma Humano , Humanos , Cadeias de Markov , Polimorfismo Genético
7.
Nat Methods ; 15(4): 279-282, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29457793

RESUMO

Most approaches that capture signatures of selective sweeps in population genomics data do not identify the specific mutation favored by selection. We present iSAFE (for "integrated selection of allele favored by evolution"), a method that enables researchers to accurately pinpoint the favored mutation in a large region (∼5 Mbp) by using a statistic derived solely from population genetics signals. iSAFE does not require knowledge of demography, the phenotype under selection, or functional annotations of mutations.


Assuntos
Genômica , Técnicas de Amplificação de Ácido Nucleico , Hibridização de Ácido Nucleico/métodos , Alelos , Evolução Biológica , Haplótipos , Humanos , Mutação
8.
Stem Cell Res Ther ; 8(1): 40, 2017 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-28222801

RESUMO

BACKGROUND: Anal sphincter defects are a major cause of fecal incontinence causing negative effects on daily life, social interactions, and mental health. Because human adipose-derived stromal/stem cells (hADSCs) are easier and safer to access, secrete high levels of growth factor, and have the potential to differentiate into muscle cells, we investigated the ability of hADSCs to improve anal sphincter incontinence. METHODS: The present randomized double-blind clinical trial was performed on patients with sphincter defects. They were categorized into a cell group (n = 9) and a control group (n = 9). Either 6 × 106 hADSCs per 3 ml suspended in phosphate buffer saline (treatment) or 3 ml phosphate buffer saline (placebo) was injected. Two months after surgery, the Wexner score, endorectal sonography, and electromyography (EMG) results were recorded. RESULTS: Comparing Wexner scores in the cell group and the control group showed no significant difference. In our EMG and endorectal sonography analysis using ImageJ/Fiji 1.46 software, the ratio of the area occupied by the muscle to total area of the lesion showed a 7.91% increase in the cell group compared with the control group. CONCLUSION: The results of the current study show that injection of hADSCs during repair surgery for fecal incontinence may cause replacement of fibrous tissue, which acts as a mechanical support to muscle tissue with contractile function. This is a key point in treatment of fecal incontinence especially in the long term and may be a major step forward. TRIAL REGISTRATION: Iranian Registry of Clinical Trials IRCT2016022826316N2 . Retrospectively registered 7 May 2016.


Assuntos
Adipócitos/citologia , Incontinência Fecal/terapia , Células Musculares/citologia , Transplante de Células-Tronco , Células-Tronco/citologia , Adipócitos/fisiologia , Tecido Adiposo/citologia , Tecido Adiposo/fisiologia , Adulto , Idoso , Canal Anal/diagnóstico por imagem , Canal Anal/fisiopatologia , Canal Anal/cirurgia , Diferenciação Celular , Método Duplo-Cego , Eletromiografia , Incontinência Fecal/diagnóstico por imagem , Incontinência Fecal/fisiopatologia , Incontinência Fecal/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Células Musculares/fisiologia , Esfincterotomia Transduodenal/métodos , Células-Tronco/fisiologia , Transplante Homólogo , Ultrassonografia
9.
Neuropeptides ; 61: 39-47, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27484347

RESUMO

BACKGROUND: Although stem cell therapy has become a major focus as a new option for management of spinal cord injury (SCI), its effectiveness should be promoted. In this study, we investigated the effects of co-administrating human adipose-derived stem cells (hADSCs) and Chondroitinase ABC (ChABC) in a rat model of spinal cord injury. MATERIAL AND METHODS: hADSCs derived from superficial layer of abdominal adipose tissue were used to treat a contusion-induced SCI. Animals were randomly allocated to five equal groups including sham (only laminectomy), SCI (SCI+vehicle injection), hADSCs (1×106 hADSCs/10µl intra-spinal injection), ChABC (10µl of 100U/ml ChABC intra-spinal injection injection), and hADSCs+ChABC. Basso, Beattie and Bresnahan tests were used to evaluate locomotor function. 8weeks after treatment, cavity size, myelination, cell differentiation (neuron and astrocyte), and chondroitin sulfate amount were analyzed. RESULTS: hADSC transplanted animals, ChABC injected animals (P<0.001), and hADSC+ChABC treated rats (P<0.001) displayed significant motor improvement compared to SCI group. Combination therapy of hADSCs and ChABC led to greater locomotor recovery compared to using hADSCs (P<0.001) or ChABC (P<0.01) alone. Spinal cords in the combined and single therapy groups had cavities filled with myelinated areas and less chondroitin sulfate content in comparison with the control group (P<0.001). hADSCs expressed GFAP, B III tubulin and Map2. CONCLUSION: Combination therapy with ChABC and hADSCs exhibits more significant functional recovery than single therapy using either. This result may be applicable in selection of the best therapeutic strategy for SCI.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Condroitina ABC Liase/uso terapêutico , Traumatismos da Medula Espinal/terapia , Transplante de Células-Tronco , Animais , Condroitina ABC Liase/farmacologia , Terapia Combinada , Modelos Animais de Doenças , Humanos , Laminectomia , Masculino , Regeneração Nervosa/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ratos , Ratos Wistar , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/fisiopatologia , Resultado do Tratamento
10.
Iran J Basic Med Sci ; 17(9): 685-93, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25691946

RESUMO

OBJECTIVES: Spinal cord injury (SCI) is one of the most serious clinical diseases and its treatment has been a subject of interest to researchers. There are two important therapeutic strategies in the treatment of SCI: replacing lost tissue cells through cells implantation and scar elimination. Therefore, in this study we used human adipose-derived stem cells (hADSCs) implantation and injection of Chondroitinase ABC. Aim of present study was to answer to this question: which one is more efficient for Improvement of locomotor recovery after SCI in rat? Transplantation of hADSCs or injection of ChABC. MATERIALS AND METHODS: The spinal cord of rats was injured by contusion using a weight-drop at the level of T8-9, the hADSCs and Chondroitinase ABC were infused in to the spinal cord tissue after injury. BBB test was performed and recorded for each animal weekly for 8 weeks. After the 8(th) weeks, Serial cross-sections were stained with cresyl violet and examined under a light microscope and area of cavity in the spinal cord was measured. RESULTS: At 8(th) weeks after injection, hADSCs and ChABC significantly promote locomotor function (P<0.01) and spinal cords of hADSCs and ChABC group had cavities much smaller than those of the control group (P<0.001). CONCLUSION: Results of the present study shows dealing with inappropriate neuro-inhibitory environment and glial scar by ChABC have equal role compare to cell therapy (with hADSCs) for improving motor function after SCI and this result in adoption of proper therapeutic strategies for SCI intervention is important.

11.
Iran Biomed J ; 16(4): 193-201, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23183618

RESUMO

BACKGROUND: The aim of this study was to fabricate the poly caprolactone (PCL) aligned nanofiber scaffold and to evaluate the survival, adhesion, proliferation, and differentiation of rat hair follicle stem cells (HFSC) in the graft material using electrospun PCL nanofiber scaffold for tissue engineering applications. METHODS: The bulge region of rat whisker was isolated and cultured in DMEM: nutrient mixture F-12 supplemented with epidermal growth factor. The morphological and biological features of cultured bulge cells were observed by light microscopy using immunocytochemistry methods. Electrospinning was used for production of PCL nanofiber scaffolds. Scanning electron microscopy (SEM), 3-(4, 5-di-methylthiazol- 2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, and histology analysis were used to investigate the cell morphology, viability, attachment and infiltration of the HFSC on the PCL nanofiber scaffolds. RESULTS: The results of the MTT assay showed cell viability and cell proliferation of the HFSC on PCL nanofiber scaffolds. SEM microscopy images indicated that HFSC are attached, proliferated and spread on PCL nanofiber scaffolds. Also, immunocytochemical analysis showed cell infiltration and cell differentiation on the scaffolds. CONCLUSION: The results of this study reveal that PCL nanofiber scaffolds are suitable for cell culture, proliferation, differentiation and attachment. Furthermore, HFSC are attached and proliferated on PCL nanofiber scaffolds.


Assuntos
Folículo Piloso/citologia , Nanofibras , Células-Tronco/citologia , Engenharia Tecidual/métodos , Animais , Adesão Celular , Diferenciação Celular , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Masculino , Microscopia Eletrônica de Varredura , Nanofibras/ultraestrutura , Poliésteres , Ratos , Ratos Wistar
12.
Cell J ; 13(4): 213-22, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23508042

RESUMO

OBJECTIVE: Several studies have shown that, although transplantation of neural stem cells into the contusion model of spinal cord injury (SCI) promotes locomotor function and improves functional recovery, it induces a painful response, Allodynia. Different studies indicate that bone marrow stromal cells (BMSCs) and Schwann cells (SCs) can improve locomotor recovery when transplanted into the injured rat spinal cord. Since these cells are commonly used in cell therapy, we investigated whether co-transplantation of these cells leads to the development of Allodynia. MATERIALS AND METHODS: In this experimental research, the contusion model of SCI was induced by laminectomy at the T8-T9 level of the spinal cord in adult female wistar rats (n=40) weighting (250-300g) using the New York University Device. BMSCs and SCs were cultured and prelabeled with 5-bromo-2-deoxyuridine (BrdU) and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) respectively. The rats were divided into five groups of 8 including: a control group (laminectomy only), three experimental groups (BMSC, SC and Co-transplant) and a sham group. The experimental groups received BMSCs, SCs, and BMSCs and SCs respectively by intraspinal injection 7 days after injury and the sham group received serum only. Locomotion was assessed using Basso, Beattie and Bresnahan (BBB) test and Allodynia by the withdrawal threshold test using Von Frey Filaments at 1, 7, 14, 21, 28, 35, 42, 49 and 56 days after SCI. The statistical comparisons between groups were carried out by using repeated measures analysis of variances (ANOVA). RESULTS: Significant differences were observed in BBB scores in the Co- transplant group compared to the BMSC and SC groups (p< 0.05). There were also significant differences in the withdrawal threshold means between animals in the sham group and the BMSC, SC and the Co-transplant groups (p<0.05).BBB scores and withdrawal threshold means showed that co-transplation improved functioning but greater Allodynia compared to the other experimental groups. CONCLUSION: The present study has shown that, although transplantation of BMSCs, SCs and a combination of these cells into the injured rat spinal cord can improve functional recovery, it leads to the development of mechanical Allodynia. This finding indicates that strategies to reduce Allodynia in cell transplantation studies are required.

13.
Pathophysiology ; 18(4): 317-24, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21703827

RESUMO

OBJECTIVE: This study assessed the ability of a combination treatment of bone marrow stromal cell (BMSC) graft and oral coenzyme (CoQ10) in a rat model of Parkinson's disease (PD) as an appropriate substitute for current Parkinson treatments. The combination treatment was compared to sole treatments of BMSC and CoQ10. MATERIALS AND METHODS: In this experimental study, there were six groups of male Wistar rats: control, sham, lesion, CoQ10, graft BMSC and graft BMSC plus CoQ10. Oral administration of CoQ10 began 1 week before the PD and continued during the entire treatment period. To simulate PD, we injected 6 hydroxydopamine (6OHDA) in rats. BMSC were labelled by 5-bromo-2'-deoxyuridine (Brdu) before transplantation. We assessed behaviour before PD, 2 weeks after PD and 8 weeks after cell transplantation. At the end of the second month of treatment, immunohistochemistry, histology and molecular studies were performed. RESULTS: Behavioural assessment of the CoQ10 group and BMSC group indicated equal recovery in comparison with the lesion group (P<0.01), while the combined treatment of BMSC and CoQ10 showed considerably better recovery compared with the lesion group (P<0.001). There were no signs of gliosis and graft rejection. Immunohistochemistry analysis of Brdu indicated that cells were alive after 2 months of application in host tissue. Cell counts showed significantly greater numbers of neural cells in the combination treatment of BMSC and CoQ10 compared to the other groups. Tyrosine hydroxylase (TH) gene expression levels in the combined therapy group was significantly more than the other experimental groups (P<0.001). CONCLUSION: The combined use of two neuroprotective treatments and cell replacement therapy can be effective in the treatment of PD, at least in experimental settings.

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