Geometry and symmetry presculpt the free-energy landscape of proteins

We present a simple physical model which demonstrates that the native state folds of proteins can emerge on the basis of considerations of geometry and symmetry. We show that the inherent anisotropy of a chain molecule, the geometrical and energetic constraints placed by the hydrogen bonds and sterics, and hydrophobicity are sufficient to yield a free energy landscape with broad minima even for a homopolymer. These minima correspond to marginally compact structures comprising the menu of folds that proteins choose from to house their native-states in. Our results provide a general framework for understanding the common characteristics of globular proteins.Comment: 23 pages, 5 figure

Long‐lived plasmaspheric drainage plumes: Where does the plasma come from?

Long‐lived (weeks) plasmaspheric drainage plumes are explored. The long‐lived plumes occur during long‐lived high‐speed‐stream‐driven storms. Spacecraft in geosynchronous orbit see the plumes as dense plasmaspheric plasma advecting sunward toward the dayside magnetopause. The older plumes have the same densities and local time widths as younger plumes, and like younger plumes they are lumpy in density and they reside in a spatial gap in the electron plasma sheet (in sort of a drainage corridor). Magnetospheric‐convection simulations indicate that drainage from a filled outer plasmasphere can only supply a plume for 1.5–2 days. The question arises for long‐lived plumes (and for any plume older than about 2 days): Where is the plasma coming from? Three candidate sources appear promising: (1) substorm disruption of the nightside plasmasphere which may transport plasmaspheric plasma outward onto open drift orbits, (2) radial transport of plasmaspheric plasma in velocity‐shear‐driven instabilities near the duskside plasmapause, and (3) an anomalously high upflux of cold ionospheric protons from the tongue of ionization in the dayside ionosphere, which may directly supply ionospheric plasma into the plume. In the first two cases the plume is drainage of plasma from the magnetosphere; in the third case it is not. Where the plasma in long‐lived plumes is coming from is a quandary: to fix this dilemma, further work and probably full‐scale simulations are needed. Key Points Plasmaspheric drainage plumes can persist for weeks The source of the plasma supplying the long‐lived plumes is unknown Candidate sources include outflow from the tongue of ionizationPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108632/1/jgra51234.pd

Reconstruction of three-dimensional porous media using generative adversarial neural networks

To evaluate the variability of multi-phase flow properties of porous media at the pore scale, it is necessary to acquire a number of representative samples of the void-solid structure. While modern x-ray computer tomography has made it possible to extract three-dimensional images of the pore space, assessment of the variability in the inherent material properties is often experimentally not feasible. We present a novel method to reconstruct the solid-void structure of porous media by applying a generative neural network that allows an implicit description of the probability distribution represented by three-dimensional image datasets. We show, by using an adversarial learning approach for neural networks, that this method of unsupervised learning is able to generate representative samples of porous media that honor their statistics. We successfully compare measures of pore morphology, such as the Euler characteristic, two-point statistics and directional single-phase permeability of synthetic realizations with the calculated properties of a bead pack, Berea sandstone, and Ketton limestone. Results show that GANs can be used to reconstruct high-resolution three-dimensional images of porous media at different scales that are representative of the morphology of the images used to train the neural network. The fully convolutional nature of the trained neural network allows the generation of large samples while maintaining computational efficiency. Compared to classical stochastic methods of image reconstruction, the implicit representation of the learned data distribution can be stored and reused to generate multiple realizations of the pore structure very rapidly.Comment: 21 pages, 20 figure

Religious Identity, Religious Attendance, and Parental Control

Using a national sample of adolescents aged 10–18 years and their parents (N = 5,117), this article examines whether parental religious identity and religious participation are associated with the ways in which parents control their children. We hypothesize that both religious orthodoxy and weekly religious attendance are related to heightened levels of three elements of parental control: monitoring activities, normative regulations, and network closure. Results indicate that an orthodox religious identity for Catholic and Protestant parents and higher levels of religious attendance for parents as a whole are associated with increases in monitoring activities and normative regulations of American adolescents

Systematic analysis of the literature in search of defining systemic sclerosis subsets

OBJECTIVE: Systemic sclerosis (SSc) is a multisystem disease with heterogeneity in presentation and prognosis. An international collaboration to develop new SSc subset criteria is underway. Our objectives were to identify systems of SSc subset classification and synthesize novel concepts to inform development of new criteria. METHODS: Medline, Cochrane MEDLINE, the Cumulative Index to Nursing and Allied Health Literature, EMBASE, and Web of Science were searched from their inceptions to December 2019 for studies related to SSc subclassification, limited to humans and without language or sample size restrictions. RESULTS: Of 5686 citations, 102 studies reported original data on SSc subsets. Subset classification systems relied on extent of skin involvement and/or SSc-specific autoantibodies (n = 61), nailfold capillary patterns (n = 29), and molecular, genomic, and cellular patterns (n = 12). While some systems of subset classification confer prognostic value for clinical phenotype, severity, and mortality, only subsetting by gene expression signatures in tissue samples has been associated with response to therapy. CONCLUSION: Subsetting on extent of skin involvement remains important. Novel disease attributes including SSc-specific autoantibodies, nailfold capillary patterns, and tissue gene expression signatures have been proposed as innovative means of SSc subsetting

Propulsion in a viscoelastic fluid

Flagella beating in complex fluids are significantly influenced by viscoelastic stresses. Relevant examples include the ciliary transport of respiratory airway mucus and the motion of spermatozoa in the mucus-filled female reproductive tract. We consider the simplest model of such propulsion and transport in a complex fluid, a waving sheet of small amplitude free to move in a polymeric fluid with a single relaxation time. We show that, compared to self-propulsion in a Newtonian fluid occurring at a velocity U_N, the sheet swims (or transports fluid) with velocity U / U_N = [1+De^2 (eta_s)/(eta) ]/[1+De^2], where eta_s is the viscosity of the Newtonian solvent, eta is the zero-shear-rate viscosity of the polymeric fluid, and De is the Deborah number for the wave motion, product of the wave frequency by the fluid relaxation time. Similar expressions are derived for the rate of work of the sheet and the mechanical efficiency of the motion. These results are shown to be independent of the particular nonlinear constitutive equations chosen for the fluid, and are valid for both waves of tangential and normal motion. The generalization to more than one relaxation time is also provided. In stark contrast with the Newtonian case, these calculations suggest that transport and locomotion in a non-Newtonian fluid can be conveniently tuned without having to modify the waving gait of the sheet but instead by passively modulating the material properties of the liquid.Comment: 21 pages, 1 figur

Heterogeneities in Supercooled liquids: A Density Functional Study

A metastable state, characterized by a low degree of mass localization is identified using Density Functional Theory. This free energy minimum, located through the proper evaluation of the competing terms in the free energy functional, is independent of the specific form of the DFT used. Computer simulation results on particle motion indicate that this heterogeneous state corresponds to the supercooled state.Comment: 10 pages, 6 figure

Discovery, Characterization, and Structure–Activity Relationships of an Inhibitor of Inward Rectifier Potassium (Kir) Channels with Preference for Kir2.3, Kir3.X, and Kir7.1

The inward rectifier family of potassium (Kir) channels is comprised of at least 16 family members exhibiting broad and often overlapping cellular, tissue, or organ distributions. The discovery of disease-causing mutations in humans and experiments on knockout mice has underscored the importance of Kir channels in physiology and in some cases raised questions about their potential as drug targets. However, the paucity of potent and selective small-molecule modulators targeting specific family members has with few exceptions mired efforts to understand their physiology and assess their therapeutic potential. A growing body of evidence suggests that G protein-coupled inward rectifier K (GIRK) channels of the Kir3.X subfamily may represent novel targets for the treatment of atrial fibrillation. In an effort to expand the molecular pharmacology of GIRK, we performed a thallium (Tl+) flux-based high-throughput screen of a Kir1.1 inhibitor library for modulators of GIRK. One compound, termed VU573, exhibited 10-fold selectivity for GIRK over Kir1.1 (IC50 = 1.9 and 19 μM, respectively) and was therefore selected for further study. In electrophysiological experiments performed on Xenopus laevis oocytes and mammalian cells, VU573 inhibited Kir3.1/3.2 (neuronal GIRK) and Kir3.1/3.4 (cardiac GIRK) channels with equal potency and preferentially inhibited GIRK, Kir2.3, and Kir7.1 over Kir1.1 and Kir2.1.Tl+ flux assays were established for Kir2.3 and the M125R pore mutant of Kir7.1 to support medicinal chemistry efforts to develop more potent and selective analogs for these channels. The structure–activity relationships of VU573 revealed few analogs with improved potency, however two compounds retained most of their activity toward GIRK and Kir2.3 and lost activity toward Kir7.1. We anticipate that the VU573 series will be useful for exploring the physiology and structure–function relationships of these Kir channels

Polydispersity and ordered phases in solutions of rodlike macromolecules

We apply density functional theory to study the influence of polydispersity on the stability of columnar, smectic and solid ordering in the solutions of rodlike macromolecules. For sufficiently large length polydispersity (standard deviation $\sigma>0.25$) a direct first-order nematic-columnar transition is found, while for smaller $\sigma$ there is a continuous nematic-smectic and first-order smectic-columnar transition. For increasing polydispersity the columnar structure is stabilized with respect to solid perturbations. The length distribution of macromolecules changes neither at the nematic-smectic nor at the nematic-columnar transition, but it does change at the smectic-columnar phase transition. We also study the phase behaviour of binary mixtures, in which the nematic-smectic transition is again found to be continuous. Demixing according to rod length in the smectic phase is always preempted by transitions to solid or columnar ordering.Comment: 13 pages (TeX), 2 Postscript figures uuencode