172 research outputs found
Potassium self-diffusion in a K-rich single-crystal alkali feldspar
The paper reports potassium diffusion measurements performed on gem-quality
single-crystal alkali feldspar in the temperature range from to 1021 \,
\mbox{K}. Natural sanidine from Volkesfeld, Germany was implanted with
\mbox{}^{43}\mbox{K} at the ISOLDE/CERN radioactive ion-beam facility normal
to the (001) crystallographic plane. Diffusion coefficients are well described
by the Arrhenius equation with an activation energy of 2.4 \, \mbox{eV} and a
pre-exponential factor of 5\times10^{-6} \, \mbox{m}^{2}/\mbox{s}, which is
more than three orders of magnitude lower than the \mbox{}^{22}\mbox{Na}
diffusivity in the same feldspar and the same crystallographic direction.
State-of-the-art considerations including ionic conductivity data on the same
crystal and Monte Carlo simulations of diffusion in random binary alloy
structures point to a correlated motion of K and Na through the interstitialcy
mechanism
Characterization of Voltage-Gated Potassium Channels in Human Neural Progenitor Cells
Voltage-gated potassium (K(v)) channels are among the earliest ion channels to appear during brain development, suggesting a functional requirement for progenitor cell proliferation and/or differentiation. We tested this hypothesis, using human neural progenitor cells (hNPCs) as a model system.In proliferating hNPCs a broad spectrum of K(v) channel subtypes was identified using quantitative real-time PCR with a predominant expression of the A-type channel K(v)4.2. In whole-cell patch-clamp recordings K(v) currents were separated into a large transient component characteristic for fast-inactivating A-type potassium channels (I(A)) and a small, sustained component produced by delayed-rectifying channels (I(K)). During differentiation the expression of I(A) as well as A-type channel transcripts dramatically decreased, while I(K) producing delayed-rectifiers were upregulated. Both K(v) currents were differentially inhibited by selective neurotoxins like phrixotoxin-1 and alpha-dendrotoxin as well as by antagonists like 4-aminopyridine, ammoniumchloride, tetraethylammonium chloride and quinidine. In viability and proliferation assays chronic inhibition of the A-type currents severely disturbed the cell cycle and precluded proper hNPC proliferation, while the blockade of delayed-rectifiers by alpha-dendrotoxin increased proliferation.These findings suggest that A-type potassium currents are essential for proper proliferation of immature multipotent hNPCs
Functional differentiation of midbrain neurons from human cord blood-derived induced pluripotent stem cells
INTRODUCTION: Human induced pluripotent stem cells (hiPSCs) offer great promise for regenerative therapies or in vitro modelling of neurodegenerative disorders like Parkinson’s disease. Currently, widely used cell sources for the generation of hiPSCs are somatic cells obtained from aged individuals. However, a critical issue concerning the potential clinical use of these iPSCs is mutations that accumulate over lifetime and are transferred onto iPSCs during reprogramming which may influence the functionality of cells differentiated from them. The aim of our study was to establish a differentiation strategy to efficiently generate neurons including dopaminergic cells from human cord blood-derived iPSCs (hCBiPSCs) as a juvenescent cell source and prove their functional maturation in vitro. METHODS: The differentiation of hCBiPSCs was initiated by inhibition of transforming growth factor-β and bone morphogenetic protein signaling using the small molecules dorsomorphin and SB 431542 before final maturation was carried out. hCBiPSCs and differentiated neurons were characterized by immunocytochemistry and quantitative real time-polymerase chain reaction. Since functional investigations of hCBiPSC-derived neurons are indispensable prior to clinical applications, we performed detailed analysis of essential ion channel properties using whole-cell patch-clamp recordings and calcium imaging. RESULTS: A Sox1 and Pax6 positive neuronal progenitor cell population was efficiently induced from hCBiPSCs using a newly established differentiation protocol. Neuronal progenitor cells could be further maturated into dopaminergic neurons expressing tyrosine hydroxylase, the dopamine transporter and engrailed 1. Differentiated hCBiPSCs exhibited voltage-gated ion currents, were able to fire action potentials and displayed synaptic activity indicating synapse formation. Application of the neurotransmitters GABA, glutamate and acetylcholine induced depolarizing calcium signal changes in neuronal cells providing evidence for the excitatory effects of these ligand-gated ion channels during maturation in vitro. CONCLUSIONS: This study demonstrates for the first time that hCBiPSCs can be used as a juvenescent cell source to generate a large number of functional neurons including dopaminergic cells which may serve for the development of novel regenerative treatment strategies
Decreased inflammatory cytokine production of antigen-specific CD4+ T cells in NMDA receptor encephalitis
Anti-N-methyl-D-aspartate-receptor (NMDAR) encephalitis is the most common autoimmune encephalitis with psychosis, amnesia, seizures and dyskinesias. The disease is mediated by pathogenic autoantibodies against the NR1 subunit that disrupt NMDAR function. Antibody infusion into mouse brains can recapitulate encephalitis symptoms, while active immunization resulted also in strong T cell infiltration into the hippocampus. However, whether T cells react against NMDAR and their specific contribution to disease development are poorly understood. Here we characterized the ex vivo frequency and phenotype of circulating CD4(+) T helper (T-H) cells reactive to NR1 protein using antigen-reactive T cell enrichment (ARTE) in 24 patients with NMDAR encephalitis, 13 patients with LGI1 encephalitis and 51 matched controls. Unexpectedly, patients with NMDAR encephalitis had lower frequencies of CD154-expressing NR1-reactive T-H cells than healthy controls and produced significantly less inflammatory cytokines. No difference was seen in T cells reactive to the synaptic target LGI1 (Leucine-rich glioma-inactivated 1), ubiquitous Candida antigens or neoantigens, suggesting that the findings are disease-specific and not related to therapeutic immunosuppression. Also, patients with LGI1 encephalitis showed unaltered numbers of LGI1 antigen-reactive T cells. The data reveal disease-specific functional alterations of circulating NMDAR-reactive T-H cells in patients with NMDAR encephalitis and challenge the idea that increased pro-inflammatory NMDAR-reactive T cells contribute to disease pathogenesis
Varicella zoster-associated retinal and central nervous system vasculitis in a patient with multiple sclerosis treated with natalizumab
Severe Progressive Multifocal Leukoencephalopathy (PML) and Spontaneous Immune Reconstitution Inflammatory Syndrome (IRIS) in an Immunocompetent Patient
Background: Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection with JC-virus (JCV), a papova-virus, affecting mostly oligodendrocytes and the white matter of the central nervous system. Progressive Multifocal Leukoencephalopathy (PML) almost exclusively occurs in immunocompromised patients based on different underlying conditions of severe cellular immunodeficiency such as HIV/AIDS, secondary to neoplastic and autoimmune diseases, or during immunosuppressive therapy.Case presentation: We present the case of an otherwise healthy and immunocompetent patient without immunosuppressive therapy who was admitted with hemianopsia to the right side, sensory aphasia and changes of behavior. Magnet resonance imaging (MRI) and laboratory testing confirmed the diagnosis of PML, although functional tests did not show any evidence for cellular immunodeficiency. Extensive immunological tests did not reveal an apparent immunodeficiency. During symptomatic therapy the patient developed seizures which were assumed to be caused by a spontaneous immune reconstitution inflammatory syndrome (IRIS) demonstrated by MRI. We added a high dose of intravenous corticosteroids to the antiepileptic treatment and seizures ended shortly thereafter. However, the impairments of vision, behavior and language persisted.Conclusions: Our case report highlights that an apparently immunocompetent patient can develop PML and IRIS spontaneously. Therefore, MRI should be applied immediately whenever a rapid progression of PML symptoms occurs as treatment of IRIS with corticosteroids can result in a marked clinical improvement
The Great Escape: The Role of Self-esteem and Self-related Cognition in Terror Management
Integrating terror management theory and objective self-awareness theory, we propose the
existential escape hypothesis, which states that people with low self-esteem should be
especially prone to escaping self-awareness as a distal response to thoughts of death. This is
because they lack the means to bolster the self as a defense, and the propensity to bolster the
self reduces the motivation to escape from self-awareness. Five studies supported this
hypothesis. Individuals low, but not high, in self-esteem scored lower on a measure of private
self-awareness (Study 1), showed less implicit self-activation (Studies 2 & 3), were more
likely to choose to write about others than themselves (Study 4), and consumed more alcohol
in a field study at a nightclub (Study 5) in response to mortality reminders. Implications for
terror management theory (highlighting an additional route to defend against mortality
awareness), self-regulation, physical health and well-being are discussed
Excited States of Ladder-type Poly-p-phenylene Oligomers
Ground state properties and excited states of ladder-type paraphenylene
oligomers are calculated applying semiempirical methods for up to eleven
phenylene rings. The results are in qualitative agreement with experimental
data. A new scheme to interpret the excited states is developed which reveals
the excitonic nature of the excited states. The electron-hole pair of the
S1-state has a mean distance of approximately 4 Angstroem.Comment: 24 pages, 21 figure
Knocking out C9ORF72 Exacerbates Axonal Trafficking Defects Associated with Hexanucleotide Repeat Expansion and Reduces Levels of Heat Shock Proteins
In amyotrophic lateral sclerosis (ALS) motor neurons (MNs) undergo dying-back, where the distal axon degenerates before the soma. The hexanudeotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of ALS, but the mechanism of pathogenesis is largely unknown with both gain- and loss-of-function mechanisms being proposed. To better understand C9ORF72-ALS pathogenesis, we generated isogenic induced pluripotent stem cells. MNs with HRE in C9ORF72 showed decreased axonal trafficking compared with gene corrected MNs. However, knocking out C9ORF72 did not recapitulate these changes in MNs from healthy controls, suggesting a gain-of-function mechanism. In contrast, knocking out C9ORF72 in MNs with HRE exacerbated axonal trafficking defects and increased apoptosis as well as decreased levels of HSP70 and HSP40, and inhibition of HSPs exacerbated ALS phenotypes in MNs with HRE. Therefore, we propose that the HRE in C9ORF72 induces ALS pathogenesis via a combination of gain- and loss-of-function mechanisms
A systematic outbreak investigation of SARS-CoV-2 transmission clusters in a tertiary academic care center
BACKGROUND
We sought to decipher transmission pathways in healthcare-associated infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within our hospital by epidemiological work-up and complementary whole genome sequencing (WGS). We report the findings of the four largest epidemiologic clusters of SARS-CoV-2 transmission occurring during the second wave of the pandemic from 11/2020 to 12/2020.
METHODS
At the University Hospital Basel, Switzerland, systematic outbreak investigation is initiated at detection of any nosocomial case of SARS-CoV-2 infection, as confirmed by polymerase chain reaction, occurring more than five days after admission. Clusters of nosocomial infections, defined as the detection of at least two positive patients and/or healthcare workers (HCWs) within one week with an epidemiological link, were further investigated by WGS on respective strains.
RESULTS
The four epidemiologic clusters included 40 patients and 60 HCWs. Sequencing data was available for 70% of all involved cases (28 patients and 42 HCWs), confirmed epidemiologically suspected in house transmission in 33 cases (47.1% of sequenced cases) and excluded transmission in the remaining 37 cases (52.9%). Among cases with identical strains, epidemiologic work-up suggested transmission mainly through a ward-based exposure (24/33, 72.7%), more commonly affecting HCWs (16/24, 66.7%) than patients (8/24, 33.3%), followed by transmission between patients (6/33, 18.2%), and among HCWs and patients (3/33, 9.1%, respectively two HCWs and one patient).
CONCLUSIONS
Phylogenetic analyses revealed important insights into transmission pathways supporting less than 50% of epidemiologically suspected SARS-CoV-2 transmissions. The remainder of cases most likely reflect community-acquired infection randomly detected by outbreak investigation. Notably, most transmissions occurred between HCWs, possibly indicating lower perception of the risk of infection during contacts among HCWs
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