Pervasive selection for and against antibiotic resistance in inhomogeneous multistress environments

Antibiotic-sensitive and -resistant bacteria coexist in natural environments with low, if detectable, antibiotic concentrations. Except possibly around localized antibiotic sources, where resistance can provide a strong advantage, bacterial fitness is dominated by stresses unaffected by resistance to the antibiotic. How do such mixed and heterogeneous conditions influence the selective advantage or disadvantage of antibiotic resistance? Here we find that sub-inhibitory levels of tetracyclines potentiate selection for or against tetracycline resistance around localized sources of almost any toxin or stress. Furthermore, certain stresses generate alternating rings of selection for and against resistance around a localized source of the antibiotic. In these conditions, localized antibiotic sources, even at high strengths, can actually produce a net selection against resistance to the antibiotic. Our results show that interactions between the effects of an antibiotic and other stresses in inhomogeneous environments can generate pervasive, complex patterns of selection both for and against antibiotic resistance

Mechanisms of antibiotic action shape the fitness landscapes of resistance mutations

Antibiotic-resistant pathogens are a major public health threat. A deeper understanding of how an antibiotic’s mechanism of action influences the emergence of resistance would aid in the design of new drugs and help to preserve the effectiveness of existing ones. To this end, we developed a model that links bacterial population dynamics with antibiotic-target binding kinetics. Our approach allows us to derive mechanistic insights on drug activity from population-scale experimental data and to quantify the interplay between drug mechanism and resistance selection. We find that both bacteriostatic and bactericidal agents can be equally effective at suppressing the selection of resistant mutants, but that key determinants of resistance selection are the relationships between the number of drug-inactivated targets within a cell and the rates of cellular growth and death. We also show that heterogeneous drug-target binding within a population enables resistant bacteria to evolve fitness-improving secondary mutations even when drug doses remain above the resistant strain’s minimum inhibitory concentration. Our work suggests that antibiotic doses beyond this ‘‘secondary mutation selection window” could safeguard against the emergence of high-fitness resistant strains during treatment

Viscoelasticity near the gel-point: a molecular dynamics study

We report on extensive molecular dynamics simulations on systems of soft spheres of functionality f, i.e. particles that are capable of bonding irreversibly with a maximum of f other particles. These bonds are randomly distributed throughout the system and imposed with probability p. At a critical concentration of bonds, p_c approximately equal to 0.2488 for f=6, a gel is formed and the shear viscosity \eta diverges according to \eta ~ (p_c-p)^{-s}. We find s is approximately 0.7 in agreement with some experiments and with a recent theoretical prediction based on Rouse dynamics of phantom chains. The diffusion constant decreases as the gel point is approached but does not display a well-defined power law.Comment: 4 pages, 4 figure

Visualizing tephra deposits and sedimentary processes in the marine environment: The potential of X‐ray microtomography

Localized tephra deposition in marine sequences is the product of many complex primary and secondary depositional processes. These can significantly influence the potential applicability of tephra deposits as isochronous marker horizons and current techniques, used in isolation, may be insufficient to fully unravel these processes. Here we demonstrate the innovative application of X-ray microtomography (µCT) to successfully identify tephra deposits preserved within marine sediments and use these parameters to reconstruct their internal three-dimensional structure. Three-dimensional visualizations and animations of tephra dispersal in the sediment permit a more thorough assessment of postdepositional processes revealing a number of complex microsedimentological features that are not revealed by conventional methods. These features include bioturbation burrows and horizontally discontinuous tephra packages, which have important ramifications for the stratigraphic placement of the isochron in a sedimentary sequence. Our results demonstrate the potential for utilizing rigorous two and three-dimensional microsedimentological analysis of the ichnofabric to enhance and support the use of tephra deposits as isochronous marker horizons and to identify the stratigraphic position that best reflects the primary fallout of ash. The application also provides an exceptional insight into the style and rate of sedimentation processes and permits an assessment of the stratigraphic integrity of a tephra deposit. We discuss the possibility of applying these µCT methods to the identification of cryptotephras within various paleoclimatic sequences and to enhance our understanding of marine sedimentation processes

An angle-scanned cryogenic Fabry-Pérot interferometer for far-infrared astronomy

The sensitivity of state-of-the-art superconducting far-infrared detectors used in conjunction with cryogenically cooled space telescopes and instrumentation is such that spectroscopic observations are generally limited by photon noise from the astronomical source or by galactic foreground or zodiacal emission within the field-of-view. Therefore, an instrument design that restricts the spectral bandpass viewed by the detector must be employed. One method of achieving background limited, high resolution spectroscopy is to combine a high resolution component such as a Fabry–Pérot interferometer (FPI) with a lower resolution, post-dispersing system, such as a grating spectrometer, the latter serving to restrict the spectral bandpass. The resonant wavelength of an FPI is most often tuned by changing the spacing or medium between the parallel reflecting plates of the etalon. In this paper, we present a novel design for an FPI in which the wavelength is tuned by scanning the angle of incidence on a high refractive index etalon. This concept simplifies the cryomechanical design, actuation, and metrology. The first results from the realized instrument are presented and compared with theory. The effects on the spectral response as a function of the incident angle have been simulated and shown to agree well with the observation

Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series

The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers

Increased TNF-α/IFN-γ/IL-2 and Decreased TNF-α/IFN-γ Production by Central Memory T Cells Are Associated with Protective Responses against Bovine Tuberculosis Following BCG Vaccination

Central memory T cells (Tcm) and polyfunctional CD4 T cell responses contribute to vaccine-elicited protection with both human and bovine tuberculosis (TB); however, their combined role in protective immunity to TB is unclear. To address this question, we evaluated polyfunctional cytokine responses by CD4 T cell effector / memory populations from bacille Calmette Guerin (BCG) vaccinated and non-vaccinated calves prior to and after aerosol challenge with virulent Mycobacterium bovis. Polyfunctional cytokine expression patterns in the response by Tcm, effector memory, and effector T cell subsets were similar between BCG-vaccinated and M. bovis-infected calves; only differing in magnitude (i.e., infected > vaccinated). BCG vaccination, however, did alter the kinetics of the ensuing response to virulent M. bovis infection. Early after challenge (three weeks post-infection), non-vaccinates had greater antigen-specific IFN-γ/TNF-α and lesser IFN-γ/TNF-α/IL-2 responses by Tcm cells than did vaccinated animals. Importantly, these differences were also associated with mycobacterial burden upon necropsy. Polyfunctional responses to ESAT-6:CFP10 (antigens not synthesized by BCG strains) were detected in memory subsets, as well as in effector cells, as early as three weeks after challenge. These findings suggest that cell fate divergence may occur early after antigen priming in the response to bovine TB and that memory and effector T cells may expand concurrently during the initial phase of the immune response. In summary, robust IFN-γ/TNF-α response by Tcm cells is associated with greater mycobacterial burden while IFN-γ/TNF-α/IL-2 response by Tcm cells are indicative of a protective response to bovine TB

Glassiness and constrained dynamics of a short-range non-disordered spin model

We study the low temperature dynamics of a two dimensional short-range spin system with uniform ferromagnetic interactions, which displays glassiness at low temperatures despite the absence of disorder or frustration. The model has a dual description in terms of free defects subject to dynamical constraints, and is an explicit realization of the ``hierarchically constrained dynamics'' scenario for glassy systems. We give a number of exact results for the statics of the model, and study in detail the dynamical behaviour of one-time and two-time quantities. We also consider the role played by the configurational entropy, which can be computed exactly, in the relation between fluctuations and response.Comment: 10 pages, 9 figures; minor changes, references adde

GPI spectra of HR 8799 c, d, and e from 1.5 to 2.4μ\mum with KLIP Forward Modeling

We explore KLIP forward modeling spectral extraction on Gemini Planet Imager coronagraphic data of HR 8799, using PyKLIP and show algorithm stability with varying KLIP parameters. We report new and re-reduced spectrophotometry of HR 8799 c, d, and e in H & K bands. We discuss a strategy for choosing optimal KLIP PSF subtraction parameters by injecting simulated sources and recovering them over a range of parameters. The K1/K2 spectra for HR 8799 c and d are similar to previously published results from the same dataset. We also present a K band spectrum of HR 8799 e for the first time and show that our H-band spectra agree well with previously published spectra from the VLT/SPHERE instrument. We show that HR 8799 c and d show significant differences in their H & K spectra, but do not find any conclusive differences between d and e or c and e, likely due to large error bars in the recovered spectrum of e. Compared to M, L, and T-type field brown dwarfs, all three planets are most consistent with mid and late L spectral types. All objects are consistent with low gravity but a lack of standard spectra for low gravity limit the ability to fit the best spectral type. We discuss how dedicated modeling efforts can better fit HR 8799 planets' near-IR flux and discuss how differences between the properties of these planets can be further explored.Comment: Accepted to AJ, 25 pages, 16 Figure

Nanometer Scale Dielectric Fluctuations at the Glass Transition

Using non-contact scanning probe microscopy (SPM) techniques, dielectric properties were studied on 50 nanometer length scales in poly-vinyl-acetate (PVAc) films in the vicinity of the glass transition. Low frequency (1/f) noise observed in the measurements, was shown to arise from thermal fluctuations of the electric polarization. Anomalous variations observed in the noise spectrum provide direct evidence for cooperative nano-regions with heterogeneous kinetics. The cooperative length scale was determined. Heterogeneity was long-lived only well below the glass transition for faster than average processes.Comment: 4 pages, 4 embedded PS figures, RevTeX - To appear in Phys. Rev. Let