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.
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► A single FG Nup, Nup98, dominates the permeability barrier of vertebrate NPC ► Nup98 FG repeats are highly cohesive and form hydrogels of NPC-like permeability ► Nuclei with engineered NPCs reveal barrier-relevant features of FG repeat domain ► The NPC barrier requires multivalent cohesion between FG repeats
Cohesive FG repeats of Nups interact with one another to form a sieve-like barrier that can be locally disrupted by the binding of nuclear transport receptors, allowing selective passage of cargo, but not inert macromolecules.
A
bstract
We perform a high precision measurement of the static
q
q
¯
potential in three-dimensional SU(
N
) gauge theory with
N
= 2
,
3 and compare the results to the potential obtained from the ...effective string theory. In particular, we show that the exponent of the leading order correction in 1
/R
is 4, as predicted, and obtain accurate results for the continuum limits of the string tension and the non-universal boundary coefficient
b
¯
2
, including an extensive analysis of all types of systematic uncertainties. We find that the magnitude of
b
¯
2
decreases with increasing
N
, leading to the possibility of a vanishing
b
¯
2
in the large
N
limit. In the standard form of the effective string theory possible massive modes and the presence of a rigidity term are usually not considered, even though they might give a contribution to the energy levels. To investigate the effect of these terms, we perform a second analysis, including these contributions. We find that the associated expression for the potential also provides a good description of the data. The resulting continuum values for
b
¯
2
are about a factor of 2 smaller than in the standard analysis, due to contaminations from an additional 1
/R
4
term. However,
b
¯
2
shows a similar decrease in magnitude with increasing
N
. In the course of this extended analysis we also obtain continuum results for the masses appearing in the additional terms and we find that they are around twice as large as the square root of the string tension in the continuum and compatible between SU(2) and SU(3) gauge theory. In the follow up papers we will extend our investigations to the large
N
limit and excited states of the open flux tube.
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.
Summary
Cancer is caused by the accumulation of pathogenic alterations of the genome and epigenome that result in permanent changes that disrupt cellular homeostasis. The genes that become corrupted ...in this process vary among different tumour types, reflecting specific vulnerabilities and dependencies of the cell from which the cancer originated. This also applies to ‘melanoma’, a cancer that constitutes not one, but multiple diseases that can be separated based on their cell of origin, aetiology, clinical appearance and course, and response to treatment. In this article, we review the current classification of melanoma within distinct evolutionary pathways and the associated genetic alterations. In addition, we review the application of molecular diagnostics to the diagnosis of melanocytic tumours in the context of histopathological assessment.
Plain language summary available online
Nuclear pore complexes (NPCs) control the traffic between cell nucleus and cytoplasm. While facilitating translocation of nuclear transport receptors (NTRs) and NTR·cargo complexes, they suppress ...passive passage of macromolecules ⩾30 kDa. Previously, we reconstituted the NPC barrier as hydrogels comprising S. cerevisiae FG domains. We now studied FG domains from 10 Xenopus nucleoporins and found that all of them form hydrogels. Related domains with low FG motif density also substantially contribute to the NPC's hydrogel mass. We characterized all these hydrogels and observed the strictest sieving effect for the Nup98‐derived hydrogel. It fully blocks entry of GFP‐sized inert objects, permits facilitated entry of the small NTR NTF2, but arrests importin β‐type NTRs at its surface. O‐GlcNAc modification of the Nup98 FG domain prevented this arrest and allowed also large NTR·cargo complexes to enter. Solid‐state NMR spectroscopy revealed that the O‐GlcNAc‐modified Nup98 gel lacks amyloid‐like β‐structures that dominate the rigid regions in the S. cerevisiae Nsp1 FG hydrogel. This suggests that FG hydrogels can assemble through different structural principles and yet acquire the same NPC‐like permeability.
The phenylalanine‐glycine (FG) domains of vertebrate nucleoporins assemble into hydrogels with different sieving characteristics for macromolecules. Nup98 forms the tightest filter, which is relieved by O‐linked glycosylation.
Nuclear pore complexes (NPCs) conduct nucleocytoplasmic transport and gain transport selectivity through nucleoporin FG domains. Here, we report a structural analysis of the FG Nup62•58•54 complex, ...which is a crucial component of the transport system. It comprises a ≈13 nanometer-long trimerization interface with an unusual 2W3F coil, a canonical heterotrimeric coiled coil, and a kink that enforces a compact six-helix bundle. Nup54 also contains a ferredoxin-like domain. We further identified a heterotrimeric Nup93-binding module for NPC anchorage. The quaternary structure alternations in the Nup62 complex, which were previously proposed to trigger a general gating of the NPC, are incompatible with the trimer structure. We suggest that the highly elongated Nup62 complex projects barrier-forming FG repeats far into the central NPC channel, supporting a barrier that guards the entire cross section.
Nuclear pore complexes form a gateway between the cytoplasm and the nucleus (see the Perspective by Ullman and Powers). Stuwe et al. combined structural, biochemical, and functional analyses to ...elucidate the architecture of a six-protein complex that makes up the inner ring of the fungal nuclear pore. This includes a central trimeric complex homologous to the Nup62 complex found in metazoans that is incorporated into the nuclear pore inner-ring complex. Chug et al. report the structure of the metazoan trimeric Nup62 complex. Neither study supports a model in which the pore can dilate and constrict. Instead they suggest a rigid pore in which flexible domains called FG repeats fill the channel and form a barrier that can be traversed by receptors that carry cargos across. Science, this issue pp. 56 and 106; see also p. 33 Nuclear pore complexes (NPCs) conduct nucleocytoplasmic transport and gain transport selectivity through nucleoporin FG domains. Here, we report a structural analysis of the FG Nup62*58*54 complex, which is a crucial component of the transport system. It comprises a approximate13 nanometer-long trimerization interface with an unusual 2W3F coil, a canonical heterotrimeric coiled coil, and a kink that enforces a compact six-helix bundle. Nup54 also contains a ferredoxin-like domain. We further identified a heterotrimeric Nup93-binding module for NPC anchorage. The quaternary structure alternations in the Nup62 complex, which were previously proposed to trigger a general gating of the NPC, are incompatible with the trimer structure. We suggest that the highly elongated Nup62 complex projects barrier-forming FG repeats far into the central NPC channel, supporting a barrier that guards the entire cross section.
We compute and analyze correlation functions in the isovector vector channel at vanishing spatial momentum across the deconfinement phase transition in lattice QCD. The simulations are carried out at ...temperatures T/T sub()c0.156, 0.8, 1.0, 1.25 and 1.67 with T sub()cAsympto tically = to 203MeV for two flavors of Wilson-Clover fermions with a zero-temperature pion mass of Asymptotically = to 270MeV. Exploiting exact sum rules and applying a phenomenologically motivated Ansatz allows us to determine the spectral function rho(omega,T) via a fit to the lattice correlation function data. From these results we estimate the electrical conductivity across the deconfinement phase transition via a Kubo formula and find evidence for the dissociation of the rho meson by resolving its spectral weight at the available temperatures. We also apply the Backus-Gilbert method as a model-independent approach to this problem. At any given frequency, it yields a local weighted average of the true spectral function. We use this method to compare kinetic theory predictions and previously published phenomenological spectral functions to our lattice study.
QCD at finite isospin chemical potential Brandt, Bastian B.; Endrődi, Gergely; Schmalzbauer, Sebastian
EPJ Web of Conferences,
01/2018, Letnik:
175
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
We investigate the properties of QCD at finite isospin chemical potential at zero and non-zero temperatures. This theory is not affected by the sign problem and can be simulated using Monte-Carlo ...techniques. With increasing isospin chemical potential and temperatures below the deconfinement transition the system changes into a phase where charged pions condense, accompanied by an accumulation of low modes of the Dirac operator. The simulations are enabled by the introduction of a pionic source into the action, acting as an infrared regulator for the theory, and physical results are obtained by removing the regulator via an extrapolation. We present an update of our study concerning the associated phase diagram using 2+1 flavours of staggered fermions with physical quark masses and the comparison to Taylor expansion. We also present first results for our determination of the equation of state at finite isospin chemical potential and give an example for a cosmological application. The results can also be used to gain information about QCD at small baryon chemical potentials using reweighting with respect to the pionic source parameter and the chemical potential and we present first steps in this direction.
We investigate the possible formation of a Bose-Einstein condensed phase of pions in the early Universe at nonvanishing values of lepton flavor asymmetries. A hadron resonance gas model with pion ...interactions, based on first-principle lattice QCD simulations at nonzero isospin density, is used to evaluate cosmic trajectories at various values of electron, muon, and tau lepton asymmetries that satisfy the available constraints on the total lepton asymmetry. The cosmic trajectory can pass through the pion condensed phase if the combined electron and muon asymmetry is sufficiently large: |l_{e}+l_{μ}|≳0.1, with little sensitivity to the difference l_{e}-l_{μ} between the individual flavor asymmetries. Future constraints on the values of the individual lepton flavor asymmetries will thus be able to either confirm or rule out the condensation of pions during the cosmic QCD epoch. We demonstrate that the pion condensed phase leaves an imprint both on the spectrum of primordial gravitational waves and on the mass distribution of primordial black holes at the QCD scale, e.g., the black hole binary of recent LIGO event GW190521 can be formed in that phase.
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