hCOA3 Stabilizes Cytochrome c Oxidase 1 (COX1) and Promotes Cytochrome c Oxidase Assembly in Human Mitochondria

Cytochrome c oxidase (COX) or complex IV of the mitochondrial respiratory chain plays a fundamental role in energy production of aerobic cells. In humans, COX deficiency is the most frequent cause of mitochondrial encephalomyopathies. Human COX is composed of 13 subunits of dual genetic origin, whose assembly requires an increasing number of nuclear-encoded accessory proteins known as assembly factors. Here, we have identified and characterized human CCDC56, an 11.7-kDa mitochondrial transmembrane protein, as a new factor essential for COX biogenesis. CCDC56 shares sequence similarity with the yeast COX assembly factor Coa3 and was termed hCOA3. hCOA3-silenced cells display a severe COX functional alteration owing to a decreased stability of newly synthesized COX1 and an impairment in the holoenzyme assembly process. We show that hCOA3 physically interacts with both the mitochondrial translation machinery and COX structural subunits. We conclude that hCOA3 stabilizes COX1 co-translationally and promotes its assembly with COX partner subunits. Finally, our results identify hCOA3 as a new candidate when screening for genes responsible for mitochondrial diseases associated with COX deficiency.     

Cocaine Inhibits Dopamine D2 Receptor Signaling via Sigma-1-D2 Receptor Heteromers

Under normal conditions the brain maintains a delicate balance between inputs of reward seeking controlled by neurons containing the D₁-like family of dopamine receptors and inputs of aversion coming from neurons containing the D₂-like family of dopamine receptors. Cocaine is able to subvert these balanced inputs by altering the cell signaling of these two pathways such that D₁ reward seeking pathway dominates. Here, we provide an explanation at the cellular and biochemical level how cocaine may achieve this. Exploring the effect of cocaine on dopamine D₂ receptors function, we present evidence of σ₁ receptor molecular and functional interaction with dopamine D₂ receptors. Using biophysical, biochemical, and cell biology approaches, we discovered that D₂ receptors (the long isoform of the D₂ receptor) can complex with σ₁ receptors, a result that is specific to D₂ receptors, as D₃ and D₄ receptors did not form heteromers. We demonstrate that the σ₁-D₂ receptor heteromers consist of higher order oligomers, are found in mouse striatum and that cocaine, by binding to σ₁ -D₂ receptor heteromers, inhibits downstream signaling in both cultured cells and in mouse striatum. In contrast, in striatum from σ₁ knockout animals these complexes are not found and this inhibition is not seen. Taken together, these data illuminate the mechanism by which the initial exposure to cocaine can inhibit signaling via D₂ receptor containing neurons, destabilizing the delicate signaling balance influencing drug seeking that emanates from the D₁ and D₂ receptor containing neurons in the brain.     

Genetics of frost hardiness in <Emphasis Type="Italic">Juglans regia</Emphasis> L. and relationship with growth and phenology

The growing interest in broadleaf timber plantations in the Mediterranean area has promoted several studies focusing on the identification and characterization of variability sources in main timber-producing species. J. regia is one of these species, well-adapted to this area, but with freezing, damages registrations. Breeding focused on productive traits should include knowledge of adaptation, required to obtain a good selection capable of producing a suitable turnover in timber plantations. In this study, the features evaluated were autumn and winter frost hardiness and some vegetative traits on 22 half-sib J. regia progenies. Budsticks were exposed to sub-zero temperatures in a controlled chamber and using measurements of relative electrolyte content, the LT50 values (°C) were calculated by each individual. The study was carried out on seven-year-old progenies. The familiar heritability of autumn frost hardiness was 0.68, and on winter, it was 0.77. The autumn frost behaviour correlated genetically with the length of the growing season (0.574 ± 0.351), and both autumn and winter frost hardiness correlated inversely with secondary annual growth measured at breast height (?0.654 ± 0.259 and ?0.740 ± 0.227, respectively). These results pointed that growth could therefore be improved without increasing the frost vulnerability. This should be important for growers, particularly under climate change conditions.     

Antioxidant Defenses in Wild Growing Halophyte Crithmum maritimum from Inland and Coastline Populations

Traditional Mediterranean diet includes the halophyte Crithmum maritimum L. (Apiaceae) which can be found in the coastline of the Balearic Islands but also inland. Both areas differed in the environmental conditions, mainly in salinity which can affect the oxidative status of this species. The aim was to evaluate the antioxidant enzyme activities, polyphenols and the lipid peroxidation in leaves of wild C. maritimum growing in a natural coastal area influenced by marine salinity and an inland area without marine influence. The activities of the antioxidant enzymes catalase, superoxide dismutase and glutathione peroxidase as well as polyphenol and reduced glutathione content were significantly higher in the samples from coastline population, whereas no significant differences were found in glutathione reductase activity and in malondialdehyde levels. The production of H₂O₂ was also significantly higher in the population from coastline. In conclusion, C. maritimum adapt their antioxidant defense machinery to the different salinity conditions, avoiding the instauration of oxidative stress.     

Toward Standardization of Mesenchymal Stromal Cell‐Derived Extracellular Vesicles for Therapeutic Use: A Call for Action

Extracellular vesicles (EVs), which include a variety of nano‐sized membrane‐encapsulated particles, are released to the extracellular microenvironment by the vast majority of cells and carry lipids, proteins, mRNA, and miRNA or non‐coding RNA. Increasing evidence suggests the great versatility and potential of EV‐based applications in humans. In this issue, van Balkom et al. explore and compare the reported proteomic signature of mesenchymal stromal cell (MSC)‐derived small EVs. In particular, their paper offers a valuable approach and point of view on MSC‐EV manufacturing and therapeutic potential. Briefly, van Balkom et al. aimed to identify a common protein signature that may be useful in ensuring the homogeneity of therapeutic MSC‐EVs. In addition to excessive variability in EV‐producing cell sources and culture conditions, the harvesting time for the EV‐containing conditioned medium, and EV isolation procedure, the authors found a specific protein signature from the publicly available MSC‐EVs proteome. In light of their findings and those from the plentiful studies published in this continuously growing area of research, potential focus areas and issues are outlined for the more rational design and optimization of MSC‐EV production and potency for therapeutics.     

Ni‐Metalloid (B,Si, P,As, and Te) Alloys as Water Oxidation Electrocatalysts

Breakthroughs toward effective water‐splitting electrocatalysts for mass hydrogen production will necessitate material design strategies based on unexplored material chemistries. Herein, Ni‐metalloid (B, Si, P, As, Te) alloys are reported as an emergent class of highly promising electrocatalysts for the oxygen evolution reaction (OER) and insight is offered into the origin of activity enhancement on the premise of the surface electronic structure, the OER activation energy, influence of the guest metalloid elements on the lattice structure of the host metal (Ni), and surface‐oxidized metalloid oxoanions. The metalloids modify the lattice structure of Ni, causing changes in the nearest Ni–Ni interatomic distance (d_Ni–Ni). The activation energy E_a scales with d_Ni–Ni indicating an apparent dependence of the OER activity on lattice properties. During the OER, surface Ni atoms are oxidized to nickel oxyhydroxide, which is the active state of the catalyst, meanwhile, the surface metalloids are oxidized to the corresponding oxoanions that affect the interfacial electrode/electrolyte properties and hence the adsorption/desorption interaction energies of the reacting species.     

Synthesis and NMR experiments of (4,5,6-13C)-deoxymannojirimycin. A new entry to 13C-labeled glycosidase inhibitors

The synthesis of (4,5,6-13C)-deoxymannojirimycin is described. The route employed is based on Sharpless asymmetric epoxidation of (1,2,3-13C)(E)-2,4-pentadien-1-ol and uses ring-closing metathesis as a key step. The labeled compound may be easily used for protein-binding experiments using NMR spectroscopic methods.     

Beak morphology predicts apparent survival of crossbills: due to selective survival or selective dispersal?

Dozens of morphologically differentiated populations, subspecies and species of crossbills (genus Loxia) exist. It has been suggested that this divergence is due to variation in the conifer cones that each population specialises upon, requiring a specific beak size to efficiently separate the cone scales. If so, apparent survival should depend on beak size. To test this hypothesis, we undertook multievent capture–recapture modelling for 6844 individuals monitored during 27 years in a Pyrenean common crossbill L. curvirostra population in a forest of mountain pine Pinus uncinata. Apparent survival was indeed related to beak width, resulting in stabilizing selection around an optimum that was close to the observed mean beak width, indicating that local crossbill beak morphology is adapted to the conifer they feed upon. Both natural selection (selective mortality) and selective emigration of maladapted individuals may explain our findings. As is often the case in capture–recapture analyses but rarely recognised, we could not formally decompose apparent survival into selective mortality versus selective permanent emigration. Nonetheless, there are several indications that selective permanent emigration should not be fully excluded. First, natural selection by itself would have to be unusually strong compared to other empirical estimates to create the observed pattern of apparent survival. Second, the observed mean beak width was a bit lower than the estimated optimum beak width. This can be explained by immigration of crossbills with smaller beaks originating from southern populations, which may subsequently have left the study area permanently in response to low food intake. This is in line with a detected transient effect in the data, yet apparently little influx from crossbills from northern Europe. When permanent emigration is phenotypically selective this will have ecological and evolutionary consequences, so this possibility deserves more attention in general.