Hypersensitivity of BRCA1 Heterozygote Lymphoblastoid cells to Gamma radiation and PARP inhibitors

PARP inhibitors can be used to induce synthetic lethality in cells with bi-allelic BRCA1 and BRCA2 mutations. However the effect of PARP inhibitors in combination with radiation on cells with mono-allelic mutations of BRCA1 and BRCA2 is unknown. We have examined the cell survival response of lymphoblastoid cells derived from normal individuals and those derived from carriers of BRCA1 and BRCA2 mutations, following exposure to ionising radiation and the PARP inhibitor Olaparib. Two lymphoblastoid cell lines from normal individuals and three with mono-allelic mutations in BRCA1 and BRCA2 were exposed to increasing doses of gamma radiation either alone or in combination with 5 μM Olaparib. Cell survival was measured using the MTT assay. Exposure to increasing doses of gamma radiation caused a reduction in cell survival of all cell types. The combined exposure to gamma radiation and 5 μM Olaparib did not enhance cell kill in normal or BRCA2 heterozygote lymphoblastoid cells but significantly enhanced cell kill in cells derived from BRCA1 carriers (P = 0.02). The treatment of cancer patients carrying mutations in the BRCA1 gene with radiotherapy and the PARP inhibitor Olaparib may significantly enhance radiation induced normal tissue toxicity in these patients.

Metals and linear alkylbenzene sulphonate as inhibitors of the algae Pseudokirchneriella subcapitata acid phosphatase activity.

Sewage sludge applied to soils as a fertilizer often contains metals and linear alkylbenzene sulphonate (LAS) as contaminants. These pollutants can be transported to the aquatic environment where they can alter the phosphatase activity in living organisms. The acid phosphatase of algae plays important roles in metabolism such as decomposing organic phosphate into free phosphate and autophagic digestive processes. The order of in vitro inhi- bition of Pseudokirchneriella subcapitata acid phosphatase at the highest concentration tested was LAS[Hg2? = Al 3?[Se4? = Pb2?[Cd2?. A non-competitive inhibi- tion mechanism was obtained for Hg2? (Ki = 0.040 mM) and a competitive inhibition for LAS (Ki = 0.007 mM). In vivo studies with treated algae cultures showed that the inhibition of specific activity was observed in algae exposed during 7 days, in contrast to short term (24 h) treatments with both these chemicals. Our results suggest that the inhibition parameters in vitro did not markedly differ between the two chemicals. On the other hand, in vivo evaluations showed strong differences between both pollu- tants regarding the concentration values and the degree of response.

Entry inhibitors and Carbosilane dendrimers are potent inhibitors of cell-associated HIV-2 infection

Poster presented at the 2015 Keystone Symposia Conference X5: HIV Vaccines. Banff, Alberta, Canada, 22-27 March 2015

Development of synthetic light-chain antibodies as novel and potent HIV fusion inhibitors

This is a non-final version of an article published in final form in AIDS. 2016 Jul 17;30(11):1691-701.

A facile approach to spinning multifunctional conductive elastomer fibres with nanocarbon fillers

Electrically conductive elastomeric fibres prepared using a wet-spinning process are promising materials for intelligent textiles, in particular as a strain sensing component of the fabric. However, these fibres, when reinforced with conducting fillers, typically result in a compromise between mechanical and electrical properties and, ultimately, in the strain sensing functionality. Here we investigate the wet-spinning of polyurethane (PU) fibres with a range of conducting fillers such as carbon black (CB), single-walled carbon nanotubes (SWCNTs), and chemically converted graphene. We show that the electrical and mechanical properties of the composite fibres were strongly dependent on the aspect ratio of the filler and the interaction between the filler and the elastomer. The high aspect ratio SWCNT filler resulted in fibres with the highest electrical properties and reinforcement, while the fibres produced from the low aspect ratio CB had the highest stretchability. Furthermore, PU/SWCNT fibres presented the largest sensing range (up to 60% applied strain) and the most consistent and stable cyclic sensing behaviour. This work provides an understanding of the important factors that influence the production of conductive elastomer fibres by wet-spinning, which can be woven or knitted into textiles for the development of wearable strain sensors.

Innovators or inhibitors? Accounting faculty resistance to new educational technologies in higher education

While technology affords new opportunities and benefits for educators in their teaching practice, a significant number of faculty are resistant to adopting new technologies. Unprompted, 93% of faculty interviewed in the Australian study to be discussed in this paper pointed to accounting educator resistance as a key barrier to technology adoption and use. Adopting the Technology Acceptance Model (TAM) as a framework, this paper argues that one of the greatest challenges facing business schools and Higher Education Institutions (HEIs) in the 21st century is not new technologies themselves, but the ability of educators to embrace educational technologies. Drawing on the qualitative data to emerge from interviews with accounting educators recognised as exemplary in their use of innovative technologies, this paper explores the reasons for lack of faculty uptake and argues for academics to become innovators rather than inhibitors. The findings offer a timely insight into a twenty-first century issue affecting HEIs and, specifically, accounting academics. While carried out in the Accounting discipline, the findings may be relatable and applicable to all disciplines. A suite of recommendations are proposed for institutions, business schools and academics to consider.

High-performance multifunctional graphene-PLGA fibers: toward biomimetic and conducting 3D scaffolds

The development of electrically conducting fibers based on known cytocompatible materials is of interest to those engaged in tissue regeneration using electrical stimulation. Herein, it is demonstrated that with the aid of rheological insights, optimized formulations of graphene containing spinnable poly(lactic-co-glycolic acid) (PLGA) dopes can be made possible. This helps extend the general understanding of the mechanics involved in order to deliberately translate the intrinsic superior electrical and mechanical properties of solution-processed graphene into the design process and practical fiber architectural engineering. The as-produced fibers are found to exhibit excellent electrical conductivity and electrochemical performance, good mechanical properties, and cellular affinity. At the highest loading of graphene (24.3 wt%), the conductivity of as-prepared fibers is as high as 150 S m-1 (more than two orders of magnitude higher than the highest conductivity achieved for any type of nanocarbon-PLGA composite fibers) reported previously. Moreover, the Young's modulus and tensile strength of the base fiber are enhanced 647- and 59-folds, respectively, through addition of graphene.

Wet-spinning of multifunctional graphene fibers using graphene oxide liquid crystals

The recent discovery of liquid crystalline (LC) behavior of graphene oxide (GO) dispersions in various organic, and aqueous media brings added control to the assembly of larger structures using the chemical process approach.[1-3] The LC state can be used to direct the ordered assembly of nanocomponents in macroscopic structures via simple methods like wet-spinning. [3] Here, we developed a scaleable fabrication route to produce graphene fibers via a facile continuoes wetspinning methode. We develop solid understanding in the required criteria to correlate processability with LC behavior, aspect ratio and the dispersion concentration to provide a viable platform for spinning of LC GO. We demonstrate a striking result that highlits the importance of GO sheet size and polydispersity in generating wetspinnable LC GO dispersions from very low spinning dope concentrations (as low as 0.075 wt. %). The new knowledge gained through rheological investigations provides a sound explanation as to why continuous spinning of binder-free GO fibers is enabled by the LC behavior at this very low concentration.

Food-derived multifunctional bioactive proteins and peptides: sources and production

Multifunctional proteins and peptides from food proteins have been studied over the past few decades to elucidate their biological potency and the beneficial roles they play in human health. Owing to their multiple biological activities, these peptides have a wider role in modulating physiological functions such as antioxidative, antimicrobial, antihypertensive, cytomodulatory, anxiolytic, anorexic, and immunomodulatory activities in living body systems. Highlighted in this chapter is the biological role of some multifunctional peptides as well as the food proteins and enzyme(s) that are responsible for their release. Other challenges to the bioprocessing of multifunctional peptides and the need for research to address them are also discussed.

Food-derived multifunctional bioactive proteins and peptides: applications and recent advances

Owing to their biological roles, multifunctional peptides constitute a new generation of biologically active molecules whose potential can be exploited in several industrial applications such as functional food, pharmaceutical, and cosmeceutical industries. With the required combination and balance of research and commercial operations, major corporations can effectively harness the diverse functionalities of these peptides for enhanced nutrition and the treatment and mitigation of ill health. However, further insightful research in vivo and clinical studies are needed to unravel the mechanism and fate of these peptides en route to the body systems. This is needed to firmly establish the therapeutic potency of these peptides.

Fabrication of multifunctional graphene decorated with bromine and nano-Sb₂O₃ towards high-performance polymer nanocomposites

Despite great advances, it remains highly attractive but challenging to create high-performance polymeric materials combining excellent flame-retardancy and outstanding thermal, mechanical and electrical properties. We herein demonstrate a novel strategy for fabricating a multifunctional nano-additive (Br-Sb2O3@RGO) based on graphene decorated with bromine and nano-Sb2O3. Cone calorimetric tests show that incorporating 10 wt% Br-Sb2O3@RGO into thermoplastic polyurethane (TPU) strikingly prolongs the time to ignition and decreases the peak heat release rate by 72%. Besides, tensile strength and Young's modulus are enhanced by 37% and 820%, respectively. Meanwhile, the electric conductibility is increased by eleven orders of magnitude relative to the TPU matrix. This work provides a promising strategy for addressing the critical bottleneck with the existing flame retardants that only enhance flame retardancy at the expense of mechanical properties of polymeric materials. As-prepared high-performance TPU composites are expected to find many applications, especially in aerospace, tissue engineering, and cables and wires.

Multifunctional Nanoparticles in Cancer: in vitro Characterization, in vivo Distribution

A novel biocompatible and biodegradable polymer, termed poly(Glycerol malate co-dodecanedioate) (PGMD), was prepared by thermal condensation method and used for fabrication of nanoparticles (NPs). PGMD NPs were prepared using the single oil emulsion technique and loaded with an imaging/hyperthermia agent (IR820) and a chemotherapeutic agent (doxorubicin, DOX). The size of the void PGMD NPs, IR820-PGMD NPs and DOX-IR820-PGMD NPs were approximately 90 nm, 110 nm, and 125 nm respectively. An acidic environment (pH=5.0) induced higher DOX and IR820 release compared to pH=7.4. DOX release was also enhanced by exposure to laser, which increased the temperature to 42°C. Cytotoxicity of DOX-IR820-PGMD NPs was comparable in MES-SA but was higher in Dx5 cells compared to free DOX plus IR820 (pIn vivomouse studies showed that NP formulation significantly improved the plasma half-life of IR820 after tail vein injection. Significant lower IR820 content was observed in kidney in DOX-IR820-PGMD NP treatment as compared to free IR820 treatment in our biodistribution studies (p

Kinetic modelling of in vitro data of PI3K, mTOR1, PTEN enzymes and on-target inhibitors Rapamycin, BEZ235, and LY294002

The phosphatidylinositide 3-kinases (PI3K) and mammalian target of rapamycin-1 (mTOR1) are two key targets for anti-cancer therapy. Predicting the response of the PI3K/AKT/mTOR1 signalling pathway to targeted therapy is made difficult because of network complexities. Systems biology models can help explore those complexities but the value of such models is dependent on accurate parameterisation. Motivated by a need to increase accuracy in kinetic parameter estimation, and therefore the predictive power of the model, we present a framework to integrate kinetic data from enzyme assays into a unified enzyme kinetic model. We present exemplar kinetic models of PI3K and mTOR1, calibrated on in vitro enzyme data and founded on Michaelis-Menten (MM) approximation. We describe the effects of an allosteric mTOR1 inhibitor (Rapamycin) and ATP-competitive inhibitors (BEZ2235 and LY294002) that show dual inhibition of mTOR1 and PI3K. We also model the kinetics of phosphatase and tensin homolog (PTEN), which modulates sensitivity of the PI3K/AKT/mTOR1 pathway to these drugs. Model validation with independent data sets allows investigation of enzyme function and drug dose dependencies in a wide range of experimental conditions. Modelling of the mTOR1 kinetics showed that Rapamycin has an IC50 independent of ATP concentration and that it is a selective inhibitor of mTOR1 substrates S6K1 and 4EBP1: it retains 40% of mTOR1 activity relative to 4EBP1 phosphorylation and inhibits completely S6K1 activity. For the dual ATP-competitive inhibitors of mTOR1 and PI3K, LY294002 and BEZ235, we derived the dependence of the IC50 on ATP concentration that allows prediction of the IC50 at different ATP concentrations in enzyme and cellular assays. Comparison of the drug effectiveness in enzyme and cellular assays showed that some features of these drugs arise from signalling modulation beyond the on-target action and MM approximation and require a systems-level consideration of the whole PI3K/PTEN/AKT/mTOR1 network in order to understand mechanisms of drug sensitivity and resistance in different cancer cell lines. We suggest that using these models in systems biology investigation of the PI3K/AKT/mTOR1 signalling in cancer cells can bridge the gap between direct drug target action and the therapeutic response to these drugs and their combinations.

The influence of HIV, HCV and inhibitors on the quality of life and behavior of the disease in patients with haemophilia: An observational study

Inhibitors are the main complication in the treatment of haemophilia. A high percentage of adult patients were infected in past decades by HIV and HCV through factor concentrates. This study compared the quality of life of patients with hemophilia (QoL) and illness behavior in adult patients with haemophilia according to the development of inhibitors and HIV or HCV co-infection. This is an observational clinical study. 69 adult patients with haemophilia participated. We used A36 Hemophilia-QoL and IBQ questionnaires to measure the QoL and illness behavior, respectively. The dependent variables were type and severity of haemophilia, type of treatment, development of inhibitors, HIV and HCV infection, or both. We observed significant differences in the perception of QoL and illness behavior in patients according to the development of inhibitor and coinfection with HIV-HCV. We obtained four groups: the first and second group, which comprise 67% of the sample, exhibit behavior patterns indicating good adaptation to the disease and good QoL. The other two groups, which comprise 33% of the sample show behavior that is not well adapted to the disease, and poor quality of life. The development of inhibitors itself does not influence the quality of life and illness behavior in patients with haemophilia. Patients infected with HIV or HCV do not have a worse illness behavior compared to those uninfected. The development of inhibitors and HIV-HCV co-infection has a negative impact on quality of life and illness behavior in patients with haemophilia.