Investigations into the potential anticancer activity of Maximin H5

Here we report the first major example of anionic amphibian host defence peptides (HDPs) with anticancer activity. Maximin H5 is a C-terminally amidated, anionic host defence peptide (MH5N) from toads of the Bombina genus, which was shown to possess activity against the glioma cell line, T98G (EC50 = 125 μM). The peptide adopted high levels of α-helical structure (57.3%) in the presence of model cancer membranes (DMPC:DMPS in a molar ratio of 10:1). MH5N also showed a strong ability to penetrate these model membranes (Π = 10.5 mN m-1), which correlated with levels of DMPS (R2 > 0.98). Taken with the high ability of the peptide to lyse these membranes (65.7%), it is proposed that maximin H5 kills cancer cells via membranolytic mechanisms that are promoted by anionic lipid. It was also found that C-terminally deaminated maximin H5 (MH5C) exhibited lower levels of α-helical structure in the presence of cancer membrane mimics (44.8%) along with a reduced ability to penetrate these membranes (Π = 8.1 mN m-1) and induce their lysis (56.6%). These data suggested that the two terminal amide groups of native maximin H5 are required for its optimal membranolytic and anticancer activity

Investigation of hydrophobic moment and hydrophobicity properties for transmembrane α-helices

Integral membrane proteins are the primary targets of novel drugs but are largely without solved structures. As a consequence, hydrophobic moment plot methodology is often used to identify putative transmembrane α-helices of integral membrane proteins, based on their local maximum mean hydrophobic moment (<μH>) and the corresponding mean hydrophobicity (<H>). To calculate these properties, the methodology identifies an optimal eleven residue window (L = 11), assuming an amino acid angular frequency, θ, fixed at 100°. Using a data set of 403 transmembrane α-helix forming sequences, the relationship between <μH> and <H>, and the effect of varying of L and / or θ on this relationship, was investigated. Confidence intervals for correlations between <μH> and <H> are established. It is shown, using bootstrapping procedures that the strongest statistically significant correlations exist for small windows where 7 ≤ L ≤ 16. Monte Carlo analysis suggests that this correlation is dependent upon amino acid residue primary structure, implying biological function and indicating that smaller values of L give better characterisation of transmembrane sequences using <μH>. However, varying window size can also lead to different regions within a given sequence being identified as the optimal window for structure / function predictions. Furthermore, it is shown that optimal periodicity varies with window size; the optimum, based on <μH> over the range of window sizes, (7 ≤ L ≤ 16), was at θ = 102° for the transmembrane α-helix data set

Encouraging this Particular Form of (Very Fun) Madness – Roles for Deans and Faculty Members

Our broader goal is to encourage experiential learning in the transactions curriculum. I know that all of you are here and do not need convincing. So my goal for this session is to try and provide some persuasive tools to help you convince people at your schools about both the value and the possibility of this type of teaching and learning

Bacterial susceptibility and resistance to modelin-5.

Modelin-5 (M5-NH ) killed with a minimum lethal concentration (MLC) of 5.86 μM and strongly bound its cytoplasmic membrane (CM) with a of 23.5 μM. The peptide adopted high levels of amphiphilic α-helical structure (75.0%) and penetrated the CM hydrophobic core (8.0 mN m ). This insertion destabilised CM structure increased lipid packing and decreased fluidity (Δ 0) and promoted only low levels of lysis (24.3%). The insertion and lysis of the CM by M5-NH showed a strong negative correlation with its lysyl phosphatidylglycerol (Lys-PG) content ( > 0.98). In combination, these data suggested that Lys-PG mediated mechanisms inhibited the membranolytic action of M5-NH against , thereby rendering the organism resistant to the peptide. These results are discussed in relation to structure/function relationships of M5-NH and CM lipids that underpin bacterial susceptibility and resistance to the peptide

Thermal Risk Mitigation Testing of the DarkNESS Observatory for Fermi NationalAccelerator Laboratory

This paper presents the prototype design and laboratory test results of the thermal control system for the Dark matter as sterile Neutrino Search Satellite (DarkNESS). A collaboration between Fermilab, CU Aerospace, and the University of Illinois Department of Aerospace Engineering’s Laboratory for Advanced Space Systems (LASSI), the 6U satellite uses a Skipper CCD to detect weak 3.55 – 3.57 keV X-ray emissions, previously discovered by the XMM-Newton and Chandra X-ray observatories. To minimize read-out noise, the thermal control system incorporates a 10 W integral rotary cryocooler and passive heat transfer elements, maintaining the CCD at an operating temperature of 170 K. Analyses of the Earth\u27s obstruction of the instrument’s field of view and the impact of external heating on the instrument aperture established performance requirements and attitude constraints for the thermal control system. A high-fidelity test of a preliminary design was performed in a thermal vacuum chamber, prompting modifications to improve the thermal system design margins. This effort precedes the Critical Design Review milestone

Young mothers in care, contributing to the contemporary debate

Teenage pregnancy has become a broad issue in contemporary society and has become a focus for concern for young women in or exiting the care system. The article draws on interviews with twenty-four young mothers in, or on the fringes of the care system. It highlights the thoughts and feelings of these young women, specifically looking at the relationships that they have with their mothers, the father of their baby and their social workers. The mothers' sources of support and their perceptions of these are discussed. Implications for practice for working with this discrete group of young mothers are explored

PEGylated graphene oxide for tumor-targeted delivery of paclitaxel.

AIM: The graphene oxide (GO) sheet has been considered one of the most promising carbon derivatives in the field of material science for the past few years and has shown excellent tumor-targeting ability, biocompatibility and low toxicity. We have endeavored to conjugate paclitaxel (PTX) to GO molecule and investigate its anticancer efficacy. MATERIALS & METHODS: We conjugated the anticancer drug PTX to aminated PEG chains on GO sheets through covalent bonds to get GO-PEG-PTX complexes. The tissue distribution and anticancer efficacy of GO-PEG-PTX were then investigated using a B16 melanoma cancer-bearing C57 mice model. RESULTS: The GO-PEG-PTX complexes exhibited excellent water solubility and biocompatibility. Compared with the traditional formulation of PTX (Taxol®), GO-PEG-PTX has shown prolonged blood circulation time as well as high tumor-targeting and -suppressing efficacy. CONCLUSION: PEGylated graphene oxide is an excellent nanocarrier for paclitaxel for cancer targeting

Anionic Host Defence Peptides from the Plant Kingdom: Their Anticancer Activity and Mechanisms of Action

It is becoming increasingly clear that plants, ranging from across the plant kingdom produce anionic host defence peptides (AHDPs) with potent activity against a wide variety of human cancers cells. In general, this activity involves membrane partitioning by AHDPs, which leads to membranolysis and / or internalization to attack intracellular targets such as DNA. Several models have been proposed to describe these events including: the toroidal pore and Shai-Matsuzaki-Huang mechanisms but, in general, the mechanisms underpinning the membrane interactions and anticancer activity of these peptides are poorly understood. Plant AHDPs with anticancer activity can be conveniently discussed with reference to two groups: cyclotides, which possess cyclic molecules stabilized by cysteine knot motifs, and other ADHPs that adopt extended and α-helical conformations. Here, we review research into the anticancer action of these two groups of peptides along with current understanding of the mechanisms underpinning this action

An atlas of anionic antimicrobial peptides from amphibians

Anionic antimicrobial peptides (AAMPs) with net charges ranging from -1 to -8 have been identified in frogs, toads, newts and salamanders across Africa, South America and China. Most of these peptides show antibacterial activity and a number of them are multifunctional, variously showing antifungal activity, anticancer action, neuropeptide function and the ability to potentiate conventional antibiotics. Antimicrobial mechanisms proposed for these AAMPs, include toroidal pore formation and the Shai-Huang-Matsazuki model of membrane interaction along with pH dependent amyloidogenesis and membranolysis via tilted peptide formation. The potential for therapeutic and biotechnical application of these AAMPs has been demonstrated, including the development of amyloid-based nanomaterials and antiviral agents. It is concluded that amphibian AAMPs represent an untapped potential source of biologically active agents and merit far greater research interest