Global temperature modes shed light on the Holocene temperature conundrum.

Reconstructions of the global mean annual temperature evolution during the Holocene yield conflicting results. One temperature reconstruction shows global cooling during the late Holocene. The other reconstruction reveals global warming. Here we show that both a global warming mode and a cooling mode emerge when performing a spatio-temporal analysis of annual temperature variability during the Holocene using data from a transient climate model simulation. The warming mode is most pronounced in the tropics. The simulated cooling mode is determined by changes in the seasonal cycle of Arctic sea-ice that are forced by orbital variations and volcanic eruptions. The warming mode dominates in the mid-Holocene, whereas the cooling mode takes over in the late Holocene. The weighted sum of the two modes yields the simulated global temperature trend evolution. Our findings have strong implications for the interpretation of proxy data and the selection of proxy locations to compute global mean temperatures.

Slowdown of the Walker circulation at solar cycle maximum.

The Pacific Walker Circulation (PWC) fluctuates on interannual and multidecadal timescales under the influence of internal variability and external forcings. Here, we provide observational evidence that the 11-y solar cycle (SC) affects the PWC on decadal timescales. We observe a robust reduction of east-west sea-level pressure gradients over the Indo-Pacific Ocean during solar maxima and the following 1-2 y. This reduction is associated with westerly wind anomalies at the surface and throughout the equatorial troposphere in the western/central Pacific paired with an eastward shift of convective precipitation that brings more rainfall to the central Pacific. We show that this is initiated by a thermodynamical response of the global hydrological cycle to surface warming, further amplified by atmosphere-ocean coupling, leading to larger positive ocean temperature anomalies in the equatorial Pacific than expected from simple radiative forcing considerations. The observed solar modulation of the PWC is supported by a set of coupled ocean-atmosphere climate model simulations forced only by SC irradiance variations. We highlight the importance of a muted hydrology mechanism that acts to weaken the PWC. Demonstration of this mechanism acting on the 11-y SC timescale adds confidence in model predictions that the same mechanism also weakens the PWC under increasing greenhouse gas forcing.

Evaluating climate geoengineering proposals in the context of the Paris Agreement temperature goals.

Current mitigation efforts and existing future commitments are inadequate to accomplish the Paris Agreement temperature goals. In light of this, research and debate are intensifying on the possibilities of additionally employing proposed climate geoengineering technologies, either through atmospheric carbon dioxide removal or farther-reaching interventions altering the Earth's radiative energy budget. Although research indicates that several techniques may eventually have the physical potential to contribute to limiting climate change, all are in early stages of development, involve substantial uncertainties and risks, and raise ethical and governance dilemmas. Based on present knowledge, climate geoengineering techniques cannot be relied on to significantly contribute to meeting the Paris Agreement temperature goals.

Mixed-Valent Molecular Triple Deckers.

Two phenothiazine (PTZ) moieties were connected via naphthalene spacers to a central arene to result in stacked PTZ-arene-PTZ structure elements. Benzene and tetramethoxybenzene units served as central arenes mediating electronic communication between the two PTZ units. Based on cyclic voltammetry, UV/Vis-NIR absorption, EPR spectroscopy, and computational studies, the one-electron oxidized forms of the resulting compounds behave as class II organic mixed-valence species in which the unpaired electron is partially delocalized over both PTZ units. The barrier for intramolecular electron transfer depends on the nature of the central arene sandwiched between the two PTZ moieties. These are the first examples of rigid organic mixed-valent triple-decker compounds with possible electron-transfer pathways directly across a stacked structure, and they illustrate the potential of oligo-naphthalene building blocks for long-range electron transfer and a future molecular electronics technology.

Electron Transfer around a Molecular Corner.

The distance dependence of electron transfer (ET) is commonly investigated in linear rigid rod-like compounds, but studies of molecular wires with integrated corners imposing 90° angles are very rare. By using spirobifluorene as a key bridging element and by substituting it at different positions, two isomeric series of donor-bridge-acceptor compounds with either nearly linear or angled geometries were obtained. Photoinduced ET in both series is dominated by rapid through-bond hole hopping across oligofluorene bridges over distances of up to 70 Å. Despite considerable conformational flexibility, direct through-space and through-solvent ET is negligible even in the angled series. The independence of the ET rate constant on the total number of fluorene units in the angled series is attributed to a rate-limiting tunneling step through the spirobifluorene corner. This finding is relevant for multidimensional ET systems and grids in which individual molecular wires are interlinked at 90° angles.

Transition to a Moist Greenhouse with CO2 and solar forcing.

Water-rich planets such as Earth are expected to become eventually uninhabitable, because liquid water turns unstable at the surface as temperatures increase with solar luminosity. Whether a large increase of atmospheric concentrations of greenhouse gases such as CO2 could also destroy the habitability of water-rich planets has remained unclear. Here we show with three-dimensional aqua-planet simulations that CO2-induced forcing as readily destabilizes the climate as does solar forcing. The climate instability is caused by a positive cloud feedback and leads to a new steady state with global-mean sea-surface temperatures above 330 K. The upper atmosphere is considerably moister in this warm state than in the reference climate, implying that the planet would be subject to substantial loss of water to space. For some elevated CO2 or solar forcings, we find both cold and warm equilibrium states, implying that the climate transition cannot be reversed by removing the additional forcing.

Charge Transfer Pathways in Three Isomers of Naphthalene-Bridged Organic Mixed Valence Compounds.

Naphthalene was substituted at different positions with two identical triarylamine moieties to result in species which are mixed-valence compounds in their one-electron oxidized forms. They were investigated by cyclic voltammetry, optical absorption, EPR spectroscopy, X-ray crystallography, and DFT calculations. When the two redox-active triarylamine moieties are connected to the 2- and 6-positions of the naphthalene bridge, their electronic communication is significantly stronger than when they are linked to the 1- and 5-positions, and this can be understood on the basis of a simple through-bond charge transfer pathway model. However, this model fails to explain why electronic communication between triarylamine moieties in the 1,5- and 1,8-isomers is similarly strong, indicating that through-space charge transfer pathways play an important role in the latter. In particular, charge transfer in the 1,8-isomer is likely to occur between the triarylamino C atoms in α-position to the naphthalene linker because the respective atoms are only about 3 Å apart from each other, and because they carry significant spin density in the one-electron oxidized forms of triarylamines. This particular through-space charge transfer pathway might be generally important in molecular structures based on the 1,8-disubstituted naphthalene pillaring motif.

An economic evaluation of solar radiation management.

Economic evaluations of solar radiation management (SRM) usually assume that the temperature will be stabilized, with no economic impacts of climate change, but with possible side-effects. We know from experiments with climate models, however, that unlike emission control the spatial and temporal distributions of temperature, precipitation and wind conditions will change. Hence, SRM may have economic consequences under a stabilization of global mean temperature even if side-effects other than those related to the climatic responses are disregarded. This paper addresses the economic impacts of implementing two SRM technologies; stratospheric sulfur injection and marine cloud brightening. By the use of a computable general equilibrium model, we estimate the economic impacts of climatic responses based on the results from two earth system models, MPI-ESM and NorESM. We find that under a moderately increasing greenhouse-gas concentration path, RCP4.5, the economic benefits of implementing climate engineering are small, and may become negative. Global GDP increases in three of the four experiments and all experiments include regions where the benefits from climate engineering are negative.

Multistage complexation of fluoride ions by a fluorescent triphenylamine bearing three dimesitylboryl groups: controlling intramolecular charge transfer.

A propeller-shaped boron-nitrogen compound (NB(3)) with three binding sites for fluoride anions was synthesized and investigated by optical absorption, luminescence, and ((1)H, (11)B, (13)C, (19)F) NMR spectroscopy. Binding of fluoride in dichloromethane solution occurs in three clearly identifiable steps and leads to stepwise blocking of the three initially present nitrogen-to-boron charge transfer pathways. As a consequence, the initially bright blue charge transfer emission is red-shifted and decreases in intensity, until it is quenched completely in presence of large fluoride excess. Fluoride binding constants were determined from global fits to optical absorption and luminescence titration data and were found to be K(a1) = 4 × 10(7) M(-1), K(a2) = 2.5 × 10(6) M(-1), and K(a3) = 3.2 × 10(4) M(-1) in room temperature dichloromethane solution. Complexation of fluoride to a given dimesitylboryl site increases the electron density at the central nitrogen atom of NB(3), and this leads to red shifts of the remaining nitrogen-to-boron charge transfer transitions involving yet unfluorinated dimesitylboryl groups.

CCR2+Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system.

The chemokine receptor CCR2 plays a vital role for the induction of autoimmunity in the central nervous system. However, it remains unclear how the pathogenic response is mediated by CCR2-bearing cells. By combining bone marrow chimerism with gene targeting we detected a mild disease-modulating role of CCR2 during experimental autoimmune encephalomyelitis, a model for central nervous system autoimmunity, on radio-resistant cells that was independent from targeted CCR2 expression on endothelia. Interestingly, absence of CCR2 on lymphocytes did not influence autoimmune demyelination. In contrast, engagement of CCR2 on accessory cells was required for experimental autoimmune encephalomyelitis induction. CCR2+Ly-6Chi monocytes were rapidly recruited to the inflamed central nervous system and were crucial for the effector phase of disease. Selective depletion of this specific monocyte subpopulation through engagement of CCR2 strongly reduced central nervous system autoimmunity. Collectively, these data indicate a disease-promoting role of CCR2+Ly-6Chi monocytes during autoimmune inflammation of the central nervous system.

Local type I IFN receptor signaling protects against virus spread within the central nervous system.

Several neurotropic viruses such as vesicular stomatitis virus (VSV) induce peripheral neutralizing Ab responses and still can infect cells within the CNS. To address whether local type I IFN receptor (IFNAR) triggering plays a role in controlling virus replication within the brain, we generated mice with a cell type-specific IFNAR deletion in neuroectodermal cells of the CNS (NesCre(+/-)IFNAR(flox/flox)). Intranasal VSV infection with 10(3) PFU was well tolerated by wild-type mice, whereas conventional IFNAR(-/-) mice died within 2-3 days. In contrast, brain-specific NesCre(+/-)IFNAR(flox/flox) mice survived until day 5-6 and then became hemiplegic and died. Terminally ill NesCre(+/-)IFNAR(flox/flox) mice showed 10- to 100-fold higher virus loads in the brain than IFNAR(-/-) mice, whereas little or no virus was found in other organs. In wild-type animals, virus could be reisolated only from the olfactory bulb until day 6 where also STAT1 activation as a measure of IFNAR triggering was detected. Virus infection was found exclusively in glomerular structures of the olfactory bulb, whereas surrounding cells that showed STAT1 phosphorylation as a measure of IFNAR trigging were free of virus. Our data indicate that upon intranasal VSV instillation, early and localized IFNAR triggering in the glomerular layer of the olfactory bulb is critically required to prevent viral spread over the entire CNS and thus confers survival.

Type I interferon receptor signalling is induced during demyelination while its function for myelin damage and repair is redundant.

The type I interferons, interferon-beta and alpha (IFN-beta, IFN-alpha), are widely used for the treatment of autoimmune demyelination in the central nervous system (CNS). Their effects on de- and remyelination through the broadly expressed type I IFN receptor (IFNAR), however, are highly speculative. In order to elucidate the role of endogenous type I interferons for myelin damage and recovery we induced toxic demyelination in the absence of IFNAR1. We demonstrate that IFNAR signalling was induced during acute demyelination since the cytokine IFN-beta as well as the IFN-dependent genes IRF7, ISG15 and UBP43 were strongly upregulated. Myelin damage, astrocytic and microglia response, however, were not significantly reduced in the absence of IFNAR1. Furthermore, motor skills of IFNAR1-deficient animals during non-immune demyelination were unaltered. Finally, myelin recovery was found to be independent from endogenous IFNAR signalling, indicating a redundant role of this receptor for non-inflammatory myelin damage and repair.

Overexpression of lymphotoxin in T cells induces fulminant thymic involution.

Activated lymphocytes and lymphoid-tissue inducer cells express lymphotoxins (LTs), which are essential for the organogenesis and maintenance of lymphoreticular microenvironments. Here we describe that T-cell-restricted overexpression of LT induces fulminant thymic involution. This phenotype was prevented by ablation of the LT receptors tumor necrosis factor receptor (TNFR) 1 or LT beta receptor (LTbetaR), representing two non-redundant pathways. Multiple lines of transgenic Ltalphabeta and Ltalpha mice show such a phenotype, which was not observed on overexpression of LTbeta alone. Reciprocal bone marrow transfers between LT-overexpressing and receptor-ablated mice show that involution was not due to a T cell-autonomous defect but was triggered by TNFR1 and LTbetaR signaling to radioresistant stromal cells. Thymic involution was partially prevented by the removal of one allele of LTbetaR but not of TNFR1, establishing a hierarchy in these signaling events. Infection with the lymphocytic choriomeningitis virus triggered a similar thymic pathology in wt, but not in Tnfr1(-/-) mice. These mice displayed elevated TNFalpha in both thymus and plasma, as well as increased LTs on both CD8(+) and CD4(-)CD8(-) thymocytes. These findings suggest that enhanced T cell-derived LT expression helps to control the physiological size of the thymic stroma and accelerates its involution via TNFR1/LTbetaR signaling in pathological conditions and possibly also in normal aging.

Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system.

The action of type I interferons in the central nervous system (CNS) during autoimmunity is largely unknown. Here, we demonstrate elevated interferon beta concentrations in the CNS, but not blood, of mice with experimental autoimmune encephalomyelitis (EAE), a model for CNS autoimmunity. Furthermore, mice devoid of the broadly expressed type I IFN receptor (IFNAR) developed exacerbated clinical disease accompanied by a markedly higher inflammation, demyelination, and lethality without shifting the T helper 17 (Th17) or Th1 cell immune response. Whereas adoptive transfer of encephalitogenic T cells led to enhanced disease in Ifnar1(-/-) mice, newly created conditional mice with B or T lymphocyte-specific IFNAR ablation showed normal EAE. The engagement of IFNAR on neuroectodermal CNS cells had no protective effect. In contrast, absence of IFNAR on myeloid cells led to severe disease with an enhanced effector phase and increased lethality, indicating a distinct protective function of type I IFNs during autoimmune inflammation of the CNS.

Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions.

Microglia are crucially important myeloid cells in the CNS and constitute the first immunological barrier against pathogens and environmental insults. The factors controlling microglia recruitment from the blood remain elusive and the direct circulating microglia precursor has not yet been identified in vivo. Using a panel of bone marrow chimeric and adoptive transfer experiments, we found that circulating Ly-6C(hi)CCR2(+) monocytes were preferentially recruited to the lesioned brain and differentiated into microglia. Notably, microglia engraftment in CNS pathologies, which are not associated with overt blood-brain barrier disruption, required previous conditioning of brain (for example, by direct tissue irradiation). Our results identify Ly-6C(hi)CCR2(+) monocytes as direct precursors of microglia in the adult brain and establish the importance of local factors in the adult CNS for microglia engraftment.

Inhibition of transcription factor NF-kappaB in the central nervous system ameliorates autoimmune encephalomyelitis in mice.

Activation of transcription factor NF-kappaB in the central nervous system (CNS) has been linked to autoimmune demyelinating disease; however, it remains unclear whether its function is protective or pathogenic. Here we show that CNS-restricted ablation of 'upstream' NF-kappaB activators NEMO or IKK2 but not IKK1 ameliorated disease pathology in a mouse model of multiple sclerosis, suggesting that 'canonical' NF-kappaB activation in cells of the CNS has a mainly pathogenic function in autoimmune demyelinating disease. NF-kappaB inhibition prevented the expression of proinflammatory cytokines, chemokines and the adhesion molecule VCAM-1 from CNS-resident cells. Thus, NF-kappaB-dependent gene expression in non-microglial cells of the CNS provides a permissive proinflammatory milieu that is critical for CNS inflammation and tissue damage in autoimmune demyelinating disease.

Circulating monocytes engraft in the brain, differentiate into microglia and contribute to the pathology following meningitis in mice.

Previous studies have demonstrated a potential role of brain endogenous microglia and meningeal macrophages in inflammation and brain injury during bacterial meningitis. However, the contribution of previously engrafted monocytes and microglia to this process is still unknown. We therefore used genetically labelled bone marrow-derived cells from transgenic mice expressing the green fluorescent protein (GFP) under the chicken beta-actin promoter to deliver fluorescently labelled monocytes to the diseased brain. Approximately 24 hours after Streptococcus pneumoniae infection, GFP-expressing parenchymal microglia changed their morphology to an activated phenotype and upregulated major histocompatibility complex class II molecules. Bacterial meningitis increased the engraftment of GFP+ monocytes and their differentiation to microglia during the post-inflammatory period, but not during acute meningitis. Importantly, these newly recruited monocytes became an integral part of the pool of parenchymal microglia and contributed to the clearance of damaged tissue by increased lysosomal activity and close location to apoptotic cells. Thus, circulating cells entering the brain such as monocytes/macrophages might provide a potential cellular target for the treatment of the tissue damage following meningitis via peripheral cell therapy.

Streptococcus pneumoniae Infection aggravates experimental autoimmune encephalomyelitis via Toll-like receptor 2.

The course of autoimmune inflammatory diseases of the central nervous system (CNS) can be influenced by infections. Here we assessed the disease-modulating effects of the most frequent respiratory pathogen Streptococcus pneumonia on the course of experimental autoimmune encephalomyelitis (EAE). Mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG(35-55)) peptide, challenged intraperitoneally with live S. pneumoniae type 3, and then treated with ceftriaxone. EAE was monitored by a clinical score for 35 days after immunization. EAE was unaltered in mice infected with S. pneumoniae 2 days before and 21 days after the first MOG(35-55) injection but was more severe in animals infected 7 days after the first MOG(35-55) injection. The antigen-driven systemic T-cell response was unaltered, and the intraspinal Th1 cytokine mRNA concentrations at the peak of disease were unchanged. The composition of CNS-infiltrating cells and subsequent tissue destruction were only slightly increased after S. pneumoniae infection. In contrast, the serum levels of tumor necrosis factor alpha and interleukin-6 and spinal interleukin-6 levels were elevated, and the expression of major histocompatibility complex class II molecules, CD80, and CD86 on splenic dendritic cells were enhanced early after infection. Serum cytokine concentrations were not elevated, and EAE was not aggravated by S. pneumoniae infection in Toll-like receptor 2 (TLR2)-deficient mice. In conclusion, infection with S. pneumoniae worsens EAE probably by elevation of proinflammatory cytokines and activation of dendritic cells in the systemic circulation via TLR2 and cross talk through the blood-brain barrier.

Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis.

Inflammatory diseases of the CNS, such as MS and its animal model EAE, are characterized by infiltration of activated lymphocytes and phagocytes into the CNS. Within the CNS, activation of resident cells initiates an inflammatory cascade, leading to tissue destruction, demyelination, and neurologic deficit. TLRs recognize microbes and are pivotal mediators of innate immunity. Within the CNS, augmented TLR expression during EAE is observed, even in the absence of any apparent microbial involvement. To determine the functional relevance of this phenomenon during sterile autoimmunity, we studied the role of different TLRs as well as their common signaling adaptor MyD88 in the development of EAE. We found that MyD88 mice were completely EAE resistant. Surprisingly, this protection is partly due to engagement of the CpG receptor TLR9. Restricting the MyD88 or TLR9 mutation to host radio-resistant cells, including the cells within the CNS, revealed that engagement of radio-resistant cells modulated the disease course and histopathological changes. Our data clearly demonstrate that both TLR9 and MyD88 are essential modulators of the autoimmune process during the effector phase of disease and suggest that endogenous "danger signals" modulate the disease pathogenesis.