1,548 research outputs found
phenix.mr_rosetta: molecular replacement and model rebuilding with Phenix and Rosetta.
The combination of algorithms from the structure-modeling field with those of crystallographic structure determination can broaden the range of templates that are useful for structure determination by the method of molecular replacement. Automated tools in phenix.mr_rosetta simplify the application of these combined approaches by integrating Phenix crystallographic algorithms and Rosetta structure-modeling algorithms and by systematically generating and evaluating models with a combination of these methods. The phenix.mr_rosetta algorithms can be used to automatically determine challenging structures. The approaches used in phenix.mr_rosetta are described along with examples that show roles that structure-modeling can play in molecular replacement
A systematic review protocol on the effectiveness of therapeutic exercises utilised by physiotherapists to improve function in patients with burns
Novel Retinoic Acid Receptor Alpha Agonists for Treatment of Kidney Disease
Development of pharmacologic agents that protect podocytes from injury is a critical strategy for the treatment of kidney glomerular diseases. Retinoic acid reduces proteinuria and glomerulosclerosis in multiple animal models of kidney diseases. However, clinical studies are limited because of significant side effects of retinoic acid. Animal studies suggest that all trans retinoic acid (ATRA) attenuates proteinuria by protecting podocytes from injury. The physiological actions of ATRA are mediated by binding to all three isoforms of the nuclear retinoic acid receptors (RARs): RARα, RARβ, and RARγ. We have previously shown that ATRA exerts its renal protective effects mainly through the agonism of RARα. Here, we designed and synthesized a novel boron-containing derivative of the RARα-specific agonist Am580. This new derivative, BD4, binds to RARα receptor specifically and is predicted to have less toxicity based on its structure. We confirmed experimentally that BD4 binds to RARα with a higher affinity and exhibits less cellular toxicity than Am580 and ATRA. BD4 induces the expression of podocyte differentiation markers (synaptopodin, nephrin, and WT-1) in cultured podocytes. Finally, we confirmed that BD4 reduces proteinuria and improves kidney injury in HIV-1 transgenic mice, a model for HIV-associated nephropathy (HIVAN). Mice treated with BD4 did not develop any obvious toxicity or side effect. Our data suggest that BD4 is a novel RARα agonist, which could be used as a potential therapy for patients with kidney disease such as HIVAN
Students and tutors' social representations of assessment in problem-based learning tutorials supporting change
Identification and Characterization of Two Functionally Unknown Genes Involved in Butanol Tolerance of Clostridium acetobutylicum
Solvents toxicity is a major limiting factor hampering the cost-effective biotechnological production of chemicals. In Clostridium acetobutylicum, a functionally unknown protein (encoded by SMB_G1518) with a hypothetical alcohol interacting domain was identified. Disruption of SMB_G1518 and/or its downstream gene SMB_G1519 resulted in increased butanol tolerance, while overexpression of SMB_G1518-1519 decreased butanol tolerance. In addition, SMB_G1518-1519 also influences the production of pyruvate:ferredoxin oxidoreductase (PFOR) and flagellar protein hag, the maintenance of cell motility. We conclude that the system of SMB_G1518-1519 protein plays a role in the butanol sensitivity/tolerance phenotype of C. acetobutylicum, and can be considered as potential targets for engineering alcohol tolerance
A Generalized Allosteric Mechanism for cis-Regulated Cyclic Nucleotide Binding Domains
Cyclic nucleotides (cAMP and cGMP) regulate multiple intracellular processes and are thus of a great general interest for molecular and structural biologists. To study the allosteric mechanism of different cyclic nucleotide binding (CNB) domains, we compared cAMP-bound and cAMP-free structures (PKA, Epac, and two ionic channels) using a new bioinformatics method: local spatial pattern alignment. Our analysis highlights four major conserved structural motifs: 1) the phosphate binding cassette (PBC), which binds the cAMP ribose-phosphate, 2) the “hinge,” a flexible helix, which contacts the PBC, 3) the β2,3 loop, which provides precise positioning of an invariant arginine from the PBC, and 4) a conserved structural element consisting of an N-terminal helix, an eight residue loop and the A-helix (N3A-motif). The PBC and the hinge were included in the previously reported allosteric model, whereas the definition of the β2,3 loop and the N3A-motif as conserved elements is novel. The N3A-motif is found in all cis-regulated CNB domains, and we present a model for an allosteric mechanism in these domains. Catabolite gene activator protein (CAP) represents a trans-regulated CNB domain family: it does not contain the N3A-motif, and its long range allosteric interactions are substantially different from the cis-regulated CNB domains
MicroRNAs in pulmonary arterial remodeling
Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH
Multifractal tubes
Tube formulas refer to the study of volumes of neighbourhoods of sets.
For sets satisfying some (possible very weak) convexity conditions, this has a
long history. However, within the past 20 years Lapidus has initiated and
pioneered a systematic study of tube formulas for fractal sets. Following this,
it is natural to ask to what extend it is possible to develop a theory of
multifractal tube formulas for multifractal measures. In this paper we propose
and develop a framework for such a theory. Firstly, we define multifractal tube
formulas and, more generally, multifractal tube measures for general
multifractal measures. Secondly, we introduce and develop two approaches for
analysing these concepts for self-similar multifractal measures, namely:
(1) Multifractal tubes of self-similar measures and renewal theory. Using
techniques from renewal theory we give a complete description of the asymptotic
behaviour of the multifractal tube formulas and tube measures of self-similar
measures satisfying the Open Set Condition.
(2) Multifractal tubes of self-similar measures and zeta-functions.
Unfortunately, renewal theory techniques do not yield "explicit" expressions
for the functions describing the asymptotic behaviour of the multifractal tube
formulas and tube measures of self-similar measures. This is clearly
undesirable. For this reason, we introduce and develop a second framework for
studying multifractal tube formulas of self-similar measures. This approach is
based on multifractal zeta-functions and allow us obtain "explicit" expressions
for the multifractal tube formulas of self-similar measures, namely, using the
Mellin transform and the residue theorem, we are able to express the
multifractal tube formulas as sums involving the residues of the zeta-function.Comment: 122 page
Multiplicity Distributions and Charged-neutral Fluctuations
Results from the multiplicity distributions of inclusive photons and charged
particles, scaling of particle multiplicities, event-by-event multiplicity
fluctuations, and charged-neutral fluctuations in 158 GeV Pb+Pb
collisions are presented and discussed. A scaling of charged particle
multiplicity as and photons as have been observed, indicating violation of naive wounded nucleon model.
The analysis of localized charged-neutral fluctuation indicates a
model-independent demonstration of non-statistical fluctuations in both charged
particles and photons in limited azimuthal regions. However, no correlated
charged-neutral fluctuations are observed.Comment: Talk given at the International Symposium on Nuclear Physics
(ISNP-2000), Mumbai, India, 18-22 Dec 2000, Proceedings to be published in
Pramana, Journal of Physic
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