RIM-BP2 primes synaptic vesicles via recruitment of Munc13-1 at hippocampal mossy fiber synapses

All synapses require fusion-competent vesicles and coordinated Ca(2+)-secretion coupling for neurotransmission, yet functional and anatomical properties are diverse across different synapse types. We show that the presynaptic protein RIM-BP2 has diversified functions in neurotransmitter release at different central murine synapses and thus contributes to synaptic diversity. At hippocampal pyramidal CA3-CA1 synapses, RIM-BP2 loss has a mild effect on neurotransmitter release, by only regulating Ca(2+)-secretion coupling. However, at hippocampal mossy fiber synapses, RIM-BP2 has a substantial impact on neurotransmitter release by promoting vesicle docking/priming and vesicular release probability via stabilization of Munc13-1 at the active zone. We suggest that differences in the active zone organization may dictate the role a protein plays in synaptic transmission and that differences in active zone architecture is a major determinant factor in the functional diversity of synapses

Annual cycle observations of aerosols capable of ice formation in central Arctic clouds

The Arctic is warming faster than anywhere else on Earth, prompting glacial melt, permafrost thaw, and sea ice decline. These severe consequences induce feedbacks that contribute to amplified warming, affecting weather and climate globally. Aerosols and clouds play a critical role in regulating radiation reaching the Arctic surface. However, the magnitude of their effects is not adequately quantified, especially in the central Arctic where they impact the energy balance over the sea ice. Specifically, aerosols called ice nucleating particles (INPs) remain understudied yet are necessary for cloud ice production and subsequent changes in cloud lifetime, radiative effects, and precipitation. Here, we report observations of INPs in the central Arctic over a full year, spanning the entire sea ice growth and decline cycle. Further, these observations are size-resolved, affording valuable information on INP sources. Our results reveal a strong seasonality of INPs, with lower concentrations in the winter and spring controlled by transport from lower latitudes, to enhanced concentrations of INPs during the summer melt, likely from marine biological production in local open waters. This comprehensive characterization of INPs will ultimately help inform cloud parameterizations in models of all scales

Reading the biomineralized book of life: expanding otolith biogeochemical research and applications for fisheries and ecosystem-based management

Chemical analysis of calcified structures continues to flourish, as analytical and technological advances enable researchers to tap into trace elements and isotopes taken up in otoliths and other archival tissues at ever greater resolution. Increasingly, these tracers are applied to refine age estimation and interpretation, and to chronicle responses to environmental stressors, linking these to ecological, physiological, and life-history processes. Here, we review emerging approaches and innovative research directions in otolith chemistry, as well as in the chemistry of other archival tissues, outlining their value for fisheries and ecosystem-based management, turning the spotlight on areas where such biomarkers can support decision making. We summarise recent milestones and the challenges that lie ahead to using otoliths and archival tissues as biomarkers, grouped into seven, rapidly expanding and application-oriented research areas that apply chemical analysis in a variety of contexts, namely: (1) supporting fish age estimation; (2) evaluating environmental stress, ecophysiology and individual performance; (3) confirming seafood provenance; (4) resolving connectivity and movement pathways; (5) characterising food webs and trophic interactions; (6) reconstructing reproductive life histories; and (7) tracing stock enhancement efforts. Emerging research directions that apply hard part chemistry to combat seafood fraud, quantify past food webs, as well as to reconcile growth, movement, thermal, metabolic, stress and reproductive life-histories provide opportunities to examine how harvesting and global change impact fish health and fisheries productivity. Ultimately, improved appreciation of the many practical benefits of archival tissue chemistry to fisheries and ecosystem-based management will support their increased implementation into routine monitoring.[GRAPHICS]

The Higgs as a Portal to Plasmon-like Unparticle Excitations

12 LaTeX pages, 2 figures.-- Published in: JHEP04(2008)028.-- Final full-text version available at: http://dx.doi.org/10.1088/1126-6708/2008/04/028.A renormalizable coupling between the Higgs and a scalar unparticle operator O_U of non-integer dimension d_U<2 triggers, after electroweak symmetry breaking, an infrared divergent vacuum expectation value for O_U. Such IR divergence should be tamed before any phenomenological implications of the Higgs-unparticle interplay can be drawn. In this paper we present a novel mechanism to cure that IR divergence through (scale-invariant) unparticle self-interactions, which has properties qualitatively different from the mechanism considered previously. Besides finding a mass gap in the unparticle continuum we also find an unparticle pole reminiscent of a plasmon resonance. Such unparticle features could be explored experimentally through their mixing with the Higgs boson.Work supported in part by the European Commission under the European Union through the Marie Curie Research and Training Networks “Quest for Unification” (MRTN-CT- 2004-503369) and “UniverseNet” (MRTN-CT-2006-035863); by the Spanish Consolider- Ingenio 2010 Programme CPAN (CSD2007-0042); by a Comunidad de Madrid project (P-ESP-00346) and by CICYT, Spain, under contracts FPA 2007-60252 and FPA 2005-02211

The HSP70 modulator MAL3-101 inhibits Merkel cell carcinoma

Merkel Cell Carcinoma (MCC) is a rare and highly aggressive neuroendocrine skin cancer for which no effective treatment is available. MCC represents a human cancer with the best experimental evidence for a causal role of a polyoma virus. Large T antigens (LTA) encoded by polyoma viruses are oncoproteins, which are thought to require support of cellular heat shock protein 70 (HSP70) to exert their transforming activity. Here we evaluated the capability of MAL3-101, a synthetic HSP70 inhibitor, to limit proliferation and survival of various MCC cell lines. Remarkably, MAL3-101 treatment resulted in considerable apoptosis in 5 out of 7 MCC cell lines. While this effect was not associated with the viral status of the MCC cells, quantitative mRNA expression analysis of the known HSP70 isoforms revealed a significant correlation between MAL3-101 sensitivity and HSC70 expression, the most prominent isoform in all cell lines. Moreover, MAL3-101 also exhibited in vivo antitumor activity in an MCC xenograft model suggesting that this substance or related compounds are potential therapeutics for the treatment of MCC in the future. © 2014 Adam et al

Neuropsychological effects of chronic low-dose exposure to polychlorinated biphenyls (PCBs): A cross-sectional study

BACKGROUND: Exposure to indoor air of private or public buildings contaminated with polychlorinated biphenyls (PCBs) has raised health concerns in long-term users. This exploratory neuropsychological group study investigated the potential adverse effects of chronic low-dose exposure to specific air-borne low chlorinated PCBs on well-being and behavioral measures in adult humans. METHODS: Thirty employees exposed to indoor air contaminated with PCBs from elastic sealants in a school building were compared to 30 non-exposed controls matched for education and age, controlling for gender (age range 37–61 years). PCB exposure was verified by external exposure data and biological monitoring (PCB 28, 101, 138, 153, 180). Subjective complaints, learning and memory, executive function, and visual-spatial function was assessed by standardized neuropsychological testing. Since exposure status depended on the use of contaminated rooms, an objectively exposed subgroup (N = 16; PCB 28 = 0.20 μg/l; weighted exposure duration 17.9 ± 7 years) was identified and compared with 16 paired controls. RESULTS: Blood analyses indicated a moderate exposure effect size (d) relative to expected background exposure for total PCB (4.45 ± 2.44 μg/l; d = 0.4). A significant exposure effect was found for the low chlorinated PCBs 28 (0.28 ± 0.25 μg/l; d = 1.5) and 101 (0.07 ± 0.09 μg/l; d = 0.7). Although no neuropsychological effects exceeded the adjusted significance level, estimation statistics showed elevated effect sizes for several variables. The objectively exposed subgroup showed a trend towards increased subjective attentional and emotional complaints (tiredness and slowing of practical activities, emotional state) as well as attenuated attentional performance (response shifting and alertness in a cued reaction task). CONCLUSION: Chronic inhalation of low chlorinated PCBs that involved elevated blood levels was associated with a subtle attenuation of emotional well-being and attentional function. Extended research is needed to replicate the potential long-term low PCB effects in a larger sample

Revealing the Functional Neuroanatomy of Intrinsic Alertness Using fMRI: Methodological Peculiarities

Clinical observations and neuroimaging data revealed a right-hemisphere fronto-parietal-thalamic-brainstem network for intrinsic alertness, and additional left fronto-parietal activity during phasic alertness. The primary objective of this fMRI study was to map the functional neuroanatomy of intrinsic alertness as precisely as possible in healthy participants, using a novel assessment paradigm already employed in clinical settings. Both the paradigm and the experimental design were optimized to specifically assess intrinsic alertness, while at the same time controlling for sensory-motor processing. The present results suggest that the processing of intrinsic alertness is accompanied by increased activity within the brainstem, thalamus, anterior cingulate gyrus, right insula, and right parietal cortex. Additionally, we found increased activation in the left hemisphere around the middle frontal gyrus (BA 9), the insula, the supplementary motor area, and the cerebellum. Our results further suggest that rather minute aspects of the experimental design may induce aspects of phasic alertness, which in turn might lead to additional brain activation in left-frontal areas not normally involved in intrinsic alertness. Accordingly, left BA 9 activation may be related to co-activation of the phasic alertness network due to the switch between rest and task conditions functioning as an external warning cue triggering the phasic alertness network. Furthermore, activation of the intrinsic alertness network during fixation blocks due to enhanced expectancy shortly before the switch to the task block might, when subtracted from the task block, lead to diminished activation in the typical right hemisphere intrinsic alertness network. Thus, we cautiously suggest that – as a methodological artifact – left frontal activations might show up due to phasic alertness involvement and intrinsic alertness activations might be weakened due to contrasting with fixation blocks, when assessing the functional neuroanatomy of intrinsic alertness with a block design in fMRI studies

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

Reading the biomineralized book of life: expanding otolith biogeochemical research and applications for fisheries and ecosystem-based management

AbstractChemical analysis of calcified structures continues to flourish, as analytical and technological advances enable researchers to tap into trace elements and isotopes taken up in otoliths and other archival tissues at ever greater resolution. Increasingly, these tracers are applied to refine age estimation and interpretation, and to chronicle responses to environmental stressors, linking these to ecological, physiological, and life-history processes. Here, we review emerging approaches and innovative research directions in otolith chemistry, as well as in the chemistry of other archival tissues, outlining their value for fisheries and ecosystem-based management, turning the spotlight on areas where such biomarkers can support decision making. We summarise recent milestones and the challenges that lie ahead to using otoliths and archival tissues as biomarkers, grouped into seven, rapidly expanding and application-oriented research areas that apply chemical analysis in a variety of contexts, namely: (1) supporting fish age estimation; (2) evaluating environmental stress, ecophysiology and individual performance; (3) confirming seafood provenance; (4) resolving connectivity and movement pathways; (5) characterising food webs and trophic interactions; (6) reconstructing reproductive life histories; and (7) tracing stock enhancement efforts. Emerging research directions that apply hard part chemistry to combat seafood fraud, quantify past food webs, as well as to reconcile growth, movement, thermal, metabolic, stress and reproductive life-histories provide opportunities to examine how harvesting and global change impact fish health and fisheries productivity. Ultimately, improved appreciation of the many practical benefits of archival tissue chemistry to fisheries and ecosystem-based management will support their increased implementation into routine monitoring. Graphical abstract</jats:p