Increasing Accumulation of Perfluorocarboxylate Contaminants Revealed in an Antarctic Firn Core (1958-2017).

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.

Testing the Efficacy of Single-Cell Stimulation in Biasing Presubicular Head Direction Activity.

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 STATEMENT The 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 neurons in vivo in 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.

NeuroAI: If grid cells are the answer, is path integration the question?

Spatially modulated neurons known as grid cells are thought to play an important role in spatial cognition. A new study has found that units with grid-cell-like properties can emerge within artificial neural networks trained to path integrate, and developed a unifying theory explaining the formation of these cells which shows what circuit constraints are necessary and how learned systems carry out path integration.

Arctic warming by abundant fine sea salt aerosols from blowing snow.

The Arctic warms nearly four times faster than the global average, and aerosols play an increasingly important role in Arctic climate change. In the Arctic, sea salt is a major aerosol component in terms of mass concentration during winter and spring. However, the mechanisms of sea salt aerosol production remain unclear. Sea salt aerosols are typically thought to be relatively large in size but low in number concentration, implying that their influence on cloud condensation nuclei population and cloud properties is generally minor. Here we present observational evidence of abundant sea salt aerosol production from blowing snow in the central Arctic. Blowing snow was observed more than 20% of the time from November to April. The sublimation of blowing snow generates high concentrations of fine-mode sea salt aerosol (diameter below 300 nm), enhancing cloud condensation nuclei concentrations up to tenfold above background levels. Using a global chemical transport model, we estimate that from November to April north of 70° N, sea salt aerosol produced from blowing snow accounts for about 27.6% of the total particle number, and the sea salt aerosol increases the longwave emissivity of clouds, leading to a calculated surface warming of +2.30 W m-2 under cloudy sky conditions.

Magnetic resonance-based eye tracking using deep neural networks.

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.

Implementation and Impacts of Surface and Blowing Snow Sources of Arctic Bromine Activation Within WRF-Chem 4.1.1.

Elevated concentrations of atmospheric bromine are known to cause ozone depletion in the Arctic, which is most frequently observed during springtime. We implement a detailed description of bromine and chlorine chemistry within the WRF-Chem 4.1.1 model, and two different descriptions of Arctic bromine activation: (1) heterogeneous chemistry on surface snow on sea ice, triggered by ozone deposition to snow (Toyota et al., 2011 https://doi.org/10.5194/acp-11-3949-2011), and (2) heterogeneous reactions on sea salt aerosols emitted through the sublimation of lofted blowing snow (Yang et al., 2008, https://doi.org/10.1029/2008gl034536). In both mechanisms, bromine activation is sustained by heterogeneous reactions on aerosols and surface snow. Simulations for spring 2012 covering the entire Arctic reproduce frequent and widespread ozone depletion events, and comparisons with observations of ozone show that these developments significantly improve model predictions during the Arctic spring. Simulations show that ozone depletion events can be initiated by both surface snow on sea ice, or by aerosols that originate from blowing snow. On a regional scale, in spring 2012, snow on sea ice dominates halogen activation and ozone depletion at the surface. During this period, blowing snow is a major source of Arctic sea salt aerosols but only triggers a few depletion events.

Interpreting wide-band neural activity using convolutional neural networks.

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.

Behavior-dependent directional tuning in the human visual-navigation network.

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.

The Toll-like receptor 2 R753Q mutation modifies cytokine production and Toll-like receptor expression in atopic dermatitis.

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-alpha, IFN-gamma, and IL-2 production. CONCLUSION: Collectively, the outcome of innate and adaptive immune responses in AD is modulated by the TLR-2 R753Q SNP.

Anatomical organization of presubicular head-direction circuits.

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.

Priming Spatial Activity by Single-Cell Stimulation in the Dentate Gyrus of Freely Moving Rats.

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.

Sparse activity of identified dentate granule cells during spatial exploration.

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.

Interaction of lipoteichoic acid and CpG-DNA during activation of innate immune cells.

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.

Novel collagen membranes for the reconstruction of the corneal surface.

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.

Four- and five-membered cobaltacycles by regioselective cyclometallation of benzyl sulfide derivatives via Co(v) intermediates.

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.

Tracing the origin and fate of NOx in the Arctic atmosphere using stable isotopes in nitrate.

Atmospheric nitrogen oxides (NOx =NO+ NO2) play a pivotal role in the cycling of reactive nitrogen (ultimately deposited as nitrate) and the oxidative capacity of the atmosphere. Combined measurements of nitrogen and oxygen stable isotope ratios of nitrate collected in the Arctic atmosphere were used to infer the origin and fate of NOx and nitrate on a seasonal basis. In spring, photochemically driven emissions of reactive nitrogen from the snowpack into the atmosphere make local oxidation of NOx by bromine oxide the major contributor to the nitrate budget. The comprehensive isotopic composition of nitrate provides strong constraints on the relative importance of the key atmospheric oxidants in the present atmosphere, with the potential for extension into the past using ice cores.

Imported typhoid fever in Switzerland, 1993 to 2004.

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.

Snowfall-driven growth in East Antarctic ice sheet mitigates recent sea-level rise.

Satellite radar altimetry measurements indicate that the East Antarctic ice-sheet interior north of 81.6 degrees S increased in mass by 45 +/- 7 billion metric tons per year from 1992 to 2003. Comparisons with contemporaneous meteorological model snowfall estimates suggest that the gain in mass was associated with increased precipitation. A gain of this magnitude is enough to slow sea-level rise by 0.12 +/- 0.02 millimeters per year.

Suppressor of cytokine signaling (SOCS) proteins indirectly regulate toll-like receptor signaling in innate immune cells.

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.