Bicyclic pyridones as potent, efficacious and orally bioavailable thrombin inhibitors

A new class of conformationally constrained thrombin inhibitors is described. These compounds contain a unique bicyclic pyridone scaffold which serves as a P3P2 dipeptide surrogate. The synthesis and antithrombotic activity of these inhibitors is reported.     

Nramp1 drives an accelerated inflammatory response during Salmonella-induced colitis in mice

A recently developed model for enterocolitis in mice involves pre-treatment with the antibiotic streptomycin prior to infection with Salmonella enterica serovar Typhimurium ( S.  Typhimurium). The contribution of Nramp1/Slc11a1 protein, a critical host defence mechanism against S.  Typhimurium, to the development of inflammation in this model has not been studied. Here, we analysed the impact of Nramp1 expression on the early development of colitis using isogenic Nramp1^+/+ and Nramp1^−/− mice. We hypothesized that Nramp1 acts by rapidly inducing an inflammatory response in the gut mucosa creating an antibacterial environment and limiting spread of S.  Typhimurium to systemic sites. We observed that Nramp1^+/+ mice showed lower numbers of S.  Typhimurium in the caecum compared with Nramp1^−/− mice at all times analysed. Acute inflammation was much more pronounced in Nramp1^+/+ mice 1 day after infection. The effect of Nramp1 on development of colitis was characterized by higher secretion of the pro-inflammatory cytokines IFN-γ, TNF-α and MIP-1α and a massive infiltration of neutrophils and macrophages, compared with Nramp1^−/− animals. These data show that an early and rapid inflammatory response results in protection against pathological effects of S.  Typhimurium infection in Nramp1^+/+ mice.     

Rhythmic Oscillations in Quantitative EEG Measured During a Continuous Performance Task

The objective of the present investigation was to determine if cyclic variations in human performance recorded during a 30 min continuous performance task would parallel cyclic variations in right-hemisphere beta-wave activity. A fast fourier transformation was performed on the quantitative electroencephalogram (qEEG) and the performance record of each participant (N = 62), producing an individual periodogram for each outcome measure. An average periodogram was then produced for both qEEG and performance by combining (averaging) the amplitudes associated with each periodicity in the 62 original periodograms. Periodicities ranging from 1.00 to 2.00 min and from 4.70 to 5.70 min with amplitudes greater than would be expected due to chance were retained (Smith et al. 2003). The results of the present investigation validate the existence of cyclic variations in human performance that have been identified previously (Smith et al. 2003) and extend those findings by implicating right-hemisphere mediated arousal in the process (Arruda et al. 1996, 1999, 2007). Significant cyclic variations in left-hemisphere beta-wave activity were not observed. Taken together, the findings of the present investigation support a model of sustained attention that predicts cyclic changes in human performance that are the result of cyclic changes in right-hemisphere arousal.

Comparison of a piezoelectric contact sensor and an accelerometer for examining mechanomyographic amplitude and mean power frequency versus torque relationships during isokinetic and isometric muscle actions of the biceps brachii.

The purpose of this study was to compare a piezoelectric contact sensor with an accelerometer for measuring the mechanomyographic (MMG) signal from the biceps brachii during submaximal to maximal isokinetic and isometric forearm flexion muscle actions. Following determination of isokinetic peak torque (PT) and the isometric maximum voluntary contraction (MVC), 10 adults (mean+/-SD age=22.8+/-2.7yrs) performed randomly ordered, submaximal step muscle actions of the dominant forearm flexors in 20% increments from 20% to 80% PT and MVC. Surface MMG signals were recorded simultaneously from a contact sensor and an accelerometer placed over the belly of the biceps brachii muscle. During the isokinetic and isometric muscle actions, the contact sensor and accelerometer resulted in linear increases in normalized MMG amplitude with torque (r(2) range=0.84-0.97) but the linear slope of the normalized MMG amplitude versus isokinetic torque relationship for the accelerometer was less (p<0.10) than that of the contact sensor. There was no significant (p>0.05) relationship for normalized MMG mean power frequency (MPF, %max) versus isokinetic and isometric torque for the contact sensor, but the accelerometer demonstrated a quadratic (R(2)=0.94) or linear (r(2)=0.83) relationship for the isokinetic and isometric muscle actions, respectively. There were also a number of significant (p<0.05) mean differences between the contact sensor and accelerometer for normalized MMG amplitude or MPF values. These findings indicated that in some cases involving dynamic and isometric muscle actions, the contact sensor and accelerometer resulted in different torque-related responses that may affect the interpretation of the motor control strategies involved.     

Mechanomyographic and electromyographic responses during submaximal to maximal eccentric isokinetic muscle actions of the biceps brachii

The purpose of this investigation was to determine the mechanomyography (MMG) and electromyography (EMG) amplitude and mean power frequency (MPF) vs. eccentric isokinetic torque relationships for the biceps brachii muscle. Nine adults (mean +/- SD age = 23.1 +/- 2.9 years) performed submaximal to maximal eccentric isokinetic muscle actions of the dominant forearm flexors. After determination of isokinetic peak torque (PT), the subjects randomly performed submaximal step muscle actions in 10% increments from 10 to 90% PT. Polynomial regression analyses indicated that the MMG amplitude vs. eccentric isokinetic torque relationship was best fit with a quadratic model (R(2) = 0.951), where MMG amplitude increased from 10 to 60% PT and then plateaued from 60 to 100% PT. There were linear increases in MMG MPF (r(2) = 0.751) and EMG amplitude (r(2) = 0.988) with increases in eccentric isokinetic torque, but there was no significant change in EMG MPF from 10 to 100% PT. The results suggested that for the biceps brachii, eccentric isokinetic torque was increased to approximately 60% PT through concurrent modulation of the number of active motor units and their firing rates, whereas additional torque above 60% PT was produced only by increases in firing rates. These findings contribute to current knowledge of motor-control strategies during eccentric isokinetic muscle actions and could be useful in the design of training programs.     

Effects of leucine and whey protein supplementation during eight weeks of unilateral resistance training

The purpose of this study was to determine the effects of resistance training in combination with a leucine and whey protein supplement or a carbohydrate placebo on strength and muscle cross-sectional area (CSA). Thirty-three men (mean age +/- SD = 22.4 +/- 2.4 years) were assigned to 1 of 3 groups: (1) supplementation group (SUPP), (2) placebo group (PL), or (3) control group (CON). The SUPP and PL performed unilateral training of the leg extensor muscles with the nondominant limb for 8 weeks. The strength of each limb, muscle CSA of the quadriceps femoris (QF), and body composition were assessed pretraining and posttraining. The results indicated significant increases in strength for both limbs in the SUPP but only the trained limb in the PL. The increase in strength for the trained limb of the SUPP was greater than that for the trained limb of the PL. There was no significant increase in strength for either limb in the CON. There were significant increases in the CSA of all muscles of the QF of the trained limb for the SUPP and PL, and of the vastus lateralis of the untrained limb for the SUPP. The increases in QF CSA did not differ between the SUPP and PL. No significant CSA changes were found for either limb in the CON. There were no significant changes in body composition for the SUPP, PL, or CON. The current findings suggest that leucine and whey protein supplementation may provide an ergogenic effect which enhances the acquisition of strength beyond that achieved with resistance training and a carbohydrate placebo.     

Synthesis and evaluation of (2-phenethyl-2H-1,2,3-triazol-4-yl)(phenyl)methanones as Kv1.5 channel blockers for the treatment of atrial fibrillation

A series of novel (2-phenethyl-2H-1,2,3-triazol-4-yl)(phenyl)methanones were prepared and examined for utility as Kv1.5 channel blockers for the treatment of atrial fibrillation.     

Antimicrobial activity of silymarin mediated zinc oxide and hydroxy apatite nanoparticles against oral pathogens

The nanoparticles such as hydroxyapatite, zinc oxide, titanium dioxide and zirconium nanoparticles have application in dentistry. Therefore, it is of interest to document the antimicrobial activity of silymarin mediated zinc oxide and hydroxy apatite nanoparticles against oral pathogens. Hence, we synthesized hydroxyapatie and zinc oxide nanoparticles with silymarin and characterized by UV-visible spectrophotometer. Data shows that silymarin mediated HAP and ZnO nanoparticles have antimicrobial activity against oral pathogens such as Pseudomonas sp, Staphylococcus aureus, Streptococcus mutans, Enterococcus faecalis and Candida albicans.     

Anthranilate Fluorescence Marks a Calcium-Propagated Necrotic Wave That Promotes Organismal Death in C. elegans

For cells the passage from life to death can involve a regulated, programmed transition. In contrast to cell death, the mechanisms of systemic collapse underlying organismal death remain poorly understood. Here we present evidence of a cascade of cell death involving the calpain-cathepsin necrosis pathway that can drive organismal death in Caenorhabditis elegans. We report that organismal death is accompanied by a burst of intense blue fluorescence, generated within intestinal cells by the necrotic cell death pathway. Such death fluorescence marks an anterior to posterior wave of intestinal cell death that is accompanied by cytosolic acidosis. This wave is propagated via the innexin INX-16, likely by calcium influx. Notably, inhibition of systemic necrosis can delay stress-induced death. We also identify the source of the blue fluorescence, initially present in intestinal lysosome-related organelles (gut granules), as anthranilic acid glucosyl esters—not, as previously surmised, the damage product lipofuscin. Anthranilic acid is derived from tryptophan by action of the kynurenine pathway. These findings reveal a central mechanism of organismal death in C. elegans that is related to necrotic propagation in mammals—e.g., in excitotoxicity and ischemia-induced neurodegeneration. Endogenous anthranilate fluorescence renders visible the spatio-temporal dynamics of C. elegans organismal death.     

A new Sphagesaurus (Mesoeucrocodylia: Notosuchia) from the Upper Cretaceous of Monte Alto City (Bauru Group,Brazil), and a revision of the Sphagesauridae

Oxygen consumption and ammonia excretion rates were assessed for Terebratulina retusa (L.) held under 3 different regimes of temperature and food availability. These were: 5.6?C, no food (cold, starved); 5.8?C, food present (cold, fed) and 10.7?C food present (warm, fed), which simulated winter conditions, summer conditions and an intermediate treatment. Regressions of oxygen consumption on ash‐free dry weight (AFDW) had slopes which were not significantly different from each other and ranged from 0.953 to 0.999. A common slope of 0.976 was calculated and intercepts based on the common slope used to compare oxygen consumption in each treatment. The rise from cold, starved conditions to warm, fed was 24.5 per cent and this was significant (P < 0.05). Other differences were not significant (P > 0.05) but the cold, fed result was 12.6 per cent higher than cold, starved. Therefore feeding and temperature probably account for equivalent proportions of the rise in metabolism from winter to summer. Ammonia production data were much more variable. Excretion rates of a 50 mg AFDW individual (in ng‐at NH₃‐N.h^‐1) were as follows: cold, starved: 30.2 cold, fed: 7.1; and warm, fed: 22.9. Oxygen to nitrogen (O:N) ratios reflected these results. Mean O:N ratios were: cold, starved: 8.0; cold, fed: 42.4; warm, fed: 16.3. This shows that the simulated winter group relied heavily on protein to fuel their metabolism, the simulated summer group were less dependent on protein and the intermediate group probably used lipids and carbohydrates to fuel metabolic demands. This possibly reflected a trade off between food supply and increased metabolism from treatment to treatment, demonstrating a flexibility which could have been a contributing factor in the ecological tolerance and geological longevity of some brachiopods.