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31.
Shobana Sekar Livia Tomasini Christos Proukakis Taejeong Bae Logan Manlove Yeongjun Jang Soraya Scuderi Bo Zhou Maria Kalyva Anahita Amiri Jessica Mariani Fritz J. Sedlazeck Alexander E. Urban Flora M. Vaccarino Alexej Abyzov 《Genome research》2020,30(12):1695
Somatic mosaicism, manifesting as single nucleotide variants (SNVs), mobile element insertions, and structural changes in the DNA, is a common phenomenon in human brain cells, with potential functional consequences. Using a clonal approach, we previously detected 200–400 mosaic SNVs per cell in three human fetal brains (15–21 wk postconception). However, structural variation in the human fetal brain has not yet been investigated. Here, we discover and validate four mosaic structural variants (SVs) in the same brains and resolve their precise breakpoints. The SVs were of kilobase scale and complex, consisting of deletion(s) and rearranged genomic fragments, which sometimes originated from different chromosomes. Sequences at the breakpoints of these rearrangements had microhomologies, suggesting their origin from replication errors. One SV was found in two clones, and we timed its origin to ∼14 wk postconception. No large scale mosaic copy number variants (CNVs) were detectable in normal fetal human brains, suggesting that previously reported megabase-scale CNVs in neurons arise at later stages of development. By reanalysis of public single nuclei data from adult brain neurons, we detected an extrachromosomal circular DNA event. Our study reveals the existence of mosaic SVs in the developing human brain, likely arising from cell proliferation during mid-neurogenesis. Although relatively rare compared to SNVs and present in ∼10% of neurons, SVs in developing human brain affect a comparable number of bases in the genome (∼6200 vs. ∼4000 bp), implying that they may have similar functional consequences.Somatic mosaicism, the presence of more than one genotype in the somatic cells of an individual, is a prominent phenomenon in the human central nervous system. Forms of mosaicism include aneuploidies and smaller copy number variants (CNVs), structural variants (SVs), mobile element insertions, indels, and single nucleotide variants (SNVs). The developing human brain exhibits high levels of aneuploidy compared to other tissues, generating genetic diversity in neurons (Pack et al. 2005; Yurov et al. 2007; Bushman and Chun 2013). Such aneuploidy was suggested to be a natural feature of neurons, rather than a distinctive feature of neurodegeneration. However, the frequency of aneuploidy in neurons has been debated, with a separate study suggesting that aneuploidies occur in only about 2.2% of mature adult neurons (Knouse et al. 2014). They hence infer that such aneuploidy could have adverse effects at the cellular and organismal levels. Additionally, analysis of single cells from normal and pathological human brains identified large, private, and likely clonal somatic CNVs in both normal and diseased brains (Gole et al. 2013; McConnell et al. 2013; Cai et al. 2014; Knouse et al. 2016; Chronister et al. 2019; Perez-Rodriguez et al. 2019), with 3%–25% of human cerebral cortical nuclei carrying megabase-scale CNVs (Chronister et al. 2019) and deletions being twice as common as duplications (McConnell et al. 2013). Given that CNVs often arise from nonhomologous recombination and replication errors, their likely time of origin is during brain development. However, when CNVs first arise in human brain development has not yet been investigated. The present work is the first to examine this question using clonal populations of neuronal progenitor cells (NPCs) obtained from fetal human brains.Detection of CNVs in single neurons is challenging, given the need to amplify DNA. Such amplification may introduce artifacts that could, in turn, be misinterpreted as CNVs. In order to address this technical limitation, Hazen et al. reprogrammed adult postmitotic neurons using somatic cell nuclear transfer (SCNT) of neuronal nuclei into enucleated oocytes (Hazen et al. 2016). These oocytes then made sufficient copies of the neuronal genome allowing for whole-genome sequencing (WGS), thus eliminating the need for amplification in vitro. Using this method, they identified a total of nine structural variants in six neurons from mice, three of which were complex rearrangements. However, it is not possible to extend such studies to humans, given the ethical issues involved, besides the technical challenges in obtaining and cloning adult neurons. To circumvent the need of single-cell DNA amplification or nuclear cloning, we examined clonal cell populations obtained from neural progenitor cells from the frontal region of the cerebral cortex (FR), parietal cortex (PA) and basal ganglia (BG) and describe here the discovery and analysis of mosaic SVs in these NPCs (Bae et al. 2018). These clones were sequenced at 30× coverage (much higher than most previous single-cell studies), allowing identification of SVs other than large deletions and duplications as well as precise breakpoint resolution. 相似文献
32.
Analysis of the immune response to Mycobacterium avium subsp. paratuberculosis in experimentally infected calves
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Koo HC Park YH Hamilton MJ Barrington GM Davies CJ Kim JB Dahl JL Waters WR Davis WC 《Infection and immunity》2004,72(12):6870-6883
Johne's disease of cattle is widespread and causes significant economic loss to producers. Control has been hindered by limited understanding of the immune response to the causative agent, Mycobacterium avium subsp. paratuberculosis, and lack of an effective vaccine and sensitive specific diagnostic assays. The present study was conducted to gain insight into factors affecting the immune response to M. avium subsp. paratuberculosis. A persistent proliferative response to M. avium subsp. paratuberculosis purified protein derivative and soluble M. avium subsp. paratuberculosis antigens was detected in orally infected neonatal calves 6 months postinfection (p.i.) by flow cytometry (FC). CD4(+) T cells with a memory phenotype (CD45R0(+)) expressing CD25 and CD26 were the predominant cell type responding to antigens. Few CD8(+) T cells proliferated in response to antigens until 18 months p.i. gammadelta T cells did not appear to respond to antigen until 18 months p.i. The majority of WC1(+) CD2(-) and a few WC1(-) CD2(+) gammadelta T cells expressed CD25 at time zero. By 18 months, however, subsets of gammadelta T cells from both control and infected animals showed an increase in expression of CD25, ACT2, and CD26 in the presence of the antigens. Two populations of CD3(-) non-T non-B null cells, CD2(+) and CD2(-), proliferated in cell cultures from some control and infected animals during the study, with and without antigen. The studies clearly show multicolor FC offers a consistent reliable way to monitor the evolution and changes in the immune response to M. avium subsp. paratuberculosis that occur during disease progression. 相似文献
33.
Oh S Yoon YW Jang GJ Ahn JB Hong Gp Gang Gh Gang MS Hong Yu Gee JH 《Journal of Korean medical science》2003,18(4):589-591
We report a case of ruptured mycotic aneurysm involving innominate artery requiring an urgent surgical treatment. A 62-yr-old woman presented with fever and dyspnea. Previously, she was diagnosed with colon cancer and received right hemicolectomy and one cycle of adjuvant chemotherapy. On echocardiogram, pericardial effusion was noted and emergency pericardiocentesis was performed. CT scan revealed aortic aneurysm involving ascending aorta and innominate artery, and thrombi surrounding those structures. Patch repair of the defect in the ascending aorta and ringed Goretex graft to bypass the innominate and ascending aorta were performed. We believe that this is the first case of ruptured mycotic aneurysm involving innominate artery. 相似文献
34.
35.
Karin Lemmer Oliver Donoso Mantke Hi-Gung Bae Jan Groen Christian Drosten Matthias Niedrig 《Journal of clinical virology》2004,30(4):291-296
BACKGROUND: Increased travelling to countries endemic for dengue fever (DF) demands efficient laboratory diagnostics. Nucleic acid amplification techniques (NAT) are now frequently used for rapid diagnosis of imported viral diseases. Different PCR systems are available. OBJECTIVES: In order to assess the quality of molecular diagnostics of dengue virus infections, an external quality assurance (EQA) in PCR diagnostics was conducted. Study design: A panel of 10 human plasma samples was prepared and spiked with dengue virus types DEN-1 to DEN-4. In addition, a 10-fold dilution series (1:10-1:10(4) ) of DEN-3 virus was included. The panel was pre-tested by nested RT-PCR, in-house real-time PCR, and a commercial real-time PCR kit. The samples were inactivated by gamma irradiation and shipped in freeze dried state. Thirteen laboratories, within the European network for the diagnostics of imported viral diseases (ENIVD) took part using either single-round, nested, or real-time RT-PCR methods. Two laboratories used two methods in parallel, summarising up to 15 comparable results. RESULTS: 33-100% correct results were achieved. All laboratories detected DEN-2 correctly, followed by DEN-1 (14 positive results of 15), DEN-3 (12/15) and DEN-4 (11/15). Testing of the serial dilution revealed low sensitivity in many labs, with results ranging from 33 to 80% of correctly tested samples. CONCLUSION: The EQA gives a feedback of the quality of the RT-PCR system used by each respective laboratory. The different test systems and amplification conditions demonstrate the importance of external quality control measures. 相似文献
36.
Hong KE Ock SM Kang MH Kim CE Bae JN Lim MK Suh CH Chung SJ Cho SC Lee JS 《Journal of Korean medical science》2002,17(4):530-536
Neuropathological deficits are an etiological factor in Tourette syndrome (TS), and implicate a network linking the basal ganglia and the cerebrum, not a particular single brain region. In this study, the volumes of 20 cerebral and cerebellar regions and their symmetries were measured in normal boys and TS boys by brain magnetic resonance imaging. Brain magnetic resonance images were obtained prospectively in 19 boys with TS and 17 age-matched normal control boys. Cerebral and cerebellar regions were segmented to gray and white fractions using algorithm for semi-automated fuzzy tissue segmentation. The frontal, parietal, temporal, and the occipital lobes and the cerebellum were defined using the semiautomated Talairach atlas-based parcellation method. Boys with TS had smaller total brain volumes than control subjects. In the gray matter, although the smaller brain volume was taken into account, TS boys had a smaller right frontal lobe and a larger left frontal lobe and increased normal asymmetry (left>right). In addition, TS boys had more frontal lobe white matter. There were no significant differences in regions of interest of the parietal, temporal, or the occipital lobes or the cerebellum. These findings suggest that boys with TS may have neuropathological abnormalities in the gray and the white matter of the frontal lobe. 相似文献
37.
Primary and revision total knee arthroplasty have become common orthopaedic procedures. The operating surgeon, at times, may be faced with a difficult surgical case due to soft tissue contractures or bone deformities. A review of multiple surgical techniques using soft tissue releases and osteotomies are presented including their potential complications. Although these techniques are aimed at the atypical operative case, the operating surgeon may utilize them for ‘routine’ exposures as well. Importance is focused on the functional integrity of the knee extensor mechanism. 相似文献
38.
The pathophysiology of meconium aspiration syndrome(MAS) is related to mechanical obstruction of the airways and to chemical pneumonitis. Meconium is also suggested to cause functional deterioration of pulmonary surfactant. Recent studies have reported that meconium inhibits the physical surface properties of pulmonary surfactant, and that administration of exogenous surfactant may provide therapeutic benefits in animal models or infants with respiratory distress due to MAS. To assess the effects of meconium on physical surface properties, especially the changes on the air-liquid interface and hypophase of pulmonary surfactant in vitro, we studied the following findings; a) the surface spreading rate(SSR) and the surface adsorption rate(SAR), b) the viscosity, c) the electron microscopic changes, on a series of mixtures with various concentrations of lyophilized human meconium and Surfactant-TA(SurfactenTM). The human meconium has significantly increased the surface tension of SSR and the viscosity of pulmonary surfactant, but had decreased the surface pressure of SAR of surfactant, and changed the electron microscopic findings of surfactant. We have concluded that these findings support the concept that meconium-induced surfactant dysfunction may play a role in the pathophysiology of MAS. 相似文献
39.
The pre-transplantation goal of the urologist is the optimization of urinary tract condition. Therefore, urologic surgery may be needed before or after renal transplantation. We analyzed the results of urologic surgery performed because of de novo urologic diseases. Between January 1986 and January 2001, 281 patients underwent renal transplantation, and 23 urologic surgical procedures were performed on 21 transplant recipients before or after renal transplantation because of de novo urologic diseases. By review the major reasons for urologic surgery in recipients were polycystic kidney diseases, vesicoureteral reflux, and dysfunctional voiding disorders. Nineteen surgical corrective procedures were done average 2.9 months before transplantation. The mortality rate was 10.5%. Four patients underwent urologic surgery at an average 57.5 months after transplantation. We highlight the fact that patients with uremia are vulnerable to surgical complications, and conclude that more intensive longterm urologic follow-ups should be conducted on recipients. 相似文献
40.
Bae SH Yoon SK Jang JW Kim CW Nam SW Choi JY Kim BS Park YM Suzuki S Sugauchi F Mizokami M 《Journal of Korean medical science》2005,20(5):816-820
Hepatitis B virus (HBV) is one of the major causative agents of chronic liver diseases in Korea. HBV has been classified into 8 genotypes by a divergence of >8% in the entire genomic sequence, and have distinct geographic distributions. There are limited data on the relevance between HBV genotypes and clinical outcomes in Korea. To investigate the clinical feature relating to HBV genotype in Korea, a total 120 serum samples with HBsAg (65 from Seoul and 55 from the other city in Korea) were obtained from each 30 chronic HBV carriers with asymptomatic carrier (ASC), chronic hepatitis (CH), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). HBV genotype was determined by either enzyme-linked immunosorbent assay (ELISA) using monoclonal antibodies against genotype-specific epitopes in the preS2-region or the direct sequencing of small S gene. HBV genotypes were determined in 105 (87.5%) of 120 samples. HBV genotype C was identified in all HBV carriers with ASC, CH, LC, and HCC. Genotypes A, B, D, E, F and G were not detected in any of them. Genotype C HBV prevails predominantly among chronic carriers of the virus in Korea, irrespective of their clinical stages of liver disease and geographic origin. 相似文献