Molecular modelling studies of binding of DACD derivatives into G-Quadruplex DNA: comparison of force field and quantum polarized ligand docking methods

The DNA G-qadruplexes are one of the targets being actively explored for anti-cancer therapy by inhibiting them through small molecules. This computational study was conducted to predict the binding strengths and orientations of a set of novel dimethyl-amino-ethyl-acridine (DACA) analogues that are designed and synthesized in our laboratory, but did not diffract in Synchrotron light.Thecrystal structure of DNA G-Quadruplex(TGGGGT)4(PDB: 1O0K) was used as target for their binding properties in our studies.We used both the force field (FF) and QM/MM derived atomic charge schemes simultaneously for comparing the predictions of drug binding modes and their energetics. This study evaluates the comparative performance of fixed point charge based Glide XP docking and the quantum polarized ligand docking schemes. These results will provide insights on the effects of including or ignoring the drug-receptor interfacial polarization events in molecular docking simulations, which in turn, will aid the rational selection of computational methods at different levels of theory in future drug design programs. Plenty of molecular modelling tools and methods currently exist for modelling drug-receptor or protein-protein, or DNA-protein interactionssat different levels of complexities.Yet, the capasity of such tools to describevarious physico-chemical propertiesmore accuratelyis the next step ahead in currentresearch.Especially, the usage of most accurate methods in quantum mechanics(QM) is severely restricted by theirtedious nature. Though the usage of massively parallel super computing environments resulted in a tremendous improvement in molecular mechanics (MM) calculations like molecular dynamics,they are still capable of dealing with only a couple of tens to hundreds of atoms for QM methods. One such efficient strategy that utilizes thepowers of both MM and QM are the QM/MM hybrid methods. Lately, attempts have been directed towards the goal of deploying several different QM methods for betterment of force field based simulations, but with practical restrictions in place. One of such methods utilizes the inclusion of charge polarization events at the drug-receptor interface, that is not explicitly present in the MM FF.

Comparative biology of mammalian telomeres: hypotheses on ancestral states and the roles of telomeres in longevity determination

Progressive telomere shortening from cell division (replicative aging) provides a barrier for human tumor progression. This program is not conserved in laboratory mice, which have longer telomeres and constitutive telomerase. Wild species that do ⁄ do not use replicative aging have been reported, but the evolution of different phenotypes and a conceptual framework for understanding their uses of telomeres is lacking. We examined telomeres ⁄ telomerase in cultured cells from > 60 mammalian species to place different uses of telomeres in a broad mammalian context. Phylogeny-based statistical analysis reconstructed ancestral states. Our analysis suggested that the ancestral mammalian phenotype included short telomeres (< 20 kb, as we now see in humans) and repressed telomerase. We argue that the repressed telomerase was a response to a higher mutation load brought on by the evolution of homeothermy. With telomerase repressed, we then see the evolution of replicative aging. Telomere length inversely correlated with lifespan, while telomerase expression co-evolved with body size. Multiple independent times smaller, shorter-lived species changed to having longer telomeres and expressing telomerase. Trade-offs involving reducing the energetic ⁄ cellular costs of specific oxidative protection mechanisms (needed to protect < 20 kb telomeres in the absence oftelomerase) could explain this abandonment of replicative aging. These observations provide a conceptual framework for understanding different uses of telomeres in mammals, support a role for human-like telomeres in allowing longer lifespans to evolve, demonstrate the need to include telomere length in the analysis of comparative studies of oxidative protection in the biology of aging, and identify which mammals can be used as appropriate model organisms for the study of the role of telomeres in human cancer and aging. Key words: evolution of telomeres; immortalization; telomerase; replicative aging; senescence.

Comparative in vitro inhibition of urinary tract pathogens by single- and multi-strain probiotics

PURPOSE: Multi-species probiotic preparations have been suggested as having a wide spectrum of application, although few studies have compared their efficacy with that of individual component strains at equal concentrations. We therefore tested the ability of 4 single probiotics and 4 probiotic mixtures to inhibit the urinary tract pathogens Escherichia coli NCTC 9001 and Enterococcus faecalis NCTC 00775. METHODS: We used an agar spot test to test the ability of viable cells to inhibit pathogens, while a broth inhibition assay was used to assess inhibition by cell-free probiotic supernatants in both pH-neutralised and non-neutralised forms. RESULTS: In the agar spot test, all probiotic treatments showed inhibition, L. acidophilus was the most inhibitory single strain against E. faecalis, L. fermentum the most inhibitory against E. coli. A commercially available mixture of 14 strains (Bio-Kult(®)) was the most effective mixture, against E. faecalis, the 3-lactobacillus mixture the most inhibitory against E. coli. Mixtures were not significantly more inhibitory than single strains. In the broth inhibition assays, all probiotic supernatants inhibited both pathogens when pH was not controlled, with only 2 treatments causing inhibition at a neutral pH. CONCLUSIONS: Both viable cells of probiotics and supernatants of probiotic cultures were able to inhibit growth of two urinary tract pathogens. Probiotic mixtures prevented the growth of urinary tract pathogens but were not significantly more inhibitory than single strains. Probiotics appear to produce metabolites that are inhibitory towards urinary tract pathogens. Probiotics display potential to reduce the incidence of urinary tract infections via inhibition of colonisation.

A comparative study of satellite and ground-based phenology

Long time series of ground-based plant phenology, as well as more than two decades of satellite-derived phenological metrics, are currently available to assess the impacts of climate variability and trends on terrestrial vegetation. Traditional plant phenology provides very accurate information on individual plant species, but with limited spatial coverage. Satellite phenology allows monitoring of terrestrial vegetation on a global scale and provides an integrative view at the landscape level. Linking the strengths of both methodologies has high potential value for climate impact studies. We compared a multispecies index from ground-observed spring phases with two types (maximum slope and threshold approach) of satellite-derived start-of-season (SOS) metrics. We focus on Switzerland from 1982 to 2001 and show that temporal and spatial variability of the multispecies index correspond well with the satellite-derived metrics. All phenological metrics correlate with temperature anomalies as expected. The slope approach proved to deviate strongly from the temporal development of the ground observations as well as from the threshold-defined SOS satellite measure. The slope spring indicator is considered to indicate a different stage in vegetation development and is therefore less suited as a SOS parameter for comparative studies in relation to ground-observed phenology. Satellite-derived metrics are, however, very susceptible to snow cover, and it is suggested that this snow cover should be better accounted for by the use of newer satellite sensors.

Peaceful coexistence? The role of religious schools and NGOs in the growth of female secondary schooling in Bangladesh

Bangladesh Rural Advancement Committee (BRAC), a non-governmental organisation (NGO), runs a large number of non-formal primary schools in Bangladesh which target out-of-school children from poor families. These schools are well-known for their effectiveness in closing the gender gap in primary school enrolment. On the other hand, registered non-government secondary madrasas (or Islamic schools) today enrol one girl against every boy student. In this article, we document a positive spillover effect of BRAC schools on female secondary enrolment in registered madrasas. Drawing upon school enrolment data aggregated at the region level, we first show that regions that had more registered madrasas experienced greater secondary female enrolment growth during 1999–2003, holding the number of secular secondary schools constant. In this context we test the impact of BRAC-run primary schools on female enrolment in registered madrasas. We deal with the potential endogeneity of placement of BRAC schools using an instrumental variable approach. Controlling for factors such as local-level poverty, road access and distance from major cities, we show that regions with a greater presence of BRAC schools have higher female enrolment growth in secondary madrasas. The effect is much bigger when compared to that on secondary schools.

The impact of milk proteins and peptides on blood pressure and vascular function: a review of evidence from human intervention studies.

CVD are the leading cause of death worldwide. Hypertension, a major controllable risk factor of CVD, is intimately associated with vascular dysfunction, a defect which is also now recognised to be a major, modifiable risk factor for the development of CVD. The purpose of the present review was to critically evaluate the evidence for the effects of milk proteins and their associated peptides on blood pressure (BP) and vascular dysfunction. After a detailed literature search, the number of human trials evaluating the antihypertensive effects of casein-derived peptides (excluding isoleucine-proline-proline and valine-proline-proline) was found to be limited; the studies were preliminary with substantial methodological limitations. Likewise, the data from human trials that examined the effects of whey protein and peptides were also scarce and inconsistent. To date, only one study has conducted a comparative investigation on the relative effects of the two main intact milk proteins on BP and vascular function. While both milk proteins were shown to reduce BP, only whey protein improved measures of arterial stiffness. In contrast, a growing number of human trials have produced evidence to support beneficial effects of both milk proteins and peptides on vascular health. However, comparison of the relative outcomes from these trials is difficult owing to variation in the forms of assessment and measures of vascular function. In conclusion, there is an accumulating body of evidence to support positive effects of milk proteins in improving and/or maintaining cardiovascular health. However, the variable quality of the studies that produced this evidence, and the lack of robust, randomised controlled intervention trials, undermines the formulation of firm conclusions on the potential benefits of milk proteins and peptides on vascular health.

Comparative Cluster/Double Star observations of the high and low latitude dayside magnetopause

The launch of the Double Star mission has provided the opportunity to monitor events at distinct locations on the dayside magnetopause, in coordination with the quartet of Cluster spacecraft. We present results of two such coordinated studies. In the first, 6 April 2004, both Cluster and the Double Star TC-1 spacecraft were on outbound transits through the dawn-side magnetosphere. Cluster observed northward moving FTEs with +/- polarity, whereas TC-1 saw -/+ polarity FTEs. The strength, motion and occurrence of the FTE signatures changes somewhat according to changes in IMF clock angle. These observations are consistent with ongoing reconnection on the dayside magnetopause, resulting in a series of flux transfer events (FTEs) seen both at Cluster and TC-1. The observed polarity and motion of each FTE signature advocates the existence of an active reconnection region consistently located between the positions of Cluster and TC-1, lying north and south of the reconnection line, respectively. This scenario is supported by the application of a model, designed to track flux tube motion, to conditions appropriate for the prevailing interplanetary conditions. The results from the model confirm the observational evidence that the low-latitude FTE dynamics is sensitive to changes in convected upstream conditions. In particular, changing the interplanetary magnetic field (IMF) clock angle in the model predicts that TC-1 should miss the resulting FTEs more often than Cluster, as is observed. For the second conjunction, on the 4 Jan 2005, the Cluster and TC-1 spacecraft all exited the dusk-side magnetosphere almost simultaneously, with TC-1 lying almost equatorial and Cluster at northern latitudes at about 4 RE from TC-1. The spacecraft traverse the magnetopause during a strong reversal in the IMF from northward to southward and a number of magnetosheath FTE signatures are subsequently observed. One coordinated FTE, studied in detail by Pu et al, [this issue], carries and inflowing energetic electron population and shows a motion and orientation which is similar at all spacecraft and consistent with the predictions of the model for the flux tube dynamics, given a near sub-solar reconnection line. This event can be interpreted either as the passage of two parallel flux tubes arising from adjacent x-line positions, or as a crossing of a single flux tube at different positions.

A comparative corpus-assisted discourse study of the representations of hosts in promotional tourism discourse

Most studies concerned with the representations of local people in tourism discourse point to the prevalence of stereotypic images asserting that contemporary tourism perpetuates colonial legacy and gendered discursive practices. This claim has been, to some extent, contested in research that explores representations of hosts in local tourism materials claiming that tourism can also discursively resist the dominant Western imagery. While the evidence for the existence of hegemonic and diverging discourses about the local ‘Other’ seems compelling, the empirical basis of this research is rather small and often limited to one geographic context. The present study addresses these shortcomings by examining representations of hosts in a larger corpus of promotional tourism materials including texts produced by Western and local tourism industries. The data is investigated using the methodology of Corpus-Assisted Discourse Studies (CADS). By comparing external with internal (self) representations, this study verifies and refines some of the claims on the subject and offers a much more nuanced picture of representations that defies the black and white scenarios proposed in previous research

A comparative study of the characteristics of French Fries produced by deep fat frying and air frying

Air frying is being projected as an alternative to deep fat frying for producing snacks such as French Fries. In air frying, the raw potato sections are essentially heated in hot air containing fine oil droplets, which dehydrates the potato and attempts to impart the characteristics of traditionally produced French fries, but with a substantially lower level of fat absorbed in the product. The aim of this research is to compare: 1) the process dynamics of air frying with conventional deep fat frying under otherwise similar operating conditions, and 2) the products formed by the two processes in terms of color, texture, microstructure, calorimetric properties and sensory characteristics Although, air frying produced products with a substantially lower fat content but with similar moisture contents and color characteristics, it required much longer processing times, typically 21 minutes in relation to 9 minutes in the case of deep fat frying. The slower evolution of temperature also resulted in lower rates of moisture loss and color development reactions. DSC studies revealed that the extent of starch gelatinization was also lower in the case of air fried product. In addition, the two types of frying also resulted in products having significantly different texture and sensory characteristics.

Comparative growth of ectomycorrhizal fungi (Hebeloma spp.) on organic and inorganic nitrogen

In the largely organic soils in which ectomycorrhizas are commonly found, a preference for absorbing organic nitrogen over mineral forms is likely to be an advantage, especially where mineralisation rates are low. To determine rates of both independent and preferential growth of ectomycorrhizal basidiomycetes on organic and inorganic nitrogen, strains of Hebeloma were grown on nutrient agar media containing either NH4+ or glutamic acid as the sole source of nitrogen, on both single medium and split plate Petri dishes. Growth rates on the split plate Petri dishes, where the fungi had access to both nitrogen sources, were generally greater than on the single medium dishes. Growth on glutamic acid was at least equal to, and usually greater than, that on NH4+. In some cases growth on NH4+ alone appeared severely inhibited, a condition that was partially alleviated by access to glutamic acid on the split plates Petri dishes. This highlights a potential pitfall of single nitrogen source growth studies. The greater growth of most strains on glutamic acid suggests an adaptation to organic nitrogen utilisation in these strains. If this is so in soils with low mineralisation rates, direct uptake of amino acids by ectomycorrhizal plants could by-pass the bottle neck that requires mineral nitrogen to be made available for plant uptake.

A cautionary note on the use of Ornstein Uhlenbeck models in macroevolutionary studies

Phylogenetic comparative methods are increasingly used to give new insights into the dynamics of trait evolution in deep time. For continuous traits the core of these methods is a suite of models that attempt to capture evolutionary patterns by extending the Brownian constant variance model. However, the properties of these models are often poorly understood, which can lead to the misinterpretation of results. Here we focus on one of these models – the Ornstein Uhlenbeck (OU) model. We show that the OU model is frequently incorrectly favoured over simpler models when using Likelihood ratio tests, and that many studies fitting this model use datasets that are small and prone to this problem. We also show that very small amounts of error in datasets can have profound effects on the inferences derived from OU models. Our results suggest that simulating fitted models and comparing with empirical results is critical when fitting OU and other extensions of the Brownian model. We conclude by making recommendations for best practice in fitting OU models in phylogenetic comparative analyses, and for interpreting the parameters of the OU model.