Potential antidiabetic activity and molecular docking studies of novel synthesized 3.6-dimethyl-5-oxo-pyrido[3,4-f][1,2,4]triazepino[2,3-a]benzimidazole and 10-amino-2-methyl-4-oxo pyrimido[1,2-a]benzimidazole derivatives

Diabetes affects a large population of the globe and is considered as a leading cause of death. Many synthetic and natural inhibitors have been developed for diabetes treatment. Herein, we report the potential antidiabetic activity of two new heterocyclic systems, namely 3.6-dimethyl-5-oxo-pyrido[3,4f][1,2,4]triazepino[2,3-a]benzimidazole (I) and 10-amino-2-methyl-4-oxo pyrimido[1,2-a]benzimidazole (II) against three related enzymes: α-amylase, α-glucosidase and β-galactosidase. Compounds I and II were synthesized by the action of DMF-DMA and dimethyl sulfate in the presence of water on 2-methyl-3H-benzimidazolo[1,2b][1,2,4]triazepin-4(5H)-one, and are characterized by single X-ray diffraction. The binding interaction modes in the active sites of I and II and targeted enzymes (stable complexes ligand-receptor) are emphasized using the molecular docking approach by applying the Lamarckian genetic algorithm method. Furthermore, plausible mechanisms have been proposed explaining their synthesis. Hirshfeld surface analysis reveals the nature of molecular interactions and fingerprint plots provide information about the percentage contribution from each individual molecular contact to the structure surface.

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Graphical abstract Left Molecular packing of 1,4-dimethyl-2-oxo-pyrimido[1,2-a]benzimidazole hydrate. Right Docking active site of α-glucosidase

     

Uvariastrol,a novel cycloartane triterpene from the stem bark of Uvariastrum zenkeri

Uvariastrol, a cycloartane triterpene with a novel tetrahydrofuran/furanone side-chain, has been isolated from the stem bark of Uvariastrum zenkeri and characterized using spectral characteristics, notably high-field ¹H NMR and ¹³C NMR spectroscopy.     

Grazing decisions of Soay sheep,Ovis aries,on St Kilda: a consequence of parasite distribution?

Relationships between the height of grass swards and herbage intake have been established for a number of large herbivores and sward height plays a major role in determining the selection of herbivore diets. However, tall grass swards also represent a more stable damp microclimate for gastrointestinal parasite larvae and tall swards contain generally greater numbers of parasites than short swards. Herbivores may then trade-off the need to maximise nutrient intake through the selection of tall swards with the need to avoid parasite ingestion. Stratified sward sampling techniques were used to determine the distribution of nutrients and parasites in a heterogeneous sward structure on the island of Hirta, St Kilda, which is grazed by a population of feral Soay sheep. The disparity between the short gap vegetation and the tall tussock vegetation was greatest in spring, when gap vegetation was some three-fold shorter than tussock vegetation; this led to tussocks offering greater nutrient and energy intake rate when compared to gap vegetation in spring. Parasites were concentrated in tussocks in spring, thus creating trade-offs. Such trade-offs were not present in summer when parasites were more evenly distributed across the gap/tussock sward structure and the nutritional advantages associated with grazing tussocks were diminished. The diet selection of the resident population of sheep was determined by recording the number of bites taken from gap and tussock vegetation by randomly selected focal animals over repeated 5-min grazing periods. Overall, all animals avoided grazing tussocks, which were most strongly avoided in the spring, and older animals avoided grazing tussocks to a greater extent. Overall, females with lambs and males avoided tussocks to a similar degree and both avoided them less than barren females. Faecal egg counts (FEC) of female sheep were negatively correlated with tussock selectivity and vice versa for male sheep. The interaction between the grazing behaviour of each sex and FEC is discussed in relation to the immunocompetence and nutrient requirements of the different sexes. The maximum disparity between the costs and benefits of the trade-off studied occurred in late winter/early spring which also represents the time of greatest nutrient demand in the Soay sheep, since many are close to starvation and/or are in the advanced stages of pregnancy. Grazing decisions of individuals at this time, determining relative nutrient and parasite intake, may then be related to subsequent fitness and survival.     

The structure of the EU mediasphere

Background

A trend towards automation of scientific research has recently resulted in what has been termed “data-driven inquiry” in various disciplines, including physics and biology. The automation of many tasks has been identified as a possible future also for the humanities and the social sciences, particularly in those disciplines concerned with the analysis of text, due to the recent availability of millions of books and news articles in digital format. In the social sciences, the analysis of news media is done largely by hand and in a hypothesis-driven fashion: the scholar needs to formulate a very specific assumption about the patterns that might be in the data, and then set out to verify if they are present or not.

Methodology/Principal Findings

In this study, we report what we think is the first large scale content-analysis of cross-linguistic text in the social sciences, by using various artificial intelligence techniques. We analyse 1.3 M news articles in 22 languages detecting a clear structure in the choice of stories covered by the various outlets. This is significantly affected by objective national, geographic, economic and cultural relations among outlets and countries, e.g., outlets from countries sharing strong economic ties are more likely to cover the same stories. We also show that the deviation from average content is significantly correlated with membership to the eurozone, as well as with the year of accession to the EU.

Conclusions/Significance

While independently making a multitude of small editorial decisions, the leading media of the 27 EU countries, over a period of six months, shaped the contents of the EU mediasphere in a way that reflects its deep geographic, economic and cultural relations. Detecting these subtle signals in a statistically rigorous way would be out of the reach of traditional methods. This analysis demonstrates the power of the available methods for significant automation of media content analysis.     

The level of hypotension during hemorrhagic shock is a major determinant of the post-resuscitation systemic inflammatory response: an experimental study

Background

To evaluate whether the level of hypotension during hemorrhagic shock may influence the oxidative and inflammatory responses developed during post-ischemic resuscitation.

Methods

Fifteen rabbits were equally allocated into three groups: sham-operated (group sham); bled within 30 minutes to mean arterial pressure (MAP) of 40 mmHg (group shock-40); bled within 30 minutes to MAP of 30 mmHg (group shock-30). Shock was maintained for 60 min. Resuscitation was performed by reinfusing shed blood with two volumes of Ringer's lactate and blood was sampled for estimation of serum levels aminotransferases, creatinine, TNF-α, IL-1β, IL-6, malondialdehyde (MDA) and total antioxidant status (TAS) and for the determination of oxidative burst of polymorhonuclears (PMNs) and mononuclear cells (MCs).

Results

Serum AST of group shock-30 was higher than that of group shock-40 at 60 and 120 minutes after start of resuscitation; serum creatinine of group shock-30 was higher than group shock-40 at 120 minutes. Measured cytokines, MDA and cellular oxidative burst of groups, shock-40 and shock-30 were higher than group sham within the first 60 minutes after start of resuscitation. Serum concentrations of IL-1β, IL-6 and TNF-α of group shock-30 were higher than group shock-40 at 120 minutes (p < 0.05). No differences were found between two groups regarding serum MDA and TAS and oxidative burst on PMNs and MCs but both groups were different to group sham.

Conclusion

The level of hypotension is a major determinant of the severity of hepatic and renal dysfunction and of the inflammatory response arising during post-ischemic hemorrhagic shock resuscitation. These findings deserve further evaluation in the clinical setting.     

Unravelling the Relationship between Animal Growth and Immune Response during Micro-Parasitic Infections

Background

Both host genetic potentials for growth and disease resistance, as well as nutrition are known to affect responses of individuals challenged with micro-parasites, but their interactive effects are difficult to predict from experimental studies alone.

Methodology/Principal Findings

Here, a mathematical model is proposed to explore the hypothesis that a host''s response to pathogen challenge largely depends on the interaction between a host''s genetic capacities for growth or disease resistance and the nutritional environment. As might be expected, the model predicts that if nutritional availability is high, hosts with higher growth capacities will also grow faster under micro-parasitic challenge, and more resistant animals will exhibit a more effective immune response. Growth capacity has little effect on immune response and resistance capacity has little effect on achieved growth. However, the influence of host genetics on phenotypic performance changes drastically if nutrient availability is scarce. In this case achieved growth and immune response depend simultaneously on both capacities for growth and disease resistance. A higher growth capacity (achieved e.g. through genetic selection) would be detrimental for the animal''s ability to cope with pathogens and greater resistance may reduce growth in the short-term.

Significance

Our model can thus explain contradicting outcomes of genetic selection observed in experimental studies and provides the necessary biological background for understanding the influence of selection and/or changes in the nutritional environment on phenotypic growth and immune response.     

Plasma pro- and anti-inflammatory cytokine levels and outcome prediction in unselected critically ill patients

Purpose. To determine the inter-relationships between cytokine levels and physiological scores in predicting outcome in unselected, critically ill patients. Methods. To this end, 127 patients (96 men), having a mean ± SD age of 45 ± 20 years, with a wide range in admission diagnoses (medical, surgical, and multiple trauma patients) were prospectively investigated. Severity of critical illness and organ dysfunction were graded by acute physiology and chronic health evaluation (APACHE II) and sequential organ failure assessment (SOFA) scores, respectively. Blood samples were drawn on admission in the ICU to determine pro- and anti-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, and IL-10. The main outcome measure was 28-day mortality. Results. Overall, 88 patients survived and 39 patients died. Univariate logistic regression analysis showed that SOFA, APACHE II, IL-8, IL-6, and IL-10 on admission in the ICU were related to mortality. Multiple logistic regression analysis in the entire cohort of critically ill patients revealed that SOFA (OR = 1.341, p < 0.001) and IL-6 (OR = 1.075, p = 0.01) constituted independent outcome predictors. receiver operator characteristics curve analysis showed that SOFA, APACHE II, and IL-6 had the highest area under the curve values. IL-6 correlated with APACHE II (r_s = 0.44, p < 0.0001) and SOFA (r_s = 0.40, p < 0.0001) scores. Conclusions. In mixed ICU patients cytokine concentrations on admission in the ICU represent independent outcome predictors in the presence of disease severity scores.     

Estimating the disease burden of 2009 pandemic influenza A(H1N1) from surveillance and household surveys in Greece

Background

The aim of this study was to assess the disease burden of the 2009 pandemic influenza A(H1N1) in Greece.

Methodology/Principal Findings

Data on influenza-like illness (ILI), collected through cross-sectional nationwide telephone surveys of 1,000 households in Greece repeated for 25 consecutive weeks, were combined with data from H1N1 virologic surveillance to estimate the incidence and the clinical attack rate (CAR) of influenza A(H1N1). Alternative definitions of ILI (cough or sore throat and fever>38°C [ILI-38] or fever 37.1–38°C [ILI-37]) were used to estimate the number of symptomatic infections. The infection attack rate (IAR) was approximated using estimates from published studies on the frequency of fever in infected individuals. Data on H1N1 morbidity and mortality were used to estimate ICU admission and case fatality (CFR) rates. The epidemic peaked on week 48/2009 with approximately 750–1,500 new cases/100,000 population per week, depending on ILI-38 or ILI-37 case definition, respectively. By week 6/2010, 7.1%–15.6% of the population in Greece was estimated to be symptomatically infected with H1N1. Children 5–19 years represented the most affected population group (CAR:27%–54%), whereas individuals older than 64 years were the least affected (CAR:0.6%–2.2%). The IAR (95% CI) of influenza A(H1N1) was estimated to be 19.7% (13.3%, 26.1%). Per 1,000 symptomatic cases, based on ILI-38 case definition, 416 attended health services, 108 visited hospital emergency departments and 15 were admitted to hospitals. ICU admission rate and CFR were 37 and 17.5 per 100,000 symptomatic cases or 13.4 and 6.3 per 100,000 infections, respectively.

Conclusions/Significance

Influenza A(H1N1) infected one fifth and caused symptomatic infection in up to 15% of the Greek population. Although individuals older than 65 years were the least affected age group in terms of attack rate, they had 55 and 185 times higher risk of ICU admission and CFR, respectively.