Contributions of Ca^(2+)-Independent Thin Filament Activation to Cardiac Muscle Function

Although Ca^(2+) is the principal regulator of contraction in striated muscle, in vitro evidence suggests that some actin-myosin interaction is still possible even in its absence. Whether this Ca^(2+)-independent activation (CIA) occurs under physiological conditions remains unclear, as does its potential impact on the function of intact cardiac muscle. The purpose of this study was to investigate CIA using computational analysis. We added a structurally motivated representation of this phenomenon to an existing myofilament model, which allowed predictions of CIA-dependent muscle behavior. We found that a certain amount of CIA was essential for the model to reproduce reported effects of nonfunctional troponin C on myofilament force generation. Consequently, those data enabled estimation of ΔG_(CIA), the energy barrier for activating a thin filament regulatory unit in the absence of Ca^(2+). Using this estimate of ΔG_(CIA) as a point of reference (∼7 kJ mol^(−1)), we examined its impact on various aspects of muscle function through additional simulations. CIA decreased the Hill coefficient of steady-state force while increasing myofilament Ca^(2+) sensitivity. At the same time, CIA had minimal effect on the rate of force redevelopment after slack/restretch. Simulations of twitch tension show that the presence of CIA increases peak tension while profoundly delaying relaxation. We tested the model’s ability to represent perturbations to the Ca^(2+) regulatory mechanism by analyzing twitch records measured in transgenic mice expressing a cardiac troponin I mutation (R145G). The effects of the mutation on twitch dynamics were fully reproduced by a single parameter change, namely lowering ΔG_(CIA) by 2.3 kJ mol^(−1) relative to its wild-type value. Our analyses suggest that CIA is present in cardiac muscle under normal conditions and that its modulation by gene mutations or other factors can alter both systolic and diastolic function

Automated computation of one-loop integrals in massless theories

We consider one-loop tensor and scalar integrals, which occur in a massless quantum field theory and we report on the implementation into a numerical program of an algorithm for the automated computation of these one-loop integrals. The number of external legs of the loop integrals is not restricted. All calculations are done within dimensional regularization.Comment: 28 pages, version to be publishe

Report of the QCD Tools Working Group

We report on the activities of the ``QCD Tools for heavy flavors and new physics searches'' working group of the Run II Workshop on QCD and Weak Bosons. The contributions cover the topics of improved parton showering and comparisons of Monte Carlo programs and resummation calculations, recent developments in Pythia, the methodology of measuring backgrounds to new physics searches, variable flavor number schemes for heavy quark electro-production, the underlying event in hard scattering processes, and the Monte Carlo MCFM for NLO processes.Comment: LaTeX, 47 pages, 41 figures, 10 tables, uses run2col.sty, to appear in the Proceedings of the Workshop on "QCD and Weak Boson Physics in Run II", Fermilab, March - November 199

Objective classification of fabric pilling based on the two-dimensional discrete wavelet transform

A number of methods for automated objective ratings of fabric pilling based on image analysis are described in the literature. The periodic structure of fabrics makes them suitable candidates for frequency domain analysis. We propose a new method of frequency domain analysis based on the two-dimensional discrete wavelet transform to objectively measure pilling intensity in sample images. We present a preliminary evaluation of the proposed method based on analysis of two series of standard pilling evaluation test images. The initial results suggest that the proposed method is feasible, and that the ability of the method to discriminate between levels of pilling intensity depends on the wavelet analysis scale being closely matched to the fabric interyarn pitch. We also present a heuristic method for optimal selection of an analysis wavelet and associated analysis scale. <br /

Use of in vivo phage display to engineer novel adenoviruses for targeted delivery to the cardiac vasculature

We performed in vivo phage display in the stroke prone spontaneously hypertensive rat, a cardiovascular disease model, and the normotensive Wistar Kyoto rat to identify cardiac targeting peptides, and then assessed each in the context of viral gene delivery. We identified both common and strain-selective peptides, potentially indicating ubiquitous markers and those found selectively in dysfunctional microvasculature of the heart. We show the utility of the peptide, DDTRHWG, for targeted gene delivery in human cells and rats in vivo when cloned into the fiber protein of subgroup D adenovirus 19p. This study therefore identifies cardiac targeting peptides by in vivo phage display and the potential of a candidate peptide for vector targeting strategies

Physical Properties of the X-ray Luminous SN 1978K in NGC 1313 from Multiwavelength Observations

We update the light curves from the X-ray, optical, and radio bandpasses which we have assembled over the past decade, and present two observations in the ultraviolet using the Hubble Space Telescope Faint Object Spectrograph. The HRI X-ray light curve is constant within the errors over the entire observation period. This behavior is confirmed in the ASCA GIS data obtained in 1993 and 1995. In the ultraviolet, we detected Ly-alpha, the [Ne IV] 2422/2424 A doublet, the Mg II doublet at 2800 A, and a line at ~3190 A we attribute to He I 3187. Only the Mg II and He I lines are detected at SN1978K's position. The optical light curve is formally constant within the errors, although a slight upward trend may be present. The radio light curve continues its steep decline. The longer time span of our radio observations compared to previous studies shows that SN1978K is in the same class of highly X-ray and radio-luminous supernovae as SN1986J and SN1988Z. The [Ne IV] emission is spatially distant from the location of SN1978K and originates in the pre-shocked matter. The Mg II doublet flux ratio implies the quantity of line optical depth times density of ~10^14 cm^-3 for its emission region. The emission site must lie in the shocked gas.Comment: 32 pages, 13 figs; LaTeX with AASTEXv5; paper accepted, scheduled for AJ, Dec 199

Social evolution in micro-organisms and a Trojan horse approach to medical intervention strategies

Medical science is typically pitted against the evolutionary forces acting upon infective populations of bacteria. As an alternative strategy, we could exploit our growing understanding of population dynamics of social traits in bacteria to help treat bacterial disease. In particular, population dynamics of social traits could be exploited to introduce less virulent strains of bacteria, or medically beneficial alleles into infective populations. We discuss how bacterial strains adopting different social strategies can invade a population of cooperative wild-type, considering public good cheats, cheats carrying medically beneficial alleles (Trojan horses) and cheats carrying allelopathic traits (anti-competitor chemical bacteriocins or temperate bacteriophage viruses). We suggest that exploitation of the ability of cheats to invade cooperative, wild-type populations is a potential new strategy for treating bacterial disease

Evc2 is a positive modulator of Hedgehog signalling that interacts with Evc at the cilia membrane and is also found in the nucleus

<p>Abstract</p> <p>Background</p> <p>Evc is essential for Indian Hedgehog (Hh) signalling in the cartilage growth plate. The gene encoding Evc2 is in close proximity in divergent orientation to <it>Evc </it>and mutations in both human genes lead to the chondrodysplasia Ellis-van Creveld syndrome.</p> <p>Results</p> <p>Bioinformatic analysis reveals that the <it>Evc </it>and <it>Evc2 </it>genes arose through a duplication event early in metazoan evolution and were subsequently lost in arthropods and nematodes. Here we demonstrate that Evc2 is essential for Hh pathway activation in response to the Smo agonist purmorphamine. A yeast two-hybrid screen using Evc as bait identified Evc2 as an Evc binding partner and we confirmed the interaction by immunoprecipitation. We developed anti-Evc2 antibodies and show that Evc2 and Evc co-localize at the basal body and also on primary cilia. In transfected cells, basal body and cilia localization is observed when Evc and Evc2 constructs are co-transfected but not when either construct is transfected individually. We show that Evc and Evc2 are cilia transmembrane proteins, the C-terminus for both being intracellular and Evc2, but not Evc, having an extracellular portion. Furthermore, Evc is absent at the basal body in Evc2 null cells. Using Western blots of cytoplasmic and nuclear protein, we also demonstrate that full length Evc2 but not Evc, is located in the nucleus.</p> <p>Conclusions</p> <p>We demonstrate for the first time that Evc2 is a positive regulator of the Hh signalling pathway and that it is located at the basal body of primary cilia. We show that the presence of Evc and Evc2 at the basal body and cilia membrane is co-dependent. In addition, Evc2, but not Evc, is present in the cell nucleus suggesting movement of Evc2 between the cilium and nucleus.</p

Adapting CALIPSO Climate Measurements for Near Real Time Analyses and Forecasting

The Cloud-Aerosol Lidar and Infrared Pathfinder satellite Observations (CALIPSO) mission was originally conceived and designed as a climate measurements mission, with considerable latency between data acquisition and the release of the level 1 and level 2 data products. However, the unique nature of the CALIPSO lidar backscatter profiles quickly led to the qualitative use of CALIPSO?s near real time (i.e., ? expedited?) lidar data imagery in several different forecasting applications. To enable quantitative use of their near real time analyses, the CALIPSO project recently expanded their expedited data catalog to include all of the standard level 1 and level 2 lidar data products. Also included is a new cloud cleared level 1.5 profile product developed for use by operational forecast centers for verification of aerosol predictions. This paper describes the architecture and content of the CALIPSO expedited data products. The fidelity and accuracy of the expedited products are assessed via comparisons to the standard CALIPSO data products

Self-driving Multimodal Studies at User Facilities

Multimodal characterization is commonly required for understanding materials. User facilities possess the infrastructure to perform these measurements, albeit in serial over days to months. In this paper, we describe a unified multimodal measurement of a single sample library at distant instruments, driven by a concert of distributed agents that use analysis from each modality to inform the direction of the other in real time. Powered by the Bluesky project at the National Synchrotron Light Source II, this experiment is a world's first for beamline science, and provides a blueprint for future approaches to multimodal and multifidelity experiments at user facilities.Comment: 36th Conference on Neural Information Processing Systems (NeurIPS 2022). AI4Mat Worksho