Present and LGM permafrost from climate simulations : contribution of statistical downscaling

We quantify the agreement between permafrost distributions from PMIP2 (Paleoclimate Modeling Intercomparison Project) climate models and permafrost data. We evaluate the ability of several climate models to represent permafrost and assess the variability between their results. <br><br> Studying a heterogeneous variable such as permafrost implies conducting analysis at a smaller spatial scale compared with climate models resolution. Our approach consists of applying statistical downscaling methods (SDMs) on large- or regional-scale atmospheric variables provided by climate models, leading to local-scale permafrost modelling. Among the SDMs, we first choose a transfer function approach based on Generalized Additive Models (GAMs) to produce high-resolution climatology of air temperature at the surface. Then we define permafrost distribution over Eurasia by air temperature conditions. In a first validation step on present climate (CTRL period), this method shows some limitations with non-systematic improvements in comparison with the large-scale fields. <br><br> So, we develop an alternative method of statistical downscaling based on a Multinomial Logistic GAM (ML-GAM), which directly predicts the occurrence probabilities of local-scale permafrost. The obtained permafrost distributions appear in a better agreement with CTRL data. In average for the nine PMIP2 models, we measure a global agreement with CTRL permafrost data that is better when using ML-GAM than when applying the GAM method with air temperature conditions. In both cases, the provided local information reduces the variability between climate models results. This also confirms that a simple relationship between permafrost and the air temperature only is not always sufficient to represent local-scale permafrost. <br><br> Finally, we apply each method on a very different climate, the Last Glacial Maximum (LGM) time period, in order to quantify the ability of climate models to represent LGM permafrost. The prediction of the SDMs (GAM and ML-GAM) is not significantly in better agreement with LGM permafrost data than large-scale fields. At the LGM, both methods do not reduce the variability between climate models results. We show that LGM permafrost distribution from climate models strongly depends on large-scale air temperature at the surface. LGM simulations from climate models lead to larger differences with LGM data than in the CTRL period. These differences reduce the contribution of downscaling

Comparison of spatial downscaling methods of general circulation model results to study climate variability during the last glacial maximum

The extent to which climate conditions influenced the spatial distribution of hominin populations in the past is highly debated. General circulation models (GCMs) and archaeological data have been used to address this issue. Most GCMs are not currently capable of simulating past surface climate conditions with sufficiently detailed spatial resolution to distinguish areas of potential hominin habitat, however. In this paper, we propose a statistical downscaling method (SDM) for increasing the resolution of climate model outputs in a computationally efficient way. Our method uses a generalised additive model (GAM), calibrated over present-day climatology data, to statistically downscale temperature and precipitation time series from the outputs of a GCM simulating the climate of the Last Glacial Maximum (19 000–23 000 BP) over western Europe. Once the SDM is calibrated, we first interpolate the coarse-scale GCM outputs to the final resolution and then use the GAM to compute surface air temperature and precipitation levels using these interpolated GCM outputs and fine-resolution geographical variables such as topography and distance from an ocean. The GAM acts as a transfer function, capturing non-linear relationships between variables at different spatial scales and correcting for the GCM biases. We tested three different techniques for the first interpolation of GCM output: bilinear, bicubic and kriging. The resulting SDMs were evaluated by comparing downscaled temperature and precipitation at local sites with paleoclimate reconstructions based on paleoclimate archives (archaeozoological and palynological data) and the impact of the interpolation technique on patterns of variability was explored. The SDM based on kriging interpolation, providing the best accuracy, was then validated on present-day data outside of the calibration period. Our results show that the downscaled temperature and precipitation values are in good agreement with paleoclimate reconstructions at local sites, and that our method for producing fine-grained paleoclimate simulations is therefore suitable for conducting paleo-anthropological research. It is nonetheless important to calibrate the GAM on a range of data encompassing the data to be downscaled. Otherwise, the SDM is likely to overcorrect the coarse-grain data. In addition, the bilinear and bicubic interpolation techniques were shown to distort either the temporal variability or the values of the response variables, while the kriging method offered the best compromise. Since climate variability is an aspect of the environment to which human populations may have responded in the past, the choice of interpolation technique is therefore an important consideration.</p

Impact of precession on the climate, vegetation and fire activity in southern Africa during MIS4

Open access journalhe relationships between climate, vegetation and fires are a major subject of investigation in the context of climate change. In southern Africa, fire is known to play a crucial role in the existence of grasslands and Mediterranean-type biomes. Microcharcoal-based reconstructions of past fire activity in that region have shown a tight correlation between grass-fueled fires and the precessional cycle, with maximum fire activity during maxima of the climatic precession index. These changes have been interpreted as the result of changes in fuel load in response to precipitation changes in eastern southern Africa. Here we use the general circulation model IPSL_CM5A (Institut Pierre Simon Laplace Climate Model version 5A) and the dynamic vegetation model LPJ-LMfire to investigate the response of climate, vegetation and fire activity to precession changes in southern Africa during marine isotopic stage 4 (74–59 kyr BP). We perform two climatic simulations, for a maximum and minimum of the precession index, and use a statistical downscaling method to increase the spatial resolution of the IPSL_CM5A outputs over southern Africa and perform high-resolution simulations of the vegetation and fire activity. Our results show an anticorrelation between the northern and southern African monsoons in response to precession changes. A decrease of the precession climatic index leads to a precipitation decrease in the summer rainfall area of southern Africa. The drying of climate leads to a decrease of vegetation cover and fire activity. Our results are in qualitative agreement with data and confirm that fire activity in southern Africa during MIS4 is mainly driven by vegetation cover.European Research Counci

A nuclear role for the respiratory enzyme CLK-1 in regulating mitochondrial stress responses and longevity

The coordinated regulation of mitochondrial and nuclear activities is essential for cellular respiration and its disruption leads to mitochondrial dysfunction, a hallmark of ageing. Mitochondria communicate with nuclei through retrograde signalling pathways that modulate nuclear gene expression to maintain mitochondrial homeostasis. The monooxygenase CLK-1 (human homologue COQ7) was previously reported to be mitochondrial, with a role in respiration and longevity. We have uncovered a distinct nuclear form of CLK-1 that independently regulates lifespan. Nuclear CLK-1 mediates a retrograde signalling pathway that is conserved from Caenorhabditis elegans to humans and is responsive to mitochondrial reactive oxygen species, thus acting as a barometer of oxidative metabolism. We show that, through modulation of gene expression, the pathway regulates both mitochondrial reactive oxygen species metabolism and the mitochondrial unfolded protein response. Our results demonstrate that a respiratory enzyme acts in the nucleus to control mitochondrial stress responses and longevity

Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR

Erratum in : Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR. [Cell. 2019]International audienceInnate immune responses are intricately linked with intracellular metabolism of myeloid cells. Toll-likereceptor (TLR) stimulation shifts intracellular metabolism toward glycolysis, while anti-inflammatorysignals depend on enhanced mitochondrial respiration. How exogenous metabolic signals affect theimmune response is unknown. We demonstrate that TLR-dependent responses of dendritic cells (DC)are exacerbated by a high fatty acid (FA) metabolic environment. FA suppress the TLR-inducedhexokinase activity and perturb tricarboxylic acid cycle metabolism. These metabolic changesenhance mitochondrial reactive oxygen species (mtROS) production and, in turn, the unfolded proteinresponse (UPR) leading to a distinct transcriptomic signature, with IL-23 as hallmark. Interestingly,chemical or genetic suppression of glycolysis was sufficient to induce this specific immune response.Conversely, reducing mtROS production or DC-specific deficiency in XBP1 attenuated IL-23expression and skin inflammation in an IL-23-dependent model of psoriasis. Thus, fine-tuning of innateimmunity depends on optimization of metabolic demands and minimization of mtROS-induced UPR

Regulating Factors of PrPres Glycosylation in Creutzfeldt-Jakob Disease - Implications for the Dissemination and the Diagnosis of Human Prion Strains

OBJECTIVE: The glycoprofile of pathological prion protein (PrP(res)) is widely used as a diagnosis marker in Creutzfeldt-Jakob disease (CJD) and is thought to vary in a strain-specific manner. However, that the same glycoprofile of PrP(res) always accumulates in the whole brain of one individual has been questioned. We aimed to determine whether and how PrP(res) glycosylation is regulated in the brain of patients with sporadic and variant Creutzfeldt-Jakob disease. METHODS: PrP(res) glycoprofiles in four brain regions from 134 patients with sporadic or variant CJD were analyzed as a function of the genotype at codon 129 of PRNP and the Western blot type of PrP(res). RESULTS: The regional distribution of PrP(res) glycoforms within one individual was heterogeneous in sporadic but not in variant CJD. PrP(res) glycoforms ratio significantly correlated with the genotype at codon 129 of the prion protein gene and the Western blot type of PrP(res) in a region-specific manner. In some cases of sCJD, the glycoprofile of thalamic PrP(res) was undistinguishable from that observed in variant CJD. INTERPRETATION: Regulations leading to variations of PrP(res) pattern between brain regions in sCJD patients, involving host genotype and Western blot type of PrP(res) may contribute to the specific brain targeting of prion strains and have direct implications for the diagnosis of the different forms of CJD

Dendritic Cell-Mediated-Immunization with Xenogenic PrP and Adenoviral Vectors Breaks Tolerance and Prolongs Mice Survival against Experimental Scrapie

In prion diseases, PrPc, a widely expressed protein, is transformed into a pathogenic form called PrPSc, which is in itself infectious. Antibodies directed against PrPc have been shown to inhibit PrPc to PrPSc conversion in vitro and protect in vivo from disease. Other effectors with potential to eliminate PrPSc-producing cells are cytotoxic T cells directed against PrP-derived peptides but their ability to protect or to induce deleterious autoimmune reactions is not known. The natural tolerance to PrPc makes difficult to raise efficient adaptive responses. To break tolerance, adenovirus (Ad) encoding human PrP (hPrP) or control Ad were administered to wild-type mice by direct injection or by transfer of Ad-transduced dendritic cells (DCs). Control Ad-transduced DCs from Tg650 mice overexpressing hPrP were also used for immunization. DC-mediated but not direct administration of AdhPrP elicited antibodies that bound to murine native PrPc. Frequencies of PrP-specific IFNγ-secreting T cells were low and in vivo lytic activity only targeted cells strongly expressing hPrP. Immunohistochemical analysis revealed that CD3+ T cell infiltration was similar in the brain of vaccinated and unvaccinated 139A-infected mice suggesting the absence of autoimmune reactions. Early splenic PrPSc replication was strongly inhibited ten weeks post infection and mean survival time prolonged from 209 days in untreated 139A-infected mice to 246 days in mice vaccinated with DCs expressing the hPrP. The efficacy appeared to be associated with antibody but not with cytotoxic cell-mediated PrP-specific responses

Repetitive Immunization Enhances the Susceptibility of Mice to Peripherally Administered Prions

The susceptibility of humans and animals to prion infections is determined by the virulence of the infectious agent, by genetic modifiers, and by hitherto unknown host and environmental risk factors. While little is known about the latter two, the activation state of the immune system was surmised to influence prion susceptibility. Here we administered prions to mice that were repeatedly immunized by two initial injections of CpG oligodeoxynucleotides followed by repeated injections of bovine serum albumin/alum. Immunization greatly reduced the required dosage of peripherally administered prion inoculum necessary to induce scrapie in 50% of mice. No difference in susceptibility was observed following intracerebral prion challenge. Due to its profound impact onto scrapie susceptibility, the host immune status may determine disease penetrance after low-dose prion exposure, including those that may give rise to iatrogenic and variant Creutzfeldt-Jakob disease

Plasmacytoid Dendritic Cells Sequester High Prion Titres at Early Stages of Prion Infection

In most transmissible spongiform encephalopathies prions accumulate in the lymphoreticular system (LRS) long before they are detectable in the central nervous system. While a considerable body of evidence showed that B lymphocytes and follicular dendritic cells play a major role in prion colonization of lymphoid organs, the contribution of various other cell types, including antigen-presenting cells, to the accumulation and the spread of prions in the LRS are not well understood. A comprehensive study to compare prion titers of candidate cell types has not been performed to date, mainly due to limitations in the scope of animal bioassays where prohibitively large numbers of mice would be required to obtain sufficiently accurate data. By taking advantage of quantitative in vitro prion determination and magnetic-activated cell sorting, we studied the kinetics of prion accumulation in various splenic cell types at early stages of prion infection. Robust estimates for infectious titers were obtained by statistical modelling using a generalized linear model. Whilst prions were detectable in B and T lymphocytes and in antigen-presenting cells like dendritic cells and macrophages, highest infectious titers were determined in two cell types that have previously not been associated with prion pathogenesis, plasmacytoid dendritic (pDC) and natural killer (NK) cells. At 30 days after infection, NK cells were more than twice, and pDCs about seven-fold, as infectious as lymphocytes respectively. This result was unexpected since, in accordance to previous reports prion protein, an obligate requirement for prion replication, was undetectable in pDCs. This underscores the importance of prion sequestration and dissemination by antigen-presenting cells which are among the first cells of the immune system to encounter pathogens. We furthermore report the first evidence for a release of prions from lymphocytes and DCs of scrapie-infected mice ex vivo, a process that is associated with a release of exosome-like membrane vesicles

Longevity in mice: is stress resistance a common factor?

A positive relationship between stress resistance and longevity has been reported in a multitude of studies in organisms ranging from yeast to mice. Several mouse lines have been discovered or developed that exhibit extended longevities when compared with normal, wild-type mice of the same genetic background. These long-living lines include the Ames dwarf, Snell dwarf, growth hormone receptor knockout (Laron dwarf), IGF-1 receptor heterozygote, Little, α-MUPA knockout, p66shc knockout, FIRKO, mClk-1 heterozygote, thioredoxin transgenic, and most recently the Klotho transgenic mouse. These mice are described in terms of the reported extended lifespans and studies involving resistance to stress. In addition, caloric restriction (CR) and stress resistance are briefly addressed for comparison with genetically altered mice. Although many of the long-living mice have GH/IGF-1/insulin signaling-related alterations and enhanced stress resistance, there are some that exhibit life extension without an obvious link to this hormone pathway. Resistance to oxidative stress is by far the most common system studied in long-living mice, but there is evidence of enhancement of resistance in other systems as well. The differences in stress resistance between long-living mutant and normal mice result from complex interrelationships among pathways that appear to coordinate signals of growth and metabolism, and subsequently result in differences in lifespan