The multiple de novo copy number variant (MdnCNV) phenotype is described by having four or more constitutional de novo CNVs (dnCNVs) arising independently throughout the human genome within one ...generation. It is a rare peri-zygotic mutational event, previously reported to be seen once in every 12,000 individuals referred for genome-wide chromosomal microarray analysis due to congenital abnormalities. These rare families provide a unique opportunity to understand the genetic factors of peri-zygotic genome instability and the impact of dnCNV on human diseases.
Chromosomal microarray analysis (CMA), array-based comparative genomic hybridization, short- and long-read genome sequencing (GS) were performed on the newly identified MdnCNV family to identify de novo mutations including dnCNVs, de novo single-nucleotide variants (dnSNVs), and indels. Short-read GS was performed on four previously published MdnCNV families for dnSNV analysis. Trio-based rare variant analysis was performed on the newly identified individual and four previously published MdnCNV families to identify potential genetic etiologies contributing to the peri-zygotic genomic instability. Lin semantic similarity scores informed quantitative human phenotype ontology analysis on three MdnCNV families to identify gene(s) driving or contributing to the clinical phenotype.
In the newly identified MdnCNV case, we revealed eight de novo tandem duplications, each ~ 1 Mb, with microhomology at 6/8 breakpoint junctions. Enrichment of de novo single-nucleotide variants (SNV; 6/79) and de novo indels (1/12) was found within 4 Mb of the dnCNV genomic regions. An elevated post-zygotic SNV mutation rate was observed in MdnCNV families. Maternal rare variant analyses identified three genes in distinct families that may contribute to the MdnCNV phenomenon. Phenotype analysis suggests that gene(s) within dnCNV regions contribute to the observed proband phenotype in 3/3 cases. CNVs in two cases, a contiguous gene duplication encompassing PMP22 and RAI1 and another duplication affecting NSD1 and SMARCC2, contribute to the clinically observed phenotypic manifestations.
Characteristic features of dnCNVs reported here are consistent with a microhomology-mediated break-induced replication (MMBIR)-driven mechanism during the peri-zygotic period. Maternal genetic variants in DNA repair genes potentially contribute to peri-zygotic genomic instability. Variable phenotypic features were observed across a cohort of three MdnCNV probands, and computational quantitative phenotyping revealed that two out of three had evidence for the contribution of more than one genetic locus to the proband's phenotype supporting the hypothesis of de novo multilocus pathogenic variation (MPV) in those families.
Recent advances on wheel-rail dynamic performance of curve negotiation are reviewed in this paper. There are four issues, the mechanism and calculation method of curve negotiation, the analysis and ...assessment of dynamic performance of vehicle, the effect of vehicle parameters on dynamic performance, and the influence of railway parameters on dynamic performance. The promising future development of wheel-rail coupled dynamics theory is analyzed in the research of curve negotiation. The framework and technique matching performance of wheel-rail dynamic interaction on the curved track are put forward for modern railways. In addition, the application of performance matching technique is introduced to the dynamic engineering, in which the wheel load is reduced obviously when the speed of train is raised to 200-250km/h.
Asphalt pavement is known to be deteriorated by the repetitive traffic loading, climatic condition, aging of asphalt mixture etc. after opening to traffic. Crack plays a critical role in pavement ...deterioration. Several studies have been conducted to obtain a better understanding with respect to climate related pavement fracture behavior. However, the limitation of the previous researches was that most of them were conducted by laboratory experiment or numerical simulation. The main objective of this study is to determine the relationship between the continuously changed temperature and the relative crack opening in asphalt base course by analyzing the data collected from an in-service asphalt pavement. To achieve this objective, four artificial transverse cracks were first induced on the asphalt subbase of a test track, and then their temperatures and crack opening were recorded by monitoring systems. Diurnal and annual trends of temperature and relative crack opening as well as their relationship were investigated and discussed. In this study, a test track with defined asphalt layers was constructed, which was specially equipped with sensors that continuously monitored the temperatures and opening widths of structural cracks in the test track. On the basis of the findings obtained, it is possible for the first time to make direct statements about the deformation conditions occurring in an asphalt base layer as a result of temperature.
Nonallelic homologous recombination (NAHR) can mediate recurrent rearrangements in the human genome and cause genomic disorders. Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are ...genomic disorders associated with a 3.7 Mb deletion and its reciprocal duplication in 17p11.2, respectively. In addition to these common recurrent rearrangements, an uncommon recurrent 5 Mb SMS-associated deletion has been identified. However, its reciprocal duplication predicted by the NAHR mechanism had not been identified. Here we report the molecular assays on 74 subjects with PTLS-associated duplications, 35 of whom are newly investigated. By both oligonucleotide-based comparative genomic hybridization and recombination hot spot analyses, we identified two cases of the predicted 5 Mb uncommon recurrent PTLS-associated duplication. Interestingly, the crossovers occur in proximity to a recently delineated allelic homologous recombination (AHR) hot spot-associated sequence motif, further documenting the common hot spot features shared between NAHR and AHR. An additional eight subjects with nonrecurrent PTLS duplications were identified. The smallest region of overlap (SRO) for all of the 74 PTLS duplications examined is narrowed to a 125 kb interval containing only
RAI1, a gene recently further implicated in autism. Sequence complexities consistent with DNA replication-based mechanisms were identified in four of eight (50%) newly identified nonrecurrent PTLS duplications. Our findings of the uncommon recurrent PTLS-associated duplication at a relative prevalence reflecting the de novo mutation rate and the distribution of 17p11.2 duplication types in PTLS reveal insights into both the contributions of new mutations and the different underlying mechanisms that generate genomic rearrangements causing genomic disorders.
In medical genetics, discovery and characterization of disease trait contributory genes and alleles depends on genetic reasoning, study design, and patient ascertainment; we suggest a segmental ...haploid genetics approach to enhance gene discovery and molecular diagnostics.
We constructed a genome-wide map for nonallelic homologous recombination (NAHR)-mediated recurrent genomic deletions and used this map to estimate population frequencies of NAHR deletions based on large-scale population cohorts and region-specific studies. We calculated recessive disease carrier burden using high-quality pathogenic or likely pathogenic variants from ClinVar and gnomAD. We developed a NIRD (NAHR deletion Impact to Recessive Disease) score for recessive disorders by quantifying the contribution of NAHR deletion to the overall allele load that enumerated all pairwise combinations of disease-causing alleles; we used a Punnett square approach based on an assumption of random mating. Literature mining was conducted to identify all reported patients with defects in a gene with a high NIRD score; meta-analysis was performed on these patients to estimate the representation of NAHR deletions in recessive traits from contemporary human genomics studies. Retrospective analyses of extant clinical exome sequencing (cES) were performed for novel rare recessive disease trait gene and allele discovery from individuals with NAHR deletions.
We present novel genomic insights regarding the genome-wide impact of NAHR recurrent segmental variants on recessive disease burden; we demonstrate the utility of NAHR recurrent deletions to enhance discovery in the challenging context of autosomal recessive (AR) traits and biallelic variation. Computational results demonstrate new mutations mediated by NAHR, involving recurrent deletions at 30 genomic regions, likely drive recessive disease burden for over 74% of loci within these segmental deletions or at least 2% of loci genome-wide. Meta-analyses on 170 literature-reported patients implicate that NAHR deletions are depleted from the ascertained pool of AR trait alleles. Exome reanalysis of personal genomes from subjects harboring recurrent deletions uncovered new disease-contributing variants in genes including COX10, ERCC6, PRRT2, and OTUD7A.
Our results demonstrate that genomic sequencing of personal genomes with NAHR deletions could dramatically improve allele and gene discovery and enhance clinical molecular diagnosis. Moreover, results suggest NAHR events could potentially enable human haploid genetic screens as an approach to experimental inquiry into disease biology.
Objective
The only one established prognostic nomogram for patients with sarcomatoid renal cell carcinoma (sRCC) was based on a small sample-sized study without external validation, and a nomogram ...can be applied to western sRCC patients has not yet been developed. Therefore, our study aimed to construct and validate an effective nomogram to predict overall survival (OS) for these patients.
Methods
The independent predictors for OS were identified and the nomogram was constructed on the basis of a retrospective study of a training cohort consisted of 428 non-Hispanic white sRCC patients registered in the Surveillance, Epidemiology and End Results (SEER) database from January 2010 to December 2015. Then, the discriminative performance of the nomogram was assessed by the concordance index (C-index). OS calibrations of the nomogram were also performed by comparing the nomogram-predicted probability to the observed survival rate. Furthermore, our nomogram was externally validated using two independent cohorts consisted of 71 non-Hispanic black patients and 82 Hispanic patients, respectively.
Results
Age at diagnosis, T stage, N stage, bone metastases, liver metastases, lung metastases and nephrectomy were identified as independent predictors for OS. In the training cohort and two validation cohorts, the C-indexes of the nomogram were 0.737, 0.801 and 0.764, respectively. Besides, excellent agreements between the nomogram prediction and the actual observation were achieved in all cohorts.
Conclusions
The current study constructed and validated an effective prognostic nomogram for patients with sRCC, which can be used to perform accurate predictions of the 0.5-, 1-, and 2-year possibilities of OS.
Embryonic formation and patterning of the vertebrate spinal column requires coordination of many molecular cues. After birth, the integrity of the spine is impacted by developmental abnormalities of ...the skeletal, muscular and nervous systems, which may result in deformities, such as kyphosis and scoliosis. We sought to identify novel genetic mouse models of severe spine deformity by implementing in vivo skeletal radiography as part of a high-throughput saturation mutagenesis screen. We report selected examples of genetic mouse models following radiographic screening of 54,497 mice from 1275 pedigrees. An estimated 30.44% of autosomal genes harbored predicted damaging alleles examined twice or more in the homozygous state. Of the 1275 pedigrees screened, 7.4% presented with severe spine deformity developing in multiple mice, and of these, meiotic mapping implicated N-ethyl-N-nitrosourea alleles in 21% of pedigrees. Our study provides proof of concept that saturation mutagenesis is capable of discovering novel mouse models of human disease, including conditions with skeletal, neural and neuromuscular pathologies. Furthermore, we report a mouse model of skeletal disease, including severe spine deformity, caused by recessive mutation in Scube3. By integrating results with a human clinical exome database, we identified a patient with undiagnosed skeletal disease who harbored recessive mutations in SCUBE3, and we demonstrated that disease-associated mutations are associated with reduced transactivation of Smad signaling in vitro. All radiographic results and mouse models are made publicly available through the Mutagenetix online database with the goal of advancing understanding of spine development and discovering novel mouse models of human disease.
This study examines the impact of foreign direct investment (FDI) on economic growth in China based on time series data for the period 1981-2018. For an empirical study, we used vector autoregressive ...(VAR) analysis. Before building our VAR model, we performed tests for unit root, normality, and heteroscedasticity to certify the data quality. The optimal lag 3 was selected using the Akaike information criterion (AIC), Schwartz (SC), and Hannan-Quinn (HQ) criteria. The Granger causality test is additionally performed. Based on the VAR model, we determined the impulse responses and variance decomposition of log FDI and log GDP in China. The results showed a positive and consistent impact of log FDI on China’s economic growth. The impact in the short-term is insignificant, as it is likely that there are multiple factors drive economic growth of China besides FDI inflows. However, the impact of FDI increases to a significant level in the long-term. Which indicates that FDI is one of the main factors to enhance Chinese economy. In conclusion, we suggest a policy implication how to sustain and promote the existing positive effects of FDI inflows on Chinese economy.
Previous research has demonstrated that 3-5-(4-chlorophenyl)-2,3-dimethyl-3-isoxazolidinylpyridine (SYP-Z048), a newly developed nitrogen heterocycle substituted isoxazolidine compound, has good ...protective and curative activities against a wide range of fungal diseases of fruits and vegetables caused by Ascomycetes, Basidiomycetes, and Deuteromycetes. In this study, the photochemical behavior of SYP-Z048 was investigated in aqueous solution and in response to solar and low-pressure mercury ultraviolet (UV) lamp irradiation. SYP-Z048 photolysis was pH- and temperature-dependent and was described by a first-order degradation reaction. A total of 11 photoproducts were separated by high-performance liquid chromatography (HPLC) and solid-phase extraction (SPE) and were identified on the basis of 1H and 13C nuclear magnetic resonance (NMR) and high-performance liquid chromatography-mass spectrometry (HPLC-MS) spectra. The photoproduct structures and kinetics suggested that the phototransformation of SYP-Z048 occurred via multiple reaction pathways that included the cleavage of the N-O bond in the isoxazolidine ring and the dechlorination of the benzene ring.
In the present study, the process of separation and purification of isohamnetin from marc of sea buckthorn was obtained. The antioxidant properties of the pure isolated isorhamnetin were evaluated by ...the scavenging of the diphenylpicrylhydrazyl radical (DPPH), iron (III) to iron (II)--reducing, and iron-chelating assays. High purity isorhamnetin (92.1%) was obtained and the results of antioxidant assays showed that isorhamnetin performed significantly compared with ascorbic acid and BHT, and the linear correlations were good in these assays. In conclusion, isorhamnetin may have potential as a natural antioxidant to alternate synthetic substances as food additive with its antioxidant activity.
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