The permeability of reconstituted nuclear pores provides direct evidence for the selective phase model.

Nuclear pore complexes (NPCs) maintain a permeability barrier between the nucleus and the cytoplasm through FG-repeat-containing nucleoporins (Nups). We previously proposed a “selective phase model” in which the FG repeats interact with one another to form a sieve-like barrier that can be locally disrupted by the binding of nuclear transport receptors (NTRs), but not by inert macromolecules, allowing selective passage of NTRs and associated cargo. Here, we provide direct evidence for this model in a physiological context. By using NPCs reconstituted from Xenopus laevis egg extracts, we show that Nup98 is essential for maintaining the permeability barrier. Specifically, the multivalent cohesion between FG repeats is required, including cohesive FG repeats close to the anchorage point to the NPC scaffold. Our data exclude alternative models that are based solely on an interaction between the FG repeats and NTRs and indicate that the barrier is formed by a sieve-like FG hydrogel

NDC1: a crucial membrane-integral nucleoporin of metazoan nuclear pore complexes

POM121 and gp210 were, until this point, the only known membrane-integral nucleoporins (Nups) of vertebrates and, thus, the only candidate anchors for nuclear pore complexes (NPCs) within the nuclear membrane. In an accompanying study (see Stavru et al. on p. 477 of this issue), we provided evidence that NPCs can exist independently of POM121 and gp210, and we predicted that vertebrate NPCs contain additional membrane-integral constituents. We identify such an additional membrane protein in the NPCs of mammals, frogs, insects, and nematodes as the orthologue to yeast Ndc1p/Cut11p. Human NDC1 (hNDC1) likely possesses six transmembrane segments, and it is located at the nuclear pore wall. Depletion of hNDC1 from human HeLa cells interferes with the assembly of phenylalanine-glycine repeat Nups into NPCs. The loss of NDC1 function in Caenorhabditis elegans also causes severe NPC defects and very high larval and embryonic mortality. However, it is not ultimately lethal. Instead, homozygous NDC1-deficient worms can be propagated. This indicates that none of the membrane-integral Nups is universally essential for NPC assembly, and suggests that NPC biogenesis is an extremely fault-tolerant process

Selenium Status in Paediatric Patients with Neurodevelopmental Diseases

Neurodevelopmental diseases are often associated with other comorbidities, especially inflammatory processes. The disease may affect the trace element (TE) status, which in turn may affect disease severity and progression. Selenium (Se) is an essential TE required for the biosynthesis of selenoproteins including the transporter selenoprotein P (SELENOP) and extracellular glutathione peroxidase (GPX3). SELENOP deficiency in transgenic mice resulted in a Se status-dependent phenotype characterized by impaired growth and disturbed neuronal development, with epileptic seizures on a Se-deficient diet. Therefore, we hypothesized that Se and SELENOP deficiencies may be prevalent in paediatric patients with a neurodevelopmental disease. In an exploratory cross-sectional study, serum samples from children with neurodevelopmental diseases (n = 147) were analysed for total serum Se, copper (Cu), and zinc (Zn) concentrations as well as for the TE biomarkers SELENOP, ceruloplasmin (CP), and GPX3 activity. Children with epilepsy displayed elevated Cu and Zn concentrations but no dysregulation of serum Se status. Significantly reduced SELENOP concentrations were found in association with intellectual disability (mean +/- SD (standard deviation); 3.9 +/- 0.9 mg/L vs. 4.4 +/- 1.2 mg/L, p = 0.015). A particularly low GPX3 activity (mean +/- SD; 172.4 +/- 36.5 vs. 192.6 +/- 46.8 U/L, p = 0.012) was observed in phacomatoses. Autoantibodies to SELENOP, known to impair Se transport, were not detected in any of the children. In conclusion, there was no general association between Se deficiency and epilepsy in this observational analysis, which does not exclude its relevance to individual cases. Sufficiently high SELENOP concentrations seem to be of relevance to the support of normal mental development. Decreased GPX3 activity in phacomatoses may be relevant to the characteristic skin lesions and merits further analysis. Longitudinal studies are needed to determine whether the observed differences are relevant to disease progression and whether correcting a diagnosed TE deficiency may confer health benefits to affected children

Compellingly high SARS-CoV-2 susceptibility of Golden Syrian hamsters suggests multiple zoonotic infections of pet hamsters during the COVID-19 pandemic

Golden Syrian hamsters (Mesocricetus auratus) are used as a research model for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Millions of Golden Syrian hamsters are also kept as pets in close contact to humans. To determine the minimum infective dose (MID) for assessing the zoonotic transmission risk, and to define the optimal infection dose for experimental studies, we orotracheally inoculated hamsters with SARS-CoV-2 doses from 1 * 105 to 1 * 10-4 tissue culture infectious dose 50 (TCID50). Body weight and virus shedding were monitored daily. 1 * 10-3 TCID50 was defined as the MID, and this was still sufficient to induce virus shedding at levels up to 102.75 TCID50/ml, equaling the estimated MID for humans. Virological and histological data revealed 1 * 102 TCID50 as the optimal dose for experimental infections. This compelling high susceptibility leading to productive infections in Golden Syrian hamsters must be considered as a potential source of SARS-CoV-2 infection for humans that come into close contact with pet hamsters

N-Cofilin Can Compensate for the Loss of ADF in Excitatory Synapses

Actin plays important roles in a number of synaptic processes, including synaptic vesicle organization and exocytosis, mobility of postsynaptic receptors, and synaptic plasticity. However, little is known about the mechanisms that control actin at synapses. Actin dynamics crucially depend on LIM kinase 1 (LIMK1) that controls the activity of the actin depolymerizing proteins of the ADF/cofilin family. While analyses of mouse mutants revealed the importance of LIMK1 for both pre- and postsynaptic mechanisms, the ADF/cofilin family member n-cofilin appears to be relevant merely for postsynaptic plasticity, and not for presynaptic physiology. By means of immunogold electron microscopy and immunocytochemistry, we here demonstrate the presence of ADF (actin depolymerizing factor), a close homolog of n-cofilin, in excitatory synapses, where it is particularly enriched in presynaptic terminals. Surprisingly, genetic ablation of ADF in mice had no adverse effects on synapse structure or density as assessed by electron microscopy and by the morphological analysis of Golgi-stained hippocampal pyramidal cells. Moreover, a series of electrophysiological recordings in acute hippocampal slices revealed that presynaptic recruitment and exocytosis of synaptic vesicles as well as postsynaptic plasticity were unchanged in ADF mutant mice. The lack of synaptic defects may be explained by the elevated n-cofilin levels observed in synaptic structures of ADF mutants. Indeed, synaptic actin regulation was impaired in compound mutants lacking both ADF and n-cofilin, but not in ADF single mutants. From our results we conclude that n-cofilin can compensate for the loss of ADF in excitatory synapses. Further, our data suggest that ADF and n-cofilin cooperate in controlling synaptic actin content

Stringy Instantons and Cascading Quivers

D-brane instantons can perturb the quantum field theories on space-time filling D-branes by interesting operators. In some cases, these D-brane instantons are novel "stringy" effects (not interpretable directly as instanton effects in the low-energy quantum field theory), while in others the D-brane instantons can be directly interpreted as field theory effects. In this note, we describe a situation where both perspectives are available, by studying stringy instantons in quivers which arise at simple Calabi-Yau singularities. We show that a stringy instanton which wraps an unoccupied node of the quiver, and gives rise to a non-perturbative mass in the space-time field theory, can be reinterpreted as a conventional gauge theory effect by going up in an appropriate renormalization group cascade. Interestingly, in the cascade, the contribution of the stringy instanton does not come from gauge theory instantons but from strong coupling dynamics.Comment: 17 pages, 6 figures, harvma

Towards a Realistic Type IIA T^6/Z_4 Orientifold Model with Background Fluxes, Part 1: Moduli Stabilization

We apply the methods of DeWolfe et al. [hep-th/0505160] to a T^6/Z_4 orientifold model. This is the first step in an attempt to build a phenomenologically interesting meta-stable de Sitter model with small cosmological constant and standard model gauge groups.Comment: 1+30 pages, 2 figures, LaTeX, v2: minor corrections, stability analysis of b_a moduli added, refs added, version accepted for publication in JHE

Semiclassical approach to fidelity amplitude

The fidelity amplitude is a quantity of paramount importance in echo type experiments. We use semiclassical theory to study the average fidelity amplitude for quantum chaotic systems under external perturbation. We explain analytically two extreme cases: the random dynamics limit --attained approximately by strongly chaotic systems-- and the random perturbation limit, which shows a Lyapunov decay. Numerical simulations help us bridge the gap between both extreme cases.Comment: 10 pages, 9 figures. Version closest to published versio

Instanton Induced Neutrino Majorana Masses in CFT Orientifolds with MSSM-like spectra

Recently it has been shown that string instanton effects may give rise to neutrino Majorana masses in certain classes of semi-realistic string compactifications. In this paper we make a systematic search for supersymmetric MSSM-like Type II Gepner orientifold constructions admitting boundary states associated with instantons giving rise to neutrino Majorana masses and other L- and/or B-violating operators. We analyze the zero mode structure of D-brane instantons on general type II orientifold compactifications, and show that only instantons with O(1) symmetry can have just the two zero modes required to contribute to the 4d superpotential. We however discuss how the addition of fluxes and/or possible non-perturbative extensions of the orientifold compactifications would allow also instantons with $Sp(2)$ and U(1) symmetries to generate such superpotentials. In the context of Gepner orientifolds with MSSM-like spectra, we find no models with O(1) instantons with just the required zero modes to generate a neutrino mass superpotential. On the other hand we find a number of models in one particular orientifold of the Gepner model $(2,4,22,22)$ with $Sp(2)$ instantons with a few extra uncharged non-chiral zero modes which could be easily lifted by the mentioned effects. A few more orientifold examples are also found under less stringent constraints on the zero modes. This class of $Sp(2)$ instantons have the interesting property that R-parity conservation is automatic and the flavour structure of the neutrino Majorana mass matrices has a simple factorized form.Comment: 68 pages, 2 figures; v2. typos corrected, refs adde