Predicting the effects of basepair mutations in DNA-protein complexes by thermodynamic integration

AbstractThermodynamically rigorous free energy methods in principle allow the exact computation of binding free energies in biological systems. Here, we use thermodynamic integration together with molecular dynamics simulations of a DNA-protein complex to compute relative binding free energies of a series of mutants of a protein-binding DNA operator sequence. A guanine-cytosine basepair that interacts strongly with the DNA-binding protein is mutated into adenine-thymine, cytosine-guanine, and thymine-adenine. It is shown that basepair mutations can be performed using a conservative protocol that gives error estimates of ∼10% of the change in free energy of binding. Despite the high CPU-time requirements, this work opens the exciting opportunity of being able to perform basepair scans to investigate protein-DNA binding specificity in great detail computationally

Tangles, trees, and flowers

A tangle of order $k$ in a matroid or graph may be thought of as a "$k$-connected component". For a tangle of order $k$ in a matroid or graph that satisfies a certain robustness condition, we describe a tree decomposition of the matroid or graph that displays, up to a certain natural equivalence, all of the $k$-separations of the matroid or graph that are non-trivial with respect to the tangle.Comment: 31 pages, 1 figur

IVLE4C a Conceptual Learning Environment for Teaching Enterprise Cybersecurity

The authors are working to improve students’ understanding of and classroom experience with enterprise cybersecurity. Central to this effort is development of the Integrated Virtual Learning Environment for Cybersecurity (IVLE4C), a teaching and learning tool intended for use by both teachers and students. The authors are endeavoring to incorporate into IVLE4C best practices from the knowledge domains of education, model-based systems engineering, and cybersecurity. A modern digital enterprise is a large-scale, complex system of systems. Enterprise cybersecurity is a special subset of the larger knowledge domain that merits special consideration when instructing students who lack relevant work experience. This lack of work experience creates a gap in students’ knowledge about the structure, operation, and control of a modern digital enterprise. Our guiding precept – coined Greer’s Rule of Thumb – is that: it is impossible to defend what cannot be visualized and described. Therefore, it is essential to address the student enterprise knowledge gap before attempting to teach the means for assuring enterprise cybersecurity. Viste and Skartveit (2004) propose using an interactive virtual learning environment with reality abstraction models when teaching the structure, operation, and control of a large-scale complex system. The creation of a virtual model enables a modern digital enterprise to be brought into the classroom. This allows for learning that is complementary to experiential learning that occurs during an internship and, possibly, a viable alternative when internships are unavailable or come later in a curriculum path. Once developed, a library of models representing different digital enterprise types can be used to accelerate student enterprise cybersecurity education in a controlled classroom environment. During the presentation, the authors will provide an update on the use of model-based system engineering practices and how they are being integrated into IVLE4C for developing a tailored, enterprise risk management strategy. This approach is consistent with guidance provided in the NIST Cybersecurity Framework. Research shows model-based systems engineering is increasingly being used for developing engineered cybersecurity solutions. An example of this is research performed by Robles-Ramirez et.al. (2020) on the application of model-based Cybersecurity Engineering for Connected and Automated Vehicles. Key is the notion of turning a cyber-attack surface into a trust boundary at targeted levels. IVLE4C version 1.0 is currently being used to teach Cyber Supply Chain Security at UNCW. Version 2.0 is a dynamic data driven web application, that is being developed for teaching Enterprise Security

Observations on the Ice-Breaking and Ice Navigation Behavior of Migrating Bowhead Whales (Balaena Mysticetus) near Point Barrow, Alaska, Spring 1985

During a four-day period from 28 April to 1 May 1985, we observed bowhead whales breaking up through sea ice in order to breathe. Our observations were made from grounded sea ice approximately 10 km northeast of Point Barrow, Alaska, during the spring bowhead migration (14 April to 10 June). From acoustic and visual data, it was estimated that 665 whales passed the observation perches during this four-day period. However, only 117(17%) whales were seen. The remaining whales either passed underneath the ice or were beyond the range of the visual observers. Whales used their heads, in the area of the blowholes, to push up against the ice (18 cm maximum thickness) and fracture it, creating a hummock of ice in which they were able to respire. Often during such breathing episodes, even at distances of only several hundred meters, the animal was not seen but its blows were clearly audible to the visual observers. Acoustic tracking of whales showed they avoided a large multi-year ice floe seaward of the observation perch. We hypothesize that bowheads use their calls to assess the thickness of ice in their migratory path. In assessing their calls, we suggest the whales can avoid areas where the ice is too thick to break through (to breath) and/or too thick to provide clearance for them to swim beneath.Key words: Balaena mysticetus, Point Barrow, bowhead whale, ice breaking, behavior, sea ice, singer, acoustic, anatomy, censusMots clés: Balaena mysticetus, Point Barrow, baleine franche, casser la glace, comportement, glace de mer, chanteuse, acoustique, anatomie, dénombremen

Longitudinal Pathogenesis Study of Young Red Deer (Cervus elaphus) after Experimental Challenge with Mycobacterium avium subsp. paratuberculosis (MAP)

Paratuberculosis progresses more quickly in young red deer than in sheep or cattle. This study describes the clinical, immunological and pathological changes over a 50-week period in fourteen 4-month-old red deer that received heavy oral challenge with Mycobacterium avium subsp. paratuberculosis (MAP). At 4 and 12 weeks post challenge they were anaesthetized and a section of jejunal lymph node was surgically removed for culture, histopathology, and genetic studies. All 14 deer became infected, none were clinically affected, and they had varying degrees of subclinical disease when killed at week 50. Week 4 biopsies showed no paratuberculosis lesions, but MAP was cultured from all animals. At weeks 12 and 50 histopathological lesions ranged from mild to severe with corresponding low-to-high antibody titres, which peaked at 12–24 weeks. IFN-γ responses peaked at 8–15 weeks and were higher in mildly affected animals than in those with severe lesions