Cleaning Study of Genesis Sample 60487

The Genesis mission collected solar wind and brought it back to Earth in order to provide precise knowledge of solar isotopic and elemental compositions. The ions in the solar wind were stopped in the collectors at depths on the order of 10 to a few hundred nanometers. This shallow implantation layer is critical for scientific analysis of the composition of the solar wind and must be preserved throughout sample handling, cleaning, processing, distribution, preparation and analysis. Particles of Genesis wafers, brine from the Utah Testing Range and an organic film have deleterious effects on many of the high-resolution instruments that have been developed to analyze the implanted solar wind. We have conducted a correlative microscopic study of the efficacy of cleaning Genesis samples with megasonically activated ultrapure water and UV/ozone cleaning. Sample 60487, the study sample, is a piece of float-zone silicon from the B/C array approximately 4.995mm x 4.145 mm in siz

Catastrophic Impact of Silicon on Silicon: Unraveling the Genesis Impact Using Sample 61881

The Genesis mission collected solar wind and brought it back to Earth in order to provide precise knowledge of solar isotopic and elemental compositions. The ions in the solar wind were stopped in the collectors at depths on the order of 10 to a few hundred nanometers. This shallow implantation layer is critical for scientific analysis of the composition of the solar wind and must be preserved throughout sample handling, cleaning, processing, distribution, preparation and analysis. The current work is motivated by the need to understand the interaction of the Genesis payload with contamination during the crash in the Utah desert. Silicon contamination has been found to be notoriously difficult to remove from silicon samples despite multiple cleanings with multiple techniques. However, the question has been posed, "Does the silicon really need to be removed for large area analyses?." If the recalcitrant silicon contamination is all pure silicon from fractured collectors, only a very tiny fraction of that bulk material will contain solar wind, which could skew the analyses. This could be complicated if the silicon trapped other materials and/or gases as it impacted the surface

Don't Stop Thinking About Leptoquarks: Constructing New Models

We discuss the general framework for the construction of new models containing a single, fermion number zero scalar leptoquark of mass $\simeq 200-220$ GeV which can both satisfy the D0/CDF search constraints as well as low energy data, and can lead to both neutral and charged current-like final states at HERA. The class of models of this kind necessarily contain new vector-like fermions with masses at the TeV scale which mix with those of the Standard Model after symmetry breaking. In this paper we classify all models of this type and examine their phenomenological implications as well as their potential embedding into SUSY and non-SUSY GUT scenarios. The general coupling parameter space allowed by low energy as well as collider data for these models is described and requires no fine-tuning of the parameters.Comment: Modified text, added table, and updated reference

Reversed halo sign in pneumocystis pneumonia: a case report

<p>Abstract</p> <p>Background</p> <p>The reversed halo sign may sometimes be seen in patients with cryptogenic organizing pneumonia, but is rarely associated with other diseases.</p> <p>Case presentation</p> <p>We present a case study of a 32-year-old male patient with acquired immunodeficiency syndrome, who had previously been treated with chemotherapy for non-Hodgkin's lymphoma. A chest X-ray showed bilateral patchy infiltrates. High-resolution computed tomography revealed the reversed halo sign in both upper lobes. The patient was diagnosed with pneumocystis pneumonia, which was successfully treated with sulfamethoxazole trimethoprim; the reversed halo sign disappeared, leaving cystic lesions. Cases such as this one are rare, but show that the reversed halo sign may occur in patients who do not have cryptogenic organizing pneumonia.</p> <p>Conclusion</p> <p>Physicians can avoid making an incorrect diagnosis and prescribing the wrong treatment by carefully evaluating all clinical criteria rather than assuming that the reversed halo sign only occurs with cryptogenic organizing pneumonia.</p

Effect of promoter architecture on the cell-to-cell variability in gene expression

According to recent experimental evidence, the architecture of a promoter, defined as the number, strength and regulatory role of the operators that control the promoter, plays a major role in determining the level of cell-to-cell variability in gene expression. These quantitative experiments call for a corresponding modeling effort that addresses the question of how changes in promoter architecture affect noise in gene expression in a systematic rather than case-by-case fashion. In this article, we make such a systematic investigation, based on a simple microscopic model of gene regulation that incorporates stochastic effects. In particular, we show how operator strength and operator multiplicity affect this variability. We examine different modes of transcription factor binding to complex promoters (cooperative, independent, simultaneous) and how each of these affects the level of variability in transcription product from cell-to-cell. We propose that direct comparison between in vivo single-cell experiments and theoretical predictions for the moments of the probability distribution of mRNA number per cell can discriminate between different kinetic models of gene regulation.Comment: 35 pages, 6 figures, Submitte

Rotational strength, range of motion, and function in people with unaffected shoulders from various stages of life

Background: Different measurements are used to assess shoulder function, including range of motion, strength, functional performance and self-report function. To understand disablement, it is necessary to understand the relationship between impairments and function in persons without shoulder problems. This study was conducted to enhance existing comparative data in subjects without upper extremity pathology, and to assess the relationships between impairments (range of motion, strength) and selfreported or measured function/disability. The impact of age, gender and dominance was determined. Methods: Two-hundred ninety-four subjects with unaffected shoulders were recruited. The subjects (mean age: 37 years old) were divided into three subgroups, 18–39, 40–59, and over 60 years of age. During a single session, at least two of the following variables were measured: self-reported function (shoulder disability scales), range of motion, isometric rotational strength, or upper limb functional performance (FIT-HaNSA). Two-way analysis of variance was used to determine, for each variable, the effects of age and gender. The relationship between the outcomes was established using Pearson product correlations. Results: Men were significantly stronger than women for all age categories. There was an age-related decline in strength in men in the over-60 age category. Significant negative correlations between strength and range of motion were demonstrated (-0.22 \u3c -0.32). Women had a significantly higher range of motion than men for external rotation in the 40–59 age category. Furthermore, the subjects in the over- 60 age category experienced a decrease of range of motion. There was minimal disability reported in all age groups on self-report scales. Only the Simple Shoulder Test demonstrated significant decreases in the over-60 age category and correlated with age (r = -0.202). Conclusion: Self-reported disability was low in individuals without upper extremity problems, although recruitment of such individuals was difficult in the older age groups due to the high prevalence of shoulder pathology. A low correlation between self-report disability and strength/range of motion in these unaffected subjects reflects the lack of disability reported by all subjects without pathology despite normal variations in strength and motion

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

Computational Design of a PDZ Domain Peptide Inhibitor that Rescues CFTR Activity

The cystic fibrosis transmembrane conductance regulator (CFTR) is an epithelial chloride channel mutated in patients with cystic fibrosis (CF). The most prevalent CFTR mutation, ΔF508, blocks folding in the endoplasmic reticulum. Recent work has shown that some ΔF508-CFTR channel activity can be recovered by pharmaceutical modulators (“potentiators” and “correctors”), but ΔF508-CFTR can still be rapidly degraded via a lysosomal pathway involving the CFTR-associated ligand (CAL), which binds CFTR via a PDZ interaction domain. We present a study that goes from theory, to new structure-based computational design algorithms, to computational predictions, to biochemical testing and ultimately to epithelial-cell validation of novel, effective CAL PDZ inhibitors (called “stabilizers”) that rescue ΔF508-CFTR activity. To design the “stabilizers”, we extended our structural ensemble-based computational protein redesign algorithm to encompass protein-protein and protein-peptide interactions. The computational predictions achieved high accuracy: all of the top-predicted peptide inhibitors bound well to CAL. Furthermore, when compared to state-of-the-art CAL inhibitors, our design methodology achieved higher affinity and increased binding efficiency. The designed inhibitor with the highest affinity for CAL (kCAL01) binds six-fold more tightly than the previous best hexamer (iCAL35), and 170-fold more tightly than the CFTR C-terminus. We show that kCAL01 has physiological activity and can rescue chloride efflux in CF patient-derived airway epithelial cells. Since stabilizers address a different cellular CF defect from potentiators and correctors, our inhibitors provide an additional therapeutic pathway that can be used in conjunction with current methods

A Linear Framework for Time-Scale Separation in Nonlinear Biochemical Systems

Cellular physiology is implemented by formidably complex biochemical systems with highly nonlinear dynamics, presenting a challenge for both experiment and theory. Time-scale separation has been one of the few theoretical methods for distilling general principles from such complexity. It has provided essential insights in areas such as enzyme kinetics, allosteric enzymes, G-protein coupled receptors, ion channels, gene regulation and post-translational modification. In each case, internal molecular complexity has been eliminated, leading to rational algebraic expressions among the remaining components. This has yielded familiar formulas such as those of Michaelis-Menten in enzyme kinetics, Monod-Wyman-Changeux in allostery and Ackers-Johnson-Shea in gene regulation. Here we show that these calculations are all instances of a single graph-theoretic framework. Despite the biochemical nonlinearity to which it is applied, this framework is entirely linear, yet requires no approximation. We show that elimination of internal complexity is feasible when the relevant graph is strongly connected. The framework provides a new methodology with the potential to subdue combinatorial explosion at the molecular level

Leukocyte Tyrosine Kinase Functions in Pigment Cell Development

A fundamental problem in developmental biology concerns how multipotent precursors choose specific fates. Neural crest cells (NCCs) are multipotent, yet the mechanisms driving specific fate choices remain incompletely understood. Sox10 is required for specification of neural cells and melanocytes from NCCs. Like sox10 mutants, zebrafish shady mutants lack iridophores; we have proposed that sox10 and shady are required for iridophore specification from NCCs. We show using diverse approaches that shady encodes zebrafish leukocyte tyrosine kinase (Ltk). Cell transplantation studies show that Ltk acts cell-autonomously within the iridophore lineage. Consistent with this, ltk is expressed in a subset of NCCs, before becoming restricted to the iridophore lineage. Marker analysis reveals a primary defect in iridophore specification in ltk mutants. We saw no evidence for a fate-shift of neural crest cells into other pigment cell fates and some NCCs were subsequently lost by apoptosis. These features are also characteristic of the neural crest cell phenotype in sox10 mutants, leading us to examine iridophores in sox10 mutants. As expected, sox10 mutants largely lacked iridophore markers at late stages. In addition, sox10 mutants unexpectedly showed more ltk-expressing cells than wild-type siblings. These cells remained in a premigratory position and expressed sox10 but not the earliest neural crest markers and may represent multipotent, but partially-restricted, progenitors. In summary, we have discovered a novel signalling pathway in NCC development and demonstrate fate specification of iridophores as the first identified role for Ltk