Synthesis of dental resins using diatomite and nano-sized SiO2 and TiO2

AbstractThe mechanical properties of dental composites were improved by porous diatomite and nano-sized silica (OX-50) used as co-fillers. The resin composites, filled with silanized OX-50 and silanized diatomite (40:60wt/wt), presented the best flexural strength (133.1MPa), elastic modulus (9.5GPa) and Vickers microhardness (104.0HV). Besides these, TiO2 nanoparticles were introduced to tune the dental resin composites colours which were valued by the CIE-Lab system. The colour parameters (L⁎, a⁎, b⁎) showed that the colour changes of resin composites could be perceived obviously, when 300–400nm TiO2 particles were introduced as fillers. The resin composite, filled with 0.5wt% TiO2, exhibited both clear discolouration (ΔE⁎=3.22) and high mechanical strength. Using scanning electron microscope (SEM) equipped with an energy dispersive X-ray (EDX), the titanium elemental mapping results indicated that the TiO2 particles were distributed evenly in the prepared dental composites

Functional factor VIII made with von Willebrand factor at high levels in transgenic milk

Background—Current manufacturing methods for recombinant human Factor VIII (rFVIII) within mammalian cell cultures are inefficient which limit the abundance needed for affordable, worldwide treatment of hemophilia A. However, rFVIII has been expressed at very high levels by the transgenic mammary gland of mice, rabbits, sheep and pigs. Unfortunately, it is secreted into milk with low specific activity due in part to the labile, heterodimeric structure that results from furin processing of its B domain. Objectives—To express biologically active rFVIII in the milk of transgenic mice through targeted bioengineering. Methods—Transgenic mice were made with a mammary specific FVIII gene (226/N6) bioengineered for efficient expression and stability containing a B domain with no furin cleavage sites. 226/N6 was expressed with and without von Willebrand Factor (VWF). 226/N6 was evaluated by ELISA, SDS-PAGE, Western blot, and one- and two-stage clotting assays. Hemostatic activity of immunoaffinity enriched 226/N6 was studied in vivo by infusion into hemophilia A knockout mice. Results and conclusions—With or without co-expression of VWF, 226/N6 was secreted into milk as a biologically active single chain molecule that retained high specific activity similar to therapeutic-grade FVIII. 226/N6 had \u3e450-fold higher IU/ml than previously reported in cell culture for rFVIII. 226/N6 exhibited similar binding to plasma-derived VWF as therapeutic-grade rFVIII and intravenous infusion of transgenic 226/N6 corrected the bleeding phenotype of hemophilia A mice. This provides proof-of-principle to study expression of 226/N6 and perhaps other single chain bioengineered rFVIII in the milk of transgenic livestock

C/EBPα is an essential collaborator in Hoxa9/Meis1-mediated leukemogenesis

Homeobox A9 (HOXA9) is a homeodomain-containing transcription factor that plays a key role in hematopoietic stem cell expansion and is commonly deregulated in human acute leukemias. A variety of upstream genetic alterations in acute myeloid leukemia (AML) lead to overexpression of HOXA9, almost always in association with overexpression of its cofactor meis homeobox 1 (MEIS1) . A wide range of data suggests that HOXA9 and MEIS1 play a synergistic causative role in AML, although the molecular mechanisms leading to transformation by HOXA9 and MEIS1 remain elusive. In this study, we identify CCAAT/enhancer binding protein alpha (C/EBPα) as a critical collaborator required for Hoxa9/Meis1-mediated leukemogenesis. We show that C/EBPα is required for the proliferation of Hoxa9/Meis1-transformed cells in culture and that loss of C/EBPα greatly improves survival in both primary and secondary murine models of Hoxa9/Meis1-induced leukemia. Over 50% of Hoxa9 genome-wide binding sites are cobound by C/EBPα, which coregulates a number of downstream target genes involved in the regulation of cell proliferation and differentiation. Finally, we show that Hoxa9 represses the locus of the cyclin-dependent kinase inhibitors Cdkn2a/b in concert with C/EBPα to overcome a block in G1 cell cycle progression. Together, our results suggest a previously unidentified role for C/EBPα in maintaining the proliferation required for Hoxa9/Meis1-mediated leukemogenesis

HOXA9 Reprograms the Enhancer Landscape to Promote Leukemogenesis

Aberrant expression of HOXA9 is a prominent feature of acute leukemia driven by diverse oncogenes. Here we show that HOXA9 overexpression in myeloid and B progenitor cells leads to significant enhancer reorganizations with prominent emergence of leukemia-specific de novo enhancers. Alterations in the enhancer landscape lead to activation of an ectopic embryonic gene program. We show that HOXA9 functions as a pioneer factor at de novo enhancers and recruits CEBPα and the MLL3/MLL4 complex. Genetic deletion of MLL3/MLL4 blocks histone H3K4 methylation at de novo enhancers and inhibits HOXA9/MEIS1-mediated leukemogenesis in vivo. These results suggest that therapeutic targeting of HOXA9-dependent enhancer reorganization can be an effective therapeutic strategy in acute leukemia with HOXA9 overexpressio

Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo

Chromosomal translocations affecting mixed lineage leukemia gene (MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Finally, we demonstrate the efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification

Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity

ASH1L histone methyltransferase plays a crucial role in the pathogenesis of different diseases, including acute leukemia. While ASH1L represents an attractive drug target, developing ASH1L inhibitors is challenging, as the catalytic SET domain adapts an inactive conformation with autoinhibitory loop blocking the access to the active site. Here, by applying fragment-based screening followed by medicinal chemistry and a structure-based design, we developed first-in-class small molecule inhibitors of the ASH1L SET domain. The crystal structures of ASH1L-inhibitor complexes reveal compound binding to the autoinhibitory loop region in the SET domain. When tested in MLL leukemia models, our lead compound, AS-99, blocks cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and reduces the leukemia burden in vivo. This work validates the ASH1L SET domain as a druggable target and provides a chemical probe to further study the biological functions of ASH1L as well as to develop therapeutic agents

Multiple Roles for the Non-Coding RNA SRA in Regulation of Adipogenesis and Insulin Sensitivity

Peroxisome proliferator-activated receptor-γ (PPARγ) is a master transcriptional regulator of adipogenesis. Hence, the identification of PPARγ coactivators should help reveal mechanisms controlling gene expression in adipose tissue development and physiology. We show that the non-coding RNA, Steroid receptor RNA Activator (SRA), associates with PPARγ and coactivates PPARγ-dependent reporter gene expression. Overexpression of SRA in ST2 mesenchymal precursor cells promotes their differentiation into adipocytes. Conversely, knockdown of endogenous SRA inhibits 3T3-L1 preadipocyte differentiation. Microarray analysis reveals hundreds of SRA-responsive genes in adipocytes, including genes involved in the cell cycle, and insulin and TNFα signaling pathways. Some functions of SRA may involve mechanisms other than coactivation of PPARγ. SRA in adipocytes increases both glucose uptake and phosphorylation of Akt and FOXO1 in response to insulin. SRA promotes S-phase entry during mitotic clonal expansion, decreases expression of the cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1, and increases phosphorylation of Cdk1/Cdc2. SRA also inhibits the expression of adipocyte-related inflammatory genes and TNFα-induced phosphorylation of c-Jun NH2-terminal kinase. In conclusion, SRA enhances adipogenesis and adipocyte function through multiple pathways

Multi-objective optimization of urban road intersection signal timing based on particle swarm optimization algorithm

Currently, signal control mode is the main control method of urban road intersections. Given that the traffic efficiency of road intersections is mainly affected by signal timing schemes, it is important to optimize signal timing at road intersections. Therefore, signal timing optimization methods of urban road intersections are explored in this work. When optimizing the timing of the signal at the intersections, the selection of optimization targets play an important role. At present, there are multiple objectives considered while designing signal timing scheme, including capacity, delays, and automobile exhaust. However, from the perspective of the traveler, they are more concerned about their own delay while passing intersections. In this work, we propose a novel multi-objective signal timing optimization model with goals of per capita delay, vehicle emissions, and intersection capacity. Considering the problem characteristics of the target problem, a meta-heuristic algorithm combining difference operator, which is based on Particle Swarm Optimization Algorithm, is developed. To test the validity of proposed approach, we applied it to real-world intersection signal timing problems in China. The results show that the optimized signal timing scheme obtained by the proposed algorithm is better than the realistic one. Also, the effectiveness of the developed algorithm is demonstrated by comparing it with other efficient algorithms.Published versio

A Study of the Insulation Mechanism and Anti-Frost Heave Effects of Polystyrene Boards in Seasonal Frozen Soil

The damages resulting from frost heaving are the main causes of channel destruction in seasonal frozen soil regions. Over the years, many experimental studies have been performed regarding the channel anti-frost heaving in the Hetao irrigation area. However, there have been few experimental research studies conducted regarding the insulation and anti-frost heave effects of polystyrene boards (EPS) of different thicknesses. Therefore, in order to explore the insulation mechanism and anti-frost heave effects of precast EPS laid under the conditions of different thicknesses, an anti-frost heave test field was established in the Hetao irrigation area for the examination of the ground temperatures, frozen depths, frost heave amounts, and water content change rules. This study’s results showed that, for the laid EPS with thicknesses between 2 and 12 cm, the frost-heave reduction rate ranged from 53.2% to 92.6%; total accumulated temperature warming ranged from 248.65% to 565.93%; and the frozen depth reduction rate was between 59.8% and 75.9%. It was determined that the EPS per cm additions could effectively improve the ground temperatures at a buried depth of 30 cm by 0.78 °C, and reduce the frozen depth by 10.1 cm. Then, by comprehensively considering the positive economic and insulation effects, it was determined that the most appropriate thickness of the EPS laid under the precast concrete slabs in the Hetao irrigation area of Inner Mongolia was 8–10 cm