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Background: Previous studies have verified the dysfunction of mesenchymal stem cells (MSCs) for immunoregulation in acquired aplastic anemia (AA) patients. Exosomes derived from MSCs can partially substitute MSCs acting as immune regulator. Dysfunction of exosomes (Exos) derived from AA-MSC (AA-Exos) may play a key role in immunologic dissonance. Method: In this study, CD3 + T cells were collected and cocultured with AA-Exos and exosomes derived from HD-MSC (HD-Exos). The proliferation, differentiation and activation of CD3 + T cells were detected to compare the immunosuppressive effects between AA-Exos and HD-Exos. An immune-mediated murine model of AA was structured to compare the therapeutic effect of AA-Exos and HD-Exos. Furthermore, total RNA including miRNA from exosomes we purified and total RNA of CD3 + T cells were extracted for RNA-seq in order to construct the miRNA–mRNA network for interactions and functional analysis. Results: AA-Exos had impaired inhibition effects on CD3 + T cells in terms of cell proliferation, activation and differentiation compared with exosomes from HD-Exos. HD-Exos showed a more effective rescue of AA mice compared to AA-Exos. Importantly, we found some differentially expressed miRNA involved in immune response, such as miR-199, miR-128 and miR-486. The Gene Ontology analysis of differentially expressed genes (DEGs) revealed involvement of various cellular processes, such as lymphocyte chemotaxis, lymphocyte migration and response to interferon-gamma. The Kyoto Encyclopedia of Genes and Genomes analysis illustrated upregulation of critical pathways associated with T cell function after coculturing with AA-Exos compared with HD-Exos, such as graft-versus-host disease, Th17 cell differentiation and JAK-STAT signaling pathway. A miRNA–mRNA network was established to visualize the interaction between them. Conclusion: In summary, AA-Exos had impaired immunosuppressive effect on T cells, less ability to rescue AA mice and differently expressed miRNA profile, which might partly account for the pathogenesis of AA as well as provide a new target of AA treatment. [ABSTRACT FROM AUTHOR]

Hazardous materials are usually stored in large tanks surrounded by bunds to prevent the disastrous consequences of catastrophic tank failure. The effectiveness of the bunds system is demonstrated by its ability to prevent liquid overtopping and withstand dynamic pressure. Therefore, this work experimentally investigates the effect of bund design parameters, including shapes, inclined angles and breakwaters, primarily on overtopping fraction, flow behavior and dynamic pressure on the bund, to provide a guideline for the effectiveness of bund parameters to reduce liquid leakage. In addition, two three-dimensional (3D) models based on the RNG k-ε and Large Eddy Simulation (LES) turbulence models were employed and systematically validated against two series of experiments to study the complex phenomenon of liquid overtopping in the bunds built according to the terrain. The overtopping fraction and dynamic pressure were studied on the petroleum products with different physical characteristics and the scale-up effect of liquid overtopping by using the RNG k-ε model. These results will contribute to the reliable design of subsequent bunds and reduce the potential risks for the safety management of tank farms. [ABSTRACT FROM AUTHOR]

Hazardous materials are stored in the large tanks in the industry, e.g., a single LNG tank can be as large as 230,000 m3. Therefore, a catastrophic tank failure can cause a disastrous incident. A secondary containment, such as a bund, is required by regulations to control the risk; however, the released liquid may overtop from the bund due to its high kinetic energy converted from potential energy. Computational Fluid Dynamic (CFD) is a proper tool for the bund overtopping study, but there has been significant discrepancy among previous CFD studies. This work developed 2D CFD models of bund overtopping using the axisymmetric approach. A screening study on several turbulence models was performed, and RNG k-ε Standard Wall Functions (RNG k-ε SWF1) and Large Eddy Simulation WALE (LES WALE) were selected for a detailed comparison in terms of overtopping fraction and flow dynamic behaviour. Both RNG k-ε and LES models were systematically validated against experimental data, and the results indicate that LES model is slightly better than RNG k-ε model, and both models are acceptable based on the criteria of statistical performance measures. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine (CsA) have been widely accepted as the standard first-line treatments for severe aplastic anemia (SAA). However, most of the patients with SAA had a slim chance to access these strategies in developing countries. Here, we reported 10-year results in a cohort of 232 patients with SAA who received a novel IST of CsA, levamisole, and danazol (CsA&LMS-based regimen). The cumulative incidence of response was 52.1% at 6 months, 66.4% at 12 months, and 77.1% at 24 months. The 10-year overall survival (OS) and failure-free survival was 60.2% and 48.3%, respectively. Positive predictors of OS in multivariate analysis were higher pretreatment ANC, younger age, higher pretreatment absolute reticulocyte count (ARC), and response within 6 months. The probability of CsA&LMS discontinuation was 50.2% at 10 years. With a slow CsA&LMS taper, the actuarial risk for relapse was only 9.5%. The cumulative incidence of MDS/AML was 8.2% at 10 years. The long-term follow-up information demonstrated that the CsA&LMS regimen could be a promising strategy for patients with SAA in developing countries. [ABSTRACT FROM AUTHOR]

Background: Longitudinal studies have verified the pivotal role of mesenchymal stem/stromal cells (MSCs) in the bone marrow microenvironment for hematopoiesis and coordinate contribution to leukemia pathogenesis. However, the precise characteristics and alternation of MSCs during acquired aplastic anemia (AA) remain obscure. Methods: In this study, we originally collected samples from both healthy donors (HD) and AA patients to dissect the hematological changes. To systematically evaluate the biological defects of AA-derived MSCs (AA-MSCs), we analyzed alterations in cellular morphology, immunophenotype, multi-lineage differentiation, cell migration, cellular apoptosis, and chromosome karyocyte, together with the immunosuppressive effect on the activation and differentiation of lymphocytes. With the aid of whole genome sequencing and bioinformatic analysis, we try to compare the differences between AA-MSCs and HD-derived MSCs (HD-MSCs) upon the molecular genetics, especially the immune-associated gene expression pattern. In addition, the efficacy of umbilical cord-derived MSC (UC-MSC) transplantation on AA mice was evaluated by utilizing survivorship curve, histologic sections, and blood cell analyses. Results: In coincidence with the current reports, AA patients showed abnormal subsets of lymphocytes and higher contents of proinflammatory cytokines. Although with similar immunophenotype and chromosome karyotype to HD-MSCs, AA-MSCs showed distinguishable morphology and multiple distinct characteristics including genetic properties. In addition, the immunosuppressive effect on lymphocytes was significantly impaired in AA-MSCs. What is more, the cardinal symptoms of AA mice were largely rescued by systemic transplantation of UC-MSCs. Conclusions: Herein, we systematically investigated the signatures and efficacy of MSCs to dissect the alterations occurred in AA both at the cellular and molecular levels. Different from HD-MSCs, AA-MSCs exhibited multifaceted defects in biological characteristics and alterative molecular genetics in the whole genome. Our findings have provided systematic and overwhelming new evidence for the defects of AA-MSCs, together with effectiveness assessments of UC-MSCs on AA as well. [ABSTRACT FROM AUTHOR]

Acquired bone marrow failure syndromes (aBMFS) encompass a wide range of diseases. A study to investigate WT1 expression in BM was conducted in 387 patients with aBMFS in China. The WT1 level in patients with aplastic anemia (AA) was significantly lower than that in patients with paroxysmal nocturnal hemoglobinuria (PNH, p = .023) and myelodysplastic syndrome (MDS, p < .001). In addition, the WT1 level in patients with MDS significantly increased as the disease progressed to an advanced stage. Patients with hypoplastic MDS had a differentiated expression level of WT1 compared with that of NSAA (p < .001). Furthermore, post-treatment patients of AA with partial response (PR) or complete response (CR) status had relatively higher WT1 levels than those with naive AA (p = .017, p = .003, respectively). Thus, the WT1 expression level could be a useful genetic marker for routine clinical work in aBMFS. [ABSTRACT FROM AUTHOR]

Hydrogen has the potential to produce energy with no emissions, and therefore offers a strategic opportunity for rapid development of renewable energy storage. However, jet flames caused by the leakage of high-pressure hydrogen may cause casualties and damage equipment, so the safety issues associated with hydrogen incidents are a key issue restricting its development. Barrier walls can be an important mitigative action to reduce the hazard of hydrogen jet flames. Previous studies have evaluated the protective effect of different vertical or inclined arrangements of a single barrier wall in the vertical direction. However, in the vertical direction, a single barrier wall is not sufficient to reduce the hazards associated with high-pressure hydrogen jet flames. In this paper, a two-dimensional CFD model of high-pressure hydrogen jet flames are established. A simplified form of the hydrogen real gas equation of state is used to describe the complex behavior of high-pressure hydrogen. This CFD study employs the standard k-ε turbulence model, the eddy dissipation concept (EDC) model, and the discrete ordinate (DO) radiation model. The results display good agreement with the experimentally obtained flame shape and thermal radiation values, which confirms the applicability of the model. Based on this model, the characteristics of high-pressure jet flames are systematically studied under different forms of barrier walls and different pressures of hydrogen storage. Compared with the vertical barrier wall, barrier walls with complex structures can block the flames in front of the wall more effectively. This is proven through a remarkable decline in the vertical flame length and a reduction in the high temperature area. Comparing the five barrier wall patterns for their combined flame shape and flame temperature, it is more preferred to choose 60° Plate. The results of this study will help to better analyze the consequences of hydrogen jet flames and provide guidance for better design of barrier walls for mitigation. [ABSTRACT FROM AUTHOR]

In this study, a SPICE model for Negative Capacitance FinFET (NC-FinFET) based on the BSIM-CMG model and Landau-Khalatnikov (L-K) equation is developed. The areas of the ferroelectric layer (A FE) and the work functions (WFs) of n-NC-FinFET and p-NC-FinFET are adjusted to reduce the shift of the threshold voltage. As a result, the NC-FinFET-based seven-stage ring oscillator (RO) has a smaller delay, and energy can down to 72.2 % compared with the FinFET-based RO under the same delay. Furthermore, the NC-FinFET-based 6T SRAM has a smaller read and write time and lower static power than the FinFET-based 6T SRAM. Besides, under two key parameters (the length of the gate (Lg), the width of gate (Wfin), of NC-FinFET), the NC-FinFET-based 6T SRAM has great advantages in static power, read and write time. Therefore, the research on NC-FinFET from the device to the circuit can provide meaningful guidance for the further application of NC-FinFET. [ABSTRACT FROM AUTHOR]

• Three novel models were developed to predict the overtopping fraction of catastrophic tank failures with circular bunds, square bunds and bunds of arbitrary shapes. • The inclination angle (θ) was first introduced into the predictive model of overtopping fraction. • The novel models were validated against existing experimental data to verify their performance. The storage tanks are usually equipped with a secondary containment, such as a dike or a bund, to control the spilled liquid after a tank failure. The bund system is extremely important for storage tanks of hazardous materials, such as Liquefied Natural Gas (LNG), because the spilled LNG tends to vaporize rapidly with a low boiling temperature, and the bund contributes to reducing the vaporization rate by controlling the contact area of conductive heat transfer. Some regulations mandate the 110% rule for the bund design; however, a bund that complies with this rule may not hold all the fluid after a catastrophic tank failure, and some fluid would overtop from the bund wall to escalate the incident. Previous works have developed several predictive models of overtopping fraction for circular bunds, but these works only used a small set of experimental data, did not include the parameter of inclination angle, and failed to verify their performance for bunds of other shapes. This work collected all reported data of experimental studies on bund overtopping, and used them to develop novel predictive models of overtopping fraction for circular bunds, square bunds and bunds of arbitrary shapes. These predictive models were evaluated using a number of statistical performance measures. The findings were used to provide recommendations on the bund design and the future work. [ABSTRACT FROM AUTHOR]

Objectives: To clear the obscure conclusion on the prediction value of paroxysmal nocturnal haemoglobinuria (PNH) clones in severe aplastic anaemia (SAA) patients treated with immunosuppressive therapy (IST). Methods: We retrospectively analyzed 219 consecutive SAA patients treated with IST from October 2008 to October 2015 and evaluated the haematological responses to IST. Results: The presence of a PNH clone was detected in 55 (25.1%) patients prior to IST [37/88 by flow cytometry (FCM) and 18/131 by fluorescent aerolysin (FLAER)] and 27 disappeared after IST (23/37 in initial FCM group, 4/18 in initial FLAER group, p = 0.005). In patients without an initial clone, 12 (30.0%) cases in FCM and 17 (19.5%) in FLAER groups presented a PNH clone at least once after IST (p < 0.001). In patients with a pre-treatment PNH clone detected by FCM, the 3-, 6- and 12-month response rates were higher than patients without (p = 0.006; 0.002 and 0.002, respectively). And in FLAER group, the 3-month response rate was significantly higher in those with a prior clone (p = 0.017), however, the 6- and 12-month response rates showed no differences (p = 0.105, p = 0.144, respectively). By multivariate analysis, a shorter interval between diagnosis and treatment is associated with a better response and survival. Conclusions: A more reliable FLAER method allows us to draw a conclusion that PNH clone predicts a faster response but not a higher response rate to IST. Once a diagnosis is confirmed, the IST should be initiated as soon as possible. [ABSTRACT FROM AUTHOR]

Introduction: Acquired aplastic anemia (AA), a heterogeneous bone marrow (BM) failure disease, is mainly mediated by the immune destruction of hematopoietic stem cells (HSCs). Given the predominant role of immunosuppressive therapy (IST) in AA, it is sensible to theorize that variants of cytokine genes might affect the outcome of IST. Methods: In this study, we analyzed three single nucleotide polymorphisms (SNPs) of interleukin (IL)‐10 gene in promoter region to clarify their relationship with susceptibility, clinical efficacy and prognosis of AA. Results: We observed that CT genotype of IL‐10 rs1800896 was associated with a decreased risk of AA (adjusted OR = 0.541 [95% CI 0.295–0.993], p =.047). Besides, the disease severity differed considerably by IL‐10 gene promoter genotypes and alleles. Furthermore, IL‐10 SNPs influenced efficacy of IST, with unfavorable response exhibited by rs1800871 and rs1800872 in dominant models (GG + AG vs. AA, adjusted OR = 0.409 [95% CI 0.178–0.943, p =.036] for rs1800871 and GG + GT vs. TT, adjusted OR = 0.396 [95% CI 0.173–0.909, p =.028] for rs1800872, respectively). Conclusion: The polymorphisms of IL‐10 promoter region were informatively genetic risk factors which might be conducive to the insights into the mechanisms of AA and the design of individual regimens. [ABSTRACT FROM AUTHOR]

• Impaired AA-MSC differentiated toward adipocytes which secreted high amounts of leptin in AA-BM. • The leptin interacted with leptin receptor to accelerate the T-cell responses in AA-BM. • The leptin induced proinflammatory bone marrow environment by activating the JAK2/STAT3 pathway in AA. Acquired aplastic anemia (AA), a paradigm of bone marrow failure syndrome, is mainly caused by abnormal immune activation. The enhanced adipogenesis of bone marrow-derived mesenchymal stem cell (BM-MSC) results in a fatty marrow of AA. Leptin, an adipokine mainly generated by adipocytes, has powerful proinflammatory effects on immune cells and is associated with various autoimmune diseases. However, the role of leptin in the hyperimmune status of AA remains unknown. In this study, we firstly discovered the higher leptin concentration in AA-BM than that in healthy donors (HD)-BM and myelodysplastic syndrome (MDS)-BM. Then, we found AA-MSC could express high amounts of leptin during the process of adipogenesis. Compared with HD, the leptin receptor was also highly expressed on T cells in AA-BM. Furthermore, leptin significantly accelerated the proliferation and activation of T cells in AA-BM. And, leptin promoted the production of interferon-γby T cells in AA-BM. However, leptin remarkably inhibited the conversion of CD4+CD25- T cells into CD4+Foxp3+ T cells. Finally, we detected the cell signaling pathway in T cells from AA patients and found leptin could activate the STAT3 pathway. In summary, our data revealed the high expression of adipokine leptin in AA-BM which shaped a proinflammatory environment for T cells in AA-BM by activating the JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]

Source engineering is an emerging technique to achieve steep-slope switching FET. To bridge the new carrier filtering mechanism and device performance, a multiscale simulation framework is presented in this article and is applied in Si nanowire (NW) cold source FET (CSFET). By the fit-parameter-free density functional theory (DFT) method, the key component of cold source (CS) design for broken-gap-like band alignment and high cold carrier injection is demonstrated. The novel device switching mechanism is also verified in the entire device scale with fully quantum atomistic tight-binding (TB) and nonequilibrium Green’s function (NEGF) methods. Although these tools are physics-based and accurate, the device scale is limited, and the computation burden is heavy. Thus, half-empirical TCAD simulation is suitable for device design and path-finding in realistic geometry. Key components of the CS and energy filtering effect can be verified by DFT-NEGF and TB-NEGF methods. Based on TCAD results, we implement a circuit-level benchmark for early stage path-finding. The results show that gate-all-around (GAA) Si NW CSFET is a potential candidate for low-power application, which enables supply voltage scaling. [ABSTRACT FROM AUTHOR]

In this work, a quasi-antiferroelectric (QAFE) model to precisely evaluate the electrical characteristics of negative capacitance Fin field-effect transistor (NC-FinFET) integrated with a QAFE gate insulator is proposed. A comparative study of the performance of transistors with ferroelectric (FE) and QAFE of different component ratios is carried out by combining the QAFE model and the BSIM-CMG model. The results demonstrate that the introduction of the QAFE gives rise to performance improvements than those of conventional FinFETs, which is ascribed to QAFE’s negative slope segment of polarization (P) versus voltage (V) around P = 0 for the QAFE NC-FinFETs. Because of the induced negative gate charges due to fringing electric field (E) coupling in the short channel of 3-D FinFET, subthreshold swing (SS) is just slightly lower than the tyrant limit of 60 mV/decade but a significant on-state current enhancement is found in the QAFE NC-FinFETs. The charge range, where the NC effect exists, shows a significant impact on the performance of the device due to the small remnant polarization of the QAFE layer. With the designed component ratio, a superior current enhancement can be obtained compared with the control device. This work provides a design guideline for the development of future high-speed and low-power NC-FinFET with QAFE material. [ABSTRACT FROM AUTHOR]

Background: X-linked sideroblastic anemia (XLSA) is the most common form of congenital sideroblastic anemia (CSA), and is associated with the mutations in the 5-aminolevulinate synthase 2 (ALAS2). The genetic basis of more than 40% of CSA cases remains unknown. Methods: A two-generation Chinese family with XLSA was studied by next-generation sequencing to identify the underlying CSA-related mutations. Results: In the study, we identified a missense ALAS2 R204Q mutation in a hemizygous Chinese Han man and in his heterozygous daughter. The male proband presented clinical manifestations at 38 years old and had a good response to pyridoxine. Conclusions: XLSA, as a hereditary disease, can present clinical manifestations later in lives, for adult male patients with ringed sideroblasts and hypochromic anemia, it should be evaluated with gene analyses to exclude CSA. [ABSTRACT FROM AUTHOR]

Dental tissue has been acknowledged as an advantaged source for high-quality dental pulp stem cell (DPSC) preparation. However, despite the accomplishment of the separation of DPSCs from permanent teeth and supernumerary teeth, the deficiency of rigorous and systematic clarification on the signatures and efficacy will hinder their prospects in regenerative medicine. In this study, we primitively isolated permanent teeth-derived DPSCs and supernumerary teeth-derived apical papillary stem cells (SCAP-Ss) with parental consent. Immunophenotype of DPSCs and SCAP-Ss was determined by a flow cytometry assay, and the cell viability was verified by multidimensional detections including cell proliferation, cell cycle, apoptosis, and senescence. The migration and clonogenic capacity were examined by a wound healing test and crystal violet staining, respectively. The multilineage differentiation potential was quantitated by utilizing Oil Red O staining and Alizarin Red staining, together with real-time PCR analysis. The efficacy on a mouse hepatic fibrosis model was evaluated by using histologic sections and liver function tests. Herein, we showed that SCAP-Ss exhibited comparable immunophenotype and adipogenic differentiation capacity as DPSCs. However, different from DPSCs, SCAP-Ss exhibited superiority in cell viability and osteogenic differentiation. Simultaneously, injection of DPSCs and SCAP-Ss significantly reduced inflammatory infiltration, enhanced liver-associated gene expression, and finally relieved symptoms of hepatic fibrosis. In conclusion, SCAP-Ss possess preferable characteristics and efficacy on hepatic fibrosis in mice. Our findings suggest that SCAP-Ss are an easily accessible postnatal stem cell source with multifaceted characteristics for regenerative medicine. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem/stromal cells (MSCs) derived from human embryonic stem cells (hESCs) are attractive for their hematopoietic-supporting or potential therapeutic effects. However, procedures for high-effective and scalable generation of MSCs from hESCs within 2 weeks are still unestablished, which also hinder the development and mechanism study of mesengenesis. Methods: In this study, we aimed to establish a strategy for programming hESC differentiation into MSCs by practicing small-scale chemical compound screening. Then, we used flow cytometry, multi-lineage differentiation, and karyotype analyses to investigate the biological phenotypes of the derived hESC-MSCs. Also, to explore whether the derived cells had hematopoietic-supporting ability in vitro, we carried out the cobblestone formation and megakaryocytic differentiation experiments. To further evaluate the function of hESC-MSCs in vivo, we transplanted the cells into a mouse model with hind limb ischemia. Results: By simultaneous treatments with a JAK/STAT antagonist and a DNA methylation inhibitor, the efficiency of generating hESCs into CD73+ hESC-MPCs could reach 60% within 7 days. The derived cells further matured into hESC-MSCs, with comparable characteristics to those of adult MSCs in terms of surface markers, normal karyotype, and the potential for adipogenic, osteogenic, and chondrogenic differentiation. Functionally, hESC-MSCs had hematopoietic-supporting effects in vitro and could notably relieve symptoms of hind limb ischemia. Conclusions: In the study, we established a high-efficient procedure for large-scale generation of MSCs from hESCs, which would be of great help for genesis and mechanism studies of MSCs. Meanwhile, the derived cells provide an alternative for translational clinical research. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells are heterogenous populations with hematopoietic supporting and immunomodulating capacities. Enormous studies have focused on their preclinical or clinical therapeutic effects, yet the systematic study of continuous in vitro passages on signatures and functions of UC-MSCs at both the cellular and molecular levels is still lacking. Methods: In this study, to systematically evaluate the biological properties of MSCs at various passages, we analyzed biomarker expression, cell proliferation and apoptosis, chromosome karyotype, and tri-lineage differentiation potential. Subsequently, we took advantage of whole-exome sequencing to compare the somatic hypermutation of hUC-MSCs at P3, P6, and P15 including SNV and INDEL mutations. In addition, to explore the safety of the abovementioned hUC-MSCs, we performed metabolic pathway enrichment analysis and in vivo transplantation analysis. Furthermore, we cocultured the abovementioned hUC-MSCs with UCB-CD34+ HSCs to evaluate their hematopoietic supporting capacity in vitro. Finally, we transplanted the cells into acute graft-versus-host disease (aGVHD) mice to further evaluate their therapeutic effect in vivo. Results: The hUC-MSCs at P3, P6, and P15 showed similar morphology, biomarker expression, and cytokine secretion. hUC-MSCs at P15 had advantages on adipogenic differentiation and some cytokine secretion such as IL-6 and VEGF, with disadvantages on cell proliferation, apoptosis, and osteogenic and chondrogenic differentiation potential. Based on the SNP data of 334,378 exons and bioinformatic analyses, we found the somatic point mutations could be divided into 96 subsets and formed 30 kinds of signatures but did not show correlation with risk of tumorigenesis, which was confirmed by the in vivo transplantation experiments. However, hUC-MSCs at P15 showed impaired hematologic supporting effect in vitro and declined therapeutic effect on aGVHD in vivo. Conclusions: In this study, we systematically evaluated the biological and genetic properties of hUC-MSCs at various passages. Our findings have provided new references for safety and effectiveness assessments, which will provide overwhelming evidence for the safety of hUC-MSCs after continuous in vitro passages both at the cellular and molecular levels for the first time. Taken together, our studies could help understand the controversial effects of disease treatment and benefit the clinical research of UC-MSCs. [ABSTRACT FROM AUTHOR]

Background: Dyskeratosis congenita (DC) is an inherited telomeropathy characterized by mucocutaneous dysplasia, bone marrow failure, cancer predisposition, and other somatic abnormalities. Cells from patients with DC exhibit short telomere. The genetic basis of the majority of DC cases remains unknown. Methods: A 2 generational Chinese Han family with DC was studied using targeted capture and next-generation sequencing to identify the underlying DC-related mutations. Results: In this study, we identified a unique homozygous WD repeat containing antisense to TP53 (WRAP53) Arg298Trp mutation in the proband with DC and heterozygous WRAP53 Arg298Trp mutations in his asymptomatic, consanguineous parents and his sister, indicating an autosomal recessive inheritance mode. The proband with the homozygous WRAP53 Arg298Trp mutation had short telomere, classic clinical symptoms, and no response to danazol, glucocorticoid or cyclosporin A. Conclusions: Thus, we reported for the first time that a unique homozygous WRAP53 mutation site underlies the development of DC. [ABSTRACT FROM AUTHOR]