1,268 research outputs found

    Giant depolarizing potentials trigger transient changes in the intracellular Cl(-) concentration in CA3 pyramidal neurons of the immature mouse hippocampus

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    Giant depolarizing potentials (GDPs) represent a typical spontaneous activity pattern in the immature hippocampus. GDPs are mediated by GABAergic and glutamatergic synaptic inputs and their initiation requires an excitatory GABAergic action, which is typical for immature neurons due to their elevated intracellular Cl(-) concentration ([Cl(-)](i)). Because GABA(A) receptors are ligand gated Cl(-) channels, activation of these receptors can potentially influence [Cl(-)](i). However, whether the GABAergic activity during GDPs influences [Cl(-)](i) is unclear. To address this question we performed whole-cell and gramicidin-perforated patch-clamp recordings from visually identified CA3 pyramidal neurons in immature hippocampal slices of mice at postnatal days 4-7. These experiments revealed that the [Cl(-)](i) of CA3 neurons displays a considerable heterogeneity, ranging from 13 to 70 mM (average 38.1 ± 3.2 mM, n = 36). In accordance with this diverse [Cl(-)] (i), GDPs induced either Cl(-)-effluxes or Cl(-)-influxes. In high [Cl(-)](i) neurons with a negative Cl(-)-driving force (DF(Cl)) the [Cl(-)](i) decreased after a GDP by 12.4 ± 3.4 mM (n = 10), while in low [Cl(-)](i) neurons with a positive DF(Cl) [Cl(-)](i) increased by 4.4 ± 0.9 mM (n = 6). Inhibition of GDP activity by application of the AMPA receptor antagonist CNQX led to a [Cl(-)](i) decrease to 24.7 ± 2.9 mM (n = 8). We conclude from these results, that Cl(-)-fluxes via GABA(A) receptors during GDPs induced substantial [Cl(-)](i) changes and that this activity dependent ionic plasticity in neuronal [Cl(-)](i) contributes to the functional consequences o

    Giant Depolarizing Potentials Trigger Transient Changes in the Intracellular Cl- Concentration in CA3 Pyramidal Neurons of the Immature Mouse Hippocampus

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    Giant depolarizing potentials (GDPs) represent a typical spontaneous activity pattern in the immature hippocampus. GDPs are mediated by GABAergic and glutamatergic synaptic inputs and their initiation requires an excitatory GABAergic action, which is typical for immature neurons due to their elevated intracellular Cl- concentration ([Cl-]i). Because GABAA receptors are ligand-gated Cl- channels, activation of these receptors can potentially influence [Cl-]i. However, whether the GABAergic activity during GDPs influences [Cl-]i is unclear. To address this question we performed whole-cell and gramicidin-perforated patch-clamp recordings from visually identified CA3 pyramidal neurons in immature hippocampal slices of mice at postnatal days 4–7. These experiments revealed that the [Cl-]i of CA3 neurons displays a considerable heterogeneity, ranging from 13 to 70 mM (average 38.1 ± 3.2 mM, n = 36). In accordance with this diverse [Cl-]i, GDPs induced either Cl--effluxes or Cl--influxes. In high [Cl-]i neurons with a negative Cl--driving force (DFCl) the [Cl-]i decreased after a GDP by 12.4 ± 3.4 mM (n = 10), while in low [Cl-]i neurons with a positive DFCl [Cl-]i increased by 4.4 ± 0.9 mM (n = 6). Inhibition of GDP activity by application of the AMPA receptor antagonist CNQX led to a [Cl-]i decrease to 24.7 ± 2.9 mM (n = 8). We conclude from these results, that Cl--fluxes via GABAA receptors during GDPs induced substantial [Cl-]i changes and that this activity-dependent ionic plasticity in neuronal [Cl-]i contributes to the functional consequences of GABAergic responses, emphasizing the concept that [Cl-]i is a state- and compartment-dependent parameter of individual cells

    A New High-Resolution Map of World Mountains and an Online Tool for Visualizing and Comparing

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    Answers to the seemingly straightforward questions “what is a mountain?” and “where are the mountains of the world?” are in fact quite complex, and there have been few attempts to map the mountains of the earth in a consistent and rigorous fashion. However, knowing exactly where mountain ecosystems are distributed on the planet is a precursor to conserving them, as called for in Sustainable Development Goals 6 and 15 of the United Nations 2030 Agenda for Sustainable Development. In this article we first compare 3 characterizations of global mountain distributions, including a new, high-resolution (250 m) map of global mountains derived from terrain characteristics. We show how differences in conceptual definition, methodology, and spatial resolution of source data can result in differences in the extent and location of lands classed as mountains. For example, the new 250-m resource documents a larger global mountain extent than previous characterizations, although it excludes plateaus, hilly forelands, and other landforms that are often considered part of mountain areas. We then introduce the Global Mountain Explorer, a new web-based application specifically developed for exploration, visualization, and comparison of these maps. This new open-access tool is an intuitive and versatile resource suitable for a broad range of users and applications

    In-flight calibration and verification of the Planck-LFI instrument

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    In this paper we discuss the Planck-LFI in-flight calibration campaign. After a brief overview of the ground test campaigns, we describe in detail the calibration and performance verification (CPV) phase, carried out in space during and just after the cool-down of LFI. We discuss in detail the functionality verification, the tuning of the front-end and warm electronics, the preliminary performance assessment and the thermal susceptibility tests. The logic, sequence, goals and results of the in-flight tests are discussed. All the calibration activities were successfully carried out and the instrument response was comparable to the one observed on ground. For some channels the in-flight tuning activity allowed us to improve significantly the noise performance.Comment: Long technical paper on Planck LFI in flight calibration campaign: 109 pages in this (not final) version, 100 page in the final JINST versio

    KiDS-450: cosmological constraints from weak-lensing peak statistics – II: Inference from shear peaks using N-body simulations

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    We study the statistics of peaks in a weak-lensing reconstructed mass map of the first 450 deg2 of the Kilo Degree Survey (KiDS-450). The map is computed with aperture masses directly applied to the shear field with an NFW-like compensated filter. We compare the peak statistics in the observations with that of simulations for various cosmologies to constrain the cosmological parameter S8=σ8Ωm/0.3−−−−−−√⁠, which probes the (Ωm, σ8) plane perpendicularly to its main degeneracy. We estimate S8 = 0.750 ± 0.059, using peaks in the signal-to-noise range 0 ≤ S/N ≤ 4, and accounting for various systematics, such as multiplicative shear bias, mean redshift bias, baryon feedback, intrinsic alignment, and shear–position coupling. These constraints are ∼ 25 per cent tighter than the constraints from the high significance peaks alone (3 ≤ S/N ≤ 4) which typically trace single-massive haloes. This demonstrates the gain of information from low-S/N peaks. However, we find that including S/N < 0 peaks does not add further information. Our results are in good agreement with the tomographic shear two-point correlation function measurement in KiDS-450. Combining shear peaks with non-tomographic measurements of the shear two-point correlation functions yields a ∼20 per cent improvement in the uncertainty on S8 compared to the shear two-point correlation functions alone, highlighting the great potential of peaks as a cosmological probe

    The masses of satellites in GAMA galaxy groups from 100 square degrees of KiDS weak lensing data

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    We use the first 100 deg2 of overlap between the Kilo-Degree Survey and the Galaxy And Mass Assembly survey to determine the average galaxy halo mass of ∼10 000 spectroscopically confirmed satellite galaxies in massive (M > 1013 h−1 M⊙) galaxy groups. Separating the sample as a function of projected distance to the group centre, we jointly model the satellites and their host groups with Navarro–Frenk–White density profiles, fully accounting for the data covariance. The probed satellite galaxies in these groups have total masses log 〈Msub/(h−1 M⊙)〉 ≈ 11.7–12.2 consistent across group-centric distance within the errorbars. Given their typical stellar masses, log 〈M⋆, sat/(h−2 M⊙)〉 ∼ 10.5, such total masses imply stellar mass fractions of 〈M⋆, sat〉/〈Msub〉 ≈ 0.04 h−1. The average subhalo hosting these satellite galaxies has a mass Msub ∼ 0.015Mhost independent of host halo mass, in broad agreement with the expectations of structure formation in a Λ cold dark matter universe.Publisher PDFPeer reviewe

    Genome-wide interrogation of hepatic FXR reveals an asymmetric IR-1 motif and synergy with LRH-1

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    We used mouse hepatic chromatin enriched with an FXR antibody and chromatin immunoprecipitation-sequencing (ChIP-seq) to evaluate FXR binding on a genome-wide scale. This identified 1656 FXR-binding sites and 10% were located within 2 kb of a transcription start site which is much higher than predicted by random occurrence. A motif search uncovered a canonical nuclear receptor IR-1 site, consistent with in vitro DNA-binding studies reported previously. A separate nuclear receptor half-site for monomeric receptors such as LRH-1 was co-enriched and FXR activation of four newly identified promoters was significantly augmented by an LRH-1 expression vector in a co-transfection assay. There were 1038 genes located within 20 kb of a peak and a gene set enrichment analysis showed that genes identified by our ChIP-seq analysis are highly correlated with genes activated by an FXR-VP16 adenovirus in primary mouse hepatocytes providing functional relevance to the genome-wide binding study. Gene Ontology analysis showed FXR-binding sites close to many genes in lipid, fatty acid and steroid metabolism. Other broad gene clusters related to metabolism, transport, signaling and glycolysis were also significantly enriched. Thus, FXR may have a much wider role in cellular metabolism than previously appreciated

    ATRT–SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance

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    Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor characterized by loss of SMARCB1/INI1 protein expression and comprises three distinct molecular groups, ATRT–TYR, ATRT–MYC and ATRT–SHH. ATRT–SHH represents the largest molecular group and is heterogeneous with regard to age, tumor location and epigenetic profile. We, therefore, aimed to investigate if heterogeneity within ATRT–SHH might also have biological and clinical importance. Consensus clustering of DNA methylation profiles and confirmatory t-SNE analysis of 65 ATRT–SHH yielded three robust molecular subgroups, i.e., SHH-1A, SHH-1B and SHH-2. These subgroups differed by median age of onset (SHH-1A: 18 months, SHH-1B: 107 months, SHH-2: 13 months) and tumor location (SHH-1A: 88% supratentorial; SHH-1B: 85% supratentorial; SHH-2: 93% infratentorial, often extending to the pineal region). Subgroups showed comparable SMARCB1 mutational profiles, but pathogenic/likely pathogenic SMARCB1 germline variants were over-represented in SHH-2 (63%) as compared to SHH-1A (20%) and SHH-1B (0%). Protein expression of proneural marker ASCL1 (enriched in SHH-1B) and glial markers OLIG2 and GFAP (absent in SHH-2) as well as global mRNA expression patterns differed, but all subgroups were characterized by overexpression of SHH as well as Notch pathway members. In a Drosophila model, knockdown of Snr1 (the fly homologue of SMARCB1) in hedgehog activated cells not only altered hedgehog signaling, but also caused aberrant Notch signaling and formation of tumor-like structures. Finally, on survival analysis, molecular subgroup and age of onset (but not ASCL1 staining status) were independently associated with overall survival, older patients (> 3 years) harboring SHH-1B experiencing relatively favorable outcome. In conclusion, ATRT–SHH comprises three subgroups characterized by SHH and Notch pathway activation, but divergent molecular and clinical features. Our data suggest that molecular subgrouping of ATRT–SHH has prognostic relevance and might aid to stratify patients within future clinical trials. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-022-02424-5

    Planck-LFI CPV: Blanking Time Verification

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    Planck LFI Commissioning and Performance Verification (CPV)This test consists in five steps, of about 15 minutes, with different blanking times: 7.5 µιχρο−s, 0 µιχρο−s, 15 µιχρο−s, 22.5 µιχρο−s, and again 7.5 µιχρο−s. In particular, we want to verify that: no current drops or abrupt variations are observed in FEM drain currents; no frequency spikes are observed besides those already characterised during the SPIKE-02 test; frequency spikes are not affected by the different blanking time values; no pop-corn noise is detected in radiometer voltage outputs
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