Footprinting with MPE•Fe(II). Complementary-strand analyses of distamycin- and actinomycin-binding sites on heterogeneous DNA

We recently reported a direct technique for determining the binding sites of small molecules on naturally occurring heterogeneous DNA (Van Dyke et al. 1982). Methidiumpropyl-EDTA·Fe(II) (MPE·Fe[II]) (Hertzberg and Dervan 1982) cleaves double-helical DNA with low sequence-specificity (Van Dyke et al. 1982). Using a combination of MPE·Fe(II) partial cleavage of drug-protected DNA fragments and Maxam-Gilbert sequencing methods, we determined the drug-protected sites on one strand of a double-helical fragment from pBR322 for the intercalator actinomycin D (Goldberg et al. 1962; Muller and Crothers 1968; Wells and Larson 1970; Sobell 1973; Krugh 1981; Patel et al. 1981; Takusagawa et al. 1982) and the minor-groove binders netropsin and distamycin A (Luck et al. 1974; Wartell et al. 1974; Zimmer 1975; Berman et al. 1979; Krylov et al. 1979). Netropsin and distamycin A gave identical DNA-cleavage inhibition patterns or footprints in regions rich in dA·dT base pairs. Actinomycin D afforded a completely different footprint..

Generalized Master Equations for Non-Poisson Dynamics on Networks

The traditional way of studying temporal networks is to aggregate the dynamics of the edges to create a static weighted network. This implicitly assumes that the edges are governed by Poisson processes, which is not typically the case in empirical temporal networks. Consequently, we examine the effects of non-Poisson inter-event statistics on the dynamics of edges, and we apply the concept of a generalized master equation to the study of continuous-time random walks on networks. We show that the equation reduces to the standard rate equations when the underlying process is Poisson and that the stationary solution is determined by an effective transition matrix whose leading eigenvector is easy to calculate. We discuss the implications of our work for dynamical processes on temporal networks and for the construction of network diagnostics that take into account their nontrivial stochastic nature

Superheating fields of superconductors: Asymptotic analysis and numerical results

The superheated Meissner state in type-I superconductors is studied both analytically and numerically within the framework of Ginzburg-Landau theory. Using the method of matched asymptotic expansions we have developed a systematic expansion for the solutions of the Ginzburg-Landau equations in the limit of small $\kappa$, and have determined the maximum superheating field $H_{\rm sh}$ for the existence of the metastable, superheated Meissner state as an expansion in powers of $\kappa^{1/2}$. Our numerical solutions of these equations agree quite well with the asymptotic solutions for $\kappa<0.5$. The same asymptotic methods are also used to study the stability of the solutions, as well as a modified version of the Ginzburg-Landau equations which incorporates nonlocal electrodynamics. Finally, we compare our numerical results for the superheating field for large-$\kappa$ against recent asymptotic results for large-$\kappa$, and again find a close agreement. Our results demonstrate the efficacy of the method of matched asymptotic expansions for dealing with problems in inhomogeneous superconductivity involving boundary layers.Comment: 14 pages, 8 uuencoded figures, Revtex 3.

Recent FUSE Observations of Diffuse O VI Emission from the Interstellar Medium

We present new results from our survey of diffuse O VI-emitting gas in the interstellar medium with the Far Ultraviolet Spectroscopic Explorer (FUSE). Background observations obtained since 2005 have yielded eleven new O VI detections of 3-sigma significance, and archival searches have revealed two more. An additional 15 sight lines yield interesting upper limits. Combined with previous results, these observations reveal the large-scale structure of the O VI-bearing gas in the quadrant of the sky centered on the Magellanic Clouds. The most prominent feature is a layer of low-velocity O VI emission extending more than 70 degrees from the Galactic plane. At low latitudes (|b| < 30 degrees), the emission comes from narrow, high-density conductive interfaces in the local ISM. At high latitudes, the emission is from extended, low-density regions in the Galactic halo. We also detect O VI emission from the interface region of the Magellanic System, a structure recently identified from H I observations. These are the first detections of emission from high-ionization species in the Magellanic System outside of the Clouds themselves.Comment: 18 pages, 11 Postscript figures. To appear in Ap

Asymptotic analysis for singularly perturbed convection-diffusion equations with a turning point

Turning points occur in many circumstances in fluid mechanics. When the viscosity is small, very complex phenomena can occur near turning points, which are not yet well understood. A model problem, corresponding to a linear convection-diffusion equation (e.g., suitable linearization of the Navier-Stokes or B&amp;#769;nard convection equations) is considered. Our analysis shows the diversity and complexity of behaviors and boundary or interior layers which already appear for our equations simpler than the Navier-Stokes or B&amp;#769;nard convection equations. Of course the diversity and complexity of these structures will have to be taken into consideration for the study of the nonlinear problems. In our case, at this stage, the full theoretical (asymptotic) analysis is provided. This study is totally new to the best of our knowledge. Numerical treatment and more complex problems will be considered elsewhere.open91

Bifunctional Ligands Allow Deliberate Extrinsic Reprogramming of the Glucocorticoid Receptor

Therapies based on conventional nuclear receptor ligands are extremely powerful, yet their broad and long-term use is often hindered by undesired side effects that are often part of the receptor\u27s biological function. Selective control of nuclear receptors such as the glucocorticoid receptor (GR) using conventional ligands has proven particularly challenging. Because they act solely in an allosteric manner, conventional ligands are constrained to act via cofactors that can intrinsically partner with the receptor. Furthermore, effective means to rationally encode a bias for specific coregulators are generally lacking. Using the (GR) as a framework, we demonstrate here a versatile approach, based on bifunctional ligands, that extends the regulatory repertoire of GR in a deliberate and controlled manner. By linking the macrolide FK506 to a conventional agonist (dexamethasone) or antagonist (RU-486), we demonstrate that it is possible to bridge the intact receptor to either positively or negatively acting coregulatory proteins bearing an FK506 binding protein domain. Using this strategy, we show that extrinsic recruitment of a strong activation function can enhance the efficacy of the full agonist dexamethasone and reverse the antagonist character of RU-486 at an endogenous locus. Notably, the extrinsic recruitment of histone deacetylase-1 reduces the ability of GR to activate transcription from a canonical GR response element while preserving ligand-mediated repression of nuclear factor-κB. By providing novel ways for the receptor to engage specific coregulators, this unique ligand design approach has the potential to yield both novel tools for GR study and more selective therapeutics

Local Causal States and Discrete Coherent Structures

Coherent structures form spontaneously in nonlinear spatiotemporal systems and are found at all spatial scales in natural phenomena from laboratory hydrodynamic flows and chemical reactions to ocean, atmosphere, and planetary climate dynamics. Phenomenologically, they appear as key components that organize the macroscopic behaviors in such systems. Despite a century of effort, they have eluded rigorous analysis and empirical prediction, with progress being made only recently. As a step in this, we present a formal theory of coherent structures in fully-discrete dynamical field theories. It builds on the notion of structure introduced by computational mechanics, generalizing it to a local spatiotemporal setting. The analysis' main tool employs the \localstates, which are used to uncover a system's hidden spatiotemporal symmetries and which identify coherent structures as spatially-localized deviations from those symmetries. The approach is behavior-driven in the sense that it does not rely on directly analyzing spatiotemporal equations of motion, rather it considers only the spatiotemporal fields a system generates. As such, it offers an unsupervised approach to discover and describe coherent structures. We illustrate the approach by analyzing coherent structures generated by elementary cellular automata, comparing the results with an earlier, dynamic-invariant-set approach that decomposes fields into domains, particles, and particle interactions.Comment: 27 pages, 10 figures; http://csc.ucdavis.edu/~cmg/compmech/pubs/dcs.ht

The Impact of Implementing Hypofractionation Prescription Regimens and Modernizing Delivery Technique on Treatment Resources in Breast Radiotherapy

Purpose/Objective(s): To determine the change in treatment resources due to the implementation of hypofractionated prescription regimen. Materials/Methods: All patients between January 1, 2012 and December 31, 2021 receiving curative intent breast radiotherapy at a tertiary cancer center were included. Plan and patient data were extracted from the patient database with the treatment planning system and direct database query. Treatment plan categorization was completed using data elements to include only curative intent. Treatment plans for seroma boost or supraclavicular irradiation were excluded to ensure this analysis did not double-count regional nodal irradiation contribution or confound boost with hypofractionation. Treatment delivery time is recorded in the database for each patient treatment delivered. Average patient treatment time per year was estimated by multiplying the average fractions each year by average time in the same year. The standard fractionation regimens (95% of patients) are 42.56 Gy in 16, 40 Gy in 16, 27 Gy in 5 (accelerated partial breast irradiation), and 26 Gy in 5 (FAST-Forward). In the analysis, implementation milestones are indicated for new prescription regimens and delivery technique changes including deep inspiration breath hold (DIBH) for left-sided patient treatments and daily verification imaging. Results: A total of 6505 patients were included. Table 1 details the total number of patients per year, the average number of fractions treated per patient, and the average treatment time of each patient plan. The average total fractions per treatment decreased from 17.5 in 2012 to 10.9 in 2021. The average treatment delivery time increased from 12.9 minutes to 21.4 minutes. Conclusion: In considering total treatment resources, the interplay between hypofractionation and modernization delivery techniques is complex. The impact of hypofractionation reduced the average number of fractions but total treatment resources are offset with the implementation of modern treatment delivery techniques. Hypofractionated prescription regimens reduce the time and travel commitment required of patients on an individual basis, contributing to person-centered care

Towards an effective potential for the monomer, dimer, hexamer, solid and liquid forms of hydrogen fluoride

We present an attempt to build up a new two-body effective potential for hydrogen fluoride, fitted to theoretical and experimental data relevant not only to the gas and liquid phases, but also to the crystal. The model is simple enough to be used in Molecular Dynamics and Monte Carlo simulations. The potential consists of: a) an intra-molecular contribution, allowing for variations of the molecular length, plus b) an inter-molecular part, with three charged sites on each monomer and a Buckingham "exp-6" interaction between fluorines. The model is able to reproduce a significant number of observables on the monomer, dimer, hexamer, solid and liquid forms of HF. The shortcomings of the model are pointed out and possible improvements are finally discussed.Comment: LaTeX, 24 pages, 2 figures. For related papers see also http://www.chim.unifi.it:8080/~valle

Safe and just operating spaces for regional social-ecological systems

Humanity faces a major global challenge in achieving wellbeing for all, while simultaneously ensuring that the biophysical processes and ecosystem services that underpin wellbeing are exploited within scientifically informed boundaries of sustainability. We propose a framework for defining the safe and just operating space for humanity that integrates social wellbeing into the original planetary boundaries concept (Rockström et al., 2009a,b) for application at regional scales. We argue that such a framework can: (1) increase the policy impact of the boundaries concept as most governance takes place at the regional rather than planetary scale; (2) contribute to the understanding and dissemination of complexity thinking throughout governance and policy-making; (3) act as a powerful metaphor and communication tool for regional equity and sustainability. We demonstrate the approach in two rural Chinese localities where we define the safe and just operating space that lies between an environmental ceiling and a social foundation from analysis of time series drawn from monitored and palaeoecological data, and from social survey statistics respectively. Agricultural intensification has led to poverty reduction, though not eradicated it, but at the expense of environmental degradation. Currently, the environmental ceiling is exceeded for degraded water quality at both localities even though the least well-met social standards are for available piped water and sanitation. The conjunction of these social needs and environmental constraints around the issue of water access and quality illustrates the broader value of the safe and just operating space approach for sustainable development