William R. Brinkley:A giant in biomedical research and public policy

Susan A. Gerbi, Robert E. Palazzo, William C. Earnshaw, and William T. Schrader discuss the life and achievements of William R. Brinkley, who passed away on November 10, 2020

Inducible DNA breaks in Ig S regions are dependent on AID and UNG

Class switch recombination (CSR) occurs by an intrachromosomal deletion whereby the IgM constant region gene (Cμ) is replaced by a downstream constant region gene. This unique recombination event involves formation of double-strand breaks (DSBs) in immunoglobulin switch (S) regions, and requires activation-induced cytidine deaminase (AID), which converts cytosines to uracils. Repair of the uracils is proposed to lead to DNA breaks required for recombination. Uracil DNA glycosylase (UNG) is required for most CSR activity although its role is disputed. Here we use ligation-mediated PCR to detect DSBs in S regions in splenic B cells undergoing CSR. We find that the kinetics of DSB induction corresponds with AID expression, and that DSBs are AID- and UNG-dependent and occur preferentially at G:C basepairs in WRC/GYW AID hotspots. Our results indicate that AID attacks cytosines on both DNA strands, and staggered breaks are processed to blunt DSBs at the initiating ss break sites. We propose a model to explain the types of end-processing events observed

Computing the local pressure in molecular dynamics simulations

Computer simulations of inhomogeneous soft matter systems often require accurate methods for computing the local pressure. We present a simple derivation, based on the virial relation, of two equivalent expressions for the local (atomistic) pressure in a molecular dynamics simulation. One of these expressions, previously derived by other authors via a different route, involves summation over interactions between particles within the region of interest; the other involves summation over interactions across the boundary of the region of interest. We illustrate our derivation using simulations of a simple osmotic system; both expressions produce accurate results even when the region of interest over which the pressure is measured is very small.Comment: 11 pages, 4 figure

Positronic lithium, an electronically stable Li-e+^+ ground state

Calculations of the positron-Li system were performed using the Stochastic Variational Method and yielded a minimum energy of -7.53208 Hartree for the L=0 ground state. Unlike previous calculations of this system, the system was found to be stable against dissociation into the Ps + Li$^+$ channel with a binding energy of 0.00217 Hartree and is therefore electronically stable. This is the first instance of a rigorous calculation predicting that it is possible to combine a positron with a neutral atom and form an electronically stable bound state.Comment: 11 pages, 2 tables. To be published in Phys.Rev.Let

Molecular Tweezers with Varying Anions: A Comparative Study

Selective binding of the phosphate-substituted molecular tweezer 1a to protein lysine residues was suggested to explain the inhibition of certain enzymes and the aberrant aggregation of amyloid petide Aβ42 or α-synuclein, which are assumed to be responsible for Alzheimer’s and Parkinson’s disease, respectively. In this work we systematically investigated the binding of four water-soluble tweezers 1a−d (substituted by phosphate, methanephosphonate, sulfate, or O-methylenecarboxylate groups) to amino acids and peptides containing lysine or arginine residues by using fluorescence spectroscopy, NMR spectroscopy, and isothermal titration calorimetry (ITC). The comparison of the experimental results with theoretical data obtained by a combination of QM/MM and ab initio 1H NMR shift calculations provides clear evidence that the tweezers 1a−c bind the amino acid or peptide guest molecules by threading the lysine or arginine side chain through the tweezers’ cavity, whereas in the case of 1d the guest molecule is preferentially positioned outside the tweezer’s cavity. Attractive ionic, CH-π, and hydrophobic interactions are here the major binding forces. The combination of experiment and theory provides deep insight into the host−guest binding modes, a prerequisite to understanding the exciting influence of these tweezers on the aggregation of proteins and the activity of enzymes

Positron and positronium affinities in the work-formalism Hartree-Fock approximation

Positron binding to anions is investigated within the work formalism proposed by Harbola and Sahni for the halide anions and the systems Li^- through O^- excluding Be^- and N^-. The toal ground-state energies of the anion-positron bound systems are empirically found to be an upper bound to the Hartree-Fock energies. The computed expectation values as well as positron and positronium affinities are in good agreement with their restricted Hartree-Fock counterparts. Binding of a positron to neutral species is also investigated using an iterative method.Comment: 12 pages, to appear in Physical Review

Existence criteria for stabilization from the scaling behaviour of ionization probabilities

We provide a systematic derivation of the scaling behaviour of various quantities and establish in particular the scale invariance of the ionization probability. We discuss the gauge invariance of the scaling properties and the manner in which they can be exploited as consistency check in explicit analytical expressions, in perturbation theory, in the Kramers-Henneberger and Floquet approximation, in upper and lower bound estimates and fully numerical solutions of the time dependent Schroedinger equation. The scaling invariance leads to a differential equation which has to be satisfied by the ionization probability and which yields an alternative criterium for the existence of atomic bound state stabilization.Comment: 12 pages of Latex, one figur

Power Spectrum Analysis of Physikalisch-Technische Bundesanstalt Decay-Rate Data: Evidence for Solar Rotational Modulation

Evidence for an anomalous annual periodicity in certain nuclear decay data has led to speculation concerning a possible solar influence on nuclear processes. We have recently analyzed data concerning the decay rates of Cl-36 and Si-32, acquired at the Brookhaven National Laboratory (BNL), to search for evidence that might be indicative of a process involving solar rotation. Smoothing of the power spectrum by weighted-running-mean analysis leads to a significant peak at frequency 11.18/yr, which is lower than the equatorial synodic rotation rates of the convection and radiative zones. This article concerns measurements of the decay rates of Ra-226 acquired at the Physikalisch-Technische Bundesanstalt (PTB) in Germany. We find that a similar (but not identical) analysis yields a significant peak in the PTB dataset at frequency 11.21/yr, and a peak in the BNL dataset at 11.25/yr. The change in the BNL result is not significant since the uncertainties in the BNL and PTB analyses are estimated to be 0.13/yr and 0.07/yr, respectively. Combining the two running means by forming the joint power statistic leads to a highly significant peak at frequency 11.23/yr. We comment briefly on the possible implications of these results for solar physics and for particle physics.Comment: 15 pages, 13 figure

Brownian Motions on Metric Graphs

Brownian motions on a metric graph are defined. Their generators are characterized as Laplace operators subject to Wentzell boundary at every vertex. Conversely, given a set of Wentzell boundary conditions at the vertices of a metric graph, a Brownian motion is constructed pathwise on this graph so that its generator satisfies the given boundary conditions.Comment: 43 pages, 7 figures. 2nd revision of our article 1102.4937: The introduction has been modified, several references were added. This article will appear in the special issue of Journal of Mathematical Physics celebrating Elliott Lieb's 80th birthda