Murine macrophage P2X7 receptors support rapid prothrombotic responses

Non-apoptotic externalization of phosphatidylserine (PS) can act as a reactive surface for the efficient assembly of the prothrombinase complex leading to thrombin generation and coagulation. Here we show that extracellular ATP, acting at the macrophage P2X(7) receptor, drives the rapid Ca(2+)-dependent formation and release of PS-rich microvesicles that enhance the assembly of the prothrombinase complex and subsequent formation of thrombin. Incubation with P2X(7) receptor antagonists (KN-62 and Brilliant Blue G) attenuates ATP induced prothrombotic responses. Consistent with the hypothesis that exposed PS enhances prothrombinase activity; pre-incubation with annexin V blocks the increase in thrombin formation. The rapid translocation of PS and formation of pro-thrombotic microvesicles occurs in the absence of cell lysis. These data demonstrate that the pro-inflammatory P2X(7) receptor can also support and propagate rapid increases in thrombin formation.     

Temporal variation and landcover influence survival in adult female mottled ducks

Adult survival is a key driver of waterfowl population growth and is subject to temporal and spatial variation. Mottled ducks (Anas fulvigula) are native to the Gulf Coast and peninsular Florida, USA, and have suffered population declines over the past decade, especially in Texas and Louisiana, USA. Although the cause of this decline is not well understood, previous research concluded variation in survival contributed to nearly a third of variation in the species' population growth rate. We used global positioning system-groupe spécial mobile (GPS-GSM) transmitters to study temporal and spatial variation in survival of adult female western Gulf Coast mottled ducks in southwestern Louisiana, 2017–2020. We evaluated weekly survival models parameterized with combinations of hunted and non-hunted periods, biological seasons, and landcover types that were used by mottled ducks. There were 3 competitive survival models, and all contained 4 parameters that parsed the annual cycle into the non-hunted period, first part of the general waterfowl season, and second part of the waterfowl season, and included the proportion of GPS locations in agricultural lands. Weekly survival was 0.979 during the first part of the general waterfowl hunting season, and 0.996 during the second part of the general waterfowl season. Daily survival rate increased with an increasing proportion of locations logged in agricultural lands. Annual survival rates were similar to other waterfowl that are not experiencing population declines, which suggests survival is not limiting population growth of mottled ducks along the western Gulf Coast. Managers should ensure the availability of refuge areas where hunting is prohibited during the first part of the general waterfowl season, when mottled ducks are at an increased risk of mortality, in addition to the targeted conservation of agricultural lands that provide cover and forage.     

Removing endogenous tau does not prevent tau propagation yet reduces its neurotoxicity

In Alzheimer's disease and tauopathies, tau protein aggregates into neurofibrillary tangles that progressively spread to synaptically connected brain regions. A prion‐like mechanism has been suggested: misfolded tau propagating through the brain seeds neurotoxic aggregation of soluble tau in recipient neurons. We use transgenic mice and viral tau expression to test the hypotheses that trans‐synaptic tau propagation, aggregation, and toxicity rely on the presence of endogenous soluble tau. Surprisingly, mice expressing human P301Ltau in the entorhinal cortex showed equivalent tau propagation and accumulation in recipient neurons even in the absence of endogenous tau. We then tested whether the lack of endogenous tau protects against misfolded tau aggregation and toxicity, a second prion model paradigm for tau, using P301Ltau‐overexpressing mice with severe tangle pathology and neurodegeneration. Crossed onto tau‐null background, these mice had similar tangle numbers but were protected against neurotoxicity. Therefore, misfolded tau can propagate across neural systems without requisite templated misfolding, but the absence of endogenous tau markedly blunts toxicity. These results show that tau does not strictly classify as a prion protein.     

Evolutionary change in testes tissue composition among experimental populations of house mice

Theory assumes that postcopulatory sexual selection favors increased investment in testes size because greater numbers of sperm within the ejaculate increase the chance of success in sperm competition, and larger testes are able to produce more sperm. However, changes in the organization of the testes tissue may also affect sperm production rates. Indeed, recent comparative analyses suggest that sperm competition selects for greater proportions of sperm‐producing tissue within the testes. Here, we explicitly test this hypothesis using the powerful technique of experimental evolution. We allowed house mice (Mus domesticus) to evolve via monogamy or polygamy in six replicate populations across 24 generations. We then used histology and image analysis to quantify the proportion of sperm‐producing tissue (seminiferous tubules) within the testes of males. Our results show that males that had evolved with sperm competition had testes with a higher proportion of seminiferous tubules compared with males that had evolved under monogamy. Previously, it had been shown that males from the polygamous populations produced greater numbers of sperm in the absence of changes in testes size. We thus provide evidence that sperm competition selects for an increase in the density of sperm‐producing tissue, and consequently increased testicular efficiency.     

Structure and Function of the Hypertension Variant A486V of G Protein-coupled Receptor Kinase 4

G-protein-coupled receptor (GPCR) kinases (GRKs) bind to and phosphorylate GPCRs, initiating the process of GPCR desensitization and internalization. GRK4 is implicated in the regulation of blood pressure, and three GRK4 polymorphisms (R65L, A142V, and A486V) are associated with hypertension. Here, we describe the 2.6 Å structure of human GRK4α A486V crystallized in the presence of 5′-adenylyl β,γ-imidodiphosphate. The structure of GRK4α is similar to other GRKs, although slight differences exist within the RGS homology (RH) bundle subdomain, substrate-binding site, and kinase C-tail. The RH bundle subdomain and kinase C-terminal lobe form a strikingly acidic surface, whereas the kinase N-terminal lobe and RH terminal subdomain surfaces are much more basic. In this respect, GRK4α is more similar to GRK2 than GRK6. A fully ordered kinase C-tail reveals interactions linking the C-tail with important determinants of kinase activity, including the αB helix, αD helix, and the P-loop. Autophosphorylation of wild-type GRK4α is required for full kinase activity, as indicated by a lag in phosphorylation of a peptide from the dopamine D₁ receptor without ATP preincubation. In contrast, this lag is not observed in GRK4α A486V. Phosphopeptide mapping by mass spectrometry indicates an increased rate of autophosphorylation of a number of residues in GRK4α A486V relative to wild-type GRK4α, including Ser-485 in the kinase C-tail.     

Protein Depalmitoylation Is Induced by Wnt5a and Promotes Polarized Cell Behavior

Wnt5a signaling regulates polarized cell behavior, but the downstream signaling events that promote cell polarity are not well understood. Our results show that Wnt5a promotes depalmitoylation of the melanoma cell adhesion molecule (MCAM) at cysteine 590. Mutation of Cys-590 to glycine is sufficient to polarize MCAM localization, similar to what is observed with Wnt5a stimulation. Inhibition of the depalmitoylating enzyme APT1 blocks Wnt5a-induced depalmitoylation, asymmetric MCAM localization, and cell invasion. Directly altering expression of the basal protein palmitoylation machinery is sufficient to promote cell invasion. Additionally, cancer mutations in palmitoyltransferases decrease MCAM palmitoylation and have impaired ability to suppress cell invasion. Our results provide evidence that Wnt5a induces protein depalmitoylation, which promotes polarized protein localization and cell invasion.     

The macroevolutionary relationship between diet and body mass across mammals

Body mass and diet are two fundamental ecological parameters that influence many other aspects of an animal's biology. Thus, the potential physiological and ecological processes linking size and diet have been the subject of extensive research, although the broad macroevolutionary relationship between the two traits remains largely unexplored phylogenetically. Using generalized Ornstein–Uhlenbeck models and data on over 1350 species of mammal, we reveal that evolutionary changes in body mass are consistently associated with dietary changes across mammals. Best‐fitting models find that herbivores are substantially heavier than other dietary groups and that omnivores are frequently intermediate in mass between herbivores and carnivores. Interestingly, although flying and swimming both place very different physical constraints on mass, bats still follow the general mammalian pattern but marine mammals do not. Such differences may be explained by reduced gravitational constraints on size in water along with ecological differences in food availability between aquatic and terrestrial realms, allowing marine carnivores to become the largest mammals on earth. © 2015 The Linnean Society of London, Biological Journal of the Linnean Society, 2015, 115 , 173–184.