Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway.

A promising new compound class for treating human malaria is the imidazolopiperazines (IZP) class. IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models. But despite the identification of resistance mechanisms in P. falciparum, the mode of action of IZPs remains unknown. To investigate, we here combine in vitro evolution and genome analysis in Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods in P. falciparum. Our findings reveal that IZP-resistant S. cerevisiae clones carry mutations in genes involved in Endoplasmic Reticulum (ER)-based lipid homeostasis and autophagy. In Plasmodium, IZPs inhibit protein trafficking, block the establishment of new permeation pathways, and cause ER expansion. Our data highlight a mechanism for blocking parasite development that is distinct from those of standard compounds used to treat malaria, and demonstrate the potential of IZPs for studying ER-dependent protein processing

Mutant mice with rod-specific VPS35 deletion exhibit retinal α-synuclein pathology-associated degeneration.

Vacuolar protein sorting 35 (VPS35), the core component of the retromer complex which regulates endosomal trafficking, is genetically linked with Parkinson's disease (PD). Impaired vision is a common non-motor manifestation of PD. Here, we show mouse retinas with VPS35-deficient rods exhibit synapse loss and visual deficit, followed by progressive degeneration concomitant with the emergence of Lewy body-like inclusions and phospho-α-synuclein (P-αSyn) aggregation. Ultrastructural analyses reveal VPS35-deficient rods accumulate aggregates in late endosomes, deposited as lipofuscins bound to P-αSyn. Mechanistically, we uncover a protein network of VPS35 and its interaction with HSC70. VPS35 deficiency promotes sequestration of HSC70 and P-αSyn aggregation in late endosomes. Microglia which engulf lipofuscins and P-αSyn aggregates are activated, displaying autofluorescence, observed as bright dots in fundus imaging of live animals, coinciding with pathology onset and progression. The Rod∆Vps35 mouse line is a valuable tool for further mechanistic investigation of αSyn lesions and retinal degenerative diseases

Global ensemble projections reveal trophic amplification of ocean biomass declines with climate change

While the physical dimensions of climate change are now routinely assessed through multimodel intercomparisons, projected impacts on the global ocean ecosystem generally rely on individual models with a specific set of assumptions. To address these single-model limitations, we present standardized ensemble projections from six global marine ecosystem models forced with two Earth system models and four emission scenarios with and without fishing. We derive average biomass trends and associated uncertainties across the marine food web. Without fishing, mean global animal biomass decreased by 5% (±4% SD) under low emissions and 17% (±11% SD) under high emissions by 2100, with an average 5% decline for every 1 °C of warming. Projected biomass declines were primarily driven by increasing temperature and decreasing primary production, and were more pronounced at higher trophic levels, a process known as trophic amplification. Fishing did not substantially alter the effects of climate change. Considerable regional variation featured strong biomass increases at high latitudes and decreases at middle to low latitudes, with good model agreement on the direction of change but variable magnitude. Uncertainties due to variations in marine ecosystem and Earth system models were similar. Ensemble projections performed well compared with empirical data, emphasizing the benefits of multimodel inference to project future outcomes. Our results indicate that global ocean animal biomass consistently declines with climate change, and that these impacts are amplified at higher trophic levels. Next steps for model development include dynamic scenarios of fishing, cumulative human impacts, and the effects of management measures on future ocean biomass trends

Projected impacts of climate change and ocean acidification on the global biogeography of planktonic Foraminifera

International audiencePlanktonic Foraminifera are a major contributor to the deep carbonate flux and their microfossil deposits form one of the richest databases for reconstructing paleoenvironments, particularly through changes in their taxonomic and shell composition. Using an empirically based planktonic foraminifer model that incorporates three known major physiological drivers of their biogeography – temperature, food and light – we investigate (i) the global redistribution of planktonic Foraminifera under anthropogenic climate change and (ii) the alteration of the carbonate chemistry of foraminiferal habitat with ocean acidification. The present-day and future (2090–2100) 3-D distributions of Foraminifera are simulated using temperature, plankton biomass and light from an Earth system model forced with a historical and a future (IPCC A2) high CO2 emission scenario. Foraminiferal abundance and diversity are projected to decrease in the tropics and subpolar regions and increase in the subtropics and around the poles. Temperature is the dominant control on the future change in the biogeography of Foraminifera. Yet food availability acts to either reinforce or counteract the temperature-driven changes. In the tropics and subtropics the largely temperature-driven shift to depth is enhanced by the increased concentration of phytoplankton at depth. In the higher latitudes the food-driven response partly offsets the temperature-driven reduction both in the subsurface and across large geographical regions. The large-scale rearrangements in foraminiferal abundance and the reduction in the carbonate ion concentrations in the habitat range of planktonic foraminifers – from 10–30 μmol kg−1 in their polar and subpolar habitats to 30–70 μmol kg−1 in their subtropical and tropical habitats – would be expected to lead to changes in the marine carbonate flux. High-latitude species are most vulnerable to anthropogenic change: their abundance and available habitat decrease and up to 10% of the volume of their habitat drops below the calcite saturation horizon

THE IMPACT OF CLIMATE CHANGE AND OCEAN ACIDIFICATION ON THE BIOGEOGRAPHY OF FORAMIFERA

participantCoupled-climate carbon cycle models (C4Ms) are linked to an eco-physiological model to determine the impact of climate-change and ocean acidification on the global 3D distribution of the most abundant foramifera species up until the end of this century. The eco-physiological model is used to estimate the growth-rate and abundance of eight distinct species of foramifera in response to temperature, light (for species with symbiotic algae), and food availability simulated by the four C4Ms. The models are forced using historical anthropogenic emissions and the high-emission IPPC AR4 scenario and all simulate a 2 to 20% reduction in global marine productivity and export production by 2100. In the first part of the study we present the change in both the distribution of the dominant species and their relative abundance in response to climate-change. In the second part, we additionally consider the influence of regional changes to the carbonate chemistry of seawater on the calcification rates of selected foramifera species, which allows us to also estimate the impact of ocean acidification on their biogeography

Diagnosing CO₂ emission-induced feedbacks between the Southern Ocean carbon cycle and the climate system: A multiple Earth System Model analysis using a water mass tracking approach

International audienceAnthropogenic CO$_2$ emission-induced feedbacks between the carbon cycle and the climate system perturb the efficiency of atmospheric CO$_2$ uptake by land and ocean carbon reservoirs. The Southern Ocean is a region where these feedbacks can be largest and differ most among Earth System Model projections of 21st century climate change. To improve our mechanistic understanding of these feedbacks, we develop an automated procedure that tracks changes in the positions of Southern Ocean water masses and their carbon uptake. In an idealised ensemble of climate change projections, we diagnose two carbon–concentration feedbacks driven by atmospheric CO$_2$ (due to increasing air-sea CO$_2$ partial pressure difference, dpCO$_2$ , and reducing carbonate buffering capacity) and two carbon–climate feedbacks driven by climate change (due to changes in the water mass surface outcrop areas and local climate impacts). Collectively these feedbacks increase the CO$_2$ uptake by the Southern Ocean and account for one-fifth of the global uptake of CO$_2$ emissions. The increase in CO$_2$ uptake is primarily dpCO$_2$ -driven, with Antarctic intermediate waters making the largest contribution; the remaining three feedbacks partially offset this increase (by ~25%), with maximum reductions in Subantarctic mode waters. The process dominating the decrease in CO$_2$ uptake is water mass-dependent: reduction in carbonate buffering capacity in Subtropical and Subantarctic mode waters, local climate impacts in Antarctic intermediate waters, and reduction in outcrop areas in circumpolar deep waters and Antarctic bottom waters. Intermodel variability in the feedbacks is predominately dpCO$_2$ –driven and should be a focus of efforts to constrain projection uncertainty

Water Mass Analysis of Effect of Climate Change on Air–Sea CO₂ Fluxes: The Southern Ocean

International audienceImpacts of climate change on air–sea CO2 exchange are strongly region dependent, particularly in the Southern Ocean. Yet, in the Southern Ocean the role of water masses in the uptake of anthropogenic carbon is still debated. Here, a methodology is applied that tracks the carbon flux of each Southern Ocean water mass in response to climate change. A global marine biogeochemical model was coupled to a climate model, making 140-yr Coupled Model Intercomparison Project phase 5 (CMIP5)-type simulations, where atmospheric CO2 increased by 1% yr−1 to 4 times the preindustrial concentration (4 × CO2). Impacts of atmospheric CO2 (carbon-induced sensitivity) and climate change (climate-induced sensitivity) on the water mass carbon fluxes have been isolated performing two sensitivity simulations. In the first simulation, the atmospheric CO2 influences solely the marine carbon cycle, while in the second simulation, it influences both the marine carbon cycle and earth’s climate. At 4 × CO2, the cumulative carbon uptake by the Southern Ocean reaches 278 PgC, 53% of which is taken up by modal and intermediate water masses. The carbon-induced and climate-induced sensitivities vary significantly between the water masses. The carbon-induced sensitivities enhance the carbon uptake of the water masses, particularly for the denser classes. But, enhancement strongly depends on the water mass structure. The climate-induced sensitivities either strengthen or weaken the carbon uptake and are influenced by local processes through changes in CO2 solubility and stratification, and by large-scale changes in outcrop surface (OS) areas. Changes in OS areas account for 45% of the climate-induced reduction in the Southern Ocean carbon uptake and are a key factor in understanding the future carbon uptake of the Southern Ocean

Nursing students' use of technology enhanced learning:A longitudinal study

In this study, we compare observed Southern Ocean temperature and salinity changes with the historical simulations from 13 models from phase 5 of the Coupled Model Intercomparison Project (CMIP5), using an optimal fingerprinting framework. We show that there is an unequivocal greenhouse gas-forced warming in the Southern Ocean. This warming is strongest in the Subantarctic Mode Waters but is also detectable in denser water masses, which has not been shown in previous studies. We also find greenhouse gas-forced salinity changes, most notably a freshening of Antarctic Intermediate Waters. Our analysis also shows that non-greenhouse gas anthropogenic forcings-anthropogenic aerosols and stratospheric ozone depletion-have played an important role in mitigating the Southern Ocean's warming. However, the detestability of these responses using optimal fingerprinting is model dependent, and this result is therefore not as robust as for the greenhouse gas response

Long-term surface pCO 2 trends from observations and models

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