The Vesicle Priming Factor CAPS Functions as a Homodimer via C2 Domain Interactions to Promote Regulated Vesicle Exocytosis.

Neurotransmitters and peptide hormones are secreted by regulated vesicle exocytosis. CAPS (also known as CADPS) is a 145-kDa cytosolic and peripheral membrane protein required for vesicle docking and priming steps that precede Ca2+-triggered vesicle exocytosis. CAPS binds phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and SNARE proteins and is proposed to promote SNARE protein complex assembly for vesicle docking and priming. We characterized purified soluble CAPS as mainly monomer in equilibrium with small amounts of dimer. However, the active form of CAPS bound to PC12 cell membranes or to liposomes containing PI(4,5)P2 and Q-SNARE proteins was mainly dimer. CAPS dimer formation required its C2 domain based on mutation or deletion studies. Moreover, C2 domain mutations or deletions resulted in a loss of CAPS function in regulated vesicle exocytosis, indicating that dimerization is essential for CAPS function. Comparison of the CAPS C2 domain to a structurally defined Munc13-1 C2A domain dimer revealed conserved residues involved in CAPS dimerization. We conclude that CAPS functions as a C2 domain-mediated dimer in regulated vesicle exocytosis. The unique tandem C2-PH domain of CAPS may serve as a PI(4,5)P2-triggered switch for dimerization. CAPS dimerization may be coupled to oligomeric SNARE complex assembly for vesicle docking and priming

Cycling Transcriptional Networks Optimize Energy Utilization on a Genome Scale

SummaryGenes expressing circadian RNA rhythms are enriched for metabolic pathways, but the adaptive significance of cyclic gene expression remains unclear. We estimated the genome-wide synthetic and degradative cost of transcription and translation in three organisms and found that the cost of cycling genes is strikingly higher compared to non-cycling genes. Cycling genes are expressed at high levels and constitute the most costly proteins to synthesize in the genome. We demonstrate that metabolic cycling is accelerated in yeast grown under higher nutrient flux and the number of cycling genes increases ∼40%, which are achieved by increasing the amplitude and not the mean level of gene expression. These results suggest that rhythmic gene expression optimizes the metabolic cost of global gene expression and that highly expressed genes have been selected to be downregulated in a cyclic manner for energy conservation

Effects of chronic cannabidiol in a mouse model of naturally occurring neuroinflammation, neurodegeneration, and spontaneous seizures

Cannabidiol (CBD) has gained attention as a therapeutic agent and is purported to have immunomodulatory, neuroprotective, and anti-seizure effects. Here, we determined the effects of chronic CBD administration in a mouse model of CLN1 disease (Cln1(−/−)) that simultaneously exhibits neuroinflammation, neurodegeneration, and spontaneous seizures. Proteomic analysis showed that putative CBD receptors are expressed at similar levels in the brains of Cln1(−/−) mice compared to normal animals. Cln1(−/−) mice received an oral dose (100 mg/kg/day) of CBD for six months and were evaluated for changes in pathological markers of disease and seizures. Chronic cannabidiol administration was well-tolerated, high levels of CBD were detected in the brain, and markers of astrocytosis and microgliosis were reduced. However, CBD had no apparent effect on seizure frequency or neuron survival. These data are consistent with CBD having immunomodulatory effects. It is possible that a higher dose of CBD could also reduce neurodegeneration and seizure frequency

Effects of chronic cannabidiol in a mouse model of naturally occurring neuroinflammation, neurodegeneration, and spontaneous seizures

Cannabidiol (CBD) has gained attention as a therapeutic agent and is purported to have immunomodulatory, neuroprotective, and anti-seizure effects. Here, we determined the effects of chronic CBD administration in a mouse model of CLN1 disease (Cln

Lost in spatial translation - A novel tool to objectively assess spatial disorientation in Alzheimer's disease and frontotemporal dementia

Spatial disorientation is a prominent feature of early Alzheimer's disease (AD) attributed to degeneration of medial temporal and parietal brain regions, including the retrosplenial cortex (RSC). By contrast, frontotemporal dementia (FTD) syndromes show generally intact spatial orientation at presentation. However, currently no clinical tasks are routinely administered to objectively assess spatial orientation in these neurodegenerative conditions. In this study we investigated spatial orientation in 58 dementia patients and 23 healthy controls using a novel virtual supermarket task as well as voxel-based morphometry (VBM). We compared performance on this task with visual and verbal memory function, which has traditionally been used to discriminate between AD and FTD. Participants viewed a series of videos from a first person perspective travelling through a virtual supermarket and were required to maintain orientation to a starting location. Analyses revealed significantly impaired spatial orientation in AD, compared to FTD patient groups. Spatial orientation performance was found to discriminate AD and FTD patient groups to a very high degree at presentation. More importantly, integrity of the RSC was identified as a key neural correlate of orientation performance. These findings confirm the notion that i) it is feasible to assess spatial orientation objectively via our novel Supermarket task; ii) impaired orientation is a prominent feature that can be applied clinically to discriminate between AD and FTD and iii) the RSC emerges as a critical biomarker to assess spatial orientation deficits in these neurodegenerative conditions

A common neural code for social and monetary rewards in the human striatum

Although managing social information and decision making on the basis of reward is critical for survival, it remains uncertain whether differing reward type is processed in a uniform manner. Previously, we demonstrated that monetary reward and the social reward of good reputation activated the same striatal regions including the caudate nucleus and putamen. However, it remains unclear whether overlapping activations reflect activities of identical neuronal populations or two overlapping but functionally independent neuronal populations. Here, we re-analyzed the original data and addressed this question using multivariate-pattern-analysis and found evidence that in the left caudate nucleus and bilateral nucleus accumbens, social vs monetary reward were represented similarly. The findings suggest that social and monetary rewards are processed by the same population of neurons within these regions of the striatum. Additional findings demonstrated similar neural patterns when participants experience high social reward compared to viewing others receiving low social reward (potentially inducing schadenfreude). This is possibly an early indication that the same population of neurons may be responsible for processing two different types of social reward (good reputation and schadenfreude). These findings provide a supplementary perspective to previous research, helping to further elucidate the mechanisms behind social vs non-social reward processing

Controls on Open‐Ocean North Atlantic ΔpCO2 at Seasonal and Interannual Time Scales Are Different

The North Atlantic is a substantial sink for anthropogenic CO2. Understanding the mechanisms driving the sink's variability is key to assessing its current state and predicting its potential response to global climate change. Here we apply a time series decomposition technique to satellite and in situ data to examine separately the factors (both biological and nonbiological) that affect the sea‐air CO2 difference (ΔpCO2) on seasonal and interannual time scales. We demonstrate that on seasonal time scales, the subpolar North Atlantic ΔpCO2 signal is predominantly correlated with biological processes, whereas seawater temperature dominates in the subtropics. However, the same factors do not necessarily control ΔpCO2 on interannual time scales. Our results imply that the mechanisms driving seasonal variability in ΔpCO2 cannot necessarily be extrapolated to predict how ΔpCO2, and thus the North Atlantic CO2 sink, may respond to increases in anthropogenic CO2 over longer time scales

Oceanic sources, sinks, and transport of atmospheric CO2

Author Posting. © American Geophysical Union, 2009. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Global Biogeochemical Cycles 23 (2009): GB1005, doi:10.1029/2008GB003349.We synthesize estimates of the contemporary net air-sea CO2 flux on the basis of an inversion of interior ocean carbon observations using a suite of 10 ocean general circulation models (Mikaloff Fletcher et al., 2006, 2007) and compare them to estimates based on a new climatology of the air-sea difference of the partial pressure of CO2 (pCO2) (Takahashi et al., 2008). These two independent flux estimates reveal a consistent description of the regional distribution of annual mean sources and sinks of atmospheric CO2 for the decade of the 1990s and the early 2000s with differences at the regional level of generally less than 0.1 Pg C a−1. This distribution is characterized by outgassing in the tropics, uptake in midlatitudes, and comparatively small fluxes in thehigh latitudes. Both estimates point toward a small (∼ −0.3 Pg C a−1) contemporary CO2 sink in the Southern Ocean (south of 44°S), a result of the near cancellation between a substantial outgassing of natural CO2 and a strong uptake of anthropogenic CO2. A notable exception in the generally good agreement between the two estimates exists within the Southern Ocean: the ocean inversion suggests a relatively uniform uptake, while the pCO2-based estimate suggests strong uptake in the region between 58°S and 44°S, and a source in the region south of 58°S. Globally and for a nominal period between 1995 and 2000, the contemporary net air-sea flux of CO2 is estimated to be −1.7 ± 0.4 Pg C a−1 (inversion) and −1.4 ± 0.7 Pg C a−1 (pCO2-climatology), respectively, consisting of an outgassing flux of river-derived carbon of ∼+0.5 Pg C a−1, and an uptake flux of anthropogenic carbon of −2.2 ± 0.3 Pg C a−1 (inversion) and −1.9 ± 0.7 Pg C a−1 (pCO2-climatology). The two flux estimates also imply a consistent description of the contemporary meridional transport of carbon with southward ocean transport throughout most of the Atlantic basin, and strong equatorward convergence in the Indo-Pacific basins. Both transport estimates suggest a small hemispheric asymmetry with a southward transport of between −0.2 and −0.3 Pg C a−1 across the equator. While the convergence of these two independent estimates is encouraging and suggests that it is now possible to provide relatively tight constraints for the net air-sea CO2 fluxes at the regional basis, both studies are limited by their lack of consideration of long-term changes in the ocean carbon cycle, such as the recent possible stalling in the expected growth of the Southern Ocean carbon sink.Core financial support for this study came from the National Aeronautics and Space Administration under grant NAG5-12528 to NG and SMF, with additional support by the U.S. National Science Foundation. M. Gloor was supported by the EBI nd EEE institutes at the University of Leeds. M. Gerber, SM, FJ, and AM thank the European Commission for support through CarboOcean (511176-2) and the NOCES project (EVK2-CT-2001- 00134). TT has been supported by NOAA grant NAO30AR4320179P27

Quantifying the drivers of ocean-atmosphere CO2 fluxes

A mechanistic framework for quantitatively mapping the regional drivers of air-sea CO2 fluxes at a global scale is developed. The framework evaluates the interplay between (1) surface heat and freshwater fluxes that influence the potential saturated carbon concentration, which depends on changes in sea surface temperature, salinity and alkalinity, (2) a residual, disequilibrium flux influenced by upwelling and entrainment of remineralized carbon- and nutrient-rich waters from the ocean interior, as well as rapid subduction of surface waters, (3) carbon uptake and export by biological activity as both soft tissue and carbonate, and (4) the effect on surface carbon concentrations due to freshwater precipitation or evaporation. In a steady state simulation of a coarse-resolution ocean circulation and biogeochemistry model, the sum of the individually determined components is close to the known total flux of the simulation. The leading order balance, identified in different dynamical regimes, is between the CO2 fluxes driven by surface heat fluxes and a combination of biologically driven carbon uptake and disequilibrium-driven carbon outgassing. The framework is still able to reconstruct simulated fluxes when evaluated using monthly averaged data and takes a form that can be applied consistently in models of different complexity and observations of the ocean. In this way, the framework may reveal differences in the balance of drivers acting across an ensemble of climate model simulations or be applied to an analysis and interpretation of the observed, real-world air-sea flux of CO2