Determination of coefficient of friction for self-expanding stent-grafts

Migration of stent-grafts (SGs) after endovascular aneurysm repair of abdominal aortic aneurysms is a serious complication that may require secondary intervention. Experimental, analytical, and computational studies have been carried out in the past to understand the factors responsible for migration. In an experimental setting, it can be very challenging to correctly capture and understand the interaction between a SG and an artery. Quantities such as coefficient of friction (COF) and contact pressures that characterize this interaction are difficult to measure using an experimental approach. This behavior can be investigated with good accuracy using finite element modeling. Although finite element models are able to incorporate frictional behavior of SGs, the absence of reliable values of coefficient of friction make these simulations unreliable. The aim of this paper is to demonstrate a method for determining the coefficients of friction of a self-expanding endovascular stent-graft. The methodology is demonstrated by considering three commercially available self-expanding SGs, labeled as A, B, and C. The SGs were compressed, expanded, and pulled out of polymeric cylinders of varying diameters and the pullout force was recorded in each case. The SG geometries were recreated using computer-aided design modeling and the entire experiment was simulated in ABAQUS 6.8/STANDARD. An optimization procedure was carried out for each SG oversize configuration to determine the COF that generated a frictional force corresponding to that measured in the experiment. The experimental pullout force and analytically determined COF for SGs A, B, and C were in the range of 6-9 N, 3-12 N, and 3-9 N and 0.08-0.16, 0.22-0.46, and 0.012-0.018, respectively. The computational model predicted COFs in the range of 0.00025-0.0055, 0.025-0.07, and 0.00025-0.006 for SGs A, B, and C, respectively. Our results suggest that for SGs A and B, which are exoskeleton based devices, the pullout forces increase upto a particular oversize beyond which they plateau, while pullout forces showed a continuous increase with oversize for SG C, which is an endoskeleton based device. The COF decreased with oversizing for both types of SGs. The proposed methodology will be useful for determining the COF between self-expanding stent-grafts from pullout tests on human arterial tissue.     

Oxidative aromatization of 1,4-dihydropyridines and pyrazolines using HbA–H2O2: An efficient biomimetic catalyst system providing metabolites of drug candidates

Human hemoglobin (HbA) efficiently catalyses the oxidative aromatization of 1,4-dihydropyridines (1,4-DHPs) and pyrazolines with hydrogen peroxide in phosphate buffer. The results of the study reveal that the rates of oxidative aromatization of 1,4-DHPs are substituent dependent. Thus, the present study is very useful in understanding the metabolism of 1,4-DHP drugs in liver by cytochrome P450 and designing novel drugs as well as modifying the existing drugs for better pharmacokinetic profile.     

Systematic workflow for studying domain contributions of bispecific antibodies to selectivity in multimodal chromatography

In this article, a systematic workflow was formulated and implemented to understand selectivity differences and preferred binding patches for bispecific monoclonal antibodies (mAbs) and their parental mAbs on three multimodal cation exchange resin systems. This workflow incorporates chromatographic screening of the parent mAbs and their fragments at various pH followed by surface property mapping and protein footprinting using covalent labeling followed by liquid chromatography–mass spectrometry analysis. The chromatography screens on multimodal resins with the intact mAbs indicated enhanced selectivity as compared to single-mode interaction systems. While the bispecific antibody (bsAb) eluted between the two parental mAbs on most of the resins, the retention of the bispecific transitioned from co-eluting with one parental mAb to the other parental mAb on Capto MMC. To investigate the contribution of different domains, mAb fragments were evaluated and the results indicated that the interactions were likely dominated by the Fab domain at higher pH. Protein surface property maps were then employed to hypothesize the potential preferred binding patches in the solvent-exposed regions of the parental Fabs. Finally, protein footprinting was carried out with the parental mAbs and the bsAb in the bound and unbound states at pH 7.5 to identify the preferred binding patches. Results with the intact mAb analysis supported the hypothesis that interactions with the resins were primarily driven by the residues in the Fab fragments and not the Fc. Furthermore, peptide mapping data indicated that the light chain may be playing a more important role in the higher binding of Parent A as compared with Parent B in these resin systems. Finally, results with the bsAb indicated that both halves of the molecule contributed to binding with the resins, albeit with subtle differences as compared to the parental mAbs. The workflow presented in this paper lays the foundation to systematically study the chromatographic selectivity of large multidomain molecules which can provide insights into improved biomanufacturability and expedited downstream bioprocess development.     

Antimicrobial activity of marine bacteria associated with sponges from the waters off the coast of South East India

Seventy-five marine bacterial strains associated with four species of sponges (Echinodictyum sp., Spongia sp., Sigmadocia fibulatus and Mycale mannarensis) were isolated from the Tuticorin coast, Gulf of Mannar region. The agar-overlay method was used to screen for antibiotic production by these strains against four bacteria, viz., Bacillus subtilis, Escherichia coli, Vibrio parahaemolyticus, and Vibrio harveyi and one fungal pathogen, viz., Candida albicans. Twenty-one per cent of the bacterial strains were found to be antibiotic producers and their activities ranged from broad spectral to species specific. A strain coded SC3 was found to be highly potent and was mass cultured. The ethyl acetate extract of the culture broth was further fractionated by reverse phase HPLC and the active fraction identified. In addition, SC3 was subjected to morphological and physiological characterization. The results of the tests showed SC3 to be a Gram-positive rod, sporulating, motile, catalase and oxidase positive. Phylogenetic analysis based on comparative analysis of sequenced 16s rRNA of the active strains indicated a preponderance of bacteria belonging to Vibrio and Bacillus genera with 95-99% sequence similarities. To our knowledge this is the first report on phylogenetic identification of antibiotic producing bacteria associated with sponges from Indian waters.     

Requirement of FADD, NEMO, and BAX/BAK for aberrant mitochondrial function in tumor necrosis factor alpha-induced necrosis

Necroptosis represents a form of alternative programmed cell death that is dependent on the kinase RIP1. RIP1-dependent necroptotic death manifests as increased reactive oxygen species (ROS) production in mitochondria and is accompanied by loss of ATP biogenesis and eventual dissipation of mitochondrial membrane potential. Here, we show that tumor necrosis factor alpha (TNF-α)-induced necroptosis requires the adaptor proteins FADD and NEMO. FADD was found to mediate formation of the TNF-α-induced pronecrotic RIP1-RIP3 kinase complex, whereas the IκB Kinase (IKK) subunit NEMO appears to function downstream of RIP1-RIP3. Interestingly, loss of RelA potentiated TNF-α-dependent necroptosis, indicating that NEMO regulates necroptosis independently of NF-κB. Using both pharmacologic and genetic approaches, we demonstrate that the overexpression of antioxidants alleviates ROS elevation and necroptosis. Finally, elimination of BAX and BAK or overexpression of Bcl-x(L) protects cells from necroptosis at a later step. These findings provide evidence that mitochondria play an amplifying role in inflammation-induced necroptosis.     

CRTC1/MAML2 directs a PGC-1α-IGF-1 circuit that confers vulnerability to PPARγ inhibition

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