70 research outputs found
Correcting pervasive errors in RNA crystallography through enumerative structure prediction
Three-dimensional RNA models fitted into crystallographic density maps
exhibit pervasive conformational ambiguities, geometric errors and steric
clashes. To address these problems, we present enumerative real-space
refinement assisted by electron density under Rosetta (ERRASER), coupled to
Python-based hierarchical environment for integrated 'xtallography' (PHENIX)
diffraction-based refinement. On 24 data sets, ERRASER automatically corrects
the majority of MolProbity-assessed errors, improves the average Rfree factor,
resolves functionally important discrepancies in noncanonical structure and
refines low-resolution models to better match higher-resolution models
Metastatic pleomorphic sarcoma to left atrium
Although several thousand patients are diagnosed with sarcoma annually in the United States, metastases to the heart are very uncommon. In this case report, an overall low frequency cancer presents masquerading with common cardiac symptomology. This case illustrates the importance for detailed diagnostic cardiac evaluations and heightened suspicion by physicians to consider metastatic disease to the heart in cancer patients with cardiovascular complications. Also discussed is a review of surgical and chemotherapeutic options for this problem
Four small puzzles that Rosetta doesn't solve
A complete macromolecule modeling package must be able to solve the simplest
structure prediction problems. Despite recent successes in high resolution
structure modeling and design, the Rosetta software suite fares poorly on
deceptively small protein and RNA puzzles, some as small as four residues. To
illustrate these problems, this manuscript presents extensive Rosetta results
for four well-defined test cases: the 20-residue mini-protein Trp cage, an even
smaller disulfide-stabilized conotoxin, the reactive loop of a serine protease
inhibitor, and a UUCG RNA tetraloop. In contrast to previous Rosetta studies,
several lines of evidence indicate that conformational sampling is not the
major bottleneck in modeling these small systems. Instead, approximations and
omissions in the Rosetta all-atom energy function currently preclude
discriminating experimentally observed conformations from de novo models at
atomic resolution. These molecular "puzzles" should serve as useful model
systems for developers wishing to make foundational improvements to this
powerful modeling suite.Comment: Published in PLoS One as a manuscript for the RosettaCon 2010 Special
Collectio
Atomic-accuracy prediction of protein loop structures through an RNA-inspired ansatz
Consistently predicting biopolymer structure at atomic resolution from
sequence alone remains a difficult problem, even for small sub-segments of
large proteins. Such loop prediction challenges, which arise frequently in
comparative modeling and protein design, can become intractable as loop lengths
exceed 10 residues and if surrounding side-chain conformations are erased. This
article introduces a modeling strategy based on a 'stepwise ansatz', recently
developed for RNA modeling, which posits that any realistic all-atom molecular
conformation can be built up by residue-by-residue stepwise enumeration. When
harnessed to a dynamic-programming-like recursion in the Rosetta framework, the
resulting stepwise assembly (SWA) protocol enables enumerative sampling of a 12
residue loop at a significant but achievable cost of thousands of CPU-hours. In
a previously established benchmark, SWA recovers crystallographic conformations
with sub-Angstrom accuracy for 19 of 20 loops, compared to 14 of 20 by KIC
modeling with a comparable expenditure of computational power. Furthermore, SWA
gives high accuracy results on an additional set of 15 loops highlighted in the
biological literature for their irregularity or unusual length. Successes
include cis-Pro touch turns, loops that pass through tunnels of other
side-chains, and loops of lengths up to 24 residues. Remaining problem cases
are traced to inaccuracies in the Rosetta all-atom energy function. In five
additional blind tests, SWA achieves sub-Angstrom accuracy models, including
the first such success in a protein/RNA binding interface, the YbxF/kink-turn
interaction in the fourth RNA-puzzle competition. These results establish
all-atom enumeration as a systematic approach to protein structure that can
leverage high performance computing and physically realistic energy functions
to more consistently achieve atomic resolution.Comment: Identity of four-loop blind test protein and parts of figures 5 have
been omitted in this preprint to ensure confidentiality of the protein
structure prior to its public releas
Testing assumptions for endophenotype studies in ADHD: Reliability and validity of tasks in a general population sample
BACKGROUND: Advances in both genetic and cognitive-experimental studies on attention deficit hyperactivity disorder (ADHD) have opened new opportunities for cognitive endophenotype research. In such genetic designs the focus is on individual differences in characteristics, associated with ADHD, that can be measured reliably over time. Genetic studies that take a 'quantitative trait loci' approach hypothesise that multiple susceptibility genes contribute to a continuous dimension of ADHD symptoms. As an important initial step, we aimed to investigate the underlying assumptions that (1) key cognitive-experimental tasks indicate adequate test-retest reliability and (2) ADHD symptom scores in a general population sample are associated with performance on these tasks. METHODS: Forty-nine children were assessed on a go/no-go task and a reaction time task (the 'fast task') that included manipulations with event rate and incentives. The children were assessed twice, with a test-retest interval of two weeks. RESULTS: The majority of the task variables demonstrated moderate-to-good test-retest reliability. The correlations between teacher ratings of ADHD symptoms and key task variables were .4–.6: ADHD symptoms were associated with poor performance (especially high reaction time variability) in a slow baseline condition, whereas there was low or no association in conditions with a faster event rate or incentives. In contrast, no clear pattern of findings emerged based on parent ratings of ADHD symptoms. CONCLUSION: The data support the usefulness of the go/no-go and fast tasks for genetic studies, which require reliable and valid indices of individual differences. The overall pattern of associations between teacher ratings of ADHD symptoms and task variables is consistent with effects of event rate and incentives on performance, as predicted by the model of activation and arousal regulation. The lack of a clear pattern of findings with parent ratings of ADHD symptoms warrants further study
S100, CD68, and MHC class II molecule expression in cervical high- and low-grade HPV-induced lesions
A new fate for old cells: brush cells and related elements
Over the past 50 years, hundreds of studies have described those cells that are characterized by a brush of rigid apical microvilli with long rootlets, and which are found in the digestive and respiratory apparatuses. These cells have been given names such as brush cells, tuft cells, fibrillovesicular cells, multivesicular cells and caveolated cells. More recently, it has been realized that all these elements may represent a single cell type, probably with a chemosensory role, even if other functions (e.g. secretory or absorptive) seem to be possible. Very recent developments have permitted a partial definition of the chemical code characterizing these elements, revealing the presence of molecules involved in chemoreceptorial cell signalling. A molecular cascade, similar to those characterizing the gustatory epithelium, seems to be present in these elements. These new data suggest that these elements can be considered solitary chemosensory cells with the presence of the apical ‘brush’ as an inconsistent feature. They seem to comprise a diffuse chemosensory system that covers large areas (probably the whole digestive and respiratory apparatuses) with analogies to chemosensory systems described in aquatic vertebrates
- …