The properties of Msh2-Msh6 ATP binding mutants suggest a signal amplification mechanism in DNA mismatch repair.

DNA mismatch repair (MMR) corrects mispaired DNA bases and small insertion/deletion loops generated by DNA replication errors. After binding a mispair, the eukaryotic mispair recognition complex Msh2-Msh6 binds ATP in both of its nucleotide-binding sites, which induces a conformational change resulting in the formation of an Msh2-Msh6 sliding clamp that releases from the mispair and slides freely along the DNA. However, the roles that Msh2-Msh6 sliding clamps play in MMR remain poorly understood. Here, using Saccharomyces cerevisiae, we created Msh2 and Msh6 Walker A nucleotide-binding site mutants that have defects in ATP binding in one or both nucleotide-binding sites of the Msh2-Msh6 heterodimer. We found that these mutations cause a complete MMR defect in vivo The mutant Msh2-Msh6 complexes exhibited normal mispair recognition and were proficient at recruiting the MMR endonuclease Mlh1-Pms1 to mispaired DNA. At physiological (2.5 mm) ATP concentration, the mutant complexes displayed modest partial defects in supporting MMR in reconstituted Mlh1-Pms1-independent and Mlh1-Pms1-dependent MMR reactions in vitro and in activation of the Mlh1-Pms1 endonuclease and showed a more severe defect at low (0.1 mm) ATP concentration. In contrast, five of the mutants were completely defective and one was mostly defective for sliding clamp formation at high and low ATP concentrations. These findings suggest that mispair-dependent sliding clamp formation triggers binding of additional Msh2-Msh6 complexes and that further recruitment of additional downstream MMR proteins is required for signal amplification of mispair binding during MMR

A concurrent precursor inflow method for Large Eddy Simulations and applications to finite length wind farms

In order to enable simulations of developing wind turbine array boundary layers with highly realistic inflow conditions a concurrent precursor method for Large Eddy Simulations is proposed. In this method we consider two domains simultaneously, i.e. in one domain a turbulent Atmospheric Boundary Layer (ABL) without wind turbines is simulated in order to generate the turbulent inflow conditions for a second domain in which the wind turbines are placed. The benefit of this approach is that a) it avoids the need for large databases in which the turbulent inflow conditions are stored and the correspondingly slow I/O operations and b) we are sure that the simulations are not negatively affected by statically swept fixed inflow fields or synthetic fields lacking the proper ABL coherent structures. Sample applications are presented, in which, in agreement with field data a strong decrease of the power output of downstream wind-turbines with respect to the first row of wind-turbines is observed for perfectly aligned inflow.Comment: 13 pages, 5 figure

Application of digital particle image velocimetry to insect aerodynamics: measurement of the leading-edge vortex and near wake of a Hawkmoth.

Some insects use leading-edge vortices to generate high lift forces, as has been inferred from qualitative smoke visualisations of the flow around their wings. Here we present the first Digital Particle Image Velocimetry (DPIV) data and quantitative analysis of an insect’s leading-edge vortex and near wake at two flight speeds. This allows us to describe objectively 2D slices through the flow field of a tethered Tobacco Hawkmoth (Manduca sexta). The near-field vortex wake appears to braodly resemble elliptical vortex loops. The presence of a leading-edge vortex towards the end of the downstroke is found to coincide with peak upward force production measured by a six-component force–moment balance. The topology of Manduca’s leading-edge vortex differs from that previously described because late in the downstroke, the structure extends continuously from wingtip across the thorax to the other wingtip

Effects of Replacing Oxygenated Functionality with Fluorine on Lipophilicity

The replacement of oxygenated functionality (hydroxy and alkoxy) with a fluorine atom is a commonly used bioisosteric replacement in medicinal chemistry. In this paper, we use molecular matched-pair analysis to better understand the effects of this replacement on lipophilicity. It seems that the reduced log P of the oxygenated compound is normally dominant in determining the size of this difference. We observe that the presence of additional electron-donating groups on an aromatic ring generally increases the difference in lipophilicity between an oxygenated compound and its fluorinated analogue, while electron-withdrawing groups lead to smaller differences. Ortho-substituted compounds generally display a reduced difference in log P compared to para- and meta-substituted compounds, particularly if an ortho-substituent can form an intramolecular hydrogen bond. Hydrogen-bond acceptors remote to an aromatic ring containing fluorine/oxygen can also reduce the difference in log P between oxygen- and fluorine-substituted compounds

Detecting gravitational radiation from neutron stars using a six-parameter adaptive MCMC method

We present a Markov chain Monte Carlo technique for detecting gravitational radiation from a neutron star in laser interferometer data. The algorithm can estimate up to six unknown parameters of the target, including the rotation frequency and frequency derivative, using reparametrization, delayed rejection and simulated annealing. We highlight how a simple extension of the method, distributed over multiple computer processors, will allow for a search over a narrow frequency band. The ultimate goal of this research is to search for sources at a known locations, but uncertain spin parameters, such as may be found in SN1987A.Comment: Submitted to Classical and Quantum Gravity for GWDAW-8 proceeding

Memories for Life: A Review of the Science and Technology

This paper discusses scientific, social and technological aspects of memory. Recent developments in our understanding of memory processes and mechanisms, and their digital implementation, have placed the encoding, storage, management and retrieval of information at the forefront of several fields of research. At the same time, the divisions between the biological, physical and the digital worlds seem to be dissolving. Hence opportunities for interdisciplinary research into memory are being created, between the life sciences, social sciences and physical sciences. Such research may benefit from immediate application into information management technology as a testbed. The paper describes one initiative, Memories for Life, as a potential common problem space for the various interested disciplines

Flow instabilities in circular Couette flow of wormlike micelle solutions with a reentrant flow curve

In this work, we numerically investigate flow instabilities of inertialess circular Couette flow of dilute wormlike micelle solutions. Using the reformulated reactive rod model (RRM-R) [Hommel and Graham, JNNFM 295 (2021) 104606], which treats micelles as rigid Brownian rods undergoing reversible scission and fusion in flow, we study the development and behavior of both vorticity banding and finger-like instabilities. In particular, we focus on solutions that exhibit reentrant constitutive curves, in which there exists some region where the shear stress, $\tau$, has a multivalued relation to shear rate, $\dot{\gamma}$. We find that the radial dependence of the shear stress in circular Couette flow allows for solutions in which parts of the domain lie in the region of the flow curve where $\partial \tau /\partial \dot{\gamma} > 0$, while others lie in the region where $\partial \tau /\partial \dot{\gamma} < 0$; this mixed behavior can lead to complex flow instabilities that manifest as finger-like structures of elongated and anisotropically-oriented micelles. In 3D simulations we find that the initial instability is 2D in origin, and 3D finger-like structures arise through the axial instability of 2D sheets. Finally, we show that the RRM-R can capture vorticity banding in narrow-gap circular Couette flow and that vorticity bands are linearly stable to perturbations.Comment: 42 pages, 27 figures, 5 supplemental movie

Trapped-ion quantum error-correcting protocols using only global operations

Quantum error-correcting codes are many-body entangled states that are prepared and measured using complex sequences of entangling operations. Each element of such an entangling sequence introduces noise to delicate quantum information during the encoding or reading out of the code. It is important therefore to find efficient entangling protocols to avoid the loss of information. Here we propose an experiment that uses only global entangling operations to encode an arbitrary logical qubit to either the five-qubit repetition code or the five-qubit code, with a six-ion Coulomb crystal architecture in a Penning trap. We show that the use of global operations enables us to prepare and read out these codes using only six and ten global entangling pulses, respectively. The proposed experiment also allows the acquisition of syndrome information during readout. We provide a noise analysis for the presented protocols, estimating that we can achieve a six-fold improvement in coherence time with noise as high as $\sim 1\%$ on each entangling operation.Comment: 7 pages, 4 figures, published version, comments are welcom

The Role of Rights in Benefit Cost Methodology: The Example of Salmon and Hydroelectric Dams

Benefit cost analysis is a well-established technique for assessing the impacts of proposed actions. Accurate benefit cost analysis is essential to making informed decisions through an understanding of the trade-offs involved in alternative actions. This Article presents a methodology for improving current benefit cost techniques and hence the usefulness of benefit cost analysis to decisionmakers. The proposed methodology is based on recognition of the roles of legal rights and psychological expectations in benefit cost analysis. Proper consideration of these rights and expectations is critical to an accurate determination of how benefits and costs are measured and whose interests are included in the analysis. Addressing these issues will provide more accurate and comprehensive information to decisionmakers. Application of the proposed methodology may significantly affect the outcome of a benefit cost analysis and hence impact the decisionmaking process

Separating baryons and dark matter in cluster cores: a full 2-D lensing and dynamic analysis of Abell 383 and MS2137-23

(abridged) We utilize existing imaging and spectroscopic data for the galaxy clusters MS2137-23 and Abell 383 to present improved measures of the distribution of dark and baryonic material in the clusters' central regions. Our method, based on the combination of gravitational lensing and dynamical data, is uniquely capable of separating the distribution of dark and baryonic components at scales below 100 kpc. We find a variety of strong lensing models fit the available data, including some with dark matter profiles as steep as expected from recent simulations. However, when combined with stellar velocity dispersion data for the brightest member, shallower inner slopes than predicted by numerical simulations are preferred. For Abell 383, the preferred shallow inner slopes are statistically a good fit only when the multiple image position uncertainties associated with our lens model are assumed to be 0\farcs5, to account for unknown substructure. No statistically satisfactory fit was obtained matching both the multiple image lensing data and the velocity dispersion profile of the brightest cluster galaxy in MS2137-23. This suggests that the mass model we are using, which comprises a pseudo-elliptical generalized NFW profile and a brightest cluster galaxy component may inadequately represent the inner cluster regions. This may plausibly arise due to halo triaxiality or by the gravitational interaction of baryons and dark matter in cluster cores. However, the progress made via this detailed study highlights the key role that complementary observations of lensed features and stellar dynamics offer in understanding the interaction between dark and baryonic matter on non-linear scales in the central regions of clusters.Comment: 18 pages, 9 figures; accepted for publication in the Astrophysical Journa