Nanoindentation analysis of αtricalcium phosphate-poly(lactide-co-glycolide) nanocomposite degradation.

The internal mechanical property characteristics as functions of position and degradation time of PLGA(50:50)-αTCP nanocomposites of varying ceramic-polymer ratios degraded in an aqueous medium have been assessed using depth-sensing nanoindentation. The addition of nanoparticulate αTCP increases the elastic modulus of undegraded specimens from 3.72 ± 0.12 GPa for pure PLGA(50:50) samples to 7.23 ± 0.16 GPa recorded for undegraded 40 wt.% TCP nanocomposites. Additionally αTCP incorporation decreases the viscoelastic loss tangent from 0.189 ± 0.040 measured for pure undegraded PLGA(50:50) to an average of 0.091 ± 0.006 for undegraded ceramic-polymer composites. No variation in viscosity for the composites with ceramic loading was evidenced. The stiffening effect of αTCP addition closely conforms to the lower Hashin-Shtrikman bounds demonstrating that an evenly dispersed nano-filler is the least amenable ceramic configuration to enhance the mechanical properties of PLGA-αTCP nanocomposites. The mechanical property evolution for all composite types in an aqueous degradation medium is dominated by material hydration which effects reduced material stiffness and increased specimen viscosity generating a core-periphery mechanical property distribution in terms of elastic modulus and viscoelastic phase angle. The mechanical property core-periphery structure correlates strongly with the core-periphery density structure characterized using X-ray microtomography. Hydrated regions exhibit significant reductions in elastic modulus and viscosity increases which are typical of elastomers.RCUKThis is the author's accepted manuscript and will be under embargo until the 2nd of June 2015. The final version is published by Elsevier in Materials Science and Engineering: C here: http://www.sciencedirect.com/science/article/pii/S0928493114003099

X-ray microtomographic analysis of α-tricalcium phosphate- poly(lactic-co-glycolic) acid nanocomposite degradation

The degradation characteristics of αTCP-PLGA(50:50) nanocomposites containing varying ceramic weight loadings in an aqueous medium have been assessed using X-ray microtomography (XμT). Also measured were bulk density changes, pharmaceutic drug release and medium acidification for the degrading materials. Calcium phosphate addition to the polymer leads to increasing delays in the onset of degradation medium acidification and tetracycline release. Bulk density changes with time for all composite materials measured using a buoyancy method were well described during the initial degradation regime by a t1/2function. PLGA density evolution follows a linear function of time which indicates a differing water absorption process occurring in the pure polymer compared with the nanocomposites. Nanocomposite microtomographic analysis over the same period elucidated a core-periphery structure caused by water imbibition. Peripheral regions closest to the specimen surface exhibit reduced attenuation coefficients compared with the core which may be characteristic of a frontal system caused by a polymer phase transition. The front position and specimen swelling are adequately described by a t1/2and complementary error function respectively which if assessed under the assumption of a diffusion controlled process yields a diffusion coefficient of water in all nanocomposites at 37 °C of 4.8 × 10-14cm2s-1. Nevertheless, a t dependence is a necessary but not sufficient condition of a Fickian diffusion process. For all nanocomposite types both XμT data and bulk density measurements exhibited no variations with ceramic filler content

Kinase inhibition leads to hormesis in a dual phosphorylation-dephosphorylation cycle

This is the final version of the article. Available from the publisher via the DOI in this record.Many antimicrobial and anti-tumour drugs elicit hormetic responses characterised by low-dose stimulation and high-dose inhibition. While this can have profound consequences for human health, with low drug concentrations actually stimulating pathogen or tumour growth, the mechanistic understanding behind such responses is still lacking. We propose a novel, simple but general mechanism that could give rise to hormesis in systems where an inhibitor acts on an enzyme. At its core is one of the basic building blocks in intracellular signalling, the dual phosphorylation-dephosphorylation motif, found in diverse regulatory processes including control of cell proliferation and programmed cell death. Our analytically-derived conditions for observing hormesis provide clues as to why this mechanism has not been previously identified. Current mathematical models regularly make simplifying assumptions that lack empirical support but inadvertently preclude the observation of hormesis. In addition, due to the inherent population heterogeneities, the presence of hormesis is likely to be masked in empirical population-level studies. Therefore, examining hormetic responses at single-cell level coupled with improved mathematical models could substantially enhance detection and mechanistic understanding of hormesis.Funding bodies: BBSRC (BB/J010340/1); EPSRC (EP/I00503X/1); Wellcome Trust (ISSF to University of Exeter)

Performance-based building and innovation: Balancing client and industry needs

One reason for the interest in performance-based building is that it is commonly advocated as a powerful way of enhancing innovation performance by articulating building performance outcomes, and by offering relevant procurement actors the discretion to innovate to meet these performance requirements more effectively and/or efficiently. The paper argues that the current approach to performance-based building assumes that relevant actors have the capacity, ability and motivation to innovate from a business perspective. It is proposed that the prevailing conceptualization of PBB is too restrictive and should be broadened explicitly to accommodate the required business logic that must be in place before actors will innovate. The relevant performance-based building and innovation literature is synthesized to support the assertion. The paper concludes with an innovation-focused definition of performance-based building

Towards the development of novel Trypanosoma brucei RNA editing ligase 1 inhibitors

Abstract Background Trypanosoma brucei (T. brucei) is an infectious agent for which drug development has been largely neglected. We here use a recently developed computer program called AutoGrow to add interacting molecular fragments to S5, a known inhibitor of the validated T. brucei drug target RNA editing ligase 1, in order to improve its predicted binding affinity. Results The proposed binding modes of the resulting compounds mimic that of ATP, the native substrate, and provide insights into novel protein-ligand interactions that may be exploited in future drug-discovery projects. Conclusions We are hopeful that these new predicted inhibitors will aid medicinal chemists in developing novel therapeutics to fight human African trypanosomiasis

Metalevel algorithms for variant satisfiability

Variant satisfiability is a theory-generic algorithm to decide quantifier-free satisfiability in an initial algebra when its corresponding theory has the finite variant property and its constructors satisfy a compactness condition. This paper: (i) gives a precise definition of several meta-level sub-algorithms needed for variant satisfiability; (ii) proves them correct; and (iii) presents a reflective implementation in Maude 2.7 of variant satisfiability using these sub-algorithms.NSF CNS 13-19109Ope

ERK1/2 signaling dominates over RhoA signaling in regulating early changes in RNA expression induced by endothelin-1 in neonatal rat cardiomyocytes

Cardiomyocyte hypertrophy is associated with changes in gene expression. Extracellular signal-regulated kinases 1/2 (ERK1/2) and RhoA [activated by hypertrophic agonists (e.g. endothelin-1)] regulate gene expression and are implicated in the response, but their relative significance in regulating the cardiomyocyte transcriptome is unknown. Our aim was to establish the significance of ERK1/2 and/or RhoA in the early cardiomyocyte transcriptomic response to endothelin-1.Cardiomyocytes were exposed to endothelin-1 (1 h) with/without PD184352 (to inhibit ERK1/2) or C3 transferase (C3T, to inhibit RhoA). RNA expression was analyzed using microarrays and qPCR. ERK1/2 signaling positively regulated approximately 65% of the early gene expression response to ET-1 with a small (approximately 2%) negative effect, whereas RhoA signaling positively regulated approximately 10% of the early gene expression response to ET-1 with a greater (approximately 14%) negative contribution. Of RNAs non-responsive to endothelin-1, 66 or 448 were regulated by PD184352 or C3T, respectively, indicating that RhoA had a more significant effect on baseline RNA expression. mRNAs upregulated by endothelin-1 encoded a number of receptor ligands (e.g. Ereg, Areg, Hbegf) and transcription factors (e.g. Abra/Srf) that potentially propagate the response.ERK1/2 dominates over RhoA in the early transcriptomic response to endothelin-1. RhoA plays a major role in maintaining baseline RNA expression but, with upregulation of Abra/Srf by endothelin-1, RhoA may regulate changes in RNA expression over longer times. Our data identify ERK1/2 as a more significant node than RhoA in regulating the early stages of cardiomyocyte hypertrophy

Incidence of insulin-requiring diabetes in the US military

The aim of the study was to determine age- and race-related, and overall incidence rates of insulin-requiring diabetes in adults in the US military. Electronic records for admissions to US military and Tricare hospitals during 1990–2005 and visits to military clinics during 2000–2005 were identified using the Career History Archival Medical and Personnel System at the Naval Health Research Center, San Diego, CA, USA. Population data were obtained from the Defense Manpower Data Center and Defense Medical Epidemiology Database. In men there were 2,918 new cases of insulin-requiring diabetes in 20,427,038 person-years at ages 18–44 years (median age 28 years) for a total age-adjusted incidence rate of 17.5 per 100,000 person-years (95% CI 16.4–18.6). Incidence rates were twice as high in black men as in white men (31.5 vs 14.5 per 100,000, p < 0.001). In women there were 414 new cases in 3,285,000 person-years at ages 18–44 years (median age 27 years), for a total age-adjusted incidence rate of 13.6 per 100,000 (95% CI 12.4–14.9). Incidence rates were twice as high in black women as in white women (21.8 vs 9.7 per 100,000, p < 0.001). In a regression model, incidence of insulin-requiring diabetes peaked annually in the winter–spring season (OR 1.46, p < 0.01). Race and seasonal differences persisted in the multivariate analysis. Differences in incidence rates by race and season suggest a need for further research into possible reasons, including the possibility of a contribution from vitamin D deficiency. Cohort studies using prediagnostic serum 25-hydroxyvitamin D should be conducted to further evaluate this relationship

Regulation of pituitary MT1 melatonin receptor expression by gonadotrophin-releasing hormone (GnRH) and early growth response factor-1 (Egr-1) : in vivo and in vitro studies

Copyright: © 2014 Bae et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC; grant BB/F020309/1; http://www.bbsrc.ac.uk/home/home.aspx). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

The TgsGP gene is essential for resistance to human serum in Trypanosoma brucei gambiense

Trypanosoma brucei gambiense causes 97% of all cases of African sleeping sickness, a fatal disease of sub-Saharan Africa. Most species of trypanosome, such as T. b. brucei, are unable to infect humans due to the trypanolytic serum protein apolipoprotein-L1 (APOL1) delivered via two trypanosome lytic factors (TLF-1 and TLF-2). Understanding how T. b. gambiense overcomes these factors and infects humans is of major importance in the fight against this disease. Previous work indicated that a failure to take up TLF-1 in T. b. gambiense contributes to resistance to TLF-1, although another mechanism is required to overcome TLF-2. Here, we have examined a T. b. gambiense specific gene, TgsGP, which had previously been suggested, but not shown, to be involved in serum resistance. We show that TgsGP is essential for resistance to lysis as deletion of TgsGP in T. b. gambiense renders the parasites sensitive to human serum and recombinant APOL1. Deletion of TgsGP in T. b. gambiense modified to uptake TLF-1 showed sensitivity to TLF-1, APOL1 and human serum. Reintroducing TgsGP into knockout parasite lines restored resistance. We conclude that TgsGP is essential for human serum resistance in T. b. gambiense