A Double-Strand Elastic Rod Theory

Abstract.: Motivated by applications in the modeling of deformations of the DNA double helix, we construct a continuum mechanics model of two elastically interacting elastic strands. The two strands are described in terms of averaged, or macroscopic, variables plus an additional small, internal or microscopic, perturbation. We call this composite structure a birod. The balance laws for the macroscopic configuration variables of the birod can be cast in the form of a classic Cosserat rod model with coupling to the internal balance laws through the constitutive relations. The internal balance laws for the microstructure variables also take a mathematical form analogous to that for a Cosserat rod, but with coupling to the macroscopic system through terms corresponding to distributed force and couple load

Analyzing ion distributions around DNA: sequence-dependence of potassium ion distributions from microsecond molecular dynamics

Microsecond molecular dynamics simulations of B-DNA oligomers carried out in an aqueous environment with a physiological salt concentration enable us to perform a detailed analysis of how potassium ions interact with the double helix. The oligomers studied contain all 136 distinct tetranucleotides and we are thus able to make a comprehensive analysis of base sequence effects. Using a recently developed curvilinear helicoidal coordinate method we are able to analyze the details of ion populations and densities within the major and minor grooves and in the space surrounding DNA. The results show higher ion populations than have typically been observed in earlier studies and sequence effects that go beyond the nature of individual base pairs or base pair steps. We also show that, in some special cases, ion distributions converge very slowly and, on a microsecond timescale, do not reflect the symmetry of the corresponding base sequenc

Analyzing ion distributions around DNA

We present a new method for analyzing ion, or molecule, distributions around helical nucleic acids and illustrate the approach by analyzing data derived from molecular dynamics simulations. The analysis is based on the use of curvilinear helicoidal coordinates and leads to highly localized ion densities compared to those obtained by simply superposing molecular dynamics snapshots in Cartesian space. The results identify highly populated and sequence-dependent regions where ions strongly interact with the nucleic and are coupled to its conformational fluctuations. The data from this approach is presented as ion populations or ion densities (in units of molarity) and can be analyzed in radial, angular and longitudinal coordinates using 1D or 2D graphics. It is also possible to regenerate 3D densities in Cartesian space. This approach makes it easy to understand and compare ion distributions and also allows the calculation of average ion populations in any desired zone surrounding a nucleic acid without requiring references to its constituent atoms. The method is illustrated using microsecond molecular dynamics simulations for two different DNA oligomers in the presence of 0.15 M potassium chloride. We discuss the results in terms of convergence, sequence-specific ion binding and coupling with DNA conformatio

Analyzing ion distributions around DNA: sequence-dependence of potassium ion distributions from microsecond molecular dynamics

Microsecond molecular dynamics simulations of B-DNA oligomers carried out in an aqueous environment with a physiological salt concentration enable us to perform a detailed analysis of how potassium ions interact with the double helix. The oligomers studied contain all 136 distinct tetranucleotides and we are thus able to make a comprehensive analysis of base sequence effects. Using a recently developed curvilinear helicoidal coordinate method we are able to analyze the details of ion populations and densities within the major and minor grooves and in the space surrounding DNA. The results show higher ion populations than have typically been observed in earlier studies and sequence effects that go beyond the nature of individual base pairs or base pair steps. We also show that, in some special cases, ion distributions converge very slowly and, on a microsecond timescale, do not reflect the symmetry of the corresponding base sequence

Practical multimodal care for cancer cachexia

Purpose of reviewCancer cachexia is common and reduces function, treatment tolerability and quality of life. Given its multifaceted pathophysiology a multimodal approach to cachexia management is advocated for, but can be difficult to realise in practice. We use a case-based approach to highlight practical approaches to the multimodal management of cachexia for patients across the cancer trajectory.Recent findingsFour cases with lung cancer spanning surgical resection, radical chemoradiotherapy, palliative chemotherapy and no anticancer treatment are presented. We propose multimodal care approaches that incorporate nutritional support, exercise, and anti-inflammatory agents, on a background of personalized oncology care and family-centred education. Collectively, the cases reveal that multimodal care is part of everyone's remit, often focuses on supported self-management, and demands buy-in from the patient and their family. Once operationalized, multimodal care approaches can be tested pragmatically, including alongside emerging pharmacological cachexia treatments.SummaryWe demonstrate that multimodal care for cancer cachexia can be achieved using simple treatments and without a dedicated team of specialists. The sharing of advice between health professionals can help build collective confidence and expertise, moving towards a position in which every team member feels they can contribute towards multimodal care

Bending modes of DNA directly addressed by cryo-electron microscopy of DNA minicircles

We use cryo-electron microscopy (cryo-EM) to study the 3D shapes of 94-bp-long DNA minicircles and address the question of whether cyclization of such short DNA molecules necessitates the formation of sharp, localized kinks in DNA or whether the necessary bending can be redistributed and accomplished within the limits of the elastic, standard model of DNA flexibility. By comparing the shapes of covalently closed, nicked and gapped DNA minicircles, we conclude that 94-bp-long covalently closed and nicked DNA minicircles do not show sharp kinks while gapped DNA molecules, containing very flexible single-stranded regions, do show sharp kinks. We corroborate the results of cryo-EM studies by using Bal31 nuclease to probe for the existence of kinks in 94-bp-long minicircle

The shapes of physical trefoil knots

We perform a compare-and-contrast investigation between the equilibrium shapes of physical and ideal trefoil knots, both in closed and open configurations. Ideal knots are purely geometric abstractions for the tightest configuration tied in a perfectly flexible, self-avoiding tube with an inextensible centerline and undeformable cross-sections. Here, we construct physical realizations of tight trefoil knots tied in an elastomeric rod, and use X-ray tomography and 3D finite element simulation for detailed characterization. Specifically, we evaluate the role of elasticity in dictating the physical knot's overall shape, self-contact regions, curvature profile, and cross-section deformation. We compare the shape of our elastic knots to prior computations of the corresponding ideal configurations. Our results on tight physical knots exhibit many similarities to their purely geometric counterparts, but also some striking dissimilarities that we examine in detail. These observations raise the hypothesis that regions of localized elastic deformation, not captured by the geometric models, could act as precursors for the weak spots that compromise the strength of knotted filaments

Analyzing ion distributions around DNA

We present a new method for analyzing ion, or molecule, distributions around helical nucleic acids and illustrate the approach by analyzing data derived from molecular dynamics simulations. The analysis is based on the use of curvilinear helicoidal coordinates and leads to highly localized ion densities compared to those obtained by simply superposing molecular dynamics snapshots in Cartesian space. The results identify highly populated and sequence-dependent regions where ions strongly interact with the nucleic and are coupled to its conformational fluctuations. The data from this approach is presented as ion populations or ion densities (in units of molarity) and can be analyzed in radial, angular and longitudinal coordinates using 1D or 2D graphics. It is also possible to regenerate 3D densities in Cartesian space. This approach makes it easy to understand and compare ion distributions and also allows the calculation of average ion populations in any desired zone surrounding a nucleic acid without requiring references to its constituent atoms. The method is illustrated using microsecond molecular dynamics simulations for two different DNA oligomers in the presence of 0.15 M potassium chloride. We discuss the results in terms of convergence, sequence-specific ion binding and coupling with DNA conformation