1,482 research outputs found
Molecular motion in cell membranes: analytic study of fence-hindered random walks
A theoretical calculation is presented to describe the confined motion of
transmembrane molecules in cell membranes. The study is analytic, based on
Master equations for the probability of the molecules moving as random walkers,
and leads to explicit usable solutions including expressions for the molecular
mean square displacement and effective diffusion constants. One outcome is a
detailed understanding of the dependence of the time variation of the mean
square displacement on the initial placement of the molecule within the
confined region. How to use the calculations is illustrated by extracting
(confinement) compartment sizes from experimentally reported published
observations from single particle tracking experiments on the diffusion of
gold-tagged G-protein coupled mu-opioid receptors in the normal rat kidney cell
membrane, and by further comparing the analytical results to observations on
the diffusion of phospholipids, also in normal rat kidney cells.Comment: 10 pages, 5 figure
Deciphering the folding kinetics of transmembrane helical proteins
Nearly a quarter of genomic sequences and almost half of all receptors that
are likely to be targets for drug design are integral membrane proteins.
Understanding the detailed mechanisms of the folding of membrane proteins is a
largely unsolved, key problem in structural biology. Here, we introduce a
general model and use computer simulations to study the equilibrium properties
and the folding kinetics of a -based two helix bundle fragment
(comprised of 66 amino-acids) of Bacteriorhodopsin. Various intermediates are
identified and their free energy are calculated toghether with the free energy
barrier between them. In 40% of folding trajectories, the folding rate is
considerably increased by the presence of non-obligatory intermediates acting
as traps. In all cases, a substantial portion of the helices is rapidly formed.
This initial stage is followed by a long period of consolidation of the helices
accompanied by their correct packing within the membrane. Our results provide
the framework for understanding the variety of folding pathways of helical
transmembrane proteins
Pion-Lambda-Sigma Coupling Extracted from Hyperonic Atoms
The latest measurements of the atomic level width in Sigma-hyperonic Pb atom
offer the most accurate datum in the region of low-energy Sigma-hyperon
physics. Atomic widths are due to the conversion of Sigma-nucleon into
Lambda-nucleon. In high angular momentum states this conversion is dominated by
the one-pion exchange. A joint analysis of the data of the scattering of
negative-Sigma on proton converting into a Lambda and a neutron and of the
atomic widths allows to extract a pseudovector pion-hyperon-Sigma coupling
constant of 0.048 with a statistical error of +-0.005 and a systematic one of
+-0.004. This corresponds to a pseudoscalar coupling constant of 13.3 with a
statistical uncertainty of 1.4 and a systematic one of 1.1.Comment: 12 pages, 1 figure, Use of Revtex.st
Mammary Gland Development as a Sensitive End Point after Acute Prenatal Exposure to an Atrazine Metabolite Mixture in Female Long-Evans Rats
BACKGROUND: Atrazine (ATR), a widely used chlorotriazine herbicide, inhibits a number of endocrine-dependent processes, including gonadotrophin surges and mammary gland development in rats. Chlorotriazine herbicides are rapidly metabolized in plants and animals to form a group of metabolites that are detected both in the environment and in exposed animals. The extent to which these metabolites are responsible directly for the observed health effects is not understood. OBJECTIVES: Our goal was to determine if a mixture of ATR metabolites, in proportions found in the environment, might produce developmental effects in Long-Evans rats following exposure late in pregnancy. METHODS: We administered an ATR metabolite mixture (AMM) containing ATR, hydroxyatrazine, diaminochlorotriazine, deethylatrazine, and deisopropylatrazine orally to pregnant Long-Evans rats at 0.09, 0.87, or 8.73 mg/kg body weight (bw)/day, on gestation days 15–19, using 0 and 100 mg ATR/kg bw/day as negative and positive controls, respectively. RESULTS: We observed no significant effect of acute AMM exposure on body weight gain in dams during the dosing period, weight loss in pups on postnatal day (PND)4, or pubertal timing, as is seen with ATR alone. However, as with ATR, we detected delayed mammary gland development, evaluated by whole mount analysis, as early as PND4 in all treatment groups. CONCLUSIONS: Our data suggest that acute exposure to AMM at levels as low as 0.09 mg/kg bw during late pregnancy causes persistent alterations in mammary gland development of female offspring, and that these effects do not appear to be related to bw or associated with pubertal timing
Entropic Tension in Crowded Membranes
Unlike their model membrane counterparts, biological membranes are richly
decorated with a heterogeneous assembly of membrane proteins. These proteins
are so tightly packed that their excluded area interactions can alter the free
energy landscape controlling the conformational transitions suffered by such
proteins. For membrane channels, this effect can alter the critical membrane
tension at which they undergo a transition from a closed to an open state, and
therefore influence protein function \emph{in vivo}. Despite their obvious
importance, crowding phenomena in membranes are much less well studied than in
the cytoplasm.
Using statistical mechanics results for hard disk liquids, we show that
crowding induces an entropic tension in the membrane, which influences
transitions that alter the projected area and circumference of a membrane
protein. As a specific case study in this effect, we consider the impact of
crowding on the gating properties of bacterial mechanosensitive membrane
channels, which are thought to confer osmoprotection when these cells are
subjected to osmotic shock. We find that crowding can alter the gating energies
by more than in physiological conditions, a substantial fraction of
the total gating energies in some cases.
Given the ubiquity of membrane crowding, the nonspecific nature of excluded
volume interactions, and the fact that the function of many membrane proteins
involve significant conformational changes, this specific case study highlights
a general aspect in the function of membrane proteins.Comment: 20 pages (inclduing supporting information), 4 figures, to appear in
PLoS Comp. Bio
Localization of Events in Space-Time
The present paper deals with the quantum coordinates of an event in
space-time, individuated by a quantum object. It is known that these
observables cannot be described by self-adjoint operators or by the
corresponding spectral projection-valued measure. We describe them by means of
a positive-operator-valued (POV) measure in the Minkowski space-time,
satisfying a suitable covariance condition with respect to the Poincare' group.
This POV measure determines the probability that a measurement of the
coordinates of the event gives results belonging to a given set in space-time.
We show that this measure must vanish on the vacuum and the one-particle
states, which cannot define any event. We give a general expression for the
Poincare' covariant POV measures. We define the baricentric events, which lie
on the world-line of the centre-of-mass, and we find a simple expression for
the average values of their coordinates. Finally, we discuss the conditions
which permit the determination of the coordinates with an arbitrary accuracy.Comment: 31 pages, latex, no figure
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Geology, hydrology, chemistry, and microbiology of the in situ bioremediation demonstration site
This report summarizes characterization information on the geology, hydrology, microbiology, contaminant distribution, and ground-water chemistry to support demonstration of in situ bioremediation at the Hanford Site. The purpose of this information is to provide baseline conditions, including a conceptual model of the aquifer being utilized for in situ bioremediation. Data were collected from sampling and other characterization activities associated with three wells drilled in the upper part of the suprabasalt aquifer. Results of point-dilution tracer tests, conducted in the upper 9 m (30 ft) of the aquifer, showed that most ground-water flow occurs in the upper part of this zone, which is consistent with hydraulic test results and geologic and geophysical data. Other tracer test results indicated that natural ground-water flow velocity is equal to or less than about 0.03 m/d (0.1 ft/d). Laboratory hydraulic conductivity measurements, which represent the local distribution of vertical hydraulic conductivity, varied up to three orders of magnitude. Based on concentration data from both the vadose and saturated zone, it is suggested that most, if not all, of the carbon tetrachloride detected is representative of the aqueous phase. Concentrations of carbon tetrachloride, associated with a contaminant plume in the 200-West Area, ranged from approximately 500 to 3,800 {mu}g/L in the aqueous phase and from approximately 10 to 290 {mu}g/L in the solid phase at the demonstration site. Carbon tetrachloride gas was detected in the vadose zone, suggesting volatilization and subsequent upward migration from the saturated zone
Structural Basis for Functional Tetramerization of Lentiviral Integrase
Experimental evidence suggests that a tetramer of integrase (IN) is the protagonist of the concerted strand transfer reaction, whereby both ends of retroviral DNA are inserted into a host cell chromosome. Herein we present two crystal structures containing the N-terminal and the catalytic core domains of maedi-visna virus IN in complex with the IN binding domain of the common lentiviral integration co-factor LEDGF. The structures reveal that the dimer-of-dimers architecture of the IN tetramer is stabilized by swapping N-terminal domains between the inner pair of monomers poised to execute catalytic function. Comparison of four independent IN tetramers in our crystal structures elucidate the basis for the closure of the highly flexible dimer-dimer interface, allowing us to model how a pair of active sites become situated for concerted integration. Using a range of complementary approaches, we demonstrate that the dimer-dimer interface is essential for HIV-1 IN tetramerization, concerted integration in vitro, and virus infectivity. Our structures moreover highlight adaptable changes at the interfaces of individual IN dimers that allow divergent lentiviruses to utilize a highly-conserved, common integration co-factor
Correction: Interactions of prototype foamy virus capsids with host cell polo-like kinases are important for efficient viral DNA integration.
[This corrects the article DOI: 10.1371/journal.ppat.1005860.]
Targeting HER proteins in cancer therapy and the role of the non-target HER3
Members of the human epidermal growth factor receptor (HER) family have been of considerable interest in the cancer arena due to their potential to induce tumorigenesis when their signalling functions are deregulated. The constitutive activation of these proteins is seen in a number of different common cancer subtypes, and in particular EGFR and HER2 have become highly pursued targets for anti-cancer drug development. Clinical studies in a number of different cancers known to be driven by EGFR or HER2 show mixed results, and further mechanistic understanding of drug sensitivity and resistance is needed to realise the full potential of this treatment modality. Signalling in trans is a key feature of HER family signalling, and the activation of the PI3K/Akt pathway, so critically important in tumorigenesis, is driven predominantly through phosphorylation in trans of the kinase inactive member HER3. An increasing body of evidence shows that HER3 plays a critical role in EGFR- and HER2-driven tumours. In particular, HER3 lies upstream of a critically important tumorigenic signalling pathway with extensive ability for feedback and cross-talk signalling, and targeting approaches that fail to account for this important trans-target of EGFR and HER2 can be undermined by its resiliency and resourcefulness. Since HER3 is kinase inactive, it is not a direct target of kinase inhibitors and not presently an easily drugable target. This review presents the current evidence highlighting the role of HER3 in tumorigenesis and its role in mediating resistance to inhibitors of EGFR and HER2
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