673 research outputs found
Smoothing a rugged protein folding landscape by sequence-based redesign
The rugged folding landscapes of functional proteins puts them at risk of misfolding and aggregation. Serine protease inhibitors, or serpins, are paradigms for this delicate balance between function and misfolding. Serpins exist in a metastable state that undergoes a major conformational change in order to inhibit proteases. However, conformational labiality of the native serpin fold renders them susceptible to misfolding, which underlies misfolding diseases such as -antitrypsin deficiency. To investigate how serpins balance function and folding, we used consensus design to create , a synthetic serpin that folds reversibly, is functional, thermostable, and polymerization resistant. Characterization of its structure, folding and dynamics suggest that consensus design has remodeled the folding landscape to reconcile competing requirements for stability and function. This approach may offer general benefits for engineering functional proteins that have risky folding landscapes, including the removal of aggregation-prone intermediates, and modifying scaffolds for use as protein therapeutics.BTP is a Medical Research Council Career Development Fellow. AAN and JJH are supported by the Wellcome Trust (grant number WT 095195). SM acknowledges fellowship support from the Australian Research Council (FT100100960). NAB is an Australian Research Council Future Fellow (110100223). GIW is an Australian Research Council Discovery Outstanding Researcher Award Fellow (DP140100087). AMB is a National Health and Medical Research Senior Research Fellow (1022688). JCW is an NHMRC Senior Principal Research fellow and also acknowledges the support of an ARC Federation Fellowship. We thank the Australian Synchrotron for beam-time and technical assistance. This work was supported by the Multi-modal Australian ScienceS Imaging and Visualisation Environment (MASSIVE) (www.massive.org.au). We acknowledge the Monash Protein Production Unit and Monash Macromolecular Crystallization Facilit
Smoothing a rugged protein folding landscape by sequence-based redesign
The rugged folding landscapes of functional proteins puts them at risk of misfolding and aggregation.
Serine protease inhibitors, or serpins, are paradigms for this delicate balance between function and
misfolding. Serpins exist in a metastable state that undergoes a major conformational change in
order to inhibit proteases. However, conformational labiality of the native serpin fold renders them
susceptible to misfolding, which underlies misfolding diseases such as α1-antitrypsin deficiency. To
investigate how serpins balance function and folding, we used consensus design to create conserpin,
a synthetic serpin that folds reversibly, is functional, thermostable, and polymerization resistant.
Characterization of its structure, folding and dynamics suggest that consensus design has remodeled
the folding landscape to reconcile competing requirements for stability and function. This approach
may offer general benefits for engineering functional proteins that have risky folding landscapes,
including the removal of aggregation-prone intermediates, and modifying scaffolds for use as protein
therapeutics
Lesion detection in demoscopy images with novel density-based and active contour approaches
<p>Abstract</p> <p>Background</p> <p>Dermoscopy is one of the major imaging modalities used in the diagnosis of melanoma and other pigmented skin lesions. Automated assessment tools for dermoscopy images have become an important field of research mainly because of inter- and intra-observer variations in human interpretation. One of the most important steps in dermoscopy image analysis is the detection of lesion borders, since many other features, such as asymmetry, border irregularity, and abrupt border cutoff, rely on the boundary of the lesion. </p> <p>Results</p> <p>To automate the process of delineating the lesions, we employed Active Contour Model (ACM) and boundary-driven density-based clustering (BD-DBSCAN) algorithms on 50 dermoscopy images, which also have ground truths to be used for quantitative comparison. We have observed that ACM and BD-DBSCAN have the same border error of 6.6% on all images. To address noisy images, BD-DBSCAN can perform better delineation than ACM. However, when used with optimum parameters, ACM outperforms BD-DBSCAN, since ACM has a higher recall ratio.</p> <p>Conclusion</p> <p>We successfully proposed two new frameworks to delineate suspicious lesions with i) an ACM integrated approach with sharpening and ii) a fast boundary-driven density-based clustering technique. ACM shrinks a curve toward the boundary of the lesion. To guide the evolution, the model employs the exact solution <abbrgrp><abbr bid="B27">27</abbr></abbrgrp> of a specific form of the Geometric Heat Partial Differential Equation <abbrgrp><abbr bid="B28">28</abbr></abbrgrp>. To make ACM advance through noisy images, an improvement of the model’s boundary condition is under consideration. BD-DBSCAN improves regular density-based algorithm to select query points intelligently.</p
Lamin A/C truncation in dilated cardiomyopathy with conduction disease
BACKGROUND: Mutations in the gene encoding the nuclear membrane protein lamin A/C have been associated with at least 7 distinct diseases including autosomal dominant dilated cardiomyopathy with conduction system disease, autosomal dominant and recessive Emery Dreifuss Muscular Dystrophy, limb girdle muscular dystrophy type 1B, autosomal recessive type 2 Charcot Marie Tooth, mandibuloacral dysplasia, familial partial lipodystrophy and Hutchinson-Gilford progeria. METHODS: We used mutation detection to evaluate the lamin A/C gene in a 45 year-old woman with familial dilated cardiomyopathy and conduction system disease whose family has been well characterized for this phenotype [1]. RESULTS: DNA from the proband was analyzed, and a novel 2 base-pair deletion c.908_909delCT in LMNA was identified. CONCLUSIONS: Mutations in the gene encoding lamin A/C can lead to significant cardiac conduction system disease that can be successfully treated with pacemakers and/or defibrillators. Genetic screening can help assess risk for arrhythmia and need for device implantation
Observation of the Charmed Baryon at CLEO
The CLEO experiment at the CESR collider has used 13.7 fb of data to
search for the production of the (css-ground state) in
collisions at {\rm GeV}. The modes used to
study the are ,
, , , and
. We observe a signal of 40.49.0(stat) events
at a mass of 2694.62.6(stat)1.9(syst) {\rm MeV/}, for all modes
combined.Comment: 10 pages postscript, also available through
http://w4.lns.cornell.edu/public/CLN
Measurement of the Relative Branching Fraction of to Charged and Neutral B-Meson Pairs
We analyze 9.7 x 10^6 B\bar{B}$ pairs recorded with the CLEO detector to
determine the production ratio of charged to neutral B-meson pairs produced at
the Y(4S) resonance. We measure the rates for B^0 -> J/psi K^{(*)0} and B^+ ->
J/psi K^{(*)+} decays and use the world-average B-meson lifetime ratio to
extract the relative widths f+-/f00 = Gamma(Y(4S) -> B+B-)/Gamma(Y(4S) ->
B0\bar{B0}) = = 1.04 +/- 0.07(stat) +/- 0.04(syst). With the assumption that
f+- + f00 = 1, we obtain f00 = 0.49 +/- 0.02(stat) +/- 0.01(syst) and f+- =
0.51 +/- 0.02(stat) +/- 0.01(syst). This production ratio and its uncertainty
apply to all exclusive B-meson branching fractions measured at the Y(4S)
resonance.Comment: 11 pages postscript, also available through
http://w4.lns.cornell.edu/public/CLN
First Observation of the Decays and B^{0}\to D^{*-}p\bar{n}$
We report the first observation of exclusive decays of the type B to D^* N
anti-N X, where N is a nucleon. Using a sample of 9.7 times 10^{6} B-Bbar pairs
collected with the CLEO detector operating at the Cornell Electron Storage
Ring, we measure the branching fractions B(B^0 \to D^{*-} proton antiproton
\pi^+) = ({6.5}^{+1.3}_{-1.2} +- 1.0) \times 10^{-4} and B(B^0 \to D^{*-}
proton antineutron) = ({14.5}^{+3.4}_{-3.0} +- 2.7) times 10^{-4}. Antineutrons
are identified by their annihilation in the CsI electromagnetic calorimeter.Comment: 9 pages postscript, also available through
http://w4.lns.cornell.edu/public/CLN
Study of the Decays B0 --> D(*)+D(*)-
The decays B0 --> D*+D*-, B0 --> D*+D- and B0 --> D+D- are studied in 9.7
million Y(4S) --> BBbar decays accumulated with the CLEO detector. We determine
Br(B0 --> D*+D*-) = (9.9+4.2-3.3+-1.2)e-4 and limit Br(B0 --> D*+D-) < 6.3e-4
and Br(B0 --> D+D-) < 9.4e-4 at 90% confidence level (CL). We also perform the
first angular analysis of the B0 --> D*+D*- decay and determine that the
CP-even fraction of the final state is greater than 0.11 at 90% CL. Future
measurements of the time dependence of these decays may be useful for the
investigation of CP violation in neutral B meson decays.Comment: 21 pages, 5 figures, submitted to Phys. Rev.
A Search for
We report results of a search for in a sample of 9.7 million
charged meson decays. The search uses both and
decay modes of the , and demands exclusive reconstruction of the
companion decay to suppress background. We set an upper limit on the
branching fraction at 90%
confidence level. With slight modification to the analysis we also establish
at 90% confidence
level.Comment: 10 ages postscript, also available through
http://w4.lns.cornell.edu/public/CLN
Measurements of B --> D_s^{(*)+} D^{*(*)} Branching Fractions
This article describes improved measurements by CLEO of the and branching fractions, and first evidence
for the decay , where
represents the sum of the , , and
L=1 charm meson states. Also reported is the first
measurement of the polarization in the decay . A partial reconstruction technique, employing only the fully
reconstructed and slow pion from the decay, enhances sensitivity. The observed branching fractions are
, , and , where the first error is statistical,
the second systematic, and the third is due to the uncertainty in the branching fraction. The measured longitudinal
polarization, , is consistent with
the factorization prediction of 54%.Comment: 26 pages (LaTeX), 15 figures. To be submitted to PR
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