Forming low-cost, high quality carbon tows for automotive application.

Carbon fiber reinforced composites are widely used in many industries due to their high performance. Its application in the aerospace industry has increased significantly, however, in mass produced automobile sector it is still limited. The current production of carbon fiber tow is slow and capital intensive. Thus, carbon manufactures produce higher tow counts to increase production rate to reduce its cost. In order to offset the higher cost of carbon fiber composite, an innovative and unique approach has been developed. The higher tow count carbon spools are split into smaller tow counts. Due to the delicate nature of carbon fiber, it is important to control the filamentation during that process. Different splitting process line strategies have been developed in this research work for understanding the process limitations and challenges involved. The process was made feasible for production by developing a fully automated process line with a laser feedback system. The system splits a 12K spool into two 6K tows. The quality of the 6K split tows has been determined statistically by recording real time data from the laser during the splitting process. It was demonstrated that the proposed process effectively controls filamentation and produces consistent tow quality.Company research funding by Bentley Motors Limite

Discovery of FNDR-20123, a histone deacetylase inhibitor for the treatment of Plasmodium falciparum malaria

BACKGROUND: Emergence of anti-malarial drug resistance and perpetual increase in malaria incidence necessitates the development of novel anti-malarials. Histone deacetylases (HDAC) has been shown to be a promising target for malaria, despite this, there are no HDAC inhibitors in clinical trials for malaria treatment. This can be attributed to the poor pharmacokinetics, bioavailability and selectivity of the HDAC inhibitors. METHODS: A collection of HDAC inhibitors were screened for anti-malarial activity, and the best candidate was profiled in parasite-killing kinetics, growth inhibition of sensitive and multi-drug resistant (MDR) strains and against gametocytes. Absorption, distribution, metabolism and excretion pharmacokinetics (ADME-PK) parameters of FNDR-20123 were determined, and in vivo efficacy was studied in a mouse model for Plasmodium falciparum infection. RESULTS: A compound library of HDAC inhibitors (180 in number) was screened for anti-malarial activity, of which FNDR-20123 was the most potent candidate. The compound had been shown to inhibit Plasmodium HDAC with IC50 of 31 nM and human HDAC with IC50 of 3 nM. The IC50 obtained for P. falciparum in asexual blood-stage assay was 42 nM. When compared to atovaquone and pyrimethamine, the killing profiles of FNDR-20123 were better than atovaquone and comparable to pyrimethamine. The IC50 values for the growth inhibition of sensitive and MDR strains were similar, indicating that there is no cross-resistance and a low risk of resistance development. The selected compound was also active against gametocytes, indicating a potential for transmission control: IC50 values being 190 nM for male and > 5 microM for female gametocytes. FNDR-20123 is a stable candidate in human/mouse/rat liver microsomes (> 75% remaining post 2-h incubation), exhibits low plasma protein binding (57% in humans) with no human Ether-a-go-go-Related Gene (hERG) liability (> 100 microM), and does not inhibit any of the cytochrome P450 (CYP) isoforms tested (IC50 > 25 microM). It also shows negligible cytotoxicity to HepG-2 and THP-1 cell lines. The oral pharmacokinetics in rats at 100 mg/kg body weight shows good exposures (Cmax = 1.1 microM) and half-life (T1/2 = 5.5 h). Furthermore, a 14-day toxicokinetic study at 100 mg/kg daily dose did not show any abnormality in body weight or gross organ pathology. FNDR-20123 is also able to reduce parasitaemia significantly in a mouse model for P. falciparum infection when dosed orally and subcutaneously. CONCLUSION: FNDR-20123 may be a suitable candidate for the treatment of malaria, which can be further developed

Tensile Properties of Martensitic Stainless Steels at Elevated Temperatures

Tensile properties of quenched and tempered martensitic alloys EP-823, HT-9, and 422 were evaluated at temperatures ranging from ambient to 600 °C as a function of three different tempering times. The results indicated that the yield strength, ultimate tensile strength, and the failure strength were gradually reduced with increasing temperature. The ductility parameters were enhanced at elevated temperatures due to increased plastic flow. However, the tempering time did not significantly influence these properties. The evaluation of the fracture surfaces by scanning electron microscopy revealed reduced cracking and dimpled microstructures, indicating enhanced ductility at higher testing temperatures

The Weighted Independent Domination Problem: ILP Model and Algorithmic Approaches

This work deals with the so-called weighted independent domination problem, which is an $NP$-hard combinatorial optimization problem in graphs. In contrast to previous work, this paper considers the problem from a non-theoretical perspective. The first contribution consists in the development of three integer linear programming models. Second, two greedy heuristics are proposed. Finally, the last contribution is a population-based iterated greedy metaheuristic which is applied in two different ways: (1) the metaheuristic is applied directly to each problem instance, and (2) the metaheuristic is applied at each iteration of a higher-level framework---known as construct, merge, solve \& adapt---to sub-instances of the tackled problem instances. The results of the considered algorithmic approaches show that integer linear programming approaches can only compete with the developed metaheuristics in the context of graphs with up to 100 nodes. When larger graphs are concerned, the application of the populated-based iterated greedy algorithm within the higher-level framework works generally best. The experimental evaluation considers graphs of different types, sizes, densities, and ways of generating the node and edge weights

The weighted independent domination problem: ILP model and algorithmic approaches

This work deals with the so-called weighted independent domination problem, which is an N P -hard combinatorial optimization problem in graphs. In contrast to previous theoretical work from the liter- ature, this paper considers the problem from an algorithmic perspective. The first contribution consists in the development of an integer linear programming model and a heuristic that makes use of this model. Sec- ond, two greedy heuristics are proposed. Finally, the last contribution is a population-based iterated greedy algorithm that takes profit from the better one of the two developed greedy heuristics. The results of the compared algorithmic approaches show that small problem instances based on random graphs are best solved by an efficient integer linear programming solver such as CPLEX. Larger problem instances are best tackled by the population-based iterated greedy algorithm. The experimental evaluation considers random graphs of different sizes, densities, and ways of generating the node and edge weights

Derivatives of a benzoquinone acyl hydrazone with activity against Toxoplasma gondii

Toxoplasma gondii is an obligate intracellular parasite with global incidence. The acute infection, toxoplasmosis, is treatable but current regimens have poor host tolerance and no cure has been found for latent infections. This work builds upon a previous high throughput screen which identified benzoquinone acyl hydrazone (KG8) as the most promising compound; KG8 displayed potent in vitro activity against T. gondii but only marginal in vivoefficacy in a T. gondii animal model. To define the potential of this new lead compound, we now describe a baseline structure-activity relationship for this chemotype. Several derivatives displayed IC50\u27s comparable to that of the control treatment pyrimethamine with little to no cytotoxicity. The best of these, KGW44 and KGW59, had higher metabolic stability than KG8. In an in vivo T. gondii murine model, KGW59 significantly increased survivorship. This work provides new insights for optimization of this novel chemotype

Targeting Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-Dependent Signaling.

Intracellular signals triggered by DNA breakage flow through proteins containing BRCT (BRCA1 C-terminal) domains. This family, comprising 23 conserved phosphopeptide-binding modules in man, is inaccessible to small-molecule chemical inhibitors. Here, we develop Bractoppin, a drug-like inhibitor of phosphopeptide recognition by the human BRCA1 tandem (t)BRCT domain, which selectively inhibits substrate binding with nanomolar potency in vitro. Structure-activity exploration suggests that Bractoppin engages BRCA1 tBRCT residues recognizing pSer in the consensus motif, pSer-Pro-Thr-Phe, plus an abutting hydrophobic pocket that is distinct in structurally related BRCT domains, conferring selectivity. In cells, Bractoppin inhibits substrate recognition detected by Förster resonance energy transfer, and diminishes BRCA1 recruitment to DNA breaks, in turn suppressing damage-induced G2 arrest and assembly of the recombinase, RAD51. But damage-induced MDC1 recruitment, single-stranded DNA (ssDNA) generation, and TOPBP1 recruitment remain unaffected. Thus, an inhibitor of phosphopeptide recognition selectively interrupts BRCA1 tBRCT-dependent signals evoked by DNA damage

Oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia

Myeloid neoplasms are clonal hematopoietic stem cell disorders driven by the sequential acquisition of recurrent genetic lesions. Truncating mutations in the chromatin remodeler ASXL1 (ASXL1MT) are associated with a high-risk disease phenotype with increased proliferation, epigenetic therapeutic resistance, and poor survival outcomes. We performed a multi-omics interrogation to define gene expression and chromatin remodeling associated with ASXL1MT in chronic myelomonocytic leukemia (CMML). ASXL1MT are associated with a loss of repressive histone methylation and increase in permissive histone methylation and acetylation in promoter regions. ASXL1MT are further associated with de novo accessibility of distal enhancers binding ETS transcription factors, targeting important leukemogenic driver genes. Chromatin remodeling of promoters and enhancers is strongly associated with gene expression and heterogenous among overexpressed genes. These results provide a comprehensive map of the transcriptome and chromatin landscape of ASXL1MT CMML, forming an important framework for the development of novel therapeutic strategies targeting oncogenic cis interactions