Endothelial cells derived from patients' induced pluripotent stem cells for sustained factor VIII delivery and the treatment of hemophilia A.

Hemophilia A (HA) is a bleeding disorder characterized by spontaneous and prolonged hemorrhage. The disease is caused by mutations in the coagulation factor 8 gene (F8) leading to factor VIII (FVIII) deficiency. Since FVIII is primarily produced in endothelial cells (ECs) in a non-diseased human being, ECs hold great potential for development as a cell therapy for HA. We showed that HA patient-specific induced pluripotent stem cells (HA-iPSCs) could provide a renewable supply of ECs. The HA-iPSC-derived ECs were transduced with lentiviral vectors to stably express the functional B domain deleted F8 gene, the luciferase gene, and the enhanced green fluorescent protein gene (GFP). When transplanted intramuscularly into neonatal and adult immune deficient mice, the HA-iPSC-derived ECs were retained in the animals for at least 10-16 weeks and maintained their expression of FVIII, GFP, and the endothelial marker CD31, as demonstrated by bioluminescence imaging and immunostaining, respectively. When transplanted into HA mice, these transduced HA-iPSC-derived ECs significantly reduced blood loss in a tail-clip bleeding test and produced therapeutic plasma levels (11.2%-369.2%) of FVIII. Thus, our studies provide proof-of-concept that HA-iPSC-derived ECs can serve as a factory to deliver FVIII for the treatment of HA not only in adults but also in newborns

Research on the Macro-Mesoscopic Response Mechanism of Multisphere Approximated Heteromorphic Tailing Particles

AbstractThe shape of tailing particles is essential factors of their macroscopic mechanical properties. Scholars have studied the effects of controllable factors, such as loading method, confining pressure, and strain rate, on the strength of tailing sand. However, research on the tailing particle structure and shape through laboratory tests has proved to be difficult due to the uncertain and discrete tailing particle distribution. Thus, the macro-mesoscopic response of heteromorphic tailing particles is rarely investigated. In this paper, the macro-mesoscopic response of heteromorphic tailing particles is studied using multisphere approximation, and numerical simulation of triaxial tests on the particles is conducted. Nonlinear evolution patterns of porosity, internal friction angle, and cohesion of heteromorphic tailing particles with the variation of angularity were investigated using the flexible boundary program developed in this study, which revealed the intrinsic relationship between the mesostructure evolution mechanism and the macroscopic engineering characteristics of heteromorphic tailing particles. The research results showed that (1) changes in angularity led to tailing particle rearrangements and, in turn, porosity changes. With increased angularity and confining pressure, particle sphericity decreased, and the deviatoric and peak stress increased accordingly. In the meantime, the softening was more significant as the peak stress was exceeded, while the cohesive force generally increased. (2) With fixed particle shape and angularity, the internal friction angle decreased slightly as the effective confining pressure increased. (3) In the shearing process, the simulated contact force chain evolution of tailing particles with different shapes was similar. The disordered contact force chains gradually undergo directional connection, i.e., the increased confining pressure reduced the number of free tailing particles and increased the number of stressed particles. (4) The triaxial stress-strain and peak stress in rigid boundary simulations under different confining pressures were slightly lower than those in the flexible boundary simulations. However, the difference was insignificant, indicating the good feasibility and reasonability of rigid boundary simulations for the macroscopic mechanical behaviors in triaxial tests. The research results could offer more direct insights into the macro-mesoscopic response and mechanical mechanisms of nonspherical particles and provide references for the simulation of tailings at the microscopic levels

Mutations in the Human naked cuticle Homolog NKD1 Found in Colorectal Cancer Alter Wnt/Dvl/β-Catenin Signaling

BACKGROUND:Mutation of Wnt signal antagonists Apc or Axin activates beta-catenin signaling in many cancers including the majority of human colorectal adenocarcinomas. The phenotype of apc or axin mutation in the fruit fly Drosophila melanogaster is strikingly similar to that caused by mutation in the segment-polarity gene, naked cuticle (nkd). Nkd inhibits Wnt signaling by binding to the Dishevelled (Dsh/Dvl) family of scaffold proteins that link Wnt receptor activation to beta-catenin accumulation and TCF-dependent transcription, but human NKD genes have yet to be directly implicated in cancer. METHODOLOGY/PRINCIPAL FINDINGS:We identify for the first time mutations in NKD1--one of two human nkd homologs--in a subset of DNA mismatch repair-deficient colorectal tumors that are not known to harbor mutations in other Wnt-pathway genes. The mutant Nkd1 proteins are defective at inhibiting Wnt signaling; in addition, the mutant Nkd1 proteins stabilize beta-catenin and promote cell proliferation, in part due to a reduced ability of each mutant Nkd1 protein to bind and destabilize Dvl proteins. CONCLUSIONS/SIGNIFICANCE:Our data raise the hypothesis that specific NKD1 mutations promote Wnt-dependent tumorigenesis in a subset of DNA mismatch-repair-deficient colorectal adenocarcinomas and possibly other Wnt-signal driven human cancers

Experimental Study on Failure Model of Tailing Dam Overtopping under Heavy Rainfall

AbstractUnusual rainfall is the primary cause of the failure of the tailing dams, and overtopping is the most representative model of the tailing dam failure. The upstream tailing dam was selected as the research object to study the whole process of breach extension and the overtopping dam-failure mechanism under the full-scale rainfall condition. The results showed that the significant size grading phenomenon in the front, middle, and end of the tailing pond was obvious due to the flow separation effect, and its average particle diameter was D50. At different moments of rainfall, the height of the infiltration line at different positions of the dam body was different; at the rainfall of 3600 s, the height of the infiltration line lagged behind the height of the tailing pond, and this phenomenon from the tail of pond to the outside of the dam slope became more obvious. After the rainfall of 3600 s, the height of the infiltration line lagging behind the water level in the pond basically disappeared, and the rate of infiltration line rise kept pace with the rate of water level. The process of overtopping dam-failure experienced dam overtopping (gully erosion), formation of a multistepped small “scarp,” breach rapid expansion, formation of large “scarp,” and burst (fan-shaped formation). The width and depth of the breach showed a positive correlation, and the widening rate of the breach was 3 to 8 times of the deepening rate, especially in the middle of the dam break, widening behavior occupied the dominant factor. The shape of the dam body after failure was parabolic, and the dam body had obvious elevation changes. These results provide the theoretical guidance and engineering application value for improving the theory and early warning model of the upstream tailing dam

Generation of integration-free neural progenitor cells from cells in human urine

Human neural stem cells hold great promise for research and therapy in neural disease. We describe the generation of integration-free and expandable human neural progenitor cells (NPCs). We combined an episomal system to deliver reprogramming factors with a chemically defined culture medium to reprogram epithelial-like cells from human urine into NPCs (hUiNPCs). These transgene-free hUiNPCs can self-renew and can differentiate into multiple functional neuronal subtypes and glial cells in vitro. Although functional in vivo analysis is still needed, we report that the cells survive and differentiate upon transplant into newborn rat brain.postprin

Pre-Absorbed Immunoproteomics: A Novel Method for the Detection of Streptococcus suis Surface Proteins

Streptococcus suis serotype 2 (SS2) is a zoonotic pathogen that can cause infections in pigs and humans. Bacterial surface proteins are often investigated as potential vaccine candidates and biomarkers of virulence. In this study, a novel method for identifying bacterial surface proteins is presented, which combines immunoproteomic and immunoserologic techniques. Critical to the success of this new method is an improved procedure for generating two-dimensional electrophoresis gel profiles of S. suis proteins. The S. suis surface proteins identified in this study include muramidase-released protein precursor (MRP) and an ABC transporter protein, while MRP is thought to be one of the main virulence factors in SS2 located on the bacterial surface. Herein, we demonstrate that the ABC transporter protein can bind to HEp-2 cells, which strongly suggests that this protein is located on the bacterial cell surface and may be involved in pathogenesis. An immunofluorescence assay confirmed that the ABC transporter is localized to the bacterial outer surface. This new method may prove to be a useful tool for identifying surface proteins, and aid in the development of new vaccine subunits and disease diagnostics

JOURNAL OF HEMATOLOGY & ONCOLOGY REVIEW

Advances in understanding the cell types and approaches used for generating induced pluripotent stem cell

Anhydrous interfacial polymerization of sub-1 Å sieving polyamide membrane

Abstract Highly permeable polyamide (PA) membrane capable of precise ionic sieving can be utilized for many energy-efficient chemical separations. To fulfill this target, it is crucial to innovate membrane-forming process to induce a narrow pore-size distribution. Herein, we report an anhydrous interfacial polymerization (AIP) at a solid-liquid interface where the amine layer sublimated is in direct contact with the alkane containing acyl chlorides. In such a heterophase interface, water-caused side reactions are eliminated, and the amines in compact arrangement enable an intensive and orderly IP reaction, leading to a unique PA layer with an ionic sieving accuracy of 0.5 Å. The AIP-PA membrane demonstrates excellent separation selectivities of monovalent and divalent cations such as Mg2+/Li+ (78.3) and anions such as Cl-/SO4 2- (29.2) together with a high water flux up to 13.6 L m−2 h−1 bar−1. Our AIP strategy may provide inspirations for engineering high-precision PA membranes available in various advanced separations

An analytical model for terahertz detection in cylindrical surrounding-gate MOSFETs

An analytical model for detection of terahertz radiation by plasma wave in cylindrical surrounding-gate (SRG) MOSFETs is presented. In comparison with traditional drain-current models, the rectification response of terahertz signal due to current self-mixing in conducting channel is considered by solving coupled plasma fluid equations using perturbation method. The resulted model is for the first time dipicting detector response in above threshold, near threshold and subthreshold regimes by a single expression valid for both resonant and nonresonant detection schemes. As no fitting parameters is adopted, the model is physical and predicative. Model validity has been extensively verified through numerically solving differential equations with a wide range of incident wave frequencies, channel doping concentrations, device working temperatures, SRG MOSFET geometry parameters as well as incident wave amplitudes. Model applicability to large input terahertz signal has also been discussed. The presented model is convenient for finding the optimum detector design from a multiparameter space. Its great universality will make it a candidate compact model for future terahertz integrated circuit simulation