Impaired immunosuppressive role of myeloid-derived suppressor cells in acquired aplastic anemia

Myeloid-derived suppressor cells (MDSC) are a group of heterogeneous immature myeloid cells and display immunosuppressive function. In this study, MDSC populations were evaluated in acquired aplastic anemia (AA) (n=65) in which aberrant immune mechanisms contributed to bone marrow destruction. Our data demonstrate that both the proportion and immunosuppressive function of MDSC are impaired in AA patients. Decreased percentage of MDSC, especially monocytic MDSC, in the blood of AA patients (n=15) is positively correlated with the frequency of T-regulatory cells, bone marrow level of WT1 and decreased plasma level of arginase-1. RNA sequencing analyses reveal that multiple pathways including DNA damage, interleukin 4, apoptosis, and Jak kinase singnal transducer and activator of transcription are upregulated, whereas transcription, IL-6, IL-18, glycolysis, transforming growth factor and reactive oxygen species are downregulated in MDSC of AA (n=4), compared with that of healthy donors (n=3). These data suggest that AA MDSC are defective. Administration of rapamycin significantly increases the absolute number of MDSC and levels of intracellular enzymes, including arginase-1 and inducible nitric-oxide synthase. Moreover, rapamycin inhibits MDSC from differentiating into mature myeloid cells. These findings reveal that impaired MDSC are involved in the immunopathogenesis of AA. Pharmacologically targeting of MDSC by rapamycin might provide a promising therapeutic strategy for AA

The landscape of tolerated genetic variation in humans and primates.

Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases

Design and Process Planning of Non-Structured Surface Spray Equipment for Ultra-Large Spaces in Ship Section Manufacturing

Sandblasting and coating constitute a critical phase in ship manufacturing, a process currently predominantly reliant on manual labor. To enhance the efficiency and quality of the coating process for shipbuilding segments, to address the challenges shipbuilding companies face in labor recruitment and shortage, and to simultaneously elevate the level of intelligent manufacturing for ship segment coating, this research investigates equipment suitable for large-scale, non-structural surface coating in shipbuilding segments, considering the unique features of ship segments and the customary techniques employed by shipbuilding companies. The structure, size parameters, and principal components of the coating equipment are determined. Regular workspace with high performance is designated and the coating process is planned based on the working environment and the curvature characteristics of the surface to be coated. The results demonstrate that the proposed coating equipment improved efficiency by 300% compared to manual painting, providing a novel automated solution for the coating of ship segments

A unique homozygous WRAP53 Arg298Trp mutation underlies dyskeratosis congenita in a Chinese Han family

Abstract 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

Study on Preparation and Properties of Glass Fibre Fabric Reinforced Polyphenylene Sulphide Composites

In this paper, glass fiber fabric reinforced polyphenylene sulfide composites were prepared by hot pressing. The effects of glass fibre modification and hot pressing temperature on the properties of the composites were investigated using a scanning electron microscope, infrared spectrometer, universal testing machine, and DIGEYE digital imaging colour measurement system. The results show that after the treatment with a silane coupling agent, the silane coupling agent was more uniformly distributed on the surface of the glass fibres, and the bonding effect between the glass fibre fabric and polyphenylene sulphide was significantly improved. The strength of the composites increased and then decreased with the increase of hot pressing temperature, and the surface colour of the composites became darker and darker. When the hot-pressing temperature is 310 °C, the mechanical properties of glass fabric-reinforced polyphenylene sulfide composites are at their best, the tensile strength reaches 51.9 MPa, and the bending strength reaches 78 MPa

Parameter Optimization of Ultrafine Comminution Based on Analytic Hierarchy Process: Fuzzy Comprehensive Evaluation

This paper proposes a fuzzy comprehensive evaluation of ultrafine powders, namely, yield and quality value-based feature selection. Three indicators reflecting product yield and quality were selected to construct a simple and practical fuzzy comprehensive evaluation protocol. The weight set of the indices and the fuzzy evaluation set were calculated based on the analytic hierarchy process (AHP) method. The fuzzy comprehensive evaluation value was worked out as the only comprehensive index for the evaluation of product. The best ultrafine comminution condition will be established through the comparison of the fuzzy comprehensive evaluation values. Single-factor experiments and orthogonal experiments of the main influencing factors of ultrafine comminution were conducted. It was concluded that the importance of each factor is sequentially the concentration, specific surface area (SSA) of the media, and percentage of critical speed (PCS). Moreover, the concentration and SSA of the media were equally important. Ultrafine comminution by ball mill had the best overall performance under the PCS of 85%, the SSA of the media of 0.24 m2/kg, and the concentration of 75%

Effect of Quaternary climatic change on modern hydrologicalsystems in the southern Chinese Loess Plateau

A systematic study was conducted to investigate the permeability, porosity, grain size, water content, mass percentage of carbonate, and magnetic susceptibility of representative Middle Pleistocene loess-palaeosol layers (from L1 to S5) on the Chinese Loess Plateau. The average infiltration rate of the loess (0.93&nbsp;mm/min) was higher than the palaeosol (0.62&nbsp;mm/min), and the porosity of loess was higher than that of palaeosol. The loess layers have greater water-bearing capacity and, therefore, they are more likely to form aquifers while the palaeosol layers are more prone to form aquitards. The greater permeability and the larger water-bearing space of the loess layers are largely the result of lower intensity pedogenesis due to the colder/drier climatic conditions at the time these sediments were deposited. Conversely, the weaker permeability and lesser water-bearing capacity of the palaeosol layers can be explained by the greater pedogenesis during the warmer/wetter climatic conditions. The studies demonstrate a compelling relationship between Pleistocene climate and modern hydrological systems in the southern Chinese Loess Plateau.</p