Models of dynamic extraction of lipid tethers from cell membranes

When a ligand that is bound to an integral membrane receptor is pulled, the membrane and the underlying cytoskeleton can deform before either the membrane delaminates from the cytoskeleton or the ligand detaches from the receptor. If the membrane delaminates from the cytoskeleton, it may be further extruded and form a membrane tether. We develop a phenomenological model for this processes by assuming that deformations obey Hooke's law up to a critical force at which the cell membrane locally detaches from the cytoskeleton and a membrane tether forms. We compute the probability of tether formation and show that they can be extruded only within an intermediate range of force loading rates and pulling velocities. The mean tether length that arises at the moment of ligand detachment is computed as are the force loading rates and pulling velocities that yield the longest tethers.Comment: 16 pages, 7 figure

Dynamic Boundaries in Asymmetric Exclusion Processes

We investigate the dynamics of a one-dimensional asymmetric exclusion process with Langmuir kinetics and a fluctuating wall. At the left boundary, particles are injected onto the lattice; from there, the particles hop to the right. Along the lattice, particles can adsorb or desorb, and the right boundary is defined by a wall particle. The confining wall particle has intrinsic forward and backward hopping, a net leftward drift, and cannot desorb. Performing Monte Carlo simulations and using a moving-frame finite segment approach coupled to mean field theory, we find the parameter regimes in which the wall acquires a steady state position. In other regimes, the wall will either drift to the left and fall off the lattice at the injection site, or drift indefinitely to the right. Our results are discussed in the context of non-equilibrium phases of the system, fluctuating boundary layers, and particle densities in the lab frame versus the frame of the fluctuating wall.Comment: 13 page

Tracking the Orbital and Super-orbital Periods of SMC X-1

The High Mass X-ray Binary (HMXB) SMC X-1 demonstrates an orbital variation of 3.89 days and a super-orbital variation with an average length of 55 days. As we show here, however, the length of the super-orbital cycle varies by almost a factor of two, even across adjacent cycles. To study both the orbital and super-orbital variation we utilize lightcurves from the Rossi X-ray Timing Explorer All Sky Monitor (RXTE-ASM). We employ the orbital ephemeris from Wojdowski et al. (1998) to obtain the average orbital profile, and we show that this profile exhibits complex modulation during non-eclipse phases. Additionally, a very interesting ``bounceback'' in X-ray count rate is seen during mid-orbital eclipse phases, with a softening of the emission during these periods. This bounceback has not been previously identified in pointed observations. We then define a super-orbital ephemeris (the phase of the super-orbital cycle as a function of date) based on the ASM lightcurve and analyze the trend and distribution of super-orbital cycle lengths. SMC X-1 exhibits a bimodal distribution of these lengths, similar to what has been observed in other systems (e.g., Her X-1), but with more dramatic changes in cycle length. There is some hint, but not conclusive evidence, for a dependence of the super-orbital cycle length upon the underlying orbital period, as has been observed previously for Her X-1 and Cyg X-2. Using our super-orbital ephemeris we are also able to create an average super-orbital profile over the 71 observed cycles, for which we witness overall hardening of the spectrum during low count rate times. We combine the orbital and super-orbital ephemerides to study the correlation between the orbital and super-orbital variations in the system.Comment: 10 pages, using emulateapj style. To be published in the Astrophysical Journa

Corona, Jet, and Relativistic Line Models for Suzaku/RXTE/Chandra-HETG Observations of the Cygnus X-1 Hard State

Using Suzaku and the Rossi X-ray Timing Explorer, we have conducted a series of four simultaneous observations of the galactic black hole candidate Cyg X-1 in what were historically faint and spectrally hard low states. Additionally, all of these observations occurred near superior conjunction with our line of sight to the X-ray source passing through the dense phases of the focused wind from the mass donating secondary. One of our observations was also simultaneous with observations by the Chandra-High Energy Transmission Grating. These latter spectra are crucial for revealing the ionized absorption due to the secondary's focused wind. Such absorption is present and must be accounted for in all four spectra. These simultaneous data give an unprecedented view of the 0.8-300 keV spectrum of Cyg X-1, and hence bear upon both corona and X-ray emitting jet models of black hole hard states. Three models fit the spectra well: coronae with thermal or mixed thermal/non-thermal electron populations, and jets. All three models require a soft component that we fit with a low temperature disk spectrum with an inner radius of only a few tens of GM/c^2. All three models also agree that the known spectral break at 10\,keV is not solely due to the presence of reflection, but each gives a different underlying explanation for the augmentation of this break. Thus whereas all three models require that there is a relativistically broadened Fe line, the strength and inner radius of such a line is dependent upon the specific model, {thus making premature line-based estimates of the black hole spin in the Cyg X-1 system. We look at the relativistic line in detail, accounting for the narrow Fe emission and ionized absorption detected by HETG. Although the specific relativistic parameters of the line are continuum-dependent, none of the broad line fits allow for an inner disk radius that is >40 GM/c^2.Comment: 22 pages, 16 figures. Uses emulateapj style. Final three tables inserted as a figure to avoid issues with astro-ph's version of latex mangling the use of lscape. To be published in the Astrophysical Journal, January, 201

Maximum Angle of Stability of a Wet Granular Pile

Anyone who has built a sandcastle recognizes that the addition of liquid to granular materials increases their stability. However, measurements of this increased stability often conflict with theory and with each other [1-7]. A friction-based Mohr-Coulomb model has been developed [3,8]. However, it distinguishes between granular friction and inter-particle friction, and uses the former without providing a physical mechanism. Albert, {\em et al.} [2] analyzed the geometric stability of grains on a pile's surface. The frictionless model for dry particles is in excellent agreement with experiment. But, their model for wet grains overestimates stability and predicts no dependence on system size. Using the frictionless model and performing stability analysis within the pile, we reproduce the dependence of the stability angle on system size, particle size, and surface tension observed in our experiments. Additionally, we account for past discrepancies in experimental reports by showing that sidewalls can significantly increase the stability of granular material.Comment: 4 pages, 4 figure

Midday Meals Do Not Impair Mouse Memory

Nocturnal mice fed in the middle of the light period exhibit food anticipatory rhythms of behavior and physiology under control of food-entrainable circadian clocks in the brain and body. This is presumed to be adaptive by aligning behavior and physiology with predictable mealtimes. This assumption is challenged by a report that daytime feeding schedules impair cognitive processes important for survival, including object memory and contextual fear conditioning assessed at two times of day. To further evaluate these effects, mice were restricted to a 6 h daily meal in the middle of the light or dark period and object memory was tested at four times of day. Object memory was not impaired by daytime feeding, and did not exhibit circadian variation in either group. To determine whether impairment might depend on methodology, experimental procedures used previously to detect impairment were followed. Daytime feeding induced food anticipatory rhythms and shifted hippocampal clock genes, but again did not impair object memory. Spontaneous alternation and contextual fear conditioning were also not impaired. Hippocampal memory function appears more robust to time of day and daytime feeding schedules than previously reported; day-fed mice can remember what they have seen, where they have been, and where it is dangerous

A Risk Model for Proactive Management of Pneumonia Epizootics in Bighorn Sheep

Pneumonia epizootics are a major challenge for management of bighorn sheep (Ovis canadensis). Risk factors associated with the disease are poorly understood, making pneumonia epizootics hard to predict; such epizootics are thus managed reactively rather than proactively. We developed a model that identifies risk factors and addresses biological questions about risk. Using Bayesian logistic regression with repeated measures, we found that private land, weed control using domestic sheep or goats, pneumonia history, and herd density were associated with risk of pneumonia in 43 herds in Montana that experienced 22 epizootics out of 637 herd years from 1979–2013. Within high-risk areas occupied by herds, risk increased with greater amounts of private land and use of domestic sheep or goats for weed control. Herds had >10 times greater odds of having a pneumonia epizootic if they or neighboring herds within high-risk areas had a history of pneumonia. Risk greatly increased when herds were at high density, with nearly 15 times greater odds of pneumonia compared to herds at low density. Number of federal sheep and goat allotments, proximity to nearest herds, ram:ewe ratios, normality of winter and spring precipitation, and herds with native versus mixed or reintroduced origin were not associated with increased risk. We conclude that factors associated with risk of pneumonia are complex and may not always be from the most obvious sources. The ability to identify high risk herds will help determine where to focus management efforts and what risk factors most affect each herd, facilitating more effective, proactive management

Rescue of skeletal muscle α-actin–null mice by cardiac (fetal) α-actin

Skeletal muscle α-actin (ACTA1) is the major actin in postnatal skeletal muscle. Mutations of ACTA1 cause mostly fatal congenital myopathies. Cardiac α-actin (ACTC) is the major striated actin in adult heart and fetal skeletal muscle. It is unknown why ACTC and ACTA1 expression switch during development. We investigated whether ACTC can replace ACTA1 in postnatal skeletal muscle. Two ACTC transgenic mouse lines were crossed with Acta1 knockout mice (which all die by 9 d after birth). Offspring resulting from the cross with the high expressing line survive to old age, and their skeletal muscles show no gross pathological features. The mice are not impaired on grip strength, rotarod, or locomotor activity. These findings indicate that ACTC is sufficiently similar to ACTA1 to produce adequate function in postnatal skeletal muscle. This raises the prospect that ACTC reactivation might provide a therapy for ACTA1 diseases. In addition, the mouse model will allow analysis of the precise functional differences between ACTA1 and ACTC

Stem cell-derived macrophages as a new platform for studying host-pathogen interactions in livestock

BACKGROUND: Infectious diseases of farmed and wild animals pose a recurrent threat to food security and human health. The macrophage, a key component of the innate immune system, is the first line of defence against many infectious agents and plays a major role in shaping the adaptive immune response. However, this phagocyte is a target and host for many pathogens. Understanding the molecular basis of interactions between macrophages and pathogens is therefore crucial for the development of effective strategies to combat important infectious diseases. RESULTS: We explored how porcine pluripotent stem cells (PSCs) can provide a limitless in vitro supply of genetically and experimentally tractable macrophages. Porcine PSC-derived macrophages (PSCdMs) exhibited molecular and functional characteristics of ex vivo primary macrophages and were productively infected by pig pathogens, including porcine reproductive and respiratory syndrome virus (PRRSV) and African swine fever virus (ASFV), two of the most economically important and devastating viruses in pig farming. Moreover, porcine PSCdMs were readily amenable to genetic modification by CRISPR/Cas9 gene editing applied either in parental stem cells or directly in the macrophages by lentiviral vector transduction. CONCLUSIONS: We show that porcine PSCdMs exhibit key macrophage characteristics, including infection by a range of commercially relevant pig pathogens. In addition, genetic engineering of PSCs and PSCdMs affords new opportunities for functional analysis of macrophage biology in an important livestock species. PSCs and differentiated derivatives should therefore represent a useful and ethical experimental platform to investigate the genetic and molecular basis of host-pathogen interactions in pigs, and also have wider applications in livestock. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12915-021-01217-8

Mechanisms of receptor/coreceptor-mediated entry of enveloped viruses

Enveloped viruses enter host cells either through endocytosis, or by direct fusion of the viral membrane envelope and the membrane of the host cell. However, some viruses, such as HIV-1, HSV-1, and Epstein-Barr can enter a cell through either mechanism, with the choice of pathway often a function of the ambient physical chemical conditions, such as temperature and pH. We develop a stochastic model that describes the entry process at the level of binding of viral glycoprotein spikes to cell membrane receptors and coreceptors. In our model, receptors attach the cell membrane to the viral membrane, while subsequent binding of coreceptors enables fusion. The model quantifies the competition between fusion and endocytotic entry pathways. Relative probabilities for each pathway are computed numerically, as well as analytically in the high viral spike density limit. We delineate parameter regimes in which fusion or endocytosis is dominant. These parameters are related to measurable and potentially controllable quantities such as membrane bending rigidity and receptor, coreceptor, and viral spike densities. Experimental implications of our mechanistic hypotheses are proposed and discussed.Comment: 10 Figure