The diversity of ACBD proteins – From lipid binding to protein modulators and organelle tethers

This is the author accepted manuscript. The final version is available on open access from Elsevier via the DOI in this record Members of the large multigene family of acyl-CoA binding domain containing proteins (ACBDs) share a conserved motif required for binding of Coenzyme A esterified fatty acids of various chain length. These proteins are present in the three kingdoms of life, and despite their predicted roles in cellular lipid metabolism, knowledge about the precise functions of many ACBD proteins remains scarce. Interestingly, several ACBD proteins are now suggested to function at organelle contact sites, and are recognized as host interaction proteins for different pathogens including viruses and bacteria. Here, we present a thorough phylogenetic analysis of the ACBD family and discuss their structure and evolution. We summarize recent findings on the various functions of animal and fungal ACBDs with particular focus on peroxisomes, the role of ACBD proteins at organelle membranes, and their increasing recognition as targets for pathogens.Biotechnology & Biological Sciences Research Council (BBSRC)European CommissionBiotechnology & Biological Sciences Research Council (BBSRC

Dexmedetomidine protects against lipid peroxidation and erythrocyte deformability alterations in experimental hepatic ischemia reperfusion injury

Background: Hepatic ischemia–reperfusion injury is a common clinical problem in hepatic surgery and transplantation. Several cellular and tissue structural and functional alterations are observed in such injury. The aim of this study was to evaluate the effect of dexmedetomidine on lipid peroxidation and erythrocyte deformability during ischemia–reperfusion injury in rats. Methods: Twenty-four Wistar Albino rats were randomly separated into three groups as control (C), ischemia–reperfusion injury (I/R) and dexmedetomidine group (I/R-D). Ischemia was induced with portal clampage for 45 min and reperfusion period was 45 min after declampage. Group I/R-D received dexmedetomidine 100 µg/kg i.p. 30 min before portal clampage. Serum malondialdehyde and superoxide dismutase activities to document lipid peroxidation and erythrocyte deformability index were investigated. Results: Serum superoxide dismutase and malondialdehyde activity levels were significantly higher and erythrocyte deformability index was decreased in hepatic ischemia–reperfusion group. However, these changes were observed to be prevented with dexmedetomidine treatment when given before portal clampage. Conclusion: These findings clearly indicate that erythrocyte deformability index is decreased in hepatic ischemia reperfusion injury and has a potential role to prevent these alterations. The protective effect of dexmedetomidine on hepatic I/R injury is also decreased lipid peroxidation. Further experimental and clinical investigations may clarify the molecular mechanisms and clinical significance of these findings

Differential roles for ACBD4 and ACBD5 in peroxisome-ER interactions and lipid metabolism

This is the author accepted manuscript. The final version is available on open access from Elsevier via the DOI in this record Data availability: The research data supporting this publication are provided within this paper, or as supplementary information.Peroxisomes and the endoplasmic reticulum (ER) are intimately linked subcellular organelles, physically connected at membrane contact sites. As well as collaborating in lipid metabolism, e.g. of very long chain fatty acids (VLCFAs) and plasmalogens, the ER also plays a role in peroxisome biogenesis. Recent work has identified tethering complexes on the ER and peroxisome membranes which connect the organelles. These include membrane contacts formed via interactions between the ER protein VAPB (vesicle-associated membrane proteinassociated protein B) and the peroxisomal proteins ACBD4 and ACBD5 (acyl-coenzyme Abinding domain protein). Loss of ACBD5 has been shown to cause a significant reduction in peroxisome-ER contacts and accumulation of VLCFAs. However, the role of ACBD4, and the relative contribution these two proteins make to contact site formation and recruitment of VLCFAs to peroxisomes remains unclear. Here, we address these questions, using a combination of molecular cell biology, biochemical and lipidomics analyses following loss of ACBD4 or ACBD5 in HEK293 cells. We show that the tethering function of ACBD5 is not absolutely required for efficient peroxisomal β-oxidation of VLCFAs. We demonstrate that loss of ACBD4 does not reduce peroxisome-ER connections or result in accumulation of VLCFAs. Instead, the loss of ACBD4 resulted in an increase in the rate of β-oxidation of VLCFAs. Finally, we observe interaction between ACBD5 and ACBD4, independent of VAPB binding. Overall, our findings suggest that ACBD5 may act as a primary tether and VLCFA recruitment factor, whereas ACBD4 may have regulatory functions in peroxisomal lipid metabolism at the peroxisome-ER interface.Biotechnology & Biological Sciences Research Council (BBSRC)UK Research and InnovationRoyal SocietyEuropean Union Horizon 2020Medical Research Council (MRC

Modeling denitrification in aquatic sediments

Author Posting. © The Author(s), 2008. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Biogeochemistry 93 (2009): 159-178, doi:10.1007/s10533-008-9270-z.Sediment denitrification is a major pathway of fixed nitrogen loss from aquatic systems. Due to technical difficulties in measuring this process and its spatial and temporal variability, estimates of local, regional and global denitrification have to rely on a combination of measurements and models. Here we review approaches to describing denitrification in aquatic sediments, ranging from mechanistic diagenetic models to empirical parameterizations of nitrogen fluxes across the sediment-water interface. We also present a compilation of denitrification measurements and ancillary data for different aquatic systems, ranging from freshwater to marine. Based on this data compilation we reevaluate published parameterizations of denitrification. We recommend that future models of denitrification use (1) a combination of mechanistic diagenetic models and measurements where bottom waters are temporally hypoxic or anoxic, and (2) the much simpler correlations between denitrification and sediment oxygen consumption for oxic bottom waters. For our data set, inclusion of bottom water oxygen and nitrate concentrations in a multivariate regression did not improve the statistical fit.Financial support for AEG to work on the manuscript came from NSF NSF-DEB-0423565. KF, DB and DDT acknowledge support from NOAA CHRP grant NA07NOS4780191

Phosphatidylserine targeting for diagnosis and treatment of human diseases

Cells are able to execute apoptosis by activating series of specific biochemical reactions. One of the most prominent characteristics of cell death is the externalization of phosphatidylserine (PS), which in healthy cells resides predominantly in the inner leaflet of the plasma membrane. These features have made PS-externalization a well-explored phenomenon to image cell death for diagnostic purposes. In addition, it was demonstrated that under certain conditions viable cells express PS at their surface such as endothelial cells of tumor blood vessels, stressed tumor cells and hypoxic cardiomyocytes. Hence, PS has become a potential target for therapeutic strategies aiming at Targeted Drug Delivery. In this review we highlight the biomarker PS and various PS-binding compounds that have been employed to target PS for diagnostic purposes. We emphasize the 35 kD human protein annexin A5, that has been developed as a Molecular Imaging agent to measure cell death in vitro, and non-invasively in vivo in animal models and in patients with cardiovascular diseases and cancer. Recently focus has shifted from diagnostic towards therapeutic applications employing annexin A5 in strategies to deliver drugs to cells that express PS at their surface

Visuomotor Cerebellum in Human and Nonhuman Primates

In this paper, we will review the anatomical components of the visuomotor cerebellum in human and, where possible, in non-human primates and discuss their function in relation to those of extracerebellar visuomotor regions with which they are connected. The floccular lobe, the dorsal paraflocculus, the oculomotor vermis, the uvula–nodulus, and the ansiform lobule are more or less independent components of the visuomotor cerebellum that are involved in different corticocerebellar and/or brain stem olivocerebellar loops. The floccular lobe and the oculomotor vermis share different mossy fiber inputs from the brain stem; the dorsal paraflocculus and the ansiform lobule receive corticopontine mossy fibers from postrolandic visual areas and the frontal eye fields, respectively. Of the visuomotor functions of the cerebellum, the vestibulo-ocular reflex is controlled by the floccular lobe; saccadic eye movements are controlled by the oculomotor vermis and ansiform lobule, while control of smooth pursuit involves all these cerebellar visuomotor regions. Functional imaging studies in humans further emphasize cerebellar involvement in visual reflexive eye movements and are discussed

Coupling of ocean redox and animal evolution during the Ediacaran-Cambrian transition

The late Ediacaran to early Cambrian interval witnessed extraordinary radiations of metazoan life. The role of the physical environment in this biological revolution, such as changes to oxygen levels and nutrient availability, has been the focus of longstanding debate. Seemingly contradictory data from geochemical redox proxies help to fuel this controversy. As an essential nutrient, nitrogen can help to resolve this impasse by establishing linkages between nutrient supply, ocean redox, and biological changes. Here we present a comprehensive N-isotope dataset from the Yangtze Basin that reveals remarkable coupling between δ¹⁵N, δ¹³C, and evolutionary events from circa 551 to 515 Ma. The results indicate that increased fixed nitrogen supply may have facilitated episodic animal radiations by reinforcing ocean oxygenation, and restricting anoxia to near, or even at the sediment–water interface. Conversely, sporadic ocean anoxic events interrupted ocean oxygenation, and may have led to extinctions of the Ediacaran biota and small shelly animals