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Understanding the mercury cycle in the Arctic is important due to the harmful bioaccumulation of its toxic form, methylmercury, in wildlife and ultimately Arctic residents. Gaseous elemental mercury (Hg(0)) is relatively well-mixed across the northern hemisphere atmosphere due to its long atmospheric lifetime. Hg(0) can be oxidized, especially in the Arctic spring during halogen-driven depletion events. The resulting gaseous oxidized mercury (Hg(II)) is relatively quickly deposited onto snow, either directly or via condensing onto particles, forming particulate mercury (PHg). It is generally understood that a large fraction of the deposited Hg(II) and PHg is photoreduced to Hg(0) and re-emitted to the atmosphere. However, mercury remaining in the snowpack till melt can become bioavailable through entering the ocean.There is a severe lack of Hg(II) and PHg observations in the central Arctic, particularly over sea ice, limiting our understanding of the mercury cycle in that region and inhibiting us from quantifying mercury budgets in all environmental compartments and particularly where it unfolds its harmful neurotoxic effects. Moreover, most of the observational efforts aiming at creating process understanding focused on spring during mercury depletion events or the snow melt period, leaving large knowledge gaps for fall and winter.Here, we show atmospheric observations of PHg during MOSAiC, measured with an aerosol mass spectrometer in fall and spring over the central Arctic pack ice. In both seasons, PHg concentrations correlate strongly with wind speed and chloride, suggesting a mechanical (wind-driven) process behind atmospheric PHg related partly to blowing snow. In addition, there are significant differences between fall and spring observations (e.g. no atmospheric mercury depletion events in fall), suggesting that various processes are at play.This wind-driven process has hitherto not been reported and is different from observations at land-based stations as well as previous measurements over sea ice that ascribed the formation of PHg to adsorption of Hg(II) onto pre-existing aerosols or diamond dust rather than aerosolization from the snow pack. We hypothesize, based on snow chemical analyzes and literature, that the elevated halide content in snow on sea ice creates complexes of PHg, which are much harder to photoreduce than Hg(II), leading to a larger PHg content in snow. These processes of forming PHg and wind-driven aerosolization have implications for the mercury content of snow and the distances over which PHg is re-deposited after atmospheric transport given that the lifetime of PHg is about one order of magnitude larger than that of Hg(II) in the atmosphere.

A quantitative understanding of climate change in the polar regions being more extreme than at lower latitudes requires monitoring and modelling of key climate variables in these regions. Climate models disagree with observational datasets on the magnitude of the rate of Arctic amplification, and the representation of the chemistry and microphysics of aerosol particles in models is one of the contributing factors to the uncertainty in predicting polar climate. Aerosols represents one of the key model uncertainties through its impact on the surface energy balance via the scattering and absorption of solar radiation, and by its ability to influence cloud microphysics. Sea salt aerosol originating from the sublimation of blowing snow is a newly discovered source of aerosol particles above sea ice during winter and spring, and the hypothesised formation mechanism has been validated recently in the Antarctic. However, the lack of observations over a wide range of sea ice conditions including sub-micron sized particles has been a barrier towards accurately quantifying the mechanism of formation of SSA and the resulting SSA mass flux. Moreover, current blowing snow model parameterisations do not consider the spatial and temporal variability of sea ice and atmospheric state, which has a strong impact on the strength of the particle source from blowing snow across individual storms. In this study, we use observations from the MOSAIC (Multidisciplinary drifting Observatory for the Study of Arctic Climate) expedition (Oct 2019 to Sept 2020) and N-ICE2015 (Feb-June 2015) in the Arctic, and Weddell Sea measurements (June-October 2013) in the Antarctic to better constrain the blowing snow sea salt flux. We consider snow particle size distribution and snow salinity, which are both sensitive model parameters that govern the sea salt aerosol flux over sea ice. A gamma distribution fit is used to characterise the snow particle size distribution as a function of the 10-meter wind speed (ranging from the threshold wind speed (~5ms-1) to 15ms-1). Using the observations, we were able to better constrain the shape parameter of the gamma distribution, alpha, when compared to past studies. We discuss the relationship between snow salinity and snow depth, to capture the influence of the changing sea ice and snowfall on blowing snow aerosol source. We implement these parametrisations derived from point measurements into a chemistry transport model (p-TOMCAT) to better capture the spatially and temporally variable blowing snow source across polar regions, which helps to accurately simulate the aerosol number and mass concentration, and sodium concentration in polar regions.

Sea salt aerosols play a critical role in aerosol-radiation and aerosol-cloud interactions. Salty blowing snow has been hypothesized as an important source of sea salt aerosol in polar regions. The snow over sea ice can become salty by upward brine migration or deposition of sea spray produced from leads or transported from the ice edge. Wind-driven resuspension and sublimation of the snow is hypothesized to leave salty aerosol particles behind. Our understanding of aerosol emissions from blowing snow is based mainly on modeling studies, and direct observations to validate this process are sparse. The year-long Multidisciplinary drifting Observatory for the Study of Arctic Climate (MOSAiC) expedition, with its integrated measurements and sampling of frequent winter storms, is well suited to enhance our understanding of coupled Arctic system processes. Here, we focus on the impact of blowing snow and high wind speed events on aerosol number concentrations, size distributions, optical properties and cloud condensation nuclei (CCN) concentrations. Total aerosol number concentrations were significantly enhanced during high-wind speed periods, also concurrent with increased scattering aerosol coefficients and CCN concentrations. We further present a process-based characterization of the blowing snow events during MOSAiC and identify the influence of environmental variables on aerosol emissions. Our observations provide new insights into wind-driven aerosol in the central Arctic and may help to validate modelling studies and inform parameterization improvement particularly with respect to aerosol direct and indirect radiative forcing.

Perfluoroalkyl acids (PFAAs) are synthetic chemicals with a variety of industrial and consumer applications that are now widely distributed in the global environment. Here, we report the measurement of six perfluorocarboxylates (PFCA, C4–C9) in a firn (granular compressed snow) core collected from a non-coastal, high-altitude site in Dronning Maud Land in Eastern Antarctica. Snow accumulation of the extracted core dated from 1958 to 2017, a period coinciding with the advent, use, and geographical shift in the global industrial production of poly/perfluoroalkylated substances, including PFAA. We observed increasing PFCA accumulation in snow over this time period, with chemical fluxes peaking in 2009–2013 for perfluorooctanoate (PFOA, C8) and nonanoate (PFNA, C9) with little evidence of a decline in these chemicals despite supposed recent global curtailments in their production. In contrast, the levels of perfluorobutanoate (PFBA, C4) increased markedly since 2000, with the highest fluxes in the uppermost snow layers. These findings are consistent with those previously made in the Arctic and can be attributed to chlorofluorocarbon replacements (e.g., hydrofluoroethers) as an inadvertent consequence of global regulation.

Rapid progress in technologies such as calcium imaging and electrophysiology has seen a dramatic increase in the size and extent of neural recordings. Even so, interpretation of this data requires considerable knowledge about the nature of the representation and often depends on manual operations. Decoding provides a means to infer the information content of such recordings but typically requires highly processed data and prior knowledge of the encoding scheme. Here, we developed a deep-learning framework able to decode sensory and behavioral variables directly from wide-band neural data. The network requires little user input and generalizes across stimuli, behaviors, brain regions, and recording techniques. Once trained, it can be analyzed to determine elements of the neural code that are informative about a given variable. We validated this approach using electrophysiological and calcium-imaging data from rodent auditory cortex and hippocampus as well as human electrocorticography (ECoG) data. We show successful decoding of finger movement, auditory stimuli, and spatial behaviors – including a novel representation of head direction - from raw neural activity.

Viewing behavior provides a window into many central aspects of human cognition and health, and it is an important variable of interest or confound in many functional magnetic resonance imaging (fMRI) studies. To make eye tracking freely and widely available for MRI research, we developed DeepMReye, a convolutional neural network (CNN) that decodes gaze position from the magnetic resonance signal of the eyeballs. It performs cameraless eye tracking at subimaging temporal resolution in held-out participants with little training data and across a broad range of scanning protocols. Critically, it works even in existing datasets and when the eyes are closed. Decoded eye movements explain network-wide brain activity also in regions not associated with oculomotor function. This work emphasizes the importance of eye tracking for the interpretation of fMRI results and provides an open source software solution that is widely applicable in research and clinical settings.

Rapid progress in technologies such as calcium imaging and electrophysiology has seen a dramatic increase in the size and extent of neural recordings. Even so, interpretation of this data often depends on manual operations and requires considerable knowledge about the nature of the representation. Decoding provides a means to infer the information content of such recordings but typically requires highly processed data and prior knowledge of the encoding scheme. Here, we developed a deep-learning-framework able to decode sensory and behavioural variables directly from wide-band neural data. The network requires little user input and generalizes across stimuli, behaviours, brain regions, and recording techniques. Once trained, it can be analysed to determine elements of the neural code that are informative about a given variable. We validated this approach using data from rodent auditory cortex and hippocampus, identifying a novel representation of head direction encoded by putative CA1 interneurons.

The brain derives cognitive maps from sensory experience that guide memory formation and behavior. Despite extensive efforts, it still remains unclear how the underlying population activity unfolds during spatial navigation and how it relates to memory performance. To examine these processes, we combined 7T-fMRI with a kernel-based encoding model of virtual navigation to map world-centered directional tuning across the human cortex. First, we present an in-depth analysis of directional tuning in visual, retrosplenial, parahippocampal and medial temporal cortices. Second, we show that tuning strength, width and topology of this directional code during memory-guided navigation depend on successful encoding of the environment. Finally, we show that participants’ locomotory state influences this tuning in sensory and mnemonic regions such as the hippocampus. We demonstrate a direct link between neural population tuning and human cognition, where high-level memory processing interacts with network-wide visuospatial coding in the service of behavior., Our brain derives a sense of direction from visual inputs. Here, the authors combine 7T-fMRI with predictive modeling of virtual navigation to show that the strength, width and topology of directional coding in the human brain reflect ongoing memory-guided behavior.

To support navigation, the firing of head direction (HD) neurons must be tightly anchored to the external space. Indeed, inputs from external landmarks can rapidly reset the preferred direction of HD cells. Landmark stimuli have often been simulated as excitatory inputs from “visual cells” (encoding landmark information) to the HD attractor network; when excitatory visual inputs are sufficiently strong, preferred directions switch abruptly to the landmark location. In the present work, we tested whether mimicking such inputs via juxtacellular stimulation would be sufficient for shifting the tuning of individual presubicular HD cells recorded in passively rotated male rats. We recorded 81 HD cells in a cue-rich environment, and evoked spikes trains outside of their preferred direction (distance range, 11–178°). We found that HD tuning was remarkably resistant to activity manipulations. Even strong stimulations, which induced seconds-long spike trains, failed to induce a detectable shift in directional tuning. HD tuning curves before and after stimulation remained highly correlated, indicating that postsynaptic activation alone is insufficient for modifying HD output. Our data are thus consistent with the predicted stability of an HD attractor network when anchored to external landmarks. A small spiking bias at the stimulus direction could only be observed in a visually deprived environment in which both average firing rates and directional tuning were markedly reduced. Based on this evidence, we speculate that, when attractor dynamics become unstable (e.g., under disorientation), the output of HD neurons could be more efficiently controlled by strong biasing stimuli.SIGNIFICANCE STATEMENTThe activity of head direction (HD) cells is thought to provide the mammalian brain with an internal sense of direction. To support navigation, the firing of HD neurons must be anchored to external landmarks, a process thought to be supported by associative plasticity within the HD system. Here, we investigated these plasticity mechanisms by juxtacellular stimulation of single HD neuronsin vivoin awake rats. We found that HD coding is strongly resistant to external manipulations of spiking activity. Only in a visually deprived environment was juxtacellular stimulation able to induce a small activity bias in single presubicular neurons. We propose that juxtacellular stimulation can bias HD tuning only when competing anchoring inputs are reduced or not available.

In the dentate gyrus – a key component of spatial memory circuits – granule cells (GCs) are known to be morphologically diverse and to display heterogeneous activity profiles during behavior. To resolve structure–function relationships, we juxtacellularly recorded and labeled single GCs in freely moving rats. We found that the vast majority of neurons were silent during exploration. Most active GCs displayed a characteristic spike waveform, fired at low rates and showed spatial activity. Primary dendritic parameters were sufficient for classifying neurons as active or silent with high accuracy. Our data thus support a sparse coding scheme in the dentate gyrus and provide a possible link between structural and functional heterogeneity among the GC population. DOI: http://dx.doi.org/10.7554/eLife.20252.001

Neurons coding for head-direction are crucial for spatial navigation. Here we explored the cellular basis of head-direction coding in the rat dorsal presubiculum (PreS). We found that layer2 is composed of two principal cell populations (calbindin-positive and calbindin-negative neurons) which targeted the contralateral PreS and retrosplenial cortex, respectively. Layer3 pyramidal neurons projected to the medial entorhinal cortex (MEC). By juxtacellularly recording PreS neurons in awake rats during passive-rotation, we found that head-direction responses were preferentially contributed by layer3 pyramidal cells, whose long-range axons branched within layer3 of the MEC. In contrast, layer2 neurons displayed distinct spike-shapes, were not modulated by head-direction but rhythmically-entrained by theta-oscillations. Fast-spiking interneurons showed only weak directionality and theta-rhythmicity, but were significantly modulated by angular velocity. Our data thus indicate that PreS neurons differentially contribute to head-direction coding, and point to a cell-type- and layer-specific routing of directional and non-directional information to downstream cortical targets. DOI: http://dx.doi.org/10.7554/eLife.14592.001

(2-Diphenylphosphanyl)thiophenol (P^pSH) or (3-diphenylphosphanyl)-2-thionaphthol (P^nSH) react with Ni(PMe3)4 to form NiH(P^pS)(PMe3)2 (1) or NiH(P^nS)(PMe3)2 (2). 1,3-Bis(diphenylphosphanyl)propane (P^P) replaces the monodentate phosphane ligands to give NiH(P^pS)(P^P) (3). NiMe(OMe)(PMe3) or NiMe2(PMe3)3 react with P^pSH to form NiMe(P^pS)(PMe3) (4) and NiMe(P^pS)(PMe3)2 (5), respectively, and P^nSH affords NiMe(P^nS)(PMe3)2 (6), NiMe(P^nS)(PMe3) (7). Dissociation of PMe3 ligands induces transformation of 1 to Ni(P^pS)(PMe3)2 (8) and Ni(P^pS)2. Crystal and molecular structures are given for 1, 5–8, and dynamic solution spectra (NMR, EPR) are discussed.

BACKGROUND: In industrialized countries, typhoid fever occurs mainly in returned travelers. To determine the need for preventive strategies, eg, for vaccination, continuous monitoring is needed to assess where the risk for travelers is highest. METHODS: To investigate where the risk for travelers to acquire typhoid fever is highest, 208 patients with typhoid fever and recent travel were matched with travelers' statistics collected by the Swiss Federal Office of Statistics. RESULTS: At the beginning of the study period, up to 30 infections with Salmonella typhi were recorded per year in Switzerland. Since 2001, less than 15 confirmed cases per year occurred. A majority of the 208 (88.5%) typhoid cases were associated with recent travel. Countries with highest risk were Pakistan (24 per 100,000), Cambodia (20 per 100,000), Nepal (14 per 100,000), India (12 per 100,000), and Sri Lanka (9 per 100,000). CONCLUSIONS: We found that over a 12-year period (1993-2004), the travel-associated risk of typhoid fever is highest for destinations in the Indian subcontinent. All other regions showed a decline, most markedly in southern Europe. Our results suggest that typhoid fever vaccination should be recommended for all travelers to countries in South Asia. Otherwise, vaccination of tourists to frequently visited low- and intermediate-risk areas is not necessary, unless there are behavioral risk factors.

An essential requirement for hippocampal circuits to function in episodic memory is the ability to rapidly disambiguate and store incoming sensory information. This "pattern separation" function has been classically associated to the dentate gyrus, where spatial learning is accompanied by rapid and persistent modifications of place-cell representation. How these rapid modifications are implemented at the cellular level has remained largely unresolved. Here, we tested whether plasticity-inducing stimuli--spike trains--evoked in postsynaptic neurons are sufficient for the rapid induction of place-field activity in the dentate gyrus. We juxtacellularly stimulated 67 silent granule cells while rats explored a maze for the first time. Spike trains with different characteristics (e.g., number of spikes, frequency, and theta-rhythmicity) were evoked at randomly selected spatial locations. We found that, under novelty, ∼30% (10/33) of the stimulated neurons fired selectively at the "primed" spatial location on subsequent laps. Induced place fields were either transient or persisted for multiple laps. The "priming" effect was experience dependent, as it was less frequently observed in habituated animals (3/34 neurons), and it correlated with the number of spikes and theta-rhythmicity of the stimulus trains. These data indicate that, albeit with low efficiency, evoked theta-rhythmic spike trains can be sufficient for priming spatial activity in the dentate gyrus and thus recruiting silent granule cells into the coding population.

Reactions of alkynes with nickel hydride complexes bearing a [P, S]-ligand and supported by trimethylphosphine were investigated. Tetracoordinate vinyl nickel(II) complexes 3, 5, and 6 with square-planar geometry were obtained by reacting phenylacetylene, trimethylsilylacetylene, and 1-hexyne with the hydrido nickel complex 1. Reaction of 1,4-bis(trimethylsilylethynyl)benzene with complex 1 proceeds as a monoinsertion and afforded complex 7, while reaction of 1,4-bis(ethynyl)benzene with 1 leads to the dinuclear vinyl nickel(II) complex 8.

(Diphenylphosphanyl)phenols C6H3(1-OH)(2-PPh2)(4-R1)(6-R2), abbreviated as (P∧OH), oxidatively add to Fe(PMe3)4 affording hydridoiron(II) compounds fac-FeH(P∧O)(PMe3)3 (1: R1=R2=H; 2: R1=Me, R2=H; 3: R1=OMe, R2=H; 4: R1=Me, R2=CMe3; 5: R1=R2=CMe3) with high stereoselectivity. (2-diphenylphosphanyl)thiophenol (P∧SH) reacts accordingly forming fac-FeH(P∧S)(PMe3)3 (9). Complete assignment of 1H, 13C, and 31P signals is achieved by 2D heteronuclear shift correlations. 4,6-Di-tert-butyl-(2-diphenylphosphanyl)phenol reacts with FeI(Me)(PMe3)4 to form FeI(P∧O)(PMe3)2 (6). 4, 5 and 9 under 1 bar of CO are converted to monocarbonyl derivatives FeH(P∧X)(CO)(PMe3)2 (7, 8: X = O; 10: X = S) which in solution form mixtures of two isomers A and B. 4 and 5 react with their parent phosphanylphenols, respectively, to give diamagnetic complexes Fe(P∧O)2(PMe3) (11, 12) which dissociate trimethylphosphane to give paramagnetic compounds Fe(P∧O)2. The same phosphanylphenols react with FeCl3 to afford racemic mixtures of complexes Fe(P∧O)3 (13, 14). Structural data were also obtained from single crystals of compounds 1, 5, and 11.

Suppressor of cytokine signaling (SOCS) proteins constitute a class of negative regulators for Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways. These intracellular proteins are induced by cytokine signaling, but they can also be induced by stimulation of Toll-like receptors (TLR). It has even been suggested that SOCS proteins are important negative regulators of TLR signaling. Here we have elucidated the nature of the regulatory role of SOCS in TLR signaling. Induction of SOCS-3 and cytokine-inducible Src homology 2-containing protein (CIS) by TLR stimulation was strictly dependent on MyD88 but showed differing needs in case of SOCS-1. However, induction of SOCS proteins by TLR ligands was independent of type I interferon. In macrophages overexpressing SOCS, we were not able to observe an inhibitory effect of SOCS-1, SOCS-2, SOCS-3, or CIS on prototypical TLR target genes such as tumor necrosis factor-alpha. However, we found that TLR-2, TLR-3, TLR-4, and TLR-9 stimulation induced interferon-beta (IFN-beta), which is able to exert auto- and paracrine signaling, leading to the activation of secondary genes like IP-10. SOCS-1 and, to a lesser extent, SOCS-3 and CIS were able to inhibit this indirect signaling pathway following TLR stimulation, whereas neither MAP kinase nor NF kappa B signaling were affected. However, STAT-1 tyrosine phosphorylation following TLR triggering was severely impaired by SOCS-1 overexpression. Thus, our data suggest that SOCS proteins induced by TLR stimulation limit the extent of TLR signaling by inhibiting type I IFN signaling but not the main NF kappa B pathway.

Sterically hindered N-alkoxy amines 3 are synthesized in good yields by coupling nitroxides 2 with hydrocarbyl radicals generated in situ by t-BuOOH hydrogen abstraction from hydrocarbons. The reaction is catalyzed by copper halides as well as by onium iodides.

Bacterial DNA containing motifs of unmethylated CpG dinucleotides (CpG-DNA) triggers innate immune cells through the pattern recognition receptor Toll-like receptor 9 (TLR-9). CpG-DNA possesses potent immunostimulatory effects on macrophages, dendritic cells, and B lymphocytes. Therefore, CpG-DNA contributes to inflammation during the course of bacterial infections. In contrast to other TLR-dependent microbial patterns, CpG-DNA is a strong inductor of IL-12. Thus, it acts as a Th1-polarizing agent that can be utilized as potent vaccine adjuvant. To assess the role of CpG-DNA in immune reactions in the CNS, we analyzed the effects of CpG-DNA on microglial cells in vitro and in vivo. Primary microglial cells as well as microglial cell lines express TLR-9 mRNA. Consequently, CpG-DNA activated microglial cells in vitro and induced TNF-α, IL-12p40, IL-12p70, and NO. Furthermore, MHC class II, B7-1, B7-2, and CD40 molecules were up-regulated. In addition, phagocytic activity of microglia was enhanced. After intracerebroventricular injection of CpG-DNA, microglial cells were activated and produced TNF-α and IL-12p40 transcripts, as shown by in situ hybridization. These results indicate that microglia is sensitive to CpG-DNA. Thus, bacterial DNA containing CpG motifs could not only play an important role during infections of the CNS, but also might trigger and sustain Th1-dominated immunopathogenic reactions.

No standardized biomaterial exists for the surgical treatment of persistent corneal erosions and ulcerations. We analyzed the suitability and biocompatibility of defined noncross-linked and UV/riboflavin cross-linked equine type I collagen membranes for the reconstruction of the corneal surface. Isolated human oral mucosa epithelial cells, a cell type in clinical use for the treatment of ocular surface diseases, were subcultivated on both types of membranes and examined concerning cell adhesion, proliferation, and differentiation. Biocompatibility was evaluated following superficial and intrastromal corneal transplantation in New Zealand white rabbits. In cell cultures all collagen membranes supported adhesion of oral mucosa epithelial cells leading to the formation of multilayered epithelial cell sheets. After intrastromal corneal implantation clinical signs of degradation were seen in all variants of collagen membranes, which was fastest in noncross-linked variants. The histological and ultrastructural level invasion of keratocytes and production of new collagen fibers inside the collagen membranes could be detected in noncross-linked variants. After superficial corneal implantation covering of the membranes by corneal epithelium over time was visible. Ultrastructural analysis showed a slower rate of degradation and less invading keratocytes in cross-linked variants compared with noncross-linked collagen membranes. Cross-linked and noncross-linked variants of the collagen membrane proofed to be suitable to serve as a carrier for epithelial stem cells in vitro and showed a high biocompatibility in vivo. These results indicate that the tested collagen membranes might be suitable for the reconstruction of the corneal surface in patients with nonhealing ulcerations. Whether membranes with faster or slower degradation properties are preferable for the treatment of persistent corneal ulcerations might depend on the underlying corneal pathology and the degree of concomitant inflammation.

Trotz ihrer unbestreitbaren Potenziale sehen sich Tiefe Geothermieprojekte einer zunehmend kritischen Offentlichkeit gegenuber. Die Einstellung vieler Menschen ist gepragt durch Angst vor seismischen Ereignissen und schwer einschatzbaren Risiken. Als Erfolg versprechend zur Steigerung der Akzeptanz haben sich neben umfassender, fruhzeitiger und ehrlicher Kommunikation insbesondere Formen der direkten Burgerbeteiligung und offene Dialoge uber Chancen und Risiken Tiefer Geothermie erwiesen. Auch die Nutzung von Social Media kann neue Zielgruppen erschliesen und die bewahrten PR‐Instrumentarien sinnvoll erganzen.

The active form of pyruvate formate-lyase (PFL) from Escherichia coli contains a glycyl radical in position 734 of the polypeptide chain which is produced post-translationally by pyruvate formate-lyase-activating enzyme (PFL activase) using S-adenosylmethionine (AdoMet) and dihydroflavodoxin as co-substrates (Wagner, A.F. V., Frey, M., Neugebauer, F.A., Schafer, W., and Knappe, J. (1992) Proc. Natl. Acad. Sci. U. S. A. 89, 996-1000). Studying radical synthesis with [2-2H]glycine-labeled PFL, we have now found stoichiometric incorporation of a 2H atom into the 5‘-deoxyadenosine (dAdo) co-product via mass and NMR spectroscopic analyses. Furthermore, a series of peptides homologous to the Gly-734 site of PFL have been synthesized for analyzing recognition determinants of PFL activase. Peptides that proved active as substrates (monitored by [14C]dAdo formation from [14C]AdoMet) were also competitive inhibitors of PFL conversion to the radical form. In the sequence of the standard peptide Arg-Val-Ser-Gly-Tyr-Ala-Val, which corresponds to amino acid residues 731-737 of PFL, the Gly residue was replaceable by D-Ala (actually displaying enhanced efficiency), whereas a normal Ala totally abolished the interaction with PFL activase. Our results show that the radical in pyruvate formatelyase is produced by stereospecific abstraction of the pro-S hydrogen of glycine 734 by the 5‘-dAdo radical generated in the active center of PFL activase. Gly-734 is probably located in a beta-turn segment of the protein.

C–H activation through the coordination of a benzyl sulfide anchoring group with a C–S bond cleavage at a Co(V) center constitutes a regiospecific access to four- and five-membered metallacycles under mild conditions.

An iron carbonyl π-complex of the oxyallyl species was synthesized in two steps by complexation of a silylenol ether of α-bromoacetone and subsequent dehydrohalogenation by pyridine/AgBF 4 . The isolated intermediate, bromotricarbonyl (η 3 -2-hydroxy-2-propenyl)iron, shows an unexpectedly high acidity. The tricarbonyl(oxyallyl)iron complex exists as [(CH 2 COCH 2 )5CO) 3 Fe] 2 only, a head-to-tail dimer, as revealed by 1 H and 13 C NMR spectroscopy as well as by X-ray diffraction analysis

Background Impaired host defense mechanisms may crucially modulate the pathogenesis of atopic dermatitis (AD). More than 10% of patients with AD are heterozygous for the Toll-like receptor 2 (TLR-2) R753Q single nucleotide polymorphism (SNP) and exhibit severe eczema. Objective To elucidate the functional effect of the TLR-2 mutation and its putative relevance for AD. Methods Using the human embryonic kidney 293 transfection system, we characterized the properties of the TLR-2 R753Q SNP. Moreover, TLR-2 expression, IL-8 production, and cytokine secretion were analyzed in monocytes and CD4 + T cells of patients with AD with and without the mutant TLR-2 gene. Results Human embryonic kidney 293 transfectants mimicking this heterozygous mutation produced less IL-8 when stimulated with lipoteichoic acid (LTA), heat-inactivated Staphylococcus aureus or triacylated lipopeptides requiring the TLR-2/1 heterodimer. Suppressed production of IL-8 was confirmed in monocytes from patients with mutant AD after stimulation with peptidoglycan. Cell surface TLR-2 expression was severely impaired in CD3/CD28 activated CD4 + T cells of patients with AD bearing the mutant receptor, which could be restored on LTA stimulation. In contrast, LTA decreased TLR-2 expression among nonatopic individuals and patients with AD with the TLR-2 wild-type gene. T cells from patients with AD exhibited markedly suppressed IL-2 production after macrophage-activating lipopeptide-2 activation. However, no difference was found between mutant and wild-type patients with AD for IL-5, TNF-α, IFN-γ, and IL-2 production. Conclusion Collectively, the outcome of innate and adaptive immune responses in AD is modulated by the TLR-2 R753Q SNP.

El infarto agudo de miocardio (IAM) se ha descrito basandose en observaciones que van desde la presentacion clinica hasta los datos electrocardiograficos y/o bioquimicos y las caracteristicas anatomopatologicas. Ademas, las definiciones de IAM han variado en los diferentes paises. Por estos motivos, un comite conjunto que representa a la European Society of Cardiology y al American College of Cardiology elaboro una declaracion de consenso, publicada en septiembre de 2000, que describe los criterios diagnosticos del IAM (v. mas adelante en este capitulo).

Microbial stimuli activate cells of the innate immune system by triggering Toll-like receptors (TLR). Activation of macrophages and dendritic cells is further enhanced by secondary signals like IFN-gamma. Here we analyzed the interplay of IFN-gamma and TLR signaling in cells of the innate immune system. Using a STAT1-dependent reporter construct we show that IFN-gamma signaling can be enhanced as well as inhibited by simultaneous stimulation with either defined TLR agonists or whole-bacterial lysates. Short costimulation resulted in the amplification of IFN-gamma signaling and was attributable to the p38 mitogen-activated protein kinase (MAPK)-dependent phosphorylation of signal transducer and activator of transcription (STAT)1 on serine 727. In contrast, prolonged co-incubation as well as pre-incubation with TLR agonists led to an inhibition of IFN-gamma signaling. TLR triggering induced expression of suppressor of cytokine signaling (SOCS)-1, SOCS-3 and cytokine-inducible SH2 domain-containing protein (CIS). Overexpression of SOCS-1 and, to a lesser extend, of SOCS-3 and CIS inhibited IFN-gamma signaling as measured by activation of STAT1. Moreover, pre-incubation with TLR-dependent stimuli impaired IFN-gamma-induced MHC class II regulation but enhanced CD40 and CD86 expression. Taken together, the results indicate a tight interplay between TLR and IFN-gamma signaling pathways which involve induction of SOCS proteins and serine phosphorylation of STAT1.

The innate immune system recognizes pathogen-associated molecular patterns (PAMP) to cope with evolving infections. Toll-like receptors (TLRs) play a pivotal role in recognition of PAMPs. In the course of infection not a single but rather a full panel of different microbial components interacts with distinct TLRs simultaneously. Only limited information is available on effects of combinations of TLR agonists. Here, we have analyzed the effects of lipoteichoic acid (LTA), CpG-DNA and combinations thereof on innate immune cells in vitro. Although proinflammatory cytokines like TNF-alpha were induced by these agonists in quite similar amounts, CpG DNA was superior in its potency to induce IL-12p40 reflecting important differences in the biological valence of LTA and CpG-DNA. When given in combination, LTA and CpG-DNA were additive in induction of TNF-alpha, IL-6 and nitric oxide in RAW 264 macrophages, peritoneal macrophages and dendritic cells. Additive effects were also observed in regard to TNF-alpha mRNA. In contrast, LTA suppressed IL12p40 secretion induced by CpG-DNA in RAW cells and peritoneal macrophages but not in dendritic cells. Intracellular signal cascades (NFkappaB and p38 MAP kinase) showed additive effects after simultaneous triggering. mRNA expression ofTLRs showed only minor regulation after CpG or LTA application and thus does not account for the additive/suppressive effects observed. These results indicate that the consequences of interaction of innate immune cells with microbial pattern depend on the responding cell type and might be differential for certain effector mechanisms. Thus, the pathogen-characteristic panel of TLR ligands will induce pathogen-specific innate responses decisive for the inflammatory reactions.