5,896 research outputs found
Targeting Specific PDZ Domains of PSD-95 Structural Basis for Enhanced Affinity and Enzymatic Stability of a Cyclic Peptide
AbstractA cyclic peptide, Tyr-Lys-c[-Lys-Thr-Glu(βAla)-]-Val, incorporating a β-Ala lactam side chain linker and designed to target the PDZ domains of the postsynaptic density protein 95 (PSD-95), has been synthesized and structurally characterized by NMR while free and bound to the PDZ1 domain of PSD-95. While bound, the lactam linker of the peptide makes a number of unique contacts outside the canonical PDZ binding motif, providing a novel target for PDZ-domain specificity as well as producing a 10-fold enhancement in binding affinity. Additionally, the cyclization greatly enhances the enzymatic stability, increasing the duration that the peptide inhibits the association between PSD-95 and glutamate receptors, effectively inhibiting the clustering of kainate receptors for over 14 hr after application. Highly specific regulation of kainate receptor action may provide a novel route for treatment of drug addiction and epilepsy
The Sloan Digital Sky Survey Reverberation Mapping Project: No Evidence for Evolution in the M-sigma Relation to z~1
We present host stellar velocity dispersion measurements for a sample of 88
broad-line quasars at 0.10.6) from the Sloan Digital Sky Survey
Reverberation Mapping (SDSS-RM) project. High signal-to-noise ratio coadded
spectra (average S/N~30 per 69 km/s pixel) from SDSS-RM allowed decomposition
of the host and quasar spectra, and measurement of the host stellar velocity
dispersions and black hole (BH) masses using the single-epoch (SE) virial
method. The large sample size and dynamic range in luminosity
(L5100=10^(43.2-44.7) erg/s) lead to the first clear detection of a correlation
between SE virial BH mass and host stellar velocity dispersion far beyond the
local universe. However, the observed correlation is significantly flatter than
the local relation, suggesting that there are selection biases in high-z
luminosity-threshold quasar samples for such studies. Our uniform sample and
analysis enable an investigation of the redshift evolution of the M-sigma
relation free of caveats by comparing different samples/analyses at disjoint
redshifts. We do not observe evolution of the M-sigma relation in our sample,
up to z~1, but there is an indication that the relation flattens towards higher
redshifts. Coupled with the increasing threshold luminosity with redshift in
our sample, this again suggests certain selection biases are at work, and
simple simulations demonstrate that a constant M-sigma relation is favored to
z~1. Our results highlight the scientific potential of deep coadded
spectroscopy from quasar monitoring programs, and offer a new path to probe the
co-evolution of BHs and galaxies at earlier times.Comment: replaced with the accepted version (minor changes and updated
references); ApJ in press; changed title to highlight the main resul
Characterization Of Commercial Magnetorheological Fluids At High Shear Rate: Influence Of The Gap
This paper reports the experimental tests on the behaviour of a commercial MR fluid at high shear rates and the effect of the gap. Three gaps were considered at multiple magnetic fields and shear rates. From an extended set of almost two hundred experimental flow curves, a set of parameters for the apparent viscosity are retrieved by using the Ostwald de Waele model for non-Newtonian fluids. It is possible to simplify the parameter correlation by making the following considerations: the consistency of the model depends only on the magnetic field, the flow index depends on the fluid type and the gap shows an important effect only at null or very low magnetic fields. This lead to a simple and useful model, especially in the design phase of a MR based product. During the off state, with no applied field, it is possible to use a standard viscous model. During the active state, with high magnetic field, a strong non-Newtonian nature becomes prevalent over the viscous one even at very high shear rate; the magnetic field dominates the apparent viscosity change, while the gap does not play any relevant role on the system behaviour. This simple assumption allows the designer to dimension the gap only considering the non-active state, as in standard viscous systems, and taking into account only the magnetic effect in the active state, where the gap does not change the proposed fluid model
Sterically Induced Binding Selectivity of Single m-Terphenyl Isocyanide Ligands
Sterically encumbering m-terphenyl isocyanides are a class of metal-binding
group that foster low-coordinate metal-center environments in coordination
chemistry by exerting considerable intermolecular steric pressures between
neighboring ligands. In the context of metal surfaces, the encumbering steric
properties of the m-terphenyl isocyanides are shown to weaken the interaction
between the metal-binding group and a planar substrate, leading to a preference
for molecular adsorption at sites with convex curvature, such as the step edges
and herringbone elbow sites on Au(111). Here, we investigate the site-selective
binding of individual m-terphenyl isocyanide ligands on a Au(111) surface
through scanning tunneling microscopy (STM) and inelastic electron tunneling
spectroscopy (IETS). The site-dependent steric pressure alters the vibrational
fingerprint of the m-terphenyl isocyanides, which is characterized with
single-molecule precision through joint experimental and theoretical
approaches. This study for the first time provides molecular-level insights
into the steric-pressure-enabled surface binding selectivity as well as its
effect on the chemical properties of individual m-terphenyl isocyanide ligands,
thereby highlighting the potential to control the physical and chemical
properties of metal surfaces through tailored ligand design
XRCC4 deficiency in human subjects causes a marked neurological phenotype but no overt immunodeficiency
Background
Nonhomologous end-joining (NHEJ) is the major DNA double-strand break (DSB) repair mechanism in human cells. The final rejoining step requires DNA ligase IV (LIG4) together with the partner proteins X-ray repair cross-complementing protein 4 (XRCC4) and XRCC4-like factor. Patients with mutations in genes encoding LIG4, XRCC4-like factor, or the other NHEJ proteins DNA-dependent protein kinase catalytic subunit and Artemis are DSB repair defective and immunodeficient because of the requirement for NHEJ during V(D)J recombination.
Objective
We found a patient displaying microcephaly and progressive ataxia but a normal immune response. We sought to determine pathogenic mutations and to describe the molecular pathogenesis of the patient.
Methods
We performed next-generation exome sequencing. We evaluated the DSB repair activities and V(D)J recombination capacity of the patient's cells, as well as performing a standard blood immunologic characterization.
Results
We identified causal mutations in the XRCC4 gene. The patient's cells are radiosensitive and display the most severe DSB repair defect we have encountered using patient-derived cell lines. In marked contrast, a V(D)J recombination plasmid assay revealed that the patient's cells did not display the junction abnormalities that are characteristic of other NHEJ-defective cell lines. The mutant protein can interact efficiently with LIG4 and functions normally in in vitro assays and when transiently expressed in vivo. However, the mutation makes the protein unstable, and it undergoes proteasome-mediated degradation.
Conclusion
Our findings reveal a novel separation of impact phenotype: there is a pronounced DSB repair defect and marked clinical neurological manifestation but no clinical immunodeficiency
Proteomic analysis of the Plasmodium male gamete reveals the key role for glycolysis in flagellar motility.
BACKGROUND: Gametogenesis and fertilization play crucial roles in malaria transmission. While male gametes are thought to be amongst the simplest eukaryotic cells and are proven targets of transmission blocking immunity, little is known about their molecular organization. For example, the pathway of energy metabolism that power motility, a feature that facilitates gamete encounter and fertilization, is unknown.
METHODS: Plasmodium berghei microgametes were purified and analysed by whole-cell proteomic analysis for the first time. Data are available via ProteomeXchange with identifier PXD001163.
RESULTS: 615 proteins were recovered, they included all male gamete proteins described thus far. Amongst them were the 11 enzymes of the glycolytic pathway. The hexose transporter was localized to the gamete plasma membrane and it was shown that microgamete motility can be suppressed effectively by inhibitors of this transporter and of the glycolytic pathway.
CONCLUSIONS: This study describes the first whole-cell proteomic analysis of the malaria male gamete. It identifies glycolysis as the likely exclusive source of energy for flagellar beat, and provides new insights in original features of Plasmodium flagellar organization
Changes in reflectin protein phosphorylation are associated with dynamic iridescence in squid
Author Posting. Š The Author(s), 2009. This is the author's version of the work. It is posted here by permission of The Royal Society for personal use, not for redistribution. The definitive version was published in Journal of The Royal Society Interface 6 (2010): 549-560, doi:10.1098/rsif.2009.0299.Many cephalopods exhibit remarkable dermal iridescence, a component of their complex,
dynamic camouflage and communication. In the species Euprymna scolopes, the light-organ iridescence
is static and is due to reflectin protein-based platelets assembled into lamellar thin-film
reflectors called iridosomes, contained within iridescent cells called iridocytes. Squid in the
family Loliginidae appear to be unique in that the dermis possesses a dynamic iridescent component,
with reflective, colored structures that are assembled and disassembled under the control of
the muscarinic cholinergic system and the associated neurotransmitter acetylcholine (Mathger et
al. 2004). Here we present the sequences and characterization of three new members of the reflectin
family associated with the dynamically changeable iridescence in Loligo and not found in
static Euprymna iridophores. In addition, we show that application of genistein, a protein tyrosine
kinase inhibitor, suppresses acetylcholine- and calcium-induced iridescence in Loligo. We
further demonstrate that two of these novel reflectins are extensively phosphorylated in concert
with the activation of iridescence by exogenous acetylcholine. This phosphorylation and the correlated
iridescence can be blocked with genistein. Our results suggest that tyrosine phosphorylation
of reflectin proteins is involved in the regulation of dynamic iridescence in Loligo.We gratefully acknowledge support from Anteon contract F33615-03-D-5408 to the Marine
Biological Laboratory, Woods Hole, MA and grant # W911NF-06-1-0285 from the Army
Research Office to D.E.M
Search for the standard model Higgs boson in the H to ZZ to 2l 2nu channel in pp collisions at sqrt(s) = 7 TeV
A search for the standard model Higgs boson in the H to ZZ to 2l 2nu decay
channel, where l = e or mu, in pp collisions at a center-of-mass energy of 7
TeV is presented. The data were collected at the LHC, with the CMS detector,
and correspond to an integrated luminosity of 4.6 inverse femtobarns. No
significant excess is observed above the background expectation, and upper
limits are set on the Higgs boson production cross section. The presence of the
standard model Higgs boson with a mass in the 270-440 GeV range is excluded at
95% confidence level.Comment: Submitted to JHE
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