424 research outputs found
Evidence for an evolutionary relationship between the large adaptor nucleoporin Nup192 and karyopherins
Nucleocytoplasmic transport is facilitated by nuclear pore complexes (NPCs), which are massive proteinaceous transport channels embedded in the nuclear envelope. Nup192 is a major component of an adaptor nucleoporin subcomplex proposed to link the NPC coat with the central transport channel. Here, we present the structure of the âŒ110-kDa N-terminal domain (NTD) of Nup192 at 2.7-Ă
resolution. The structure reveals an open ring-shaped architecture composed of Huntingtin, EF3, PP2A, and TOR1 (HEAT) and Armadillo (ARM) repeats. A comparison of different conformations indicates that the NTD consists of two rigid halves connected by a flexible hinge. Unexpectedly, the two halves of the ring are structurally related to karyopherin-α (Kap-α) and ÎČ-karyopherin family members. Biochemically, we identify a conserved patch that binds an unstructured segment in Nup53 and show that a C-terminal tail region binds to a putative helical fragment in Nic96. The Nup53 segment that binds Nup192 is a classical nuclear localization-like sequence that interacts with Kap-α in a mutually exclusive and mechanistically distinct manner. The disruption of the Nup53 and Nic96 binding sites in vivo yields growth and mRNA export defects, revealing their critical role in proper NPC function. Surprisingly, both interactions are dispensable for NPC localization, suggesting that Nup192 possesses another nucleoporin interaction partner. These data indicate that the structured domains in the adaptor nucleoporin complex are held together by peptide interactions that resemble those found in karyopherinâącargo complexes and support the proposal that the adaptor nucleoporins arose from ancestral karyopherins
Are the Psychophysical Laws Fine-Tuned?
Neil Sinhababu (2017) has recently argued against the fine-tuning argument for God. They claim that the question of the universeâs fine-tuning ought not be âwhy is the universe so hospitable to life?â but rather âwhy is the universe so hospitable to morally valuable minds?â and that, moreover, the universe isnât so hospitable. For it is metaphysically possible that psychophysical laws be substantially more permissive than they in fact are, allowing for the realisation of morally valuable consciousness by exceptionally simple physical states and systems, rather than the complex states of brains. I reply that Sinhababuâs argument rests upon unsupported claims and that we have reason to doubt that an omnibenevolent God would make the psychophysical laws more permissive than they in fact are
Structural and Functional Characterization of the α-Tubulin Acetyltransferase MEC-17
Tubulin protomers undergo an extensive array of post-translational modifications to tailor microtubules to specific tasks. One such modification, the acetylation of lysine-40 of α-tubulin, located in the lumen of microtubules, is associated with stable, long-living microtubule structures. MEC-17 was recently identified as the acetyltransferase that mediates this event. We have determined the crystal structure of the catalytic core of human MEC-17 in complex with its cofactor acetyl-CoA at 1.7 Ă
resolution. The structure reveals that the MEC-17 core adopts a canonical Gcn5-related N-acetyltransferase (GNAT) fold that is decorated with extensive surface loops. An enzymatic analysis of 33 MEC-17 surface mutants identifies hot-spot residues for catalysis and substrate recognition. A large, evolutionarily conserved hydrophobic surface patch is identified that is critical for enzymatic activity, suggesting that specificity is achieved by interactions with the α-tubulin substrate that extend outside of the modified surface loop. An analysis of MEC-17 mutants in C. elegans shows that enzymatic activity is dispensable for touch sensitivity
KELT-1b: A Strongly Irradiated, Highly Inflated, Short Period, 27 Jupiter-mass Companion Transiting a mid-F Star
We present the discovery of KELT-1b, the first transiting low-mass companion
from the wide-field Kilodegree Extremely Little Telescope-North (KELT-North)
survey. The V=10.7 primary is a mildly evolved, solar-metallicity, mid-F star.
The companion is a low-mass brown dwarf or super-massive planet with mass of
27.23+/-0.50 MJ and radius of 1.110+0.037-0.024 RJ, on a very short period
(P=1.21750007) circular orbit. KELT-1b receives a large amount of stellar
insolation, with an equilibrium temperature assuming zero albedo and perfect
redistribution of 2422 K. Upper limits on the secondary eclipse depth indicate
that either the companion must have a non-zero albedo, or it must experience
some energy redistribution. Comparison with standard evolutionary models for
brown dwarfs suggests that the radius of KELT-1b is significantly inflated.
Adaptive optics imaging reveals a candidate stellar companion to KELT-1, which
is consistent with an M dwarf if bound. The projected spin-orbit alignment
angle is consistent with zero stellar obliquity, and the vsini of the primary
is consistent with tidal synchronization. Given the extreme parameters of the
KELT-1 system, we expect it to provide an important testbed for theories of the
emplacement and evolution of short-period companions, and theories of tidal
dissipation and irradiated brown dwarf atmospheres.Comment: 30 pages, 19 figures. Submitted to Ap
KELT-2Ab: A Hot Jupiter Transiting the Bright (V=8.77) Primary Star of a Binary System
We report the discovery of KELT-2Ab, a hot Jupiter transiting the bright
(V=8.77) primary star of the HD 42176 binary system. The host is a slightly
evolved late F-star likely in the very short-lived "blue-hook" stage of
evolution, with \teff=6148\pm48{\rm K}, and
\feh=0.034\pm0.78. The inferred stellar mass is
\msun\ and the star has a relatively large radius
of \rsun. The planet is a typical hot Jupiter with
period days and a mass of \mj\ and
radius of \rj. This is mildly inflated as compared
to models of irradiated giant planets at the 4 Gyr age of the system.
KELT-2A is the third brightest star with a transiting planet identified by
ground-based transit surveys, and the ninth brightest star overall with a
transiting planet. KELT-2Ab's mass and radius are unique among the subset of
planets with host stars, and therefore increases the diversity of bright
benchmark systems. We also measure the relative motion of KELT-2A and -2B over
a baseline of 38 years, robustly demonstrating for the first time that the
stars are bound. This allows us to infer that KELT-2B is an early K-dwarf. We
hypothesize that through the eccentric Kozai mechanism KELT-2B may have
emplaced KELT-2Ab in its current orbit. This scenario is potentially testable
with Rossiter-McLaughlin measurements, which should have an amplitude of
44 m s.Comment: 9 pages, 2 tables, 4 figures. A short video describing this paper is
available at http://www.youtube.com/watch?v=wVS8lnkXXlE. Revised to reflect
the ApJL version. Note that figure 4 is not in the ApJL versio
Architecture of the fungal nuclear pore inner ring complex
The nuclear pore complex (NPC) constitutes the sole gateway for bidirectional nucleocytoplasmic transport. We present the reconstitution and interdisciplinary analyses of the ~425-kDa inner ring complex (IRC), which forms the central transport channel and diffusion barrier of the NPC, revealing its interaction network and equimolar stoichiometry. The Nsp1âąNup49âąNup57 channel nucleoporin hetero-trimer (CNT) attaches to the IRC solely through the adaptor nucleoporin Nic96. The CNTâąNic96 structure reveals that Nic96 functions as an assembly sensor that recognizes the three dimensional architecture of the CNT, thereby mediating the incorporation of a defined CNT state into the NPC. We propose that the IRC adopts a relatively rigid scaffold that recruits the CNT to primarily form the diffusion barrier of the NPC, rather than enabling channel dilation
Everolimus for patients with mantle cell lymphoma refractory to or intolerant of bortezomib: multicentre, singleâarm, phase 2 study
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106815/1/bjh12780.pd
Direct measurement of the pion valence quark momentum distribution, the pion light-cone wave function squared
We present the first direct measurements of the pion valence quark momentum
distribution which is related to the square of the pion light-cone wave
function. The measurements were carried out using data on diffractive
dissociation of 500 GeV/c into di-jets from a platinum target at
Fermilab experiment E791. The results show that the light-cone
asymptotic wave function, which was developed using perturbative QCD methods,
describes the data well for or more. We also
measured the transverse momentum distribution of the diffractive di-jets.Comment: 13 pages, 4 figure
Anti-cancer effects and mechanism of actions of aspirin analogues in the treatment of glioma cancer
INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-ÎșB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS â 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma
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