Path Similarity Analysis: a Method for Quantifying Macromolecular Pathways

Diverse classes of proteins function through large-scale conformational changes; sophisticated enhanced sampling methods have been proposed to generate these macromolecular transition paths. As such paths are curves in a high-dimensional space, they have been difficult to compare quantitatively, a prerequisite to, for instance, assess the quality of different sampling algorithms. The Path Similarity Analysis (PSA) approach alleviates these difficulties by utilizing the full information in 3N-dimensional trajectories in configuration space. PSA employs the Hausdorff or Fr\'echet path metrics---adopted from computational geometry---enabling us to quantify path (dis)similarity, while the new concept of a Hausdorff-pair map permits the extraction of atomic-scale determinants responsible for path differences. Combined with clustering techniques, PSA facilitates the comparison of many paths, including collections of transition ensembles. We use the closed-to-open transition of the enzyme adenylate kinase (AdK)---a commonly used testbed for the assessment enhanced sampling algorithms---to examine multiple microsecond equilibrium molecular dynamics (MD) transitions of AdK in its substrate-free form alongside transition ensembles from the MD-based dynamic importance sampling (DIMS-MD) and targeted MD (TMD) methods, and a geometrical targeting algorithm (FRODA). A Hausdorff pairs analysis of these ensembles revealed, for instance, that differences in DIMS-MD and FRODA paths were mediated by a set of conserved salt bridges whose charge-charge interactions are fully modeled in DIMS-MD but not in FRODA. We also demonstrate how existing trajectory analysis methods relying on pre-defined collective variables, such as native contacts or geometric quantities, can be used synergistically with PSA, as well as the application of PSA to more complex systems such as membrane transporter proteins.Comment: 9 figures, 3 tables in the main manuscript; supplementary information includes 7 texts (S1 Text - S7 Text) and 11 figures (S1 Fig - S11 Fig) (also available from journal site

Plastron properties of a superhydrophobic surface

Most insects and spiders drown when submerged during flooding or tidal inundation, but some are able to survive and others can remain submerged indefinitely without harm. Many achieve this by natural adaptations to their surface morphology to trap films of air, creating plastrons which fix the water-vapor interface and provide an incompressible oxygen-carbon dioxide exchange surface. Here the authors demonstrate how the surface of an extremely water-repellent foam mimics this mechanism of underwater respiration and allows direct extraction of oxygen from aerated water. The biomimetic principle demonstrated can be applied to a wide variety of man-made superhydrophobic materials

Synthesizing empirical and modelling studies to predict past and future primary production in the North Sea

Understanding change at the base of the marine foodwebs is fundamental to understanding how climate change can impact fisheries. However, there is a shortage of empirical measurements of primary productivity, and models estimates often disagree with each other by an order of magnitude or more. In this study we incorporate information from empirical studies and a suite of Earth system models statistically downscaled using an ensemble model to produce estimates of North Sea primary production with robust quantification of uncertainties under two different climate scenarios. The results give a synthesised estimate of primary production that can feed into regional fisheries models. We found that Earth system models describe the dynamics of primary production in the North Sea poorly, and therefore the effects of climate change on future primary production are uncertain. The methods demonstrated here can be applied to other geographical locations and are not limited in application to primary production

More questions than answers to the diagnosis and management of cauda equina syndrome-Authors' reply

No abstract available

Frequency-stabilization to 6x10^-16 via spectral-hole burning

We demonstrate two-stage laser stabilization based on a combination of Fabry- Perot and spectral-hole burning techniques. The laser is first pre-stabilized by the Fabry-Perot cavity to a fractional-frequency stability of sigma_y(tau) < 10^-13. A pattern of spectral holes written in the absorption spectrum of Eu3+:Y2SiO5 serves to further stabilize the laser to sigma_y(tau) = 6x10^-16 for 2 s < tau < 8 s. Measurements characterizing the frequency sensitivity of Eu3+:Y2SiO5 spectral holes to environmental perturbations suggest that they can be more frequency stable than Fabry-Perot cavities

Apoptosis at Inflection Point in Liquid Culture of Budding Yeasts

Budding yeasts are highly suitable for aging studies, because the number of bud scars (stage) proportionally correlates with age. Its maximum stages are known to reach at 20–30 stages on an isolated agar medium. However, their stage dynamics in a liquid culture is virtually unknown. We investigate the population dynamics by counting scars in each cell. Here one cell division produces one new cell and one bud scar. This simple rule leads to a conservation law: “The total number of bud scars is equal to the total number of cells.” We find a large discrepancy: extremely fewer cells with over 5 scars than expected. Almost all cells with 6 or more scars disappear within a short period of time in the late log phase (corresponds to the inflection point). This discrepancy is confirmed directly by the microscopic observations of broken cells. This finding implies apoptosis in older cells (6 scars or more)

Tumor markers in breast cancer - European Group on Tumor Markers recommendations

Recommendations are presented for the routine clinical use of serum and tissue-based markers in the diagnosis and management of patients with breast cancer. Their low sensitivity and specificity preclude the use of serum markers such as the MUC-1 mucin glycoproteins ( CA 15.3, BR 27.29) and carcinoembryonic antigen in the diagnosis of early breast cancer. However, serial measurement of these markers can result in the early detection of recurrent disease as well as indicate the efficacy of therapy. Of the tissue-based markers, measurement of estrogen and progesterone receptors is mandatory in the selection of patients for treatment with hormone therapy, while HER-2 is essential in selecting patients with advanced breast cancer for treatment with Herceptin ( trastuzumab). Urokinase plasminogen activator and plasminogen activator inhibitor 1 are recently validated prognostic markers for lymph node-negative breast cancer patients and thus may be of value in selecting node-negative patients that do not require adjuvant chemotherapy. Copyright (C) 2005 S. Karger AG, Basel

US Cosmic Visions: New Ideas in Dark Matter 2017: Community Report

This white paper summarizes the workshop "U.S. Cosmic Visions: New Ideas in Dark Matter" held at University of Maryland on March 23-25, 2017.Comment: 102 pages + reference

Design, Implementation, and Performance of the Astro-H Soft X-Ray Spectrometer Aperture Assembly and Blocking Filters

The calorimeter array of the JAXA Astro-H (renamed Hitomi) soft x-ray spectrometer (SXS) was designed to provide unprecedented spectral resolution of spatially extended cosmic x-ray sources and of all cosmic x-ray sources in the Fe-K band around 6 keV. The properties that made the SXS array a powerful x-ray spectrometer also made it sensitive to photons from the entire electromagnetic band as well as particles. If characterized as a bolometer, it would have had a noise equivalent power of <4 10(exp 18) W/((Hz)(exp 0.5)). Thus, it was imperative to shield the detector from thermal radiation from the instrument and optical and UV photons from the sky. In addition, it was necessary to shield the coldest stages of the instrument from the thermal radiation emanating from the warmer stages. These needs were addressed by a series of five thin-film radiation-blocking filters, anchored to the nested temperature stages, that blocked long-wavelength radiation while minimizing x-ray attenuation. The aperture assembly was a system of barriers, baffles, filter carriers, and filter mounts that supported the filters and inhibited their potential contamination. The three outer filters also had been equipped with thermometers and heaters for decontamination. We present the requirements, design, implementation, and performance of the SXS aperture assembly and blocking filters