Meteor ablation spheres from deep-sea sediments

Spheres from mid-Pacific abyssal clays (0 to 500,000 yrs old), formed from particles that completely melted and subsequently recrystallized as they separated from their meteoroid bodies, or containing relict grains of parent meteoroids that did not experience any melting were analyzed. The spheres were readily divided into three groups using their dominant mineralogy. The Fe-rich spheres were produced during ablation of Fe and metal-rich silicate meteoroids. The glassy spheres are considerably more Fe-rich than the silicate spheres. They consist of magnetite and an Fe glass which is relatively low in Si. Bulk compositions and relict grains are useful for determining the parent meteoroid types for the silicate spheres. Bulk analyses of recrystallized spheres show that nonvolatile elemental abundances are similar to chondrite abundances. Analysis of relict grains identified high temperature minerals associated with a fine-grained, low temperature, volatile-rich matrix. The obvious candidates for parent meteoroids of this type of silicate sphere is a carbonaceous chondrite

Endogeneous Versus Exogeneous Shocks in Systems with Memory

Systems with long-range persistence and memory are shown to exhibit different precursory as well as recovery patterns in response to shocks of exogeneous versus endogeneous origins. By endogeneous, we envision either fluctuations resulting from an underlying chaotic dynamics or from a stochastic forcing origin which may be external or be an effective coarse-grained description of the microscopic fluctuations. In this scenario, endogeneous shocks result from a kind of constructive interference of accumulated fluctuations whose impacts survive longer than the large shocks themselves. As a consequence, the recovery after an endogeneous shock is in general slower at early times and can be at long times either slower or faster than after an exogeneous perturbation. This offers the tantalizing possibility of distinguishing between an endogeneous versus exogeneous cause of a given shock, even when there is no ``smoking gun.'' This could help in investigating the exogeneous versus self-organized origins in problems such as the causes of major biological extinctions, of change of weather regimes and of the climate, in tracing the source of social upheaval and wars, and so on. Sornette, Malevergne and Muzy have already shown how this concept can be applied concretely to differentiate the effects on financial markets of the Sept. 11, 2001 attack or of the coup against Gorbachev on Aug., 19, 1991 (exogeneous) from financial crashes such as Oct. 1987 (endogeneous).Comment: Latex document of 14 pages with 3 eps figure

Universal geometrical factor of protein conformations as a consequence of energy minimization

The biological activity and functional specificity of proteins depend on their native three-dimensional structures determined by inter- and intra-molecular interactions. In this paper, we investigate the geometrical factor of protein conformation as a consequence of energy minimization in protein folding. Folding simulations of 10 polypeptides with chain length ranging from 183 to 548 residues manifest that the dimensionless ratio (V/(A)) of the van der Waals volume V to the surface area A and average atomic radius of the folded structures, calculated with atomic radii setting used in SMMP [Eisenmenger F., et. al., Comput. Phys. Commun., 138 (2001) 192], approach 0.49 quickly during the course of energy minimization. A large scale analysis of protein structures show that the ratio for real and well-designed proteins is universal and equal to 0.491\pm0.005. The fractional composition of hydrophobic and hydrophilic residues does not affect the ratio substantially. The ratio also holds for intrinsically disordered proteins, while it ceases to be universal for polypeptides with bad folding properties.Comment: 6 pages, 1 table, 4 figure

Inferring stabilizing mutations from protein phylogenies : application to influenza hemagglutinin

One selection pressure shaping sequence evolution is the requirement that a protein fold with sufficient stability to perform its biological functions. We present a conceptual framework that explains how this requirement causes the probability that a particular amino acid mutation is fixed during evolution to depend on its effect on protein stability. We mathematically formalize this framework to develop a Bayesian approach for inferring the stability effects of individual mutations from homologous protein sequences of known phylogeny. This approach is able to predict published experimentally measured mutational stability effects (ΔΔG values) with an accuracy that exceeds both a state-of-the-art physicochemical modeling program and the sequence-based consensus approach. As a further test, we use our phylogenetic inference approach to predict stabilizing mutations to influenza hemagglutinin. We introduce these mutations into a temperature-sensitive influenza virus with a defect in its hemagglutinin gene and experimentally demonstrate that some of the mutations allow the virus to grow at higher temperatures. Our work therefore describes a powerful new approach for predicting stabilizing mutations that can be successfully applied even to large, complex proteins such as hemagglutinin. This approach also makes a mathematical link between phylogenetics and experimentally measurable protein properties, potentially paving the way for more accurate analyses of molecular evolution

A Small Conductance Calcium-Activated K⁺ Channel in C. elegans, KCNL-2, Plays a Role in the Regulation of the Rate of Egg-Laying

In the nervous system of mice, small conductance calcium-activated potassium (SK) channels function to regulate neuronal excitability through the generation of a component of the medium afterhyperpolarization that follows action potentials. In humans, irregular action potential firing frequency underlies diseases such as ataxia, epilepsy, schizophrenia and Parkinson's disease. Due to the complexity of studying protein function in the mammalian nervous system, we sought to characterize an SK channel homologue, KCNL-2, in C. elegans, a genetically tractable system in which the lineage of individual neurons was mapped from their early developmental stages. Sequence analysis of the KCNL-2 protein reveals that the six transmembrane domains, the potassium-selective pore and the calmodulin binding domain are highly conserved with the mammalian homologues. We used widefield and confocal fluorescent imaging to show that a fusion construct of KCNL-2 with GFP in transgenic lines is expressed in the nervous system of C. elegans. We also show that a KCNL-2 null strain, kcnl-2(tm1885), demonstrates a mild egg-laying defective phenotype, a phenotype that is rescued in a KCNL-2-dependent manner. Conversely, we show that transgenic lines that overexpress KCNL-2 demonstrate a hyperactive egg-laying phenotype. In this study, we show that the vulva of transgenic hermaphrodites is highly innervated by neuronal processes and by the VC4 and VC5 neurons that express GFP-tagged KCNL-2. We propose that KCNL-2 functions in the nervous system of C. elegans to regulate the rate of egg-laying. © 2013 Chotoo et al

Health data processes. A framework for analysing and discussing efficient use and reuse of health data with focus on Patient Reported Outcome (PRO) measures

This is is the final version. Available from Journal of Medical Internet Research via the DOI in this record.The collection and use of patient health data is central to any kind of activity in the healthcare system. This data may be produced during routine clinical processes or obtained directly from the patient using patient-reported outcome (PRO) measures. Although efficiency and other reasons justify data availability for a range of potential relevant uses, these data are nearly always collected for a single specific purpose. The healthcare data literature reflects this narrow scope, and there is limited literature on the joint use of health data for daily clinical use, clinical research, surveillance and administrative purposes. The aim of this paper is to provide a framework for a discussion of the efficient use of health data with specific focus on the role of PRO measures. PRO data may be used: i) at an individual patient level to inform patient care or shared-decision making and tailor care to individual needs or ii) at group level as a complement to health record data e.g. on mortality and readmission to inform service delivery and measure real-world effectiveness of treatment. PRO may be used either for their own sake, to provide valuable information from the patient perspective, or as proxy for clinical data that would be otherwise not feasible to collect. We introduce a framework to analyse any health care activity that involves health data. The framework consists of four data processes (patient identification, data collection, data aggregation and data use), further structured into two dichotomous dimensions in each data process (level: group vs patient; and timeframe: ad hoc vs systematic). This framework is used to analyse various health activities with respect to joint use of data considering the technical, legal, organisational and logistical challenges that characterize each data process. Finally, we propose a model for joint use of health data with data collected during follow-up as basis. Demands for health data will continue to increase which will further add to the need for the concerted use and reuse of PRO data for parallel purposes. Repeated and uncoordinated PRO data collection for the same patient for different purposes results in misuse of resources for the healthcare system as well as reduced response rates owing to questionnaire fatigue. PRO data can be routinely collected both at the hospital (in- as well as outpatients) and outside of hospital settings, in primary or social care settings, or in the patient’s home provided the health informatics infrastructure is in place. In the future, clinical settings are likely to be a prominent source of PRO data; however we are also likely to see increased remote collection of PRO data by patients in their own home (telePRO). Data collection for research and quality surveillance will have to adapt to this circumstance and adopt complementary data capture methods which take advantage of the utility of PRO data collected during daily clinical practice. The European Union’s regulation with respect to the protection of personal data, General Data Protection Regulation, imposes severe restrictions on use of health data for parallel purposes and steps should be taken to alleviate the consequences while still protecting personal data against misuse.National Institute for Health Research (NIHR

In vitro and in vivo mRNA delivery using lipid-enveloped pHresponsive polymer nanoparticles

Biodegradable core−shell structured nanoparticles with a poly(β-amino ester) (PBAE) core enveloped by a phospholipid bilayer shell were developed for in vivo mRNA delivery with a view toward delivery of mRNA-based vaccines. The pH-responsive PBAE component was chosen to promote endosome disruption, while the lipid surface layer was selected to minimize toxicity of the polycation core. Messenger RNA was efficiently adsorbed via electrostatic interactions onto the surface of these net positively charged nanoparticles. In vitro, mRNA-loaded particle uptake by dendritic cells led to mRNA delivery into the cytosol with low cytotoxicity, followed by translation of the encoded protein in these difficult-to-transfect cells at a frequency of 30%. Particles loaded with mRNA administered intranasally (i.n.) in mice led to the expression of the reporter protein luciferase in vivo as soon as 6 h after administration, a time point when naked mRNA given i.n. showed no expression. At later time points, luciferase expression was detected in naked mRNA-treated mice, but this group showed a wide variation in levels of transfection, compared to particle-treated mice. This system may thus be promising for noninvasive delivery of mRNA-based vaccines.United States. Dept. of Defense (Institute for Soldier Nanotechnology, contract W911NF-07-D-0004)Ragon Institute of MGH, MIT and HarvardSingapore. Agency for Science, Technology and ResearchHoward Hughes Medical Institute (Investigator

The Impact of Small Molecule Binding on the Energy Landscape of the Intrinsically Disordered Protein C-Myc

Intrinsically disordered proteins are attractive therapeutic targets owing to their prevalence in several diseases. Yet their lack of well-defined structure renders ligand discovery a challenging task. An intriguing example is provided by the oncoprotein c-Myc, a transcription factor that is over expressed in a broad range of cancers. Transcriptional activity of c-Myc is dependent on heterodimerization with partner protein Max. This protein-protein interaction is disrupted by the small molecule 10058-F4 (1), that binds to monomeric and disordered c-Myc. To rationalize the mechanism of inhibition, structural ensembles for the segment of the c-Myc domain that binds to 1 were computed in the absence and presence of the ligand using classical force fields and explicit solvent metadynamics molecular simulations. The accuracy of the computed structural ensembles was assessed by comparison of predicted and measured NMR chemical shifts. The small molecule 1 was found to perturb the composition of the apo equilibrium ensemble and to bind weakly to multiple distinct c-Myc conformations. Comparison of the apo and holo equilibrium ensembles reveals that the c-Myc conformations binding 1 are already partially formed in the apo ensemble, suggesting that 1 binds to c-Myc through an extended conformational selection mechanism. The present results have important implications for rational ligand design efforts targeting intrinsically disordered proteins