Search

Transcription and replication both require large macromolecular complexes to act on a DNA template, yet these machineries cannot simultaneously act on the same DNA sequence. Conflicts between the replication and transcription machineries (transcription-replication conflicts, or TRCs) are widespread in both prokaryotes and eukaryotes and have the capacity to both cause DNA damage and compromise complete, faithful replication of the genome. This review will highlight recent studies investigating the genomic locations of TRCs and the mechanisms by which they may be prevented, mitigated, or resolved. We address work from both model organisms and mammalian systems but predominantly focus on multicellular eukaryotes owing to the additional complexities inherent in the coordination of replication and transcription in the context of cell type-specific gene expression and higher-order chromatin organization.

Filamentous cyanobacteria can show fascinating examples of nonequilibrium self-organization, which, however, are not well understood from a physical perspective. We investigate the motility and collective organization of colonies of these simple multicellular lifeforms. As their area density increases, linear chains of cells gliding on a substrate show a transition from an isotropic distribution to bundles of filaments arranged in a reticulate pattern. Based on our experimental observations of individual behavior and pairwise interactions, we introduce a nonreciprocal model accounting for the filaments' large aspect ratio, fluctuations in curvature, motility, and nematic interactions. This minimal model of active filaments recapitulates the observations, and rationalizes the appearance of a characteristic length scale in the system, based on the Péclet number of the cyanobacteria filaments.

Understanding and controlling transport through complex media is central for a plethora of processes ranging from technical to biological applications. Yet, the effect of micro-scale manipulations on macroscopic transport dynamics still poses conceptual conundrums. Here, we demonstrate the predictive power of a conceptual shift in describing complex media by local micro-scale correlations instead of an assembly of uncorrelated minimal units. Specifically, we show that the non-linear dependency between microscopic morphological properties and macroscopic transport characteristics in porous media is captured by transport statistics on the level of pore junctions instead of single pores. Probing experimentally and numerically transport through two-dimensional porous media while gradually increasing flow heterogeneity, we find a non-monotonic change in transport efficiency. Using analytic arguments, we built physical intuition on how this non-monotonic dependency emerges from junction statistics. The shift in paradigm presented here broadly affects our understanding of transport within the diversity of complex media., (© 2022. The Author(s).)

Importance: Racial and ethnic disparities in pain outcomes are widely reported in the United States. However, the impact of the patient-physician relationship on such outcomes remains unclear., Objective: To determine whether the patient-physician relationship mediates the association of race with pain outcomes., Design, Setting, and Participants: This cross-sectional study uses data from the Pain Registry for Epidemiological, Clinical, and Interventional Studies and Innovation, collected from April 2016 to December 2021. All registry enrollees who identified as Black or White with chronic low back pain who had a regular physician who provided pain care were included. Data were analyzed during December 2021., Exposures: Participant-reported aspects of their patient-physician relationship, including physician communication, physician empathy, and satisfaction with physician encounters., Main Outcomes and Measures: The primary outcomes included low back pain intensity, measured with a numerical rating scale and physical function, measured with the Roland-Morris Disability Questionnaire. Mediator variables were derived from the Communication Behavior Questionnaire, Consultation and Relational Empathy measure, and Patient Satisfaction Questionnaire., Results: Among 1177 participants, the mean (SD) age was 53.5 (13.1) years, and there were 876 (74.4%) women. A total of 217 participants (18.4%) were Black, and 960 participants (81.6%) were White. The only difference between Black and White participants in the patient-physician relationship involved effective and open physician communication, which favored Black participants (mean communication score, 72.1 [95% CI, 68.8-75.4] vs 67.9 [95% CI, 66.2-69.6]; P = .03). Black participants, compared with White participants reported worse outcomes for pain intensity (mean pain score, 7.1 [95% CI, 6.8-7.3] vs 5.8 [95% CI, 5.7-6.0]; P < .001) and back-related disability (mean disability score, 15.8 [95% CI, 15.1-16.6] vs 14.1 [95% CI, 13.8-14.5]; P < .001). In mediation analyses that controlled for potential confounders using disease risk scores, virtually none of the associations of race with each outcome was mediated by the individual or combined factors of physician communication, physician empathy, and patient satisfaction. Similarly, no mediation was observed in sensitivity analyses that included only participants with both chronic low back pain and the same treating physician for more than 5 years., Conclusions and Relevance: These findings suggest that factors other than the patient-physician relationship were important to pain disparities experienced by Black participants. Additional research on systemic factors, such as access to high-quality medical care, may be helpful in identifying more promising approaches to mitigating racial pain disparities.

CCNE1 amplification is an oncogenic driver for many gynecologic cancers and is associated with poor patient outcomes. In this issue, Xu et al. 1 identify a combination therapy that is responsive to high CCNE1 -copy number ovarian and endometrial cancers using PDX models., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

The mechanical properties of a disordered heterogeneous medium depend, in general, on a complex interplay between multiple length scales. Connecting local interactions to macroscopic observables, such as stiffness or fracture, is thus challenging in this type of material. Here, we study the properties of a cohesive granular material composed of glass beads held together by soft polymer bridges. We characterise the mechanical response of single bridges under traction and shear, using a setup based on the deflection of flexible micropipettes. These measurements, along with information from X-ray microtomograms of the granular packings, then inform large-scale discrete element model (DEM) simulations. Although simple, these simulations are constrained in every way by empirical measurement and accurately predict mechanical responses of the aggregates, including details on their compressive failure, and how the material's stiffness depends on the stiffness and geometry of its parts. By demonstrating how to accurately relate microscopic information to macroscopic properties, these results provide new perspectives for predicting the behaviour of complex disordered materials, such as porous rock, snow, or foam.

Strong connections exist between R-loops (three-stranded structures harbouring an RNA:DNA hybrid and a displaced single-strand DNA), genome instability and human disease 1-5 . Indeed, R-loops are favoured in relevant genomic regions as regulators of certain physiological processes through which homeostasis is typically maintained. For example, transcription termination pause sites regulated by R-loops can induce the synthesis of antisense transcripts that enable the formation of local, RNA interference (RNAi)-driven heterochromation 6 . Pause sites are also protected against endogenous single-stranded DNA breaks by BRCA1 7 . Hypotheses about how DNA repair is enacted at pause sites include a role for RNA, which is emerging as a normal, albeit unexplained, regulator of genome integrity 8 . Here we report that a species of single-stranded, DNA-damage-associated small RNA (sdRNA) is generated by a BRCA1-RNAi protein complex. sdRNAs promote DNA repair driven by the PALB2-RAD52 complex at transcriptional termination pause sites that form R-loops and are rich in single-stranded DNA breaks. sdRNA repair operates in both quiescent (G0) and proliferating cells. Thus, sdRNA repair can occur in intact tissue and/or stem cells, and may contribute to tumour suppression mediated by BRCA1.

Background/objectives: In the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) study, a multifactorial intervention was associated with a nonsignificant 8% reduction in time to first serious fall injury but a significant 10% reduction in time to first self-reported fall injury relative to enhanced usual care. The effect of the intervention on other outcomes important to patients has not yet been reported. We aimed to evaluate the effect of the intervention on patient well-being including concern about falling, anxiety, depression, physical function, and disability., Design: Pragmatic cluster-randomized trial of 5,451 community-living persons at high risk for serious fall injuries., Setting: A total of 86 primary care practices within 10 U.S. healthcare systems., Participants: A random subsample of 743 persons aged 75 and older., Measurements: The well-being measures, assessed at baseline, 12 months, and 24 months, included a modified version of the Fall Efficacy Scale, Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety and depression scales, and Late-Life Function and Disability Instrument., Results: Participants in the intervention (n = 384) and control groups (n = 359) were comparable in age: mean (standard deviation) of 81.9 (4.7) versus 81.8 (5.0) years. Mean scores were similar between groups at 12 and 24 months for concern about falling, physical function, and disability, whereas the intervention group's mean scores on anxiety and depression were .7 points lower (i.e., better) at 12 months and .6 to .8 points lower at 24 months. For each of these outcomes, differences between the groups' adjusted least square mean changes from baseline to 12 and 24 months, respectively, were quantitatively small. The overall difference in means between groups over 2 years was statistically significant only for depression, favoring the intervention: -1.19 (99% confidence interval, -2.36 to -.02), with 3.5 points representing a minimally important difference., Conclusions: STRIDE's multifactorial intervention to reduce fall injuries was not associated with clinically meaningful improvements in patient well-being., (© 2020 The American Geriatrics Society.)

The mechanics of cohesive or cemented granular materials is complex, combining the heterogeneous responses of granular media, like force chains, with clearly defined material properties. Here we use a discrete element model simulation, consisting of an assemblage of elastic particles connected by softer but breakable elastic bonds, to explore how this class of material deforms and fails under uniaxial compression. We are particularly interested in the connection between the microscopic interactions among the grains or particles and the macroscopic material response. To this end, the properties of the particles and the stiffness of the bonds are matched to experimental measurements of a cohesive granular medium with tunable elasticity. The criterion for breaking a bond is also based on an explicit Griffith energy balance, with realistic surface energies. By varying the initial volume fraction of the particle assembles we show that this simple model reproduces a wide range of experimental behaviors, both in the elastic limit and beyond it. These include quantitative details of the distinct failure modes of shear-banding, ductile failure, and compaction banding or anticracks, as well as the transitions between these modes. The present work, therefore, provides a unified framework for understanding the failure of porous materials such as sandstone, marble, powder aggregates, snow, and foam.

In this work, we investigated the effect of the suspension properties on the drying dynamics and the resulting film peeling instability. To do so, a comprehensive series of experiments were conducted using drops of aqueous mixtures of colloidal silica dispersions and polyethylene oxide (PEO) additives. Time-lapse digital microscope images of the evaporating droplets show that film peeling can be discouraged and eventually eliminated with an increase in PEO concentration and molecular weight. This is due to the additives modifying the suspension properties which in turn modify the drying front length across the evaporating surface. Our result extends the understanding of the physics of film failure which is relevant information for various industrial processes such as in inkjet printing and coating applications.

Global insights into cellular organization and genome function require comprehensive understanding of the interactome networks that mediate genotype-phenotype relationships 1,2 . Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. With approximately 53,000 protein-protein interactions, HuRI has approximately four times as many such interactions as there are high-quality curated interactions from small-scale studies. The integration of HuRI with genome 3 , transcriptome 4 and proteome 5 data enables cellular function to be studied within most physiological or pathological cellular contexts. We demonstrate the utility of HuRI in identifying the specific subcellular roles of protein-protein interactions. Inferred tissue-specific networks reveal general principles for the formation of cellular context-specific functions and elucidate potential molecular mechanisms that might underlie tissue-specific phenotypes of Mendelian diseases. HuRI is a systematic proteome-wide reference that links genomic variation to phenotypic outcomes.

Monte Carlo simulations, fully constrained by experimental parameters, are found to agree well with a measured phase diagram of aqueous dispersions of nanoparticles with a moderate size polydispersity over a broad range of salt concentrations, c&#95;{s}, and volume fractions, ϕ. Upon increasing ϕ, the colloids freeze first into coexisting compact solids then into a body centered cubic phase (bcc) before they melt into a glass forming liquid. The surprising stability of the bcc solid at high ϕ and c&#95;{s} is explained by the interaction (charge) polydispersity and vibrational entropy.

After many years of controversy, there is now recent and solid evidence that classical Borna disease virus 1 (BoDV-1) can infect humans. On the basis of six brain autopsies, we provide the first systematic overview on BoDV-1 tissue distribution and the lesion pattern in fatal BoDV-1-induced encephalitis. All brains revealed a non-purulent, lymphocytic sclerosing panencephalomyelitis with detection of BoDV-1-typical eosinophilic, spherical intranuclear Joest-Degen inclusion bodies. While the composition of histopathological changes was constant, the inflammatory distribution pattern varied interindividually, affecting predominantly the basal nuclei in two patients, hippocampus in one patient, whereas two patients showed a more diffuse distribution. By immunohistochemistry and RNA in situ hybridization, BoDV-1 was detected in all examined brain tissue samples. Furthermore, infection of the peripheral nervous system was observed. This study aims at raising awareness to human bornavirus encephalitis as differential diagnosis in lymphocytic sclerosing panencephalomyelitis. A higher attention to human BoDV-1 infection by health professionals may likely increase the detection of more cases and foster a clearer picture of the disease.

Avalanche statistics of various threshold-activated dynamical systems are known to depend on the magnitude of the drive, or stress, on the system. Such dependences exist for earthquake size distributions, in sheared granular avalanches, laboratory-scale fracture and also in the outage statistics of power grids. In this work, we model threshold-activated avalanche dynamics and investigate the time required to detect local variations in the ability of model elements to bear stress. We show that the detection time follows a scaling law where the scaling exponents depend on whether the feature that is sought is either weaker, or stronger, than its surroundings. We then look at earthquake data from Sumatra and California, demonstrate the trade-off between the spatial resolution of a map of earthquake exponents (i.e. the b -values of the Gutenberg-Richter Law) and the accuracy of those exponents, and suggest a means to maximize both.This article is part of the theme issue 'Statistical physics of fracture and earthquakes'., (© 2018 The Author(s).)

Manifestations of emergent properties in stressed disordered materials are often the result of an interplay between strong perturbations in the stress field around defects. The collective response of a long-ranged correlated multi-component system is an ideal playing field for statistical physics. Hence, many aspects of such collective responses in widely spread length and energy scales can be addressed by the tools of statistical physics. In this theme issue, some of these aspects are treated from various angles of experiments, simulations and analytical methods, and connected together by their common base of complex-system dynamics.This article is part of the theme issue 'Statistical physics of fracture and earthquakes' ., (© 2018 The Author(s).)

The drying of complex fluids provides a powerful insight into phenomena that take place on time and length scales not normally accessible. An important feature of complex fluids, colloidal dispersions and polymer solutions is their high sensitivity to weak external actions. Thus, the drying of complex fluids involves a large number of physical and chemical processes. The scope of this review is the capacity to tune such systems to reproduce and explore specific properties in a physics laboratory. A wide variety of systems are presented, ranging from functional coatings, food science, cosmetology, medical diagnostics and forensics to geophysics and art.

We present an experimental micro-model of drying porous media, based on microfluidic cells made of arrays of pillars on a regular grid, and complement these experiments with a matching two-dimensional pore-network model of drying. Disorder, or small-scale heterogeneity, was introduced into the cells by randomly varying the radii of the pillars. The microfluidic chips were filled with a volatile oil and then dried horizontally, such that gravitational effects were excluded. The experimental and simulated drying rates and patterns were then compared in detail, for various levels of disorder. The geometrical features were reproduced well, although the model under-predicted the formation of trapped clusters of drying fluid. Reproducing drying rates proved to be more challenging, but improved if the additional trapped clusters were added to the model. The methods reported can be adapted to a wide range of multi-phase flow problems, and allow for the rapid development of high-precision micro-models containing tens of thousands of individual elements.

A thin elastic sheet lying on a soft substrate develops wrinkled patterns when subject to an external forcing or as a result of geometric incompatibility. Thin sheet elasticity and substrate response equip such wrinkles with a global preferred wrinkle spacing length and with resistance to wrinkle curvature. These features are responsible for the liquid crystalline smectic-like behaviour of such systems at intermediate length scales. This insight allows better understanding of the wrinkling patterns seen in such systems, with which we explain pattern breaking into domains, the properties of domain walls and wrinkle undulation. We compare our predictions with numerical simulations and with experimental observations.

Charged colloidal dispersions make up the basis of a broad range of industrial and commercial products, from paints to coatings and additives in cosmetics. During drying, an initially liquid dispersion of such particles is slowly concentrated into a solid, displaying a range of mechanical instabilities in response to highly variable internal pressures. Here we summarize the current appreciation of this process by pairing an advection-diffusion model of particle motion with a Poisson-Boltzmann cell model of inter-particle interactions, to predict the concentration gradients in a drying colloidal film. We then test these predictions with osmotic compression experiments on colloidal silica, and small-angle X-ray scattering experiments on silica dispersions drying in Hele-Shaw cells. Finally, we use the details of the microscopic physics at play in these dispersions to explore how two macroscopic mechanical instabilities-shear-banding and fracture-can be controlled.This article is part of the themed issue 'Patterning through instabilities in complex media: theory and applications.', (© 2017 The Author(s).)

We study experimentally the fracture mechanisms of a model cohesive granular medium consisting of glass beads held together by solidified polymer bridges. The elastic response of this material can be controlled by changing the cross-linking of the polymer phase, for example. Here we show that its fracture toughness can be tuned over an order of magnitude by adjusting the stiffness and size of the polymer bridges. We extract a well-defined fracture energy from fracture testing under a range of material preparations. This energy is found to scale linearly with the cross-sectional area of the bridges. Finally, X-ray microcomputed tomography shows that crack propagation is driven by adhesive failure of about one polymer bridge per bead located at the interface, along with microcracks in the vicinity of the failure plane. Our findings provide insight into the fracture mechanisms of this model material, and the mechanical properties of disordered cohesive granular media in general.

By mixing glass beads with a curable polymer we create a well-defined cohesive granular medium, held together by solidified, and hence elastic, capillary bridges. This material has a geometry similar to a wet packing of beads, but with an additional control over the elasticity of the bonds holding the particles together. We show that its mechanical response can be varied over several orders of magnitude by adjusting the size and stiffness of the bridges, and the size of the particles. We also investigate its mechanism of failure under unconfined uniaxial compression in combination with in situ x-ray microtomography. We show that a broad linear-elastic regime ends at a limiting strain of about 8%, whatever the stiffness of the agglomerate, which corresponds to the beginning of shear failure. The possibility to finely tune the stiffness, size and shape of this simple material makes it an ideal model system for investigations on, for example, fracturing of porous rocks, seismology, or root growth in cohesive porous media., Competing Interests: A.H., M.S. and L.G. are inventors on a patent application regarding the cohesive granular material (PCT/EP2016/067079).

We report small-angle x-ray scattering experiments on aqueous dispersions of colloidal silica with a broad monomodal size distribution (polydispersity, 14%; size, 8 nm). Over a range of volume fractions, the silica particles segregate to build first one, then two distinct sets of colloidal crystals. These dispersions thus demonstrate fractional crystallization and multiple-phase (bcc, Laves AB&#95;{2}, liquid) coexistence. Their remarkable ability to build complex crystal structures from a polydisperse population originates from the intermediate-range nature of interparticle forces, and it suggests routes for designing self-assembling colloidal crystals from the bottom up.

Cracks in thin layers are influenced by what lies beneath them. From buried craters to crocodile skin, crack patterns are found over an enormous range of length scales. Regardless of absolute size, their substrates can dramatically influence how cracks form, guiding them in some cases, or shielding regions from them in others. Here we investigate how a substrate's shape affects the appearance of cracks above it, by preparing mud cracks over sinusoidally varying surfaces. We find that as the thickness of the cracking layer increases, the observed crack patterns change from wavy to ladder-like to isotropic. Two order parameters are introduced to measure the relative alignment of these crack networks, and, along with Fourier methods, are used to characterise the transitions between crack pattern types. Finally, we explain these results with a model, based on the Griffith criteria of fracture, that identifies the conditions for which straight or wavy cracks will be seen, and predicts how well-ordered the cracks will be. Our metrics and results can be applied to any situation where connected networks of cracks are expected, or found.

A modified version of the Gibbs-ensemble Monte-Carlo method reveals how polydisperse charged colloidal particles can build complex colloidal crystals. It provides general rules that are applicable to this fractionated crystallization that stems from size segregation. It explains the spontaneous formation of complex crystals with very large unit-cells in suspensions of nanoparticles with a broad size distribution.

In directionally dried colloidal dispersions regular bands can appear behind the drying front, inclined at ±45° to the drying line. Although these features have been noted to share visual similarities with shear bands in metal, no physical mechanism for their formation has ever been suggested, until very recently. Here, through microscopy of silica and polystyrene dispersions, dried in Hele-Shaw cells, we demonstrate that the bands are indeed associated with local shear strains. We further show how the bands form, that they scale with the thickness of the drying layer, and that they are eliminated by the addition of salt to the drying dispersions. Finally, we reveal the origins of these bands in the compressive forces associated with drying, and show how they affect the optical properties (birefringence) of colloidal films and coatings.

Active emulsions, i.e., emulsions whose droplets perform self-propelled motion, are of tremendous interest for mimicking collective phenomena in biological populations such as phytoplankton and bacterial colonies, but also for experimentally studying rheology, pattern formation, and phase transitions in systems far from thermal equilibrium. For fuelling such systems, molecular processes involving the surfactants which stabilize the emulsions are a straightforward concept. We outline and compare two different types of reactions, one which chemically modifies the surfactant molecules, the other which transfers them into a different colloidal state. While in the first case symmetry breaking follows a standard linear instability, the second case turns out to be more complex. Depending on the dissolution pathway, there is either an intrinsically nonlinear instability, or no symmetry breaking at all (and hence no locomotion).

Importance: For many older people, long-term functional limitations persist after a hip fracture. The efficacy of a home exercise program with minimal supervision after formal hip fracture rehabilitation ends has not been established., Objective: To determine whether a home exercise program with minimal contact with a physical therapist improved function after formal hip fracture rehabilitation ended., Design, Setting, and Participants: Randomized clinical trial conducted from September 2008 to October 2012 in the homes of 232 functionally limited older adults who had completed traditional rehabilitation after a hip fracture., Interventions: The intervention group (n = 120) received functionally oriented exercises (such as standing from a chair, climbing a step) taught by a physical therapist and performed independently by the participants in their homes for 6 months. The attention control group (n = 112) received in-home and telephone-based cardiovascular nutrition education., Main Outcomes and Measures: Physical function assessed at baseline, 6 months (ie, at completion of the intervention), and 9 months by blinded assessors. The primary outcome was change in function at 6 months measured by the Short Physical Performance Battery (SPPB; range 0-12, higher score indicates better function) and the Activity Measure for Post-Acute Care (AM-PAC) mobility and daily activity (range, 23-85 and 9-101, higher score indicates better function)., Results: Among the 232 randomized patients, 195 were followed up at 6 months and included in the primary analysis. The intervention group (n=100) showed significant improvement relative to the control group (n=95) in functional mobility (mean SPPB scores for intervention group: 6.2 [SD, 2.7] at baseline, 7.2 [SD, 3] at 6 months; control group: 6.0 [SD, 2.8] at baseline, 6.2 [SD, 3] at 6 months; and between-group differences: 0.8 [95% CI, 0.4 to 1.2], P < .001; mean AM-PAC mobility scores for intervention group: 56.2 [SD, 7.3] at baseline, 58.1 [SD, 7.9] at 6 months; control group: 56 [SD, 7.1] at baseline, 56.6 [SD, 8.1] at 6 months; and between-group difference, 1.3 [95% CI, 0.2 to 2.4], P = .03; and mean AM-PAC daily activity scores for intervention group: 57.4 [SD, 13.7] at baseline, 61.3 [SD, 15.7] at 6 months; control group: 58.2 [SD, 15.2] at baseline, 58.6 [SD, 15.3] at 6 months; and between-group difference, 3.5 [95% CI, 0.9 to 6.0], P = .03). In multiple imputation analyses, between-group differences remained significant for SPPB and AM-PAC daily activity, but not for mobility. Significant between-group differences persisted at 9 months for all functional measures with and without imputation., Conclusions and Relevance: Among patients who had completed standard rehabilitation after hip fracture, the use of a home-based functionally oriented exercise program resulted in modest improvement in physical function at 6 months after randomization. The clinical importance of these findings remains to be determined., Trial Registration: clinicaltrials.gov Identifier: NCT00592813.

Pattern formation is a natural property of nonlinear and non-equilibrium dynamical systems. Geophysical examples of such systems span practically all observable length scales, from rhythmic banding of chemical species within a single mineral crystal, to the morphology of cusps and spits along hundreds of kilometres of coastlines. This article briefly introduces the general principles of pattern formation and argues how they can be applied to open problems in the Earth sciences. Particular examples are then discussed, which summarize the contents of the rest of this Theme Issue.

Kinneyia are a class of microbially mediated sedimentary fossils. Characterized by clearly defined ripple structures, Kinneyia are generally found in areas that were formally littoral habitats and covered by microbial mats. To date, there has been no conclusive explanation of the processes involved in the formation of these fossils. Microbial mats behave like viscoelastic fluids. We propose that the key mechanism involved in the formation of Kinneyia is a Kelvin-Helmholtz-type instability induced in a viscoelastic film under flowing water. A ripple corrugation is spontaneously induced in the film and grows in amplitude over time. Theoretical predictions show that the ripple instability has a wavelength proportional to the thickness of the film. Experiments carried out using viscoelastic films confirm this prediction. The ripple pattern that forms has a wavelength roughly three times the thickness of the film. This behaviour is independent of the viscosity of the film and the flow conditions. Laboratory-analogue Kinneyia were formed via the sedimentation of glass beads, which preferentially deposit in the troughs of the ripples. Well-ordered patterns form, with both honeycomb-like and parallel ridges being observed, depending on the flow speed. These patterns correspond well with those found in Kinneyia, with similar morphologies, wavelengths and amplitudes being observed.

When cracks form in a thin contracting layer, they sequentially break the layer into smaller and smaller pieces. A rectilinear crack pattern encodes information about the order of crack formation, as later cracks tend to intersect with earlier cracks at right angles. In a hexagonal pattern, in contrast, the angles between all cracks at a vertex are near 120 degrees. Hexagonal crack patterns are typically seen when a crack network opens and heals repeatedly, in a thin layer, or advances by many intermittent steps into a thick layer. Here, it is shown how both types of pattern can arise from identical forces, and how a rectilinear crack pattern can evolve towards a hexagonal one. Such an evolution is expected when cracks undergo many opening cycles, where the cracks in any cycle are guided by the positions of cracks in the previous cycle but when they can slightly vary their position and order of opening. The general features of this evolution are outlined and compared with a review of the specific patterns of contraction cracks in dried mud, polygonal terrain, columnar joints and eroding gypsum-sand cements.

Background: Central nervous system blood vessel thrombosis is a part of the pathogenesis of equid herpesvirus-associated myeloencephalopathy (EHM). D-dimers (DD) are stable breakdown products of cross-linked fibrin, and increased DD-plasma concentrations could reflect the degree of systemic coagulation during EHV-1 infection., Hypothesis: We hypothesized that blood DD concentrations will be increased during periods of EHV-1 fever and viremia, reflecting an activated coagulation cascade with fibrinolysis., Animals: Twenty-eight equids were infected with EHV-1 in 3 experimental infection studies. Three (uninfected) horses were included in a separate study to evaluate methodology for DD concentration measurements., Methods: Clinical data and quantitative viremia were evaluated, and DD concentrations were measured in blood samples on the day before the infection and during days 1-12 postchallenge. Uninfected horses were sampled every 3 hours for 48 hours. Logistic and linear regression was used to investigate the potential association between the fever and viremia with the presence or absence of DD concentrations in peripheral blood., Results: DD concentrations were increased for 1-8 days in the majority of infected animals. Both viremia (odds ratio [OR] 6.3; 95% confidence interval [CI] 3.4-11.8; P = .0013) and fever (OR 4.9; CI 2.3-10.1; P = .001) were strongly associated with the likelihood of detecting DD in peripheral blood., Conclusions and Clinical Importance: EHV-1 viremia is associated with increases in DD concentration in horses and ponies. This indicates that EHV-1 viremia can lead to an activation of coagulation and fibrinolysis., (Copyright © 2013 by the American College of Veterinary Internal Medicine.)

Cracks in drying colloidal dispersions are typically modeled by elastic fracture mechanics, which assumes that all strains are linear, elastic, and reversible. We tested this assumption in films of a hard latex, by intermittently blocking evaporation over a drying film, thereby relieving the film stress. Here we show that although the deformation around a crack tip has some features of brittle fracture, only 20%-30% of the crack opening is relieved when it is unloaded. Atomic force micrographs of crack tips also show evidence of plastic deformation, such as microcracks and particle rearrangement. Finally, we present a simple scaling argument showing that the yield stress of a drying colloidal film is generally comparable to its maximum capillary pressure, and thus that the plastic strain around a crack will normally be significant. This also suggests that a film's fracture toughness may be increased by decreasing the interparticle adhesion.

We present the results from a small-angle X-ray scattering (SAXS) study of lateral drying in thin films. The films, initially 10 μm thick, are cast by dip-coating a mica sheet in an aqueous silica dispersion (particle radius 8 nm, volume fraction ϕ(s) = 0.14). During evaporation, a drying front sweeps across the film. An X-ray beam is focused on a selected spot of the film, and SAXS patterns are recorded at regular time intervals. As the film evaporates, SAXS spectra measure the ordering of particles, their volume fraction, the film thickness, and the water content, and a video camera images the solid regions of the film, recognized through their scattering of light. We find that the colloidal dispersion is first concentrated to ϕ(s) = 0.3, where the silica particles begin to jam under the effect of their repulsive interactions. Then the particles aggregate until they form a cohesive wet solid at ϕ(s) = 0.68 ± 0.02. Further evaporation from the wet solid leads to evacuation of water from pores of the film but leaves a residual water fraction ϕ(w) = 0.16. The whole drying process is completed within 3 min. An important finding is that, in any spot (away from boundaries), the number of particles is conserved throughout this drying process, leading to the formation of a homogeneous deposit. This implies that no flow of particles occurs in our films during drying, a behavior distinct to that encountered in the iconic coffee-stain drying. It is argued that this type of evolution is associated with the formation of a transition region that propagates ahead of the drying front. In this region the gradient of osmotic pressure balances the drag force exerted on the particles by capillary flow toward the liquid-solid front.

Gauging the systemic effects of non-synonymous single nucleotide polymorphisms (nsSNPs) is an important topic in the pursuit of personalized medicine. However, it is a non-trivial task to understand how a change at the protein structure level eventually affects a cell's behavior. This is because complex information at both the protein and pathway level has to be integrated. Given that the idea of integrating both protein and pathway dynamics to estimate the systemic impact of missense mutations in proteins remains predominantly unexplored, we investigate the practicality of such an approach by formulating mathematical models and comparing them with experimental data to study missense mutations. We present two case studies: (1) interpreting systemic perturbation for mutations within the cell cycle control mechanisms (G2 to mitosis transition) for yeast; (2) phenotypic classification of neuron-related human diseases associated with mutations within the mitogen-activated protein kinase (MAPK) pathway. We show that the application of simplified mathematical models is feasible for understanding the effects of small sequence changes on cellular behavior. Furthermore, we show that the systemic impact of missense mutations can be effectively quantified as a combination of protein stability change and pathway perturbation.

Infection with equine herpesvirus-1 (EHV-1) causes respiratory disease, late term abortions and equine herpesvirus myeloencephalitis (EHM) and remains an important problem in horses worldwide. Despite increasing outbreaks of EHM in recent years, our understanding of EHM pathogenesis is still limited except for the knowledge that a cell-associated viremia in peripheral blood mononuclear cells (PBMCs) is a critical link between primary respiratory EHV-1 infection and secondary complications such as late-term abortion or EHM. To address this question our objective was to identify which PBMC subpopulation(s) are infected during viremia and may therefore play a role in transmitting the virus to the vascular endothelium of the spinal cord or pregnant uterus. PBMCs from 3 groups of animals were collected between days 4 and 9 following experimental infection with EHV-1 strain Findlay/OH03 or strain Ab4. PBMCs were labeled with primary antibodies selective for CD4+ or CD8+ T lymphocytes, B-lymphocytes, or monocytes and positively selected using magnetic bead separation. Cell numbers and EHV-1 genome numbers in each subpopulation were then determined using quantitative PCR for β-actin and the EHV-1 glycoprotein B, respectively. Viral genomic DNA was found in all PBMC subpopulations; the CD8+ lymphocytes were most frequently positive for viral DNA, followed by B-lymphocytes. These differences were statistically significant in horses infected with the EHV-1 strain Findlay/OH03, and ponies with Ab4. These results differ from what has been reported in in vitro studies, and indicate that different PBMC subpopulations may play different roles in EHV-1 viremia., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Infection with equine herpesvirus-1 (EHV-1) causes respiratory disease, late-term abortions and equine herpesvirus myeloencephalitis (EHM). Our understanding of EHM pathogenesis is limited except for the knowledge that EHV-1 infected, circulating peripheral blood mononuclear cells (PBMC) transport virus to the central nervous system vasculature causing endothelial cell infection leading to development of EHM. Our objective was to develop a model of CNS endothelial cell infection using EHV-1 infected, autologous PBMC. PBMCs, carotid artery and brain endothelial cells (EC) from 14 horses were harvested and grown to confluency. PBMC or ConA-stimulated PBMCs (ConA-PBMCs) were infected with EHV-1, and sedimented directly onto EC monolayers ('contact'), or placed in inserts on a porous membrane above the EC monolayer ('no contact'). Cells were cultured in medium with or without EHV-1 virus neutralizing antibody. Viral infection of ECs was detected by cytopathic effect. Both brain and carotid artery ECs became infected when cultured with EHV-1 infected PBMCs or ConA-PBMCs, either in direct contact or no contact: infection was higher in carotid artery than in brain ECs, and when using ConA-PBMCs compared to PBMCs. Virus neutralizing antibody eliminated infection of ECs in the no contact model only. This was consistent with cell-to-cell spread of EHV-1 infection from leucocytes to ECs, demonstrating the importance of this mode of infection in the presence of antibody, and the utility of this model for study of cellular interactions in EHV-1 infection of ECs., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The stress at which latex films crack during drying was investigated using beam bending. Two systems were investigated: (i) poly(methyl methacrylate/butyl acrylate) particles cast as thin films to examine the effect of film thickness on cracking film stress and (ii) polystyrene particles dried as drops to investigate the effect of particle size. Results indicated an inverse relationship between film thickness and film stress, whilst film stress was shown to be independent of the original particle size. These outcomes were in good agreement with Tirumkudulu and Russel's theoretical analysis [M.S. Tirumkudulu and W.B. Russel, Langmuir 21 (2005) 4938], albeit the measured stress values were almost twice the theoretical estimation., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Equine herpesvirus-1 is a cause of outbreaks of abortion and neurological disease. The pathogenesis of both these diseases depends on establishment of viremia. An experiment was performed to determine the protective efficacy of two commercially available vaccines used with an optimized 3-dose vaccination regime: a modified-live viral (MLV) and a high antigen load killed vaccine licensed for abortion control. The study design was a blinded, randomized challenge trial. Three groups of 8 yearling ponies received one of three treatments: MLV vaccine (Rhinomune, Boehringer Ingelheim Vetmedica, Inc.); killed vaccine (Pneumabort-K, Pfizer Animal Health); or a placebo (control group). Three vaccinations were administered at intervals of 27 and 70 days followed by challenge infection 24 days later. Clinical disease after challenge was significantly reduced in both vaccine groups; the reduction was greater in the MLV vaccine group. Nasal shedding was reduced by at least 1-2 logs in both vaccine groups. The number of days of viremia was significantly reduced in the killed vaccine group only. This study demonstrated that both commercial vaccines significantly suppressed EHV-1 disease and nasal viral shedding, and one vaccine suppressed days of viremia., ((c) 2010 Elsevier Ltd. All rights reserved.)

During drying, colloidal dispersions undergo processes such as solidification, cracking, and the draining of interstitial pores. Here we show that the solidification of polystyrene and silica dispersions, during directional drying, occurs in two separate stages. These correspond to the initial ordering and subsequent aggregation of the colloidal particles. Transitions between these stages are observed as changes in transparency and color that propagate as distinct fronts along the drying layer. The dynamics of these fronts are shown to arise from a balance between compressive capillary forces and the electrostatic and van der Waals forces described by DLVO theory. This suggests a simple method by which the maximum interparticle repulsion between particles can be measured through the optical inspection of the dynamics of a drying dispersion, under a microscope.

Starch-water slurries are commonly used to study fracture dynamics. Drying starch cakes benefit from being simple, economical, and reproducible systems, and have been used to model desiccation fracture in soils, thin-film fracture in paint, and columnar joints in lava. In this paper, the physical properties of starch-water mixtures are studied, and used to interpret and develop a multiphase transport model of drying. Starch cakes are observed to have a nonlinear elastic modulus, and a desiccation strain that is comparable to that generated by their maximum achievable capillary pressure. It is shown that a large material porosity is divided between pore spaces between starch grains, and pores within starch grains. This division of pore space leads to two distinct drying regimes, controlled by liquid and vapor transport of water, respectively. The relatively unique ability for drying starch to generate columnar fracture patterns is shown to be linked to the unusually strong separation of these two transport mechanisms.

Crack patterns in laboratory experiments on thick samples of drying cornstarch are geometrically similar to columnar joints in cooling lava found at geological sites such as the Giant's Causeway. We present measurements of the crack spacing from both laboratory and geological investigations of columnar jointing, and show how these data can be collapsed onto a single master scaling curve. This is due to the underlying mathematical similarity between theories for the cracking of solids induced by differential drying or by cooling. We use this theory to give a simple quantitative explanation of how these geometrically similar crack patterns arise from a single dynamical law rooted in the nonequilibrium nature of the phenomena. We also give scaling relations for the characteristic crack spacing in other limits consistent with our experiments and observations, and discuss the implications of our results for the control of crack patterns in thin and thick solid films.

Columnar jointing is a fracture pattern common in igneous rocks in which cracks self-organize into a roughly hexagonal arrangement, leaving behind an ordered colonnade. We report observations of columnar jointing in a laboratory analog system, desiccated corn starch slurries. Using measurements of moisture density, evaporation rates, and fracture advance rates as evidence, we suggest that an advective-diffusive system is responsible for the rough scaling behavior of columnar joints. This theory explains the order of magnitude difference in scales between jointing in lavas and in starches. We investigated the scaling of average columnar cross-sectional areas due to the evaporation rate, the analog of the cooling rate of igneous columnar joints. We measured column areas in experiments where the evaporation rate depended on lamp height and time, in experiments where the evaporation rate was fixed using feedback methods, and in experiments where gelatin was added to vary the rheology of the starch. Our results suggest that the column area at a particular depth is related to both the current conditions, and hysteretically to the geometry of the pattern at previous depths. We argue that there exists a range of stable column scales allowed for any particular evaporation rate.

West Nile virus (WNV) is an arthropod-borne flavivirus that is endemic in Africa, Europe, and Eastern Asia. The recent introduction and rapid dissemination of the virus in the United States as well as an increase in WNV outbreaks in Europe, has raised concerns for its spread in Europe. A surveillance system was developed to allow timely detection of an introduction of WNV infections in The Netherlands. This program focuses on cases presenting with neurological disease and includes the monitoring of hospital discharge diagnoses, trends in cerebrospinal fluid (CSF) diagnostic requests, laboratory testing of CSF, and monitoring of neurological disease in horses. Retrospective data from the hospital discharge records showed yearly peaks of unexplained meningitis and (meningo)encephalitis in the summer. A total of 781 CSF samples from humans and 71 serum and/or CSF samples from horses presenting with neurological disease of suspected viral etiology tested negative for the presence of specific antibodies to WNV. With a coverage rate of 59% in 2003, the probability that a cluster of five WNV cases presenting with neurological symptoms would have been detected was 99%. We conclude that, from 1999 to 2004, no evidence of WNV infection could be found in either humans or horses in The Netherlands.