RCSB Protein Data Bank: Enabling biomedical research and drug discovery

Analyses of publicly available structural data reveal interesting insights into the impact of the three‐dimensional (3D) structures of protein targets important for discovery of new drugs (e.g., G‐protein‐coupled receptors, voltage‐gated ion channels, ligand‐gated ion channels, transporters, and E3 ubiquitin ligases). The Protein Data Bank (PDB) archive currently holds > 155,000 atomic‐level 3D structures of biomolecules experimentally determined using crystallography, nuclear magnetic resonance spectroscopy, and electron microscopy. The PDB was established in 1971 as the first open‐access, digital‐data resource in biology, and is now managed by the Worldwide PDB partnership (wwPDB; wwPDB.org ). US PDB operations are the responsibility of the Research Collaboratory for Structural Bioinformatics PDB (RCSB PDB). The RCSB PDB serves millions of RCSB.org users worldwide by delivering PDB data integrated with ～40 external biodata resources, providing rich structural views of fundamental biology, biomedicine, and energy sciences. Recently published work showed that the PDB archival holdings facilitated discovery of ～90% of the 210 new drugs approved by the US Food and Drug Administration 2010–2016. We review user‐driven development of RCSB PDB services, examine growth of the PDB archive in terms of size and complexity, and present examples and opportunities for structure‐guided drug discovery for challenging targets (e.g., integral membrane proteins).     

Plant–plant facilitation increases with reduced phylogenetic relatedness along an elevation gradient

Environmental conditions can modify the intensity and sign of ecological interactions. The stress gradient hypothesis (SGH) predicts that facilitation becomes more important than competition under stressful conditions. To properly test this hypothesis, it is necessary to account for all (not a subset of) interactions occurring in the communities and consider that species do not interact at random but following a specific pattern. We aim to assess elevational changes in facilitation, in terms of species richness, frequency and intensity of the interaction as a function of the evolutionary relatedness between nurses and their associated species. We sampled nurse and their facilitated plant species in two 1000–2000 m. elevation gradients in Mediterranean Chile where low temperature imposes a mortality filter on seedlings. We first estimated the relative importance of facilitation as a mechanism adding new species to communities distributed along these gradients. We then tested whether the frequency and intensity of facilitation increases with elevation, taking into account the evolutionary relatedness of the nurse species and the facilitated species. We found that nurses increase the species richness of the community by up to 35%. Facilitative interactions are more frequent than competitive interactions (56% versus 44%) and facilitation intensity increased with elevation for interactions involving distantly related lineages. Our results highlight the importance of including an evolutionary dimension in the study of facilitation to have a clearer picture of the mechanisms enabling species to coexist and survive under stressful conditions. This knowledge is especially relevant to conserve vulnerable and threatened communities facing new climate scenarios, such as those located in Mediterranean-type ecosystems.     

Reduced impact of ocean acidification on growth and swimming performance of newly hatched tropical sharks (Chiloscyllium plagiosum)

ABSTRACT

Sharks have been facing unprecedented pressure over the last decades, and ocean acidification may represent an additional threat, particularly during their most susceptible life stages. Hence, the present study aimed to investigate the effects of ocean acidification (control pCO₂ ~ 400 μatm; high pCO₂ ~ 900 μatm) on the growth, swimming performance and cholinergic system of juvenile white-spotted bamboo sharks (Chiloscyllium plagiosum). After 45 days of exposure, we observed that high CO₂ did not affect most of the end-points studied. However, somatic growth rate and the percentage of time that sharks spent swimming was significantly reduced under high CO₂ conditions. Moreover, AChE activity decreased in two of the seven brain macroareas analyzed, the telencephalon and optic lobes. As this near-threatened shark species showed small sub-lethal effects to high CO₂ levels, we argue that within a longer time-frame they can potentially reduce individual performance with cascading consequences to shark population dynamics.     

Vinpocetine attenuates the metabolic dysfunction induced by amyloid β-peptides in PC12 cells

The cytoprotective effect of vinpocetine [14-ethoxycarbonyl-(3α,16α-ethyl)-14,15-eburnamine] was investigated on PC12 cells treated with the amyloid β-peptides (Aβ) for 24 hours. Vinpocetine was shown to protect cells from the inhibition in redox status induced by exposure to Aβ_25–35 and Aβ_1–40, the maximal protection being achieved at a vinpocetine concentration of 40 μM. At this concentration, vinpocetine blocked the inhibition of the mitochondrial respiratory chain complexes II–III and IV and completely abolished the depletion of pyruvate levels induced by toxic concentrations of Aβ peptides. Furthermore, the accumulation of ROS in cells exposed to Aβ_25–35 and Aβ_1–40 evaluated using the fluorescent probe 2′,7′-dichlorofluorescin (DCF), was reduced in the presence of 40 μM vinpocetine. Taken together, the data presented herein demonstrate that vinpocetine protects cells from Aβ toxicity, preventing the generation of oxidative stress due to the excessive accumulation of ROS. This study suggests that vinpocetine can exert neuroprotective properties which might be of importance and contribute to its clinical efficacy in the treatment of Alzheimer's disease or other neurodegenerative disorders in which oxidative stress is involved.     

ReviewPart of the Series: From Dietary Antioxidants to Regulators in Cellular Signalling and Gene ExpressionReview: When is an antioxidant not an antioxidant? A review of novel actions and reactions of vitamin C

Vitamin C (or ascorbic acid) is regarded as the most important water-soluble antioxidant in human plasma and mammalian cells which have mechanisms to recycle and accumulate it against a concentration gradient, suggesting that the vitamin might also have important intracellular functions. In this review we summarize evidence from human trials that have attempted an association between vitamin C supplementation and an effect on biomarkers of oxidative DNA damage. Most studies reviewed herein showed either a vitamin C-mediated reduction in oxidative DNA damage or a null effect, whereas only a few studies showed an increase in specific base lesions. We also address the possible beneficial effects of vitamin C supplementation for the prevention of cancer and cardiovascular disease. Finally, we discuss the contribution of cell culture studies to our understanding of the mode of action of vitamin C and we review recent evidence that vitamin C is able to modulate gene expression and cellular function, with a particular interest in cell differentiation.     

Discriminating the effects of phylogenetic hypothesis,tree resolution and clade age estimates on phylogenetic signal measurements

Understanding how species traits evolved over time is the central question to comprehend assembly rules that govern the phylogenetic structure of communities. The measurement of phylogenetic signal (PS) in ecologically relevant traits is a first step to understand phylogenetically structured community patterns. The different methods available to estimate PS make it difficult to choose which is most appropriate. Furthermore, alternative phylogenetic tree hypotheses, node resolution and clade age estimates might influence PS measurements. In this study, we evaluated to what extent these parameters affect different methods of PS analysis, and discuss advantages and disadvantages when selecting which method to use. We measured fruit/seed traits and flowering/fruiting phenology of endozoochoric species occurring in Southern Brazilian Araucaria forests and evaluated their PS using Mantel regressions, phylogenetic eigenvector regressions (PVR) and K statistic. Mantel regressions always gave less significant results compared to PVR and K statistic in all combinations of phylogenetic trees constructed. Moreover, a better phylogenetic resolution affected PS, independently of the method used to estimate it. Morphological seed traits tended to show higher PS than diaspores traits, while PS in flowering/fruiting phenology depended mostly on the method used to estimate it. This study demonstrates that different PS estimates are obtained depending on the chosen method and the phylogenetic tree resolution. This finding has implications for inferences on phylogenetic niche conservatism or ecological processes determining phylogenetic community structure.     

Does My Face FIT?: A Face Image Task Reveals Structure and Distortions of Facial Feature Representation

Despite extensive research on face perception, few studies have investigated individuals’ knowledge about the physical features of their own face. In this study, 50 participants indicated the location of key features of their own face, relative to an anchor point corresponding to the tip of the nose, and the results were compared to the true location of the same individual’s features from a standardised photograph. Horizontal and vertical errors were analysed separately. An overall bias to underestimate vertical distances revealed a distorted face representation, with reduced face height. Factor analyses were used to identify separable subconfigurations of facial features with correlated localisation errors. Independent representations of upper and lower facial features emerged from the data pattern. The major source of variation across individuals was in representation of face shape, with a spectrum from tall/thin to short/wide representation. Visual identification of one’s own face is excellent, and facial features are routinely used for establishing personal identity. However, our results show that spatial knowledge of one’s own face is remarkably poor, suggesting that face representation may not contribute strongly to self-awareness.