Stochastic theory of large-scale enzyme-reaction networks: Finite copy number corrections to rate equation models

Chemical reactions inside cells occur in compartment volumes in the range of atto- to femtolitres. Physiological concentrations realized in such small volumes imply low copy numbers of interacting molecules with the consequence of considerable fluctuations in the concentrations. In contrast, rate equation models are based on the implicit assumption of infinitely large numbers of interacting molecules, or equivalently, that reactions occur in infinite volumes at constant macroscopic concentrations. In this article we compute the finite-volume corrections (or equivalently the finite copy number corrections) to the solutions of the rate equations for chemical reaction networks composed of arbitrarily large numbers of enzyme-catalyzed reactions which are confined inside a small sub-cellular compartment. This is achieved by applying a mesoscopic version of the quasi-steady state assumption to the exact Fokker-Planck equation associated with the Poisson Representation of the chemical master equation. The procedure yields impressively simple and compact expressions for the finite-volume corrections. We prove that the predictions of the rate equations will always underestimate the actual steady-state substrate concentrations for an enzyme-reaction network confined in a small volume. In particular we show that the finite-volume corrections increase with decreasing sub-cellular volume, decreasing Michaelis-Menten constants and increasing enzyme saturation. The magnitude of the corrections depends sensitively on the topology of the network. The predictions of the theory are shown to be in excellent agreement with stochastic simulations for two types of networks typically associated with protein methylation and metabolism.Comment: 13 pages, 4 figures; published in The Journal of Chemical Physic

Implementing a perioperative efficiency initiative for orthopedic surgery instrumentation at an academic center: A comparative before-and-after study.

Optimizing surgical instrumentation may contribute to value-based care, particularly in commonly performed procedures. We report our experience in implementing a perioperative efficiency program in 2 types of orthopedic surgery (primary total-knee arthroplasty, TKA, and total-hip arthroplasty, THA).A comparative before-and-after study with 2 participating surgeons, each performing both THA and TKA, was conducted. Our objective was to evaluate the effect of surgical tray optimization on operating and processing time, cost, and waste associated with preparation, delivery, and staging of sterile surgical instruments. The study was designed as a prospective quality improvement initiative with pre- and postimplementation operational measures and a provider satisfaction survey.A total of 96 procedures (38 preimplementation and 58 postimplementation) were assessed using time-stamped performance endpoints. The number and weight of trays and instruments processed were reduced substantially after the optimization intervention, particularly for TKA. Setup time was reduced by 23% (6 minutes, P = .01) for TKA procedures but did not differ for THA. The number of survey respondents was small, but satisfaction was high overall among personnel involved in implementation.Optimizing instrumentation trays for orthopedic procedures yielded reduction in processing time and cost. Future research should evaluate patient outcomes and incremental/additive impact on institutional quality measures

How accurate are the non-linear chemical Fokker-Planck and chemical Langevin equations?

The chemical Fokker-Planck equation and the corresponding chemical Langevin equation are commonly used approximations of the chemical master equation. These equations are derived from an uncontrolled, second-order truncation of the Kramers-Moyal expansion of the chemical master equation and hence their accuracy remains to be clarified. We use the system-size expansion to show that chemical Fokker-Planck estimates of the mean concentrations and of the variance of the concentration fluctuations about the mean are accurate to order $\Omega^{-3/2}$ for reaction systems which do not obey detailed balance and at least accurate to order $\Omega^{-2}$ for systems obeying detailed balance, where $\Omega$ is the characteristic size of the system. Hence the chemical Fokker-Planck equation turns out to be more accurate than the linear-noise approximation of the chemical master equation (the linear Fokker-Planck equation) which leads to mean concentration estimates accurate to order $\Omega^{-1/2}$ and variance estimates accurate to order $\Omega^{-3/2}$. This higher accuracy is particularly conspicuous for chemical systems realized in small volumes such as biochemical reactions inside cells. A formula is also obtained for the approximate size of the relative errors in the concentration and variance predictions of the chemical Fokker-Planck equation, where the relative error is defined as the difference between the predictions of the chemical Fokker-Planck equation and the master equation divided by the prediction of the master equation. For dimerization and enzyme-catalyzed reactions, the errors are typically less than few percent even when the steady-state is characterized by merely few tens of molecules.Comment: 39 pages, 3 figures, accepted for publication in J. Chem. Phy

Mössbauer spectroscopic study of some iron and antimony – containing minerals

Iron-57 Mössbauer spectra have been recorded from three minerals containing both iron and antimony. Schafarzikite of composition FeSb2O4 contains Fe2+. The 121Sb Mössbauer spectrum shows only the presence of Sb3+. The 57Fe Mössbauer spectrum corresponds with that recorded from a material of identical composition synthesised by a solid state reaction during the course of this work. Apuanite of formulation Fe20Sb16O48S4 contains both Fe2+ Fe3+ in the ratio 1:3.35 The result is consistent with crystal structure determinations and the formulation of apuanite as Fe42+Fe163+Sb16O48S4. Versiliaite of composition Fe12Sb12O32S2 contains Fe2+and Fe3+ in the ratio 1:2.12 and, also consistent with structural characterisations, can be formulated Fe42+Fe83+Sb123+O32S2

A key region of molecular specificity orchestrates unique ephrin-B1 utilization by Cedar virus

The emergent zoonotic henipaviruses, Hendra, and Nipah are responsible for frequent and fatal disease outbreaks in domestic animals and humans. Specificity of henipavirus attachment glycoproteins (G) for highly species-conserved ephrin ligands underpins their broad host range and is associated with systemic and neurological disease pathologies. Here, we demonstrate that Cedar virus (CedV)—a related henipavirus that is ostensibly nonpathogenic—possesses an idiosyncratic entry receptor repertoire that includes the common henipaviral receptor, ephrin-B2, but, distinct from pathogenic henipaviruses, does not include ephrin-B3. Uniquely among known henipaviruses, CedV can use ephrin-B1 for cellular entry. Structural analyses of CedV-G reveal a key region of molecular specificity that directs ephrin-B1 utilization, while preserving a universal mode of ephrin-B2 recognition. The structural and functional insights presented uncover diversity within the known henipavirus receptor repertoire and suggest that only modest structural changes may be required to modulate receptor specificities within this group of lethal human pathogens.Peer reviewe

Perspective using cross-species vaccination approaches to counter emerging infectious diseases

Since the initial use of vaccination in the eighteenth century, our understanding of human and animal immunology has greatly advanced and a wide range of vaccine technologies and delivery systems have been developed. The COVID-19 pandemic response leveraged these innovations to enable rapid development of candidate vaccines within weeks of the viral genetic sequence being made available. The development of vaccines to tackle emerging infectious diseases is a priority for the World Health Organization and other global entities. More than 70% of emerging infectious diseases are acquired from animals, with some causing illness and death in both humans and the respective animal host. Yet the study of critical host–pathogen interactions and the underlying immune mechanisms to inform the development of vaccines for their control is traditionally done in medical and veterinary immunology ‘silos’. In this Perspective, we highlight a ‘One Health vaccinology’ approach and discuss some key areas of synergy in human and veterinary vaccinology that could be exploited to accelerate the development of effective vaccines against these shared health threats

How Sandcastles Fall

Capillary forces significantly affect the stability of sandpiles. We analyze the stability of sandpiles with such forces, and find that the critical angle is unchanged in the limit of an infinitely large system; however, this angle is increased for finite-sized systems. The failure occurs in the bulk of the sandpile rather than at the surface. This is related to a standard result in soil mechanics. The increase in the critical angle is determined by the surface roughness of the particles, and exhibits three regimes as a function of the added-fluid volume. Our theory is in qualitative agreement with the recent experimental results of Hornbaker et al., although not with the interpretation they make of these results.Comment: 4 pages, 2 figures, revte

Structural Plasticity of the Semliki Forest Virus Glycome upon Interspecies Transmission

Cross-species viral transmission subjects parent and progeny alphaviruses to differential post-translational processing of viral envelope glycoproteins. Alphavirus biogenesis has been extensively studied, and the Semliki Forest virus E1 and E2 glycoproteins have been shown to exhibit differing degrees of processing of N-linked glycans. However the composition of these glycans, including that arising from different host cells, has not been determined. Here we determined the chemical composition of the glycans from the prototypic alphavirus, Semliki Forest virus, propagated in both arthropod and rodent cell lines, by using ion-mobility mass spectrometry and collision-induced dissociation analysis. We observe that both the membrane-proximal E1 fusion glycoprotein and the protruding E2 attachment glycoprotein display heterogeneous glycosylation that contains N-linked glycans exhibiting both limited and extensive processing. However, E1 contained predominantly highly processed glycans dependent on the host cell, with rodent and mosquito-derived E1 exhibiting complex-type and paucimannose-type glycosylation, respectively. In contrast, the protruding E2 attachment glycoprotein primarily contained conserved under-processed oligomannose-type structures when produced in both rodent and mosquito cell lines. It is likely that glycan processing of E2 is structurally restricted by steric-hindrance imposed by local viral protein structure. This contrasts E1, which presents glycans characteristic of the host cell and is accessible to enzymes. We integrated our findings with previous cryo-electron microscopy and crystallographic analyses to produce a detailed model of the glycosylated mature virion surface. Taken together, these data reveal the degree to which virally encoded protein structure and cellular processing enzymes shape the virion glycome during interspecies transmission of Semliki Forest virus

'Sarsen stones in Wessex': a society of antiquaries project contextualised and renewed

This paper reviews the Society of Antiquaries’ Evolution of the Landscape project, which started in 1974, and the project’s Sarsen Stones in Wessex survey. The survey was an ambitious public archaeology project, involving c 100 volunteers led by Fellows of the Society during the 1970s. Its aims, objectives and outcomes are described. The survey’s unique dataset, produced for the counties of Wiltshire, Hampshire and Dorset, has now been digitised. Drawing on the dataset, the paper situates the Evolution of the Landscape project in the context of later-twentieth century British archaeology. It demonstrates the importance not only of individual Fellows, but also contemporary movements in academic and development-led archaeology, to the direction of the Society’s activities in this formative period for the discipline today, and shows how the Society’s research was engaged with some of archaeology’s most pressing cultural resource management issue