The Transition State in a Noisy Environment

Transition State Theory overestimates reaction rates in solution because conventional dividing surfaces between reagents and products are crossed many times by the same reactive trajectory. We describe a recipe for constructing a time-dependent dividing surface free of such recrossings in the presence of noise. The no-recrossing limit of Transition State Theory thus becomes generally available for the description of reactions in a fluctuating environment

Simultaneous multiwavelength observations of V404 Cygni during its 2015 June outburst decay strengthen the case for an extremely energetic jet-base

We present results of multiband optical photometry of the black hole X-ray binary system V404 Cygni obtained using Wheaton College Observatory's 0.3m telescope, along with strictly simultaneous INTEGRAL and Swift observations during 2015 June 25.15--26.33 UT, and 2015 June 27.10--27.34 UT. These observations were made during the 2015 June outburst of the source when it was going through an epoch of violent activity in all wavelengths ranging from radio to $\gamma$-rays. The multiwavelength variability timescale favors a compact emission region, most likely originating in a jet outflow, for both observing epochs presented in this work. The simultaneous INTEGRAL/Imager on Board the Integral Satellite (IBIS) 20--40 keV light curve obtained during the June 27 observing run correlates very strongly with the optical light curve, with no detectable delay between the optical bands as well as between the optical and hard X-rays. The average slope of the dereddened spectral energy distribution was roughly flat between the $I_C$- and $V$-bands during the June 27 run, even though the optical and X-ray flux varied by $>$25$\times$ during the run, ruling out an irradiation origin for the optical and suggesting that the optically thick to optically thin jet synchrotron break during the observations was at a frequency larger than that of $V$-band, which is quite extreme for X-ray binaries. These observations suggest that the optical emission originated very close to the base of the jet. A strong H$\alpha$ emission line, probably originating in a quasi-spherical nebula around the source, also contributes significantly in the $R_C$-band. Our data, in conjunction with contemporaneous data at other wavelengths presented by other groups, strongly suggest that the jet-base was extremely compact and energetic during this phase of the outburst.Comment: 15 pages, 2 tables, 5 figures. Accepted for publication in Ap

Complexity of murine cardiomyocyte miRNA biogenesis, sequence variant expression and function

microRNAs (miRNAs) are critical to heart development and disease. Emerging research indicates that regulated precursor processing can give rise to an unexpected diversity of miRNA variants. We subjected small RNA from murine HL-1 cardiomyocyte cells to next generation sequencing to investigate the relevance of such diversity to cardiac biology. ∼40 million tags were mapped to known miRNA hairpin sequences as deposited in miRBase version 16, calling 403 generic miRNAs as appreciably expressed. Hairpin arm bias broadly agreed with miRBase annotation, although 44 miR* were unexpectedly abundant (>20% of tags); conversely, 33 -5p/-3p annotated hairpins were asymmetrically expressed. Overall, variability was infrequent at the 5' start but common at the 3' end of miRNAs (5.2% and 52.3% of tags, respectively). Nevertheless, 105 miRNAs showed marked 5' isomiR expression (>20% of tags). Among these was miR-133a, a miRNA with important cardiac functions, and we demonstrated differential mRNA targeting by two of its prevalent 5' isomiRs. Analyses of miRNA termini and base-pairing patterns around Drosha and Dicer cleavage regions confirmed the known bias towards uridine at the 5' most position of miRNAs, as well as supporting the thermodynamic asymmetry rule for miRNA strand selection and a role for local structural distortions in fine tuning miRNA processing. We further recorded appreciable expression of 5 novel miR*, 38 extreme variants and 8 antisense miRNAs. Analysis of genome-mapped tags revealed 147 novel candidate miRNAs. In summary, we revealed pronounced sequence diversity among cardiomyocyte miRNAs, knowledge of which will underpin future research into the mechanisms involved in miRNA biogenesis and, importantly, cardiac function, disease and therapy.This work was supported by by the Victor Chang Cardiac Research Institute and grants 573726, 573731 and 514904 from the National Health & Medical Research Council awarded to TP

Interaction of Dendritic Cells with Skin Endothelium: A New Perspective on Immunosurveillance

The goal of this study was to determine the mechanisms by which dendritic cells (DCs) in blood could interact with endothelium, a prerequisite to extravasation into tissues. Our results indicate that DCs express both HECA-452–reactive and nonreactive isoforms of P-selectin glycoprotein ligand 1 (PSGL-1) and can tether and roll efficiently on E- and P-selectin under flow conditions in vitro. Freshly isolated blood DCs were further observed to roll continuously along noninflamed murine dermal endothelium in vivo. This interaction is strictly dependent on endothelial selectins, as shown by experiments with blocking antibodies and with E- and P-selectin–deficient mice. We hypothesize that DCs in blood are constitutively poised at the interface of blood and skin, ready to extravasate upon induction of inflammation, and we showed that cutaneous inflammation results in a rapid recruitment of DCs from the blood to tissues. We propose that this is an important and previously unappreciated element of immunosurveillance

Multiwavelength Observations of A0620-00 in Quiescence

[Abridged.] We present multiwavelength observations of the black hole binary system, A0620-00. Using the Cosmic Origins Spectrograph on the Hubble Space Telescope, we have obtained the first FUV spectrum of A0620-00. The observed spectrum is flat in the FUV and very faint (with continuum fluxes \simeq 1e - 17 ergs/cm^2/s/A). We compiled the dereddened, broadband spectral energy distribution of A0620-00 and compared it to previous SEDs as well as theoretical models. The SEDs show that the source varies at all wavelengths for which we have multiple samples. Contrary to previous observations, the optical-UV spectrum does not continue to drop to shorter wavelengths, but instead shows a recovery and an increasingly blue spectrum in the FUV. We created an optical-UV spectrum of A0620-00 with the donor star contribution removed. The non-stellar spectrum peaks at \simeq3000 {\deg}A. The peak can be fit with a T=10,000 K blackbody with a small emitting area, probably originating in the hot spot where the accretion stream impacts the outer disk. However, one or more components in addition to the blackbody are needed to fit the FUV upturn and the red optical fluxes in the optical-UV spectrum. By comparing the mass accretion rate determined from the hot spot luminosity to the mean accretion rate inferred from the outburst history, we find that the latter is an order of magnitude smaller than the former, indicating that \sim90% of the accreted mass must be lost from the system if the predictions of the disk instability model and the estimated interoutburst interval are correct. The mass accretion rate at the hot spot is 10^5 the accretion rate at the black hole inferred from the X-ray luminosity. To reconcile these requires that outflows carry away virtually all of the accreted mass, a very low rate of mass transfer from the outer cold disk into the inner hot region, and/or radiatively inefficient accretion.Comment: ApJ, accepte

Human liver glycogen phosphorylase inhibitors bind at a new allosteric site

AbstractBackground: Glycogen phosphorylases catalyze the breakdown of glycogen to glucose-1-phosphate for glycolysis. Maintaining control of blood glucose levels is critical in minimizing the debilitating effects of diabetes, making liver glycogen phosphorylase a potential therapeutic target.Results: The binding site in human liver glycogen phosphorylase (HLGP) for a class of promising antidiabetic agents was identified crystallographically. The site is novel and functions allosterically by stabilizing the inactive conformation of HLGP. The initial view of the complex revealed key structural information and inspired the design of a new class of inhibitors which bind with nanomolar affinity and whose crystal structure is also described.Conclusions: We have identified the binding site of a new class of allosteric HLGP inhibitors. The crystal structure revealed the details of inhibitor binding, led to the design of a new class of compounds, and should accelerate efforts to develop therapeutically relevant molecules for the treatment of diabetes

Developing institutional capacity for reproductive health in humanitarian settings: A descriptive study

© 2015 Tran et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Introduction. Institutions play a central role in advancing the field of reproductive health in humanitarian settings (RHHS), yet little is known about organizational capacity to deliver RHHS and how this has developed over the past decade. This study aimed to document the current institutional experiences and capacities related to RHHS. Materials and Methods. Descriptive study using an online questionnaire tool. Results. Respondents represented 82 institutions from 48 countries, of which two-thirds originated from low-and middle-income countries. RHHS work was found not to be restricted to humanitarian agencies (25%), but was also embraced by development organizations (25%) and institutions with dual humanitarian and development mandates (50%). Agencies reported working with refugees (81%), internally-displaced (87%) and stateless persons (20%), in camp-based settings (78%), and in urban (83%) and rural settings (78%). Sixtyeight percent of represented institutions indicated having an RHHS-related policy, 79% an accountability mechanism including humanitarian work, and 90% formal partnerships with other institutions. Seventy-three percent reported routinely appointing RH focal points to ensure coordination of RHHS implementation. There was reported progress in RHHSrelated disaster risk reduction (DRR), emergency management and coordination, delivery of the Minimum Initial Services Package (MISP) for RH, comprehensive RH services in post-crisis/recovery situations, gender mainstreaming, and community-based programming. Other reported institutional areas of work included capacity development, program delivery, advocacy/policy work, followed by research and donor activities. Except for abortion-related services, respondents cited improved efforts in advocacy, capacity development and technical support in their institutions for RHHS to address clinical services, including maternal and newborn health, sexual violence prevention and response, HIV prevention, management of sexually-transmitted infections, adolescent RH, and family planning. Approximately half of participants reported that their institutions had experienced an increase in dedicated budget and staff for RHHS, a fifth no change, and 1 in 10 a decrease. The Interagency RH Kits were reportedly the most commonly used supplies to support RHHS implementation. Conclusion. The results suggest overall growth in institutional capacity in RHHS over the past decade, indicating that the field has matured and expanded from crisis response to include RHHS into DRR and other elements of the emergency management cycle. It is critical to consolidate the progress to date, address gaps, and sustain momentum

SPH Simulations of Negative (Nodal) Superhumps: A Parametric Study

Negative superhumps in cataclysmic variable systems result when the accretion disc is tilted with respect to the orbital plane. The line of nodes of the tilted disc precesses slowly in the retrograde direction, resulting in a photometric signal with a period slightly less than the orbital period. We use the method of smoothed particle hydrodynamics to simulate a series of models of differing mass ratio and effective viscosity to determine the retrograde precession period and superhump period deficit $\varepsilon_-$ as a function of system mass ratio $q$. We tabulate our results and present fits to both $\varepsilon_-$ and $\varepsilon_+$ versus $q$, as well as compare the numerical results with those compiled from the literature of negative superhump observations. One surprising is that while we find negative superhumps most clearly in simulations with an accretion stream present, we also find evidence for negative superhumps in simulations in which we shut off the mass transfer stream completely, indicating that the origin of the photometric signal is more complicated than previously believed.Comment: 14 pages, 15 figures. Accepted for publication in MNRA