Dual antioxidant structures with potent anti-inflammatory,hypolipidemic and cytoprotective properties

Novel amide derivatives of trolox, 3,5-di-tert-butyl-4-hydroxybenzoic acid, (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid and cinnamic acid with cysteamine and l-cysteine ethyl ester were synthesised. In four cases, the disulfide derivatives were also isolated and tested. All compounds were examined for antioxidant activity, expressed as their ability to inhibit lipid peroxidation and to scavenge free radicals. They were found to demonstrate up to 17-fold better activity than that of the parent antioxidant acids. They could reduce acute inflammation up to 87%. The most active antioxidant compounds were further tested for their in vivo hypolipidemic effect, which ranged from 47% to 73%, and for their ability to protect the liver against oxidative toxicity caused by high paracetamol dose. The disulfide derivatives of 3,5-di-tert-butyl-4-hydroxybenzoic acid and cinnamic acid had no antioxidant activity and presented equal or lower anti-inflammatory effect than their thiol analogues, indicating that their molecular characteristics may not permit biological barrier penetration.     

Bacterial diversity of the outflows of a Polichnitos (Lesvos,Greece) hot spring,laboratory studies of a <Emphasis Type="Italic">Cyanobacterium</Emphasis> sp. strain and potential medical applications

The bacterial diversity of the outflows of Polichnitos (Lesvos, Greece) hot spring has been investigated. Cyanobacteria showing high sequence homologies with Phormidium sp. and Cyanobacterium aponinum were found. Members of the Alphaproteobacteria closely related to Rhodobium sp. Albidovulum sp., Rhodobacter sp., Microvigra sp., Nitratireductor sp. and Phaeobacter sp. Gammaproteobacteria, Betaproteobacteria and Firmicutes were represented by members of Idiomarina sp., Marinobacter sp., Shinella sp., Bacillus sp. and Clostridium sp. with sequence homologies ranging from 92% to 100%. Members of the Bacteroidetes and Planctomycetes were represented by sequences of novel phylogenetic linkages exhibiting 87–90% sequence homology with type strains. When the hot spring consortium was cultivated in bioreactor repeated batch culture under photo-autotrophic growth conditions at temperature < 30 °C, Cyanobacterium sp. dominated over Phormidium sp. Cyanobacterium sp. seems to have biotechnological potential since its extracellular broth exhibited a strong insecticidal activity against larvae of Aedes aegypti (a vector of important human diseases) and significant anti-cancer activity against the PC3 human prostate cancer cell line, while its toxicity against human endothelial cells was relatively low.     

Mfn2 deletion in brown adipose tissue protects from insulin resistance and impairs thermogenesis

BAT‐controlled thermogenic activity is thought to be required for its capacity to prevent the development of insulin resistance. This hypothesis predicts that mediators of thermogenesis may help prevent diet‐induced insulin resistance. We report that the mitochondrial fusion protein Mitofusin 2 (Mfn2) in BAT is essential for cold‐stimulated thermogenesis, but promotes insulin resistance in obese mice. Mfn2 deletion in mice through Ucp1‐cre (BAT‐Mfn2‐KO) causes BAT lipohypertrophy and cold intolerance. Surprisingly however, deletion of Mfn2 in mice fed a high fat diet (HFD) results in improved insulin sensitivity and resistance to obesity, while impaired cold‐stimulated thermogenesis is maintained. Improvement in insulin sensitivity is associated with a gender‐specific remodeling of BAT mitochondrial function. In females, BAT mitochondria increase their efficiency for ATP‐synthesizing fat oxidation, whereas in BAT from males, complex I‐driven respiration is decreased and glycolytic capacity is increased. Thus, BAT adaptation to obesity is regulated by Mfn2 and with BAT‐Mfn2 absent, BAT contribution to prevention of insulin resistance is independent and inversely correlated to whole‐body cold‐stimulated thermogenesis.     

Challenges in implementing model-based phase I designs in a grant-funded clinical trials unit

Background

For a clinical trials unit to run its first model-based, phase I trial, the statistician, chief investigator, and trial manager must all acquire a new set of skills. These trials also require a different approach to funding and data collection.

Challenges and discussion

From the statisticians’ viewpoint, we highlight what is needed to move from running rule-based, early-phase trials to running a model-based phase I study as we experienced it in our trials unit located in the United Kingdom. Our example is CHARIOT, a dose-finding trial using the time-to-event continual reassessment method. It consists of three stages and aims to discover the maximum tolerated dose of the combination of radiotherapy, chemotherapy, and the ataxia telangiectasia mutated Rad3-related inhibitor M6620 (previously known as VX-970) in patients with oesophageal cancer. We present the challenges we faced in designing this trial and how we overcame them as a way of demystifying the conduct of a model-based trial in a grant-funded clinical trials unit.

Conclusions

Although we appreciate that undertaking model-based trials requires additional time and effort, they are feasible to implement and, once suitable tools such as guiding publications and document templates become available, the design and set-up process will be easier and more efficient.

     

Determinants of alpha and beta vascular plant diversity in Mediterranean island systems: the Ionian islands,Greece

The Ionian archipelago is the second largest Greek archipelago after the Aegean, but the factors driving plant species diversity in the Ionian islands are still barely known. We used stepwise multiple regressions to investigate the factors affecting plant species diversity in 17 Ionian islands. Generalized dissimilarity modelling was applied to examine variation in the magnitude and rate of species turnover along environmental gradients, as well as to assess the relative importance of geographical and climatic factors in explaining species turnover. The values of the residuals from the ISAR log₁₀‐transfomed models of native and endemic taxa were used as a measure of island floristic diversity. Area was confirmed to be the most powerful single explanatory predictor of all diversity metrics. Mean annual precipitation and temperature, as well as shortest distance to the nearest island are also significant predictors of vascular plant diversity. The island of Kalamos constitutes an important plant diversity hotspot in the Ionian archipelago. The recent formation of the islands, the close proximity to the mainland source and the relatively low dispersal filtering of the Ionian archipelago has resulted in islands with a flora principally comprising common species and a low proportion of endemics. Small islands keep a key role in conservation of plant priority sites.     

Isolation and characterization of vitellin from the fruitfly,Dacus oleae

Vitellin was isolated from mature eggs of Dacus oleae. A combination of anion-exchange chromatography and gel filtration was used for purification of the protein. The molecular weight of isolated vitellin, as determined by Sephacryl S-300 chromatography, was approximately 300,000. Electrophoresis on SDS-polyacrylamide gels demonstrated the presence of vitellin subunits with molecular weight of 47,000 and 49,000. Isoelectric focusing on polyacrylamide gels revealed a series of polypeptides with isoelectric points covering an acidic pH region of 5.7 to 6.2. Immunodiffusion, immunoelectrophoresis, and immunoblotting were used for further characterization of vitellin.     

A general modeling framework for open wildlife populations based on the Polya tree prior

Wildlife monitoring for open populations can be performed using a number of different survey methods. Each survey method gives rise to a type of data and, in the last five decades, a large number of associated statistical models have been developed for analyzing these data. Although these models have been parameterized and fitted using different approaches, they have all been designed to either model the pattern with which individuals enter and/or exit the population, or to estimate the population size by accounting for the corresponding observation process, or both. However, existing approaches rely on a predefined model structure and complexity, either by assuming that parameters linked to the entry and exit pattern (EEP) are specific to sampling occasions, or by employing parametric curves to describe the EEP. Instead, we propose a novel Bayesian nonparametric framework for modeling EEPs based on the Polya tree (PT) prior for densities. Our Bayesian nonparametric approach avoids overfitting when inferring EEPs, while simultaneously allowing more flexibility than is possible using parametric curves. Finally, we introduce the replicate PT prior for defining classes of models for these data allowing us to impose constraints on the EEPs, when required. We demonstrate our new approach using capture–recapture, count, and ring-recovery data for two different case studies.     

The <Emphasis Type="Italic">VKORC1</Emphasis> Asp36Tyr variant and <Emphasis Type="Italic">VKORC1</Emphasis> haplotype diversity in Ashkenazi and Ethiopian populations

The vitamin K epoxide reductase (VKORC1) is a key enzyme in the vitamin K cycle impacting various biological processes. VKORC1 genetic variability has been extensively studied in the context of warfarin pharmacogenetics revealing different distributions of VKORC1 haplotypes in various populations. We previously identified the VKORC1 Asp36Tyr mutation that was associated with warfarin resistance and with distinctive ethnic distribution. In this study, we performed haplotype analysis using Asp36Tyr and seven other VKORC1 markers in Ashkenazi and Ethiopian-Jewish and non-Jewish individuals. The VKORC1 variability was represented by nine haplotypes (V1-V9) that could be grouped into two distinct clusters (V1-V3 and V4-V9) with intra-cluster difference limited to two nucleotide changes. Phylogeny analysis suggested that these haplotypes could have developed from an ancestral variant, the common V8 haplotype (40 % in all population samples), after ten single mutation events. Asp36Tyr was exclusive to the V5 haplotype of the second cluster. Two haplotypes V5 and V4, distinguished only by Asp36Tyr, were prevalent in both Ethiopian population samples. The V2 haplotype, belonging to the first cluster, was the second most prevalent haplotype in the Ashkenazi population sample (15.8 %) but relatively uncommon in the Ethiopian origin (4.5-4.7 %). We discuss the genetic diversity among studied populations and its potential impact on warfarin-dose management in certain populations of African and European origin.     

A Method to Study the Impact of Chemically-induced Ovarian Failure on Exercise Capacity and Cardiac Adaptation in Mice

The risk of cardiovascular disease (CVD) increases in post-menopausal women, yet, the role of exercise, as a preventative measure for CVD risk in post-menopausal women has not been adequately studied. Accordingly, we investigated the impact of voluntary cage-wheel exercise and forced treadmill exercise on cardiac adaptation in menopausal mice. The most commonly used inducible model for mimicking menopause in women is the ovariectomized (OVX) rodent. However, the OVX model has a few dissimilarities from menopause in humans. In this study, we administered 4-vinylcyclohexene diepoxide (VCD) to female mice, which accelerates ovarian failure as an alternative menopause model to study the impact of exercise in menopausal mice. VCD selectively accelerates the loss of primary and primordial follicles resulting in an endocrine state that closely mimics the natural progression from pre- to peri- to post-menopause in humans. To determine the impact of exercise on exercise capacity and cardiac adaptation in VCD-treated female mice, two methods were used. First, we exposed a group of VCD-treated and untreated mice to a voluntary cage wheel. Second, we used forced treadmill exercise to determine exercise capacity in a separate group VCD-treated and untreated mice measured as a tolerance to exercise intensity and endurance.