Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 loaded by vectors could induce high rates of specific site genome editing and correct disease-causing mutations. However, most monogenic genetic diseases such as hemophilia are caused by different mutations dispersed in one gene, instead of an accordant mutation. Vectors developed for correcting specific mutations may not be suited to different mutations at other positions. Site-specific gene addition provides an ideal solution for long-term, stable gene therapy. We have demonstrated SaCas9-mediated homology-directed factor IX (FIX)
in situ
targeting for sustained treatment of hemophilia B. In this study, we tested a more efficient dual adeno-associated virus (AAV) strategy with lower vector dose for liver-directed genome editing that enables CRISPR-Cas9-mediated site-specific integration of therapeutic transgene within the albumin gene, and we aimed to develop a more universal gene-targeting approach. We successfully achieved coagulation function in newborn and adult hemophilia B mice by a single injection of dual AAV vectors. FIX levels in treated mice persisted even after a two-thirds partial hepatectomy, indicating stable gene integration. Our results suggest that this CRISPR-Cas9-mediated site-specific gene integration in hepatocytes could transform into a common clinical therapeutic method for hemophilia B and other genetic diseases.
Engineering, procurement, and construction (EPC) contracting does not promote collaboration and thus, may not be suitable for building information modeling (BIM) projects. Joint-contract functions that combine contractual control, coordination, and contingency adaptability may positively influence the performance of these BIM-enabled projects. This study hypothesized that perceived fairness, calculative trust, relational trust, and positive outcomes of distrust influence the relationship between joint contract functions and BIMenabled project performance. It collected 252 observations from industry practitioners in EPC oil and gas projects and analyzed them using partial least squares structural equation modelling (PLS-SEM). The results show no direct effect of joint-contract functions on BIM-enabled EPC project performance but do show significant total and indirect relationship effects that are influenced by perceived fairness and relational trust. The findings contribute to construction contracting research by empirically showing how formal contracts focusing on joint-contract functions can influence BIM-enabled EPC project performance. The current findings also shed light on appropriate contract framing for BIM-enabled EPC project stakeholders, an area not explored in the previous literature.
Highly interconnected porous polymer scaffolds were prepared by gas foaming.Poly(ε-caprolactone)/poly(lactic acid) blends were melt mixed and batch foamed using CO 2 as a physical blowing agent. The effects of the foaming temperature, pressure, and CO 2 saturation time on the foam morphology were related to the mechanical properties of the scaffolds. The cell size in cross section of scaffolds decreased and became more homogeneous until CO 2 saturation time reached 1.5 hours. With an increase in temperature, the cell size increased markedly and the cell size uniformity decreased gradually, whereas the reverse happened when the foaming pressure was increased. Meanwhile, many open cells can also be detected on the surface of scaffolds. High porosity and an open-cell content of greater than 90% were obtained. The compressive strength of scaffolds was regulated by controlling the foam architecture. The information gathered in this study may provide a theoretical basis for research into porous tissue engineering scaffolds. KEYWORDS batch foaming, mechanical properties, poly(ε-caprolactone)/poly(lactic acid), pore morphology, scaffold
A concise synthesis of phenanthridine derivatives is
achieved by
an iridium-catalyzed direct fusion of oxime ethers and heteroarenes,
which is a successful example of a cascade C–H/C–H cross-coupling/cyclization
strategy for polycyclic heteroaromatic synthesis. By subtle tuning
of the reaction conditions, both benzo- and simple five-membered heteroarenes
are suitable substrates under similar but different conditions. The
key is the right choice of a silver salt. The detailed mechanistic
study discloses that the first C–H/C–H cross-coupling
step involves an [IrII]–[IrIV] catalytic
cycle, which needs Ag2O as the oxidant. For the second
cyclization step, a radical process takes control in the reactions
of benzoheteroarenes and Ag2O is required; however, a C–H
cyclization functions in the reactions of simple five-membered heteroarenes
involving an [IrI]–[IrIII] catalytic
cycle, and AgTFA is necessary.
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