The physiological roles of carnosine and β-alanine in exercising human skeletal muscle

Carnosine (β-alanyl-L-histidine) plays an important role in exercise performance and skeletal muscle homeostasis. Dietary supplementation with the rate-limiting precursor β-alanine leads to an increase in skeletal muscle carnosine content, which further potentiates its effects. There is significant interest in carnosine and β-alanine across athletic and clinical populations. Traditionally, attention has been given to performance outcomes with less focus on the underlying mechanism(s). Putative physiological roles in human skeletal muscle include acting as an intracellular pH buffer, modulating energy metabolism, regulating Ca2+ handling and myofilament sensitivity, and scavenging of reactive species. Emerging evidence shows that carnosine could also act as a cytoplasmic Ca2+–H+ exchanger and form stable conjugates with exercise-induced reactive aldehydes. The enigmatic nature of carnosine means there is still much to learn regarding its actions and applications in exercise, health and disease. In this review, we examine the research relating to each physiological role attributed to carnosine, and its precursor β-alanine, in exercising human skeletal muscle

The intracellular plasma membrane-connected compartment in the assembly of HIV-1 in human macrophages

Background In HIV-infected macrophages, newly formed progeny virus particles accumulate in intracellular plasma membrane-connected compartments (IPMCs). Although the virus is usually seen in these compartments, it is unclear whether HIV assembly is specifically targeted to IPMCs or whether some viruses may also form at the cell surface but are not detected, as particles budding from the latter site will be released into the medium. Results To investigate the fidelity of HIV-1 targeting to IPMCs compared to the cell surface directly, we generated mutants defective in recruitment of the Endosomal Sorting Complexes Required for Transport (ESCRT) proteins required for virus scission. For mutants unable to bind the ESCRT-I component Tsg101, HIV release was inhibited and light and electron microscopy revealed that budding was arrested. When expressed in human monocyte-derived macrophages (MDM), these mutants formed budding-arrested, immature particles at their assembly sites, allowing us to capture virtually all of the virus budding events. A detailed morphological analysis of the distribution of the arrested viruses by immunofluorescence staining and confocal microscopy, and by electron microscopy, demonstrated that HIV assembly in MDMs is targeted primarily to IPMCs, with fewer than 5 % of budding events seen at the cell surface. Morphometric analysis of the relative membrane areas at the cell surface and IPMCs confirmed a large enrichment of virus assembly events in IPMCs. Serial block-face scanning electron microscopy of macrophages infected with a budding-defective HIV mutant revealed high-resolution 3D views of the complex organisation of IPMCs, with in excess of 15,000 associated HIV budding sites, and multiple connections between IPMCs and the cell surface

Optimization of quantitative susceptibility mapping for regional estimation of oxygen extraction fraction in the brain

Purpose: We sought to determine the degree to which oxygen extraction fraction (OEF) estimated using quantitative susceptibility mapping (QSM) depends on two critical acquisition parameters that have a significant impact on acquisition time: voxel size and final echo time. Methods: Four healthy volunteers were imaged using a range of isotropic voxel sizes and final echo times. The 0.7 mm data were downsampled at different stages of QSM processing by a factor of 2 (to 1.4 mm), 3 (2.1 mm), or 4 (2.8 mm) to determine the impact of voxel size on each analysis step. OEF was estimated from 11 veins of varying diameter. Inter- and intra- session repeatability were estimated for the opti-mal protocol by repeat scanning in 10 participants. Results: Final echo time was found to have no significant effect on OEF. The effect of voxel size was significant, with larger voxel sizes underestimating OEF, depending on the proximity of the vein to the superficial surface of the brain and on vein diameter. The last analysis step of estimating vein OEF values from susceptibility images had the largest dependency on voxel size. Inter- session coefficients of variation on OEF estimates of between 5.2% and 8.7% are reported, depending on the vein. Conclusion: QSM acquisition times can be minimized by reducing the final echo time but an isotropic voxel size no larger than 1 mm is needed to accurately estimate OEF in most medium/large veins in the brain. Such acquisitions can be achieved in under 4 mi

Post-fossilization processes and their implications for understanding Ediacaran macrofossil assemblages

Fossil assemblages from Newfoundland’s Avalon Peninsula preserve diverse examples of the enigmatic Ediacaran macrobiota, offering some of the earliest evidence for large and complex multicellular life. These fossils are exposed on extensive coastal bedding planes in extraordinary abundances, permitting palaeoecological studies based on census data from spatially extensive palaeocommunities. Such studies have been used to constrain the reproductive strategy and phylogenetic placement of Ediacaran organisms. Geological mapping and stratigraphic correlation in the Mistaken Point Ecological Reserve reveal that some fossil-bearing surfaces can be tracked over distances of several kilometres. These laterally extensive surfaces reveal that the modern processes by which the sediment overlying a fossil surface is removed may impose important controls on the observed composition of fossil assemblages. Weathering and erosion – along with factors associated with tectonics, metamorphism and discovery – are here grouped as ‘post-fossilization processes’ and introduce biases that are often not explicitly accounted for in palaeoecological studies. Specifically, post-fossilization processes may differentially influence the preservational fidelity of individual specimens on a given surface and generate features that could be mistaken for original morphological characters. We therefore recommend that post-fossilization processes must be considered when undertaking palaeoecological studies in Ediacaran successions in Newfoundland and, potentially, elsewhere.This research was supported by the Natural Environment Research Council [grant numbers NE/J5000045/1 to JJM, and NE/L011409/1 to AGL]. Joe Stewart and Tom Hearing are thanked for assistance in gathering field data. Thanks are also extended to Martin Brasier, without whom this research would never have taken place. Reviews from Matthew Clapham and one anonymous reviewer greatly improved the manuscript. The Parks and Natural Areas Division, Department of Environment and Conservation, Government of Newfoundland and Labrador, provided permits to conduct research within the Mistaken Point Ecological Reserve. Access to fossil localities within the Mistaken Point Ecological Reserve for research is by permit only. The fossils around Cape Race are protected by the Paleontological Resource Regulations 67/11, under the Historic Resources Act, 1990

Aquatic community response to volcanic eruptions on the Ecuadorian Andean flank: evidence from the palaeoecological record

Aquatic ecosystems in the tropical Andes are under increasing pressure from human modification of the landscape (deforestation and dams) and climatic change (increase of extreme events and 1.5 °C on average temperatures are projected for AD 2100). However, the resilience of these ecosystems to perturbations is poorly understood. Here we use a multi-proxy palaeoecological approach to assess the response of aquatic ecosystems to a major mechanism for natural disturbance, volcanic ash deposition. Specifically, we present data from two Neotropical lakes located on the eastern Andean flank of Ecuador. Laguna Pindo (1°27.132′S–78°04.847′W) is a tectonically formed closed basin surrounded by a dense mid-elevation forest, whereas Laguna Baños (0°19.328′S–78°09.175′W) is a glacially formed lake with an inflow and outflow in high Andean Páramo grasslands. In each lake we examined the dynamics of chironomids and other aquatic and semi-aquatic organisms to explore the effect of thick (> 5 cm) volcanic deposits on the aquatic communities in these two systems with different catchment features. In both lakes past volcanic ash deposition was evident from four large tephras dated to c.850 cal year BP (Pindo), and 4600, 3600 and 1500 cal year BP (Baños). Examination of the chironomid and aquatic assemblages before and after the ash depositions revealed no shift in composition at Pindo, but a major change at Baños occurred after the last event around 1500 cal year BP. Chironomids at Baños changed from an assemblage dominated by Pseudochironomus and Polypedilum nubifer-type to Cricotopus/Paratrichocladius type-II, and such a dominance lasted for approximately 380 years. We suggest that, despite potential changes in the water chemistry, the major effect on the chironomid community resulted from the thickness of the tephra being deposited, which acted to shallow the water body beyond a depth threshold. Changes in the aquatic flora and fauna at the base of the trophic chain can promote cascade effects that may deteriorate the ecosystem, especially when already influenced by human activities, such as deforestation and dams, which is frequent in the high Andes

Relationships between speed, change of direction and jump performance with cricket specific speed tests in male academy cricketers

Objectives: The aim of this study was to investigate the relationships between general speed and change of direction speed and‘cricket specific’ speed tests and the relationships between jump performance and speed and change of direction ability in male academy cricketers. Design and Methods: Sixteen academy male cricketers (age: 17 ± 0.7 years; height: 176.9 ± 6.2 cm; mass: 72.2 ± 13.2 kg) performed tests of 20 m sprint, 505 change of direction (COD) on both left and right legs, “quick single” with bat (WB) (17.68m), running-a-two WB, running-a-three WB, countermovement jump (CMJ), and drop jump (DJ). Results: Intra-class correlation coefficients (ICC’s) revealed high within-session reliability for all tests (ICC ≥ 0.92; p ≤ 0.001),except 0-5 m (ICC = 0.642; p ≤ 0.001) and 0-10 m (ICC = 0.708; p ≤ 0.001) tests. General speed tests showed strong relationships to ‘cricket specific’ speed tests (20 m sprint - running-a-two; r = 0.951; p ≤ 0.01; 20 m sprint - running-a-three; r = 0.937; p ≤ 0.01; ‘quick single’; r = 0.951; p ≤ 0.01). Strong relationships were also observed between the 505 right foot COD times and all cricket specific tests (r = 0.909- 0.934; p ≤ 0.01). CMJ height showed the strongest correlations with: 20 m (r = -0.668;p ≤ 0.01); 505 left (r = -0.789; p ≤ 0.01); 505 right (r = -0.807; p ≤ 0.01); “quick single” WB (r = -0.739; p ≤ 0.01); running-a two WB (r = -0.742; p ≤ 0.01); running-a-three (WB) (r = -0.733; p ≤ 0.01). Conclusions: The findings suggest that general speed and COD tests are highly appropriate to assess cricket specific qualities in youth cricketers

From Nonspecific DNA–Protein Encounter Complexes to the Prediction of DNA–Protein Interactions

©2009 Gao, Skolnick. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.doi:10.1371/journal.pcbi.1000341DNA–protein interactions are involved in many essential biological activities. Because there is no simple mapping code between DNA base pairs and protein amino acids, the prediction of DNA–protein interactions is a challenging problem. Here, we present a novel computational approach for predicting DNA-binding protein residues and DNA–protein interaction modes without knowing its specific DNA target sequence. Given the structure of a DNA-binding protein, the method first generates an ensemble of complex structures obtained by rigid-body docking with a nonspecific canonical B-DNA. Representative models are subsequently selected through clustering and ranking by their DNA–protein interfacial energy. Analysis of these encounter complex models suggests that the recognition sites for specific DNA binding are usually favorable interaction sites for the nonspecific DNA probe and that nonspecific DNA–protein interaction modes exhibit some similarity to specific DNA–protein binding modes. Although the method requires as input the knowledge that the protein binds DNA, in benchmark tests, it achieves better performance in identifying DNA-binding sites than three previously established methods, which are based on sophisticated machine-learning techniques. We further apply our method to protein structures predicted through modeling and demonstrate that our method performs satisfactorily on protein models whose root-mean-square Ca deviation from native is up to 5 Å from their native structures. This study provides valuable structural insights into how a specific DNA-binding protein interacts with a nonspecific DNA sequence. The similarity between the specific DNA–protein interaction mode and nonspecific interaction modes may reflect an important sampling step in search of its specific DNA targets by a DNA-binding protein