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Based on the finite element limit analysis method, the stability of the face in case of active failure under three constitutive models, the Mohr-Coulomb model (MC), the modified Cambridge model (MCC) and the Drucker-Prager model (DP), were analyzed. The ultimate support pressure of the face and the influence of factors such as different burial depth ratios (C/D), cohesion (c) and friction angle (φ) in the MC model are also discussed. The results show that the safety factor obtained by the MCC model under the same support pressure is always smaller than that of the MC model, and the difference is the largest when there is no support pressure. As the support pressure increases, it will gradually approach the MC model. When the support pressure is small, the safety factor obtained by the DP model is larger than the MC model, but when the support pressure is large, it is smaller than the MC model, and the final difference tends to be stable. It is necessary to select an appropriate constitutive model according to different rock masses in practical engineering. The self-stabilizing performance of the face is not affected by C/D, and the ultimate support pressure will increase with the increase of C/D, decrease linearly with the increase of cohesion, and decrease with the increase of friction angle. When the friction angle is small, the ultimate support pressure is greatly affected by C/D, and when the friction angle is large, it is hardly affected by C/D.

BackgroundWilson's disease (WD) is an autosomal recessive disorder characterized by copper accumulation. ATP7B gene mutations lead to ATP7B protein dysfunction, which in turn causes Wilson's disease.Case presentationWe describe a male case of Wilson's disease diagnosed at 10 years after routine biochemical test that showed low serum ceruloplasmin levels and Kayser-Fleischer rings in both corneas. Analysis of the ATP7B gene revealed compound heterozygous mutations in the proband, including the reported c.3517G > A mutation and a novel c.532_574del mutation. The c.532_574del mutation covered a 43-bp region in exon 2, and resulted in a frameshift mutation (p.Leu178PhefsX10). By base sequence analysis, two microhomologies (TCTCA) were observed on both deletion breakpoints in the ATP7B gene. Meanwhile, the presence of some sequence motifs associated with DNA breakage near the deletion region promoted DNA strand break.ConclusionsBy comparison, a replication-based mechanism named fork stalling and template switching/ microhomology-mediated break-induced replication (FoSTeS/MMBIR) was used to explain the formation of this novel deletion mutation.

Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disorder caused by mutations in the BCKDHA, BCKDHB, DBT, and DLD genes. Among the wide range of disease-causing mutations in BCKDHB, only one large deletion has been associated with MSUD. Compound heterozygous mutations in BCKDHB were identified in a Chinese patient with typical MSUD using next-generation sequencing, quantitative PCR, and array comparative genomic hybridization. One allele presented a missense mutation (c.391G > A), while the other allele had a large deletion; both were inherited from the patient's unaffected parents. The deletion breakpoints were characterized using long-range PCR and sequencing. A novel 383,556 bp deletion (chr6: g.80811266_81194921del) was determined, which encompassed the entire BCKDHB gene. The junction site of the deletion was localized within a homologous sequence in two AluYa5 elements. Hence, Alu-mediated non-allelic homologous recombination is speculated as the mutational event underlying the large deletion. In summary, this study reports a recombination mechanism in the BCKDHB gene causing a whole gene deletion in a newborn with MSUD.

Here, we aimed to validate a noninvasive method using capture sequencing for prenatal diagnosis of congenital adrenal hyperplasia due to 21-Hydroxylase deficiency (21-OHD). Noninvasive prenatal diagnosis (NIPD) of 21-OHD was based on 14 plasma samples collected from 12 families, including four plasma sample collected during the first trimester. Targeted capture sequencing was performed using genomic DNA from the parents and child trios to determine the pathogenic and wild-type alleles associated with the haplotypes. Maternal plasma DNA was also sequenced to determine the fetal inheritance of the allele using hidden Markov model-based haplotype linkage analysis. The effect of fetal DNA fraction and sequencing depth on the accuracy of NIPD was investigated. The lower limit of fetal DNA fraction was 2% and the threshold mean sequence depth was 38, suggesting potential advantage if used in early gestation. The CYP21A2 genotype of the fetus was accurately determined in all the 14 plasma samples as early as day 1 and 8 weeks of gestation. Results suggest the accuracy and feasibility of NIPD of 21-OHD using a small target capture region with a low threshold for fetal DNA fraction and sequence depth. Our method is cost-effective and suggests diagnostic applications in clinical practice.

Background: SERPINB2, a biomarker of Type‐2 (T2) inflammatory processes, has been described in the context of asthma. Chronic rhinosinusitis with nasal polyps (CRSwNP) is also correlated with T2 inflammation and elevated 15LO1 induced by IL‐4/13 in nasal epithelial cells. The aim of this study was to evaluate the expression and location of SERPINB2 in nasal epithelial cells (NECs) and determine whether SERPINB2 regulates 15LO1 and downstream T2 markers in NECs via STAT6 signalling. Methods: SERPINB2 gene expression in bulk and single‐cell RNAseq database was analysed by bioinformatics analysis. SERPINB2, 15LO1 and other T2 markers were evaluated from CRSwNP and HCs NECs. The colocalization of SERPINB2 and 15LO1 was evaluated by immunofluorescence. Fresh NECs were cultured at an air‐liquid interface with or without IL‐13, SERPINB2 Dicer‐substrate short interfering RNAs (DsiRNAs) transfection, exogenous SERPINB2, 15‐HETE recombinant protein and pSTAT6 inhibitors. 15LO1, 15‐HETE and downstream T2 markers were analysed by qRT‐PCR, western blot and ELISA. Results: SERPINB2 expression was increased in eosinophilic nasal polyps compared with that in noneosinophilic nasal polyps and control tissues and positively correlated with 15LO1 and other downstream T2 markers. SERPINB2 was predominantly expressed by epithelial cells in NP tissue and was colocalized with 15LO1. In primary NECs in vitro, SERPINB2 expression was induced by IL‐13. Knockdown or overexpression SERPINB2 decreased or enhanced expression of 15LO1 and 15‐HETE in NECs, respectively, in a STAT6‐dependent manner. SERPINB2 siRNA also inhibited the expression of the 15LO1 downstream genes, such as CCL26, POSTN and NOS2. STAT6 inhibition similarly decreased SERPINB2‐induced 15LO1. Conclusions: SERPINB2 is increased in NP epithelial cells of eosinophilic CRSwNP (eCRSwNP) and contributes to T2 inflammation via STAT6 signalling. SERPINB2 could be considered a novel therapeutic target for eCRSwNP. [ABSTRACT FROM AUTHOR]

The design of anchor bolt in tunnel engineering mostly depends on empirical method and analogy method. In order to study the mechanical effect of surrounding rock in prestressed anchor bolt support system, a mechanical coupling model of prestressed anchor bolt and surrounding rock is established. Considering the damage effect of surrounding rock excavation, the analytical expressions of stress distribution and radial displacement of surrounding rock after tunnel excavation are derived by elastic-plastic mechanics theory. The finite difference software FLAC3D is used to verify and analyze the influence of prestressed anchor parameters on the state of surrounding rock. The results show that the maximum tangential stress and the radius of plastic zone of surrounding rock in theoretical analysis and numerical simulation are 4.77 MPa, 15 m and 4.49 MPa, 15.86 m respectively. The stress distribution and displacement of tunnel surrounding rock calculated by theoretical analysis and numerical simulation are basically the same. The rationality of theoretical analytical solution is verified in IV and V grade surrounding rock strata. With the increase of pre-tightening force, the radial displacement of surrounding rock in plastic zone and the radius of plastic zone gradually decrease, while the elastic zone is basically unaffected. When the length of the free section of the bolt is located in the plastic zone, the radial displacement of the plastic zone and the radius of the plastic zone of the surrounding rock gradually decrease with the increase of the length of the bolt. In practical engineering, the pre-tightening force of bolt should be increased as much as possible. The increase of bolt length has limited control effect on the displacement of surrounding rock and the development of plastic zone. The length of free section of bolt should be controlled in plastic zone. [ABSTRACT FROM AUTHOR]

Optical genome mapping (OGM) has been known as an all-in-one technology for chromosomal aberration detection. However, there are also aberrations beyond the detection range of OGM. This study aimed to report the aberrations missed by OGM and analyze the contributing factors. OGM was performed by taking both GRCh37 and GRCh38 as reference genomes. The OGM results were analyzed in blinded fashion and compared to standard assays. Quality control (QC) metrics, sample types, reference genome, effective coverage and classes and locations of aberrations were then analyzed. In total, 154 clinically reported variations from 123 samples were investigated. OGM failed to detect 10 (6.5%, 10/154) aberrations with GRCh37 assembly, including five copy number variations (CNVs), two submicroscopic balanced translocations, two pericentric inversion and one isochromosome (mosaicism). All the samples passed pre-analytical and analytical QC. With GRCh38 assembly, the false-negative rate of OGM fell to 4.5% (7/154). The breakpoints of the CNVs, balanced translocations and inversions undetected by OGM were located in segmental duplication (SD) regions or regions with no DLE-1 label. In conclusion, besides variations with centromeric breakpoints, structural variations (SVs) with breakpoints located in large repetitive sequences may also be missed by OGM. GRCh38 is recommended as the reference genome when OGM is performed. Our results highlight the necessity of fully understanding the detection range and limitation of OGM in clinical practice. [ABSTRACT FROM AUTHOR]