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N-Alpha-Acetylation of α-Synuclein Increases Its Helical Folding Propensity, GM1 Binding Specificity and Resistance to Aggregation

July 30, 2014 - 5:00pm

by Tim Bartels, Nora C. Kim, Eric S. Luth, Dennis J. Selkoe

A switch in the conformational properties of α-synuclein (αS) is hypothesized to be a key step in the pathogenic mechanism of Parkinson’s disease (PD). Whereas the beta-sheet-rich state of αS has long been associated with its pathological aggregation in PD, a partially alpha-helical state was found to be related to physiological lipid binding; this suggests a potential role of the alpha-helical state in controlling synaptic vesicle cycling and resistance to β-sheet rich aggregation. N-terminal acetylation is the predominant post-translational modification of mammalian αS. Using circular dichroism, isothermal titration calorimetry, and fluorescence spectroscopy, we have analyzed the effects of N-terminal acetylation on the propensity of recombinant human αS to form the two conformational states in interaction with lipid membranes. Small unilamellar vesicles of negatively charged lipids served as model membranes. Consistent with previous NMR studies using phosphatidylserine, we found that membrane-induced α-helical folding was enhanced by N-terminal acetylation and that greater exothermic heat could be measured upon vesicle binding of the modified protein. Interestingly, the folding and lipid binding enhancements with phosphatidylserine in vitro were weak when compared to that of αS with GM1, a lipid enriched in presynaptic membranes. The resultant increase in helical folding propensity of N-acetylated αS enhanced its resistance to aggregation. Our findings demonstrate the significance of the extreme N-terminus for folding nucleation, for relative GM1 specificity of αS-membrane interaction, and for a protective function of N-terminal-acetylation against αS aggregation mediated by GM1.
Categories: Bioscience

A Computational Approach towards a Gene Regulatory Network for the Developing Nematostella vectensis Gut

July 30, 2014 - 5:00pm

by Daniel Botman, Eric Röttinger, Mark Q. Martindale, Johann de Jong, Jaap A. Kaandorp

Background

The starlet sea anemone Nematostella vectensis is a diploblastic cnidarian that expresses a set of conserved genes for gut formation during its early development. During the last decade, the spatial distribution of many of these genes has been visualized with RNA hybridization or protein immunolocalization techniques. However, due to N. vectensis' curved and changing morphology, quantification of these spatial data is problematic. A method is developed for two-dimensional gene expression quantification, which enables a numerical analysis and dynamic modeling of these spatial patterns.

Methods/Result

In this work, first standardized gene expression profiles are generated from publicly available N. vectensis embryo images that display mRNA and/or protein distributions. Then, genes expressed during gut formation are clustered based on their expression profiles, and further grouped based on temporal appearance of their gene products in embryonic development. Representative expression profiles are manually selected from these clusters, and used as input for a simulation-based optimization scheme. This scheme iteratively fits simulated profiles to the selected profiles, leading to an optimized estimation of the model parameters. Finally, a preliminary gene regulatory network is derived from the optimized model parameters.

Outlook

While the focus of this study is N. vectensis, the approach outlined here is suitable for inferring gene regulatory networks in the embryonic development of any animal, thus allowing to comparatively study gene regulation of gut formation in silico across various species.

Categories: Bioscience

Plasma Clusterin (ApoJ) Levels Are Associated with Adiposity and Systemic Inflammation

July 30, 2014 - 5:00pm

by Jong Chul Won, Cheol-Young Park, Sang Woo Oh, Eon Sook Lee, Byung-Soo Youn, Min-Seon Kim

Obesity and insulin resistance are hallmarks of the metabolic syndrome, which is associated with low-grade chronic inflammation. Clusterin/apolipoprotein J is an abundant plasma chaperone protein that has recently been suggested as a potential biomarker that reflects the inflammatory process in Alzheimer's disease. In the present study, we investigated anthropometric and clinical factors affecting the plasma levels of clusterin in healthy Korean subjects. We measured fasting plasma clusterin levels in healthy Korean adults (111 men and 93 women) using ELISA kit. We analyzed the relationship between plasma clusterin concentrations and anthropometric and clinical parameters. Fasting plasma clusterin concentrations were higher in overweight and obese subjects than in lean subjects. Correlation analysis revealed that the plasma clusterin levels were positively associated with indices of obesity such as body mass index (BMI), waist circumference and waist-hip ratio and markers of systemic inflammation such as high sensitivity C-reactive protein (hsCRP), uric acid, ferritin and retinol binding protein-4. Multiple linear regression analysis showed that sex, BMI and hsCRP were independent determinants of plasma clusterin levels. Furthermore, plasma clusterin levels showed an upward trend with increasing numbers of metabolic syndrome components. These findings suggest that fasting plasma clusterin levels correlate with the parameters of adiposity and systemic inflammation in healthy adults. Therefore, the circulating clusterin level may be a surrogate marker for obesity-associated systemic inflammation.
Categories: Bioscience

Effect of Tree Nuts on Glycemic Control in Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Dietary Trials

July 30, 2014 - 5:00pm

by Effie Viguiliouk, Cyril W. C. Kendall, Sonia Blanco Mejia, Adrian I. Cozma, Vanessa Ha, Arash Mirrahimi, Viranda H. Jayalath, Livia S. A. Augustin, Laura Chiavaroli, Lawrence A. Leiter, Russell J. de Souza, David J. A. Jenkins, John L. Sievenpiper

Background

Tree nut consumption has been associated with reduced diabetes risk, however, results from randomized trials on glycemic control have been inconsistent.

Objective

To provide better evidence for diabetes guidelines development, we conducted a systematic review and meta-analysis of randomized controlled trials to assess the effects of tree nuts on markers of glycemic control in individuals with diabetes.

Data Sources

MEDLINE, EMBASE, CINAHL, and Cochrane databases through 6 April 2014.

Study Selection

Randomized controlled trials ≥3 weeks conducted in individuals with diabetes that compare the effect of diets emphasizing tree nuts to isocaloric diets without tree nuts on HbA1c, fasting glucose, fasting insulin, and HOMA-IR.

Data Extraction and Synthesis

Two independent reviewer’s extracted relevant data and assessed study quality and risk of bias. Data were pooled by the generic inverse variance method and expressed as mean differences (MD) with 95% CI’s. Heterogeneity was assessed (Cochran Q-statistic) and quantified (I2).

Results

Twelve trials (n = 450) were included. Diets emphasizing tree nuts at a median dose of 56 g/d significantly lowered HbA1c (MD = −0.07% [95% CI:−0.10, −0.03%]; P = 0.0003) and fasting glucose (MD = −0.15 mmol/L [95% CI: −0.27, −0.02 mmol/L]; P = 0.03) compared with control diets. No significant treatment effects were observed for fasting insulin and HOMA-IR, however the direction of effect favoured tree nuts.

Limitations

Majority of trials were of short duration and poor quality.

Conclusions

Pooled analyses show that tree nuts improve glycemic control in individuals with type 2 diabetes, supporting their inclusion in a healthy diet. Owing to the uncertainties in our analyses there is a need for longer, higher quality trials with a focus on using nuts to displace high-glycemic index carbohydrates.

Trial Registration

ClinicalTrials.gov NCT01630980

Categories: Bioscience

NAC Attenuates LPS-Induced Toxicity in Aspirin-Sensitized Mouse Macrophages via Suppression of Oxidative Stress and Mitochondrial Dysfunction

July 30, 2014 - 5:00pm

by Haider Raza, Annie John, Jasmin Shafarin

Bacterial endotoxin lipopolysaccharide (LPS) induces the production of inflammatory cytokines and reactive oxygen species (ROS) under in vivo and in vitro conditions. Acetylsalicylic acid (ASA, aspirin) is a commonly used anti-inflammatory drug. Our aim was to study the effects of N-acetyl cysteine (NAC), an antioxidant precursor of GSH synthesis, on aspirin-sensitized macrophages treated with LPS. We investigated the effects of LPS alone and in conjunction with a sub-toxic concentration of ASA, on metabolic and oxidative stress, apoptosis, and mitochondrial function using J774.2 mouse macrophage cell line. Protection from LPS-induced toxicity by NAC was also studied. LPS alone markedly induced ROS production and oxidative stress in macrophage cells. When ASA was added to LPS-treated macrophages, the increase in oxidative stress was significantly higher than that with LPS alone. Similarly, alteration in glutathione-dependent redox metabolism was also observed in macrophages after treatment with LPS and ASA. The combination of LPS and ASA selectively altered the CYP 3A4, CYP 2E1 and CYP 1A1 catalytic activities. Mitochondrial respiratory complexes and ATP production were also inhibited by LPS-ASA treatment. Furthermore a higher apoptotic cell death was also observed in LPS-ASA treated macrophages. NAC pre-treatment showed protection against oxidative stress induced apoptosis and mitochondrial dysfunction. These effects are presumed, at least in part, to be associated with alterations in NF-κB/Nrf-2 mediated cell signaling. These results suggest that macrophages are more sensitive to LPS when challenged with ASA and that NAC pre-treatment protects the macrophages from these deleterious effects.
Categories: Bioscience

Phenotype Refinement Strengthens the Association of AHR and CYP1A1 Genotype with Caffeine Consumption

July 30, 2014 - 5:00pm

by George McMahon, Amy E. Taylor, George Davey Smith, Marcus R. Munafò

Two genetic loci, one in the cytochrome P450 1A1 (CYP1A1) and 1A2 (CYP1A2) gene region (rs2472297) and one near the aryl-hydrocarbon receptor (AHR) gene (rs6968865), have been associated with habitual caffeine consumption. We sought to establish whether a more refined and comprehensive assessment of caffeine consumption would provide stronger evidence of association, and whether a combined allelic score comprising these two variants would further strengthen the association. We used data from between 4,460 and 7,520 women in the Avon Longitudinal Study of Parents and Children, a longitudinal birth cohort based in the United Kingdom. Self-report data on coffee, tea and cola consumption (including consumption of decaffeinated drinks) were available at multiple time points. Both genotypes were individually associated with total caffeine consumption, and with coffee and tea consumption. There was no association with cola consumption, possibly due to low levels of consumption in this sample. There was also no association with measures of decaffeinated drink consumption, indicating that the observed association is most likely mediated via caffeine. The association was strengthened when a combined allelic score was used, accounting for up to 1.28% of phenotypic variance. This was not associated with potential confounders of observational association. A combined allelic score accounts for sufficient phenotypic variance in caffeine consumption that this may be useful in Mendelian randomization studies. Future studies may therefore be able to use this combined allelic score to explore causal effects of habitual caffeine consumption on health outcomes.
Categories: Bioscience

Adaptive Neuro-Fuzzy Methodology for Noise Assessment of Wind Turbine

July 30, 2014 - 5:00pm

by Shahaboddin Shamshirband, Dalibor Petković, Roslan Hashim, Shervin Motamedi

Wind turbine noise is one of the major obstacles for the widespread use of wind energy. Noise tone can greatly increase the annoyance factor and the negative impact on human health. Noise annoyance caused by wind turbines has become an emerging problem in recent years, due to the rapid increase in number of wind turbines, triggered by sustainable energy goals set forward at the national and international level. Up to now, not all aspects of the generation, propagation and perception of wind turbine noise are well understood. For a modern large wind turbine, aerodynamic noise from the blades is generally considered to be the dominant noise source, provided that mechanical noise is adequately eliminated. The sources of aerodynamic noise can be divided into tonal noise, inflow turbulence noise, and airfoil self-noise. Many analytical and experimental acoustical studies performed the wind turbines. Since the wind turbine noise level analyzing by numerical methods or computational fluid dynamics (CFD) could be very challenging and time consuming, soft computing techniques are preferred. To estimate noise level of wind turbine, this paper constructed a process which simulates the wind turbine noise levels in regard to wind speed and sound frequency with adaptive neuro-fuzzy inference system (ANFIS). This intelligent estimator is implemented using Matlab/Simulink and the performances are investigated. The simulation results presented in this paper show the effectiveness of the developed method.
Categories: Bioscience

Deep-Sea Octopus (Graneledone boreopacifica) Conducts the Longest-Known Egg-Brooding Period of Any Animal

July 30, 2014 - 5:00pm

by Bruce Robison, Brad Seibel, Jeffrey Drazen

Octopuses typically have a single reproductive period and then they die (semelparity). Once a clutch of fertilized eggs has been produced, the female protects and tends them until they hatch. In most shallow-water species this period of parental care can last from 1 to 3 months, but very little is known about the brooding of deep-living species. In the cold, dark waters of the deep ocean, metabolic processes are often slower than their counterparts at shallower depths. Extrapolations from data on shallow-water octopus species suggest that lower temperatures would prolong embryonic development periods. Likewise, laboratory studies have linked lower temperatures to longer brooding periods in cephalopods, but direct evidence has not been available. We found an opportunity to directly measure the brooding period of the deep-sea octopus Graneledone boreopacifica, in its natural habitat. At 53 months, it is by far the longest egg-brooding period ever reported for any animal species. These surprising results emphasize the selective value of prolonged embryonic development in order to produce competitive hatchlings. They also extend the known boundaries of physiological adaptations for life in the deep sea.
Categories: Bioscience

Female Mate Choice Can Drive the Evolution of High Frequency Echolocation in Bats: A Case Study with Rhinolophus mehelyi

July 30, 2014 - 5:00pm

by Sébastien J. Puechmaille, Ivailo M. Borissov, Sándor Zsebok, Benjamin Allegrini, Mohammed Hizem, Sven Kuenzel, Maike Schuchmann, Emma C. Teeling, Björn M. Siemers

Animals employ an array of signals (i.e. visual, acoustic, olfactory) for communication. Natural selection favours signals, receptors, and signalling behaviour that optimise the received signal relative to background noise. When the signal is used for more than one function, antagonisms amongst the different signalling functions may constrain the optimisation of the signal for any one function. Sexual selection through mate choice can strongly modify the effects of natural selection on signalling systems ultimately causing maladaptive signals to evolve. Echolocating bats represent a fascinating group in which to study the evolution of signalling systems as unlike bird songs or frog calls, echolocation has a dual role in foraging and communication. The function of bat echolocation is to generate echoes that the calling bat uses for orientation and food detection with call characteristics being directly related to the exploitation of particular ecological niches. Therefore, it is commonly assumed that echolocation has been shaped by ecology via natural selection. Here we demonstrate for the first time using a novel combined behavioural, ecological and genetic approach that in a bat species, Rhinolophus mehelyi: (1) echolocation peak frequency is an honest signal of body size; (2) females preferentially select males with high frequency calls during the mating season; (3) high frequency males sire more off-spring, providing evidence that echolocation calls may play a role in female mate choice. Our data refute the sole role of ecology in the evolution of echolocation and highlight the antagonistic interplay between natural and sexual selection in shaping acoustic signals.
Categories: Bioscience

The Vocal Repertoire of the African Penguin (Spheniscus demersus): Structure and Function of Calls

July 30, 2014 - 5:00pm

by Livio Favaro, Laura Ozella, Daniela Pessani

The African Penguin (Spheniscus demersus) is a highly social and vocal seabird. However, currently available descriptions of the vocal repertoire of African Penguin are mostly limited to basic descriptions of calls. Here we provide, for the first time, a detailed description of the vocal behaviour of this species by collecting audio and video recordings from a large captive colony. We combine visual examinations of spectrograms with spectral and temporal acoustic analyses to determine vocal categories. Moreover, we used a principal component analysis, followed by signal classification with a discriminant function analysis, for statistical validation of the vocalisation types. In addition, we identified the behavioural contexts in which calls were uttered. The results show that four basic vocalisations can be found in the vocal repertoire of adult African Penguin, namely a contact call emitted by isolated birds, an agonistic call used in aggressive interactions, an ecstatic display song uttered by single birds, and a mutual display song vocalised by pairs, at their nests. Moreover, we identified two distinct vocalisations interpreted as begging calls by nesting chicks (begging peep) and unweaned juveniles (begging moan). Finally, we discussed the importance of specific acoustic parameters in classifying calls and the possible use of the source-filter theory of vocal production to study penguin vocalisations.
Categories: Bioscience