Anesthesia in the mouse using a combination of ketamine and promazine

An anesthetic combination of ketamine and promazine was tested in 25 male and 25 female mice of each of two strains. The mean induction time was 5 minutes for the C57BL/6We mouse and 8 minutes for the DBA/2We mouse. No sex differences were observed. The mean duration time was 45 minutes for the C57BL/6We male, 53 minutes for the C57BL/TWe female, 29 minutes for the DBA/2We male, and 35 minutes for the DBA/2We female. The mean recovery time was 39 minutes for the C57BL/6We male, 38 minutes for the C57BL/6We female, 21 minutes for the DBA/2We male, and 24 minutes for the DBA/2We female. The drug combination provided effective anesthesia for these strains of the laboratory mouse for a period of 30--50 minutes after a single intramuscular injection.     

Role of Small Oligomers on the Amyloidogenic Aggregation Free-Energy Landscape

We combine atomic-force-microscopy particle-size-distribution measurements with earlier measurements on 1-anilino-8-naphthalene sulfonate, thioflavin T, and dynamic light scattering to develop a quantitative kinetic model for the aggregation of β-lactoglobulin into amyloid. We directly compare our simulations to the population distributions provided by dynamic light scattering and atomic force microscopy. We combine species in the simulation according to structural type for comparison with fluorescence fingerprint results. The kinetic model of amyloidogenesis leads to an aggregation free-energy landscape. We define the roles of and propose a classification scheme for different oligomeric species based on their location in the aggregation free-energy landscape. We relate the different types of oligomers to the amyloid cascade hypothesis and the toxic oligomer hypothesis for amyloid-related diseases. We discuss existing kinetic mechanisms in terms of the different types of oligomers. We provide a possible resolution to the toxic oligomer-amyloid coincidence.     

Stability of discrete one-dimensional population models

We give conditions for local and global stability of discrete one-dimensional population models. We give a new test for local stability when the derivative is −1. We give several sufficient conditions for global stability. We use these conditions to show that local and global stability coincide for the usual models from the literature and even for slightly more complicated models. We give population models, which are in some sense the simplest models, for which local and global stability do not coincide.     

SIS epidemics with household structure: the self-consistent field method

We consider a stochastic SIS infection model for a population partitioned into m households assuming random mixing. We solve the model in the limit m→∞ by using the self-consistent field method of statistical physics. We derive a number of explicit results, and give numerical illustrations. We then do numerical simulations of the model for finite m and without random mixing. We find in many of these cases that the self-consistent field method is a very good approximation.     

A model for the origin and properties of flicker-induced geometric phosphenes

We present a model for flicker phosphenes, the spontaneous appearance of geometric patterns in the visual field when a subject is exposed to diffuse flickering light. We suggest that the phenomenon results from interaction of cortical lateral inhibition with resonant periodic stimuli. We find that the best temporal frequency for eliciting phosphenes is a multiple of intrinsic (damped) oscillatory rhythms in the cortex. We show how both the quantitative and qualitative aspects of the patterns change with frequency of stimulation and provide an explanation for these differences. We use Floquet theory combined with the theory of pattern formation to derive the parameter regimes where the phosphenes occur. We use symmetric bifurcation theory to show why low frequency flicker should produce hexagonal patterns while high frequency produces pinwheels, targets, and spirals.     

A new Bayesian approach incorporating covariate information for heterogeneity and its comparison with HLOD

We consider a new Bayesian approach for heterogeneity that can take into account categorical covariates, if available. We use the Genetic Analysis Workshop 14 simulated data to first compare the Bayesian approach with the heterogeneity LOD, when no covariate information is used. We find that the former is more powerful, while the two approaches have comparable false-positive rates. We then include informative covariates in the Bayesian approach and find that it tends to give more precise interval estimates of the disease gene location than when covariates are not included. We had knowledge of the simulation models at the time we performed the analyses.     

快速纯化重组腺联病毒的受体结合捕捉方法

【目的】建立用于重组腺联病毒(AAV)纯化的受体结合捕捉方法。【方法】将AAV受体的多囊肾病(PKD)结构域1和2与类弹性蛋白多肽(ELP)在重组大肠杆菌中进行融合表达,利用相变循环(ITC)纯化ELP-PKD融合蛋白;分别用昆虫和AAV-293细胞制备rAAV-GFP,与ELP-PKD融合蛋白共孵育后进行ITC,从沉淀复合物提取病毒DNA进行PCR检测;在优化条件下利用ELP-PKD蛋白结合捕捉rAAV-GFP,利用电子显微镜观察、免疫转印和细胞感染试验进行rAAV鉴定。【结果】ELP-PKD融合蛋白获得正确、可溶性表达,ITC纯化的蛋白纯度大于90%;ELP-PKD蛋白能特异结合rAAV-GFP,结合具有p H、温度和时间依赖性,受体结合捕捉方法可在1h内完成,从两种细胞纯化rAAV-GFP的回收率分别为58%和56%;rAAV-GFP洗脱具有p H和温度依赖性,洗脱rAAV-GFP的回收率分别为46%和44%;纯化rAAV-GFP具有AAV的典型形态和结构蛋白。【结论】建立的ELP-PKD结合捕捉法可用于不同细胞源rAAV的快速纯化。     

The Ross-Macdonald model in a patchy environment

We generalize to n patches the Ross-Macdonald model which describes the dynamics of malaria. We incorporate in our model the fact that some patches can be vector free. We assume that the hosts can migrate between patches, but not the vectors. The susceptible and infectious individuals have the same dispersal rate. We compute the basic reproduction ratio R(0). We prove that if R(0)1, then the disease-free equilibrium is globally asymptotically stable. When R(0)>1, we prove that there exists a unique endemic equilibrium, which is globally asymptotically stable on the biological domain minus the disease-free equilibrium.     

An evolutionary strategy for all-atom folding of the 60-amino-acid bacterial ribosomal protein l20

We have investigated an evolutionary algorithm for de novo all-atom folding of the bacterial ribosomal protein L20. We report results of two simulations that converge to near-native conformations of this 60-amino-acid, four-helix protein. We observe a steady increase of "native content" in both simulated ensembles and a large number of near-native conformations in their final populations. We argue that these structures represent a significant fraction of the low-energy metastable conformations, which characterize the folding funnel of this protein. These data validate our all-atom free-energy force field PFF01 for tertiary structure prediction of a previously inaccessible structural family of proteins. We also compare folding simulations of the evolutionary algorithm with the basin-hopping technique for the Trp-cage protein. We find that the evolutionary algorithm generates a dynamic memory in the simulated population, which leads to faster overall convergence.     

The Social Burden of Resilience: A Historical Perspective

We examine the social burden associated with resilience to environmental shocks in pre-modern societies. We argue that analyses of state-level interventions to mitigate the consequences of catastrophic events tend to isolate these measures from their larger social contexts and thereby overlook the uneven distribution of their burden across different groups. We use three cases of pre-modern societies in the northeastern Mediterranean - the sixth century Roman Empire, the tenth century Byzantine Empire, and the sixteenth century Ottoman Empire. We demonstrate how the adaptive processes that reinforced resilience at the state level incurred different burdens for those at lower levels of the social hierarchy. We found that some groups sustained losses while others gained unexpected benefits in the context of temporary systemic instability. We also found that although elites enjoyed enhanced buffers against the adverse effects in comparison with non-elites, this did not consistently guarantee them a better outcome. We conclude that the differentiated burden of resilience could in some cases entrench existing political or economic configurations, and in other cases, overturn them. Our case studies indirectly address the pressing issue of environmental justice.     

Mathematical models of bacterial growth,inhibition and death under combined stress conditions

Summary In this report we review the history of growth theories. We show how classical growth models may be derived as special cases of a generic growth rate equation. We show how growth models may be modified to represent survival data. We use linear combinations of growth and survival models to represent complex growth/survival curves and give practical examples utilizing nonlinear regression analysis. We show that traditional methods of estimating D values are inappropriate for complex, multiphasic growth/survival data. We show how such data may be modeled mathematically and illustrate methods for estimating true D values from such data.     

A Bayesian Method for Deriving Species-Sensitivity Distributions: Selecting the Best-Fit Tolerance Distributions of Taxonomic Groups

We present a Bayesian method for deriving species-sensitivity distributions (SSDs). We employed four Bayesian statistical models to consider differences in tolerance to toxic substances among different taxonomic groups. We first used a Malkov chain Monte Carlo simulation based on these models to estimate the SSD parameters. We then computed deviance information criterion values of the models and compared them in order to select the model with the best predictive ability. We applied this approach to seven substances (zinc, lead, hexavalent chromium, cadmium, nickel, short-chain chloride paraffin, and chloroform) as case examples, and then compared the derived SSDs from the selected models and a model that assumed no tolerance differences among taxonomic groups. We discuss the advantages and limitations of our approach on the basis of our results.     

The influence of sexually active non-reproductive groups on persistent sexually transmitted diseases

We describe several population models exposed to a mild life-long sexually transmitted disease, i.e. without significant increased mortality among infected individuals and providing no immunity/recovery. We then modify these models to include non-reproductive groups consisting of those isolated from sexual contact and those who are sexually active but infertile due to choice, medical or other reasons. We analyse the potential effect on the dynamics of the population. We are interested in how the isolated class may curb the growth of the infected group while keeping the healthy population at acceptable levels. We also analyse the difference between being sexually active and abstained within the non-reproductive class and its impact on the epidemic reproductive number and the nature of the bifurcation around the disease-free equilibrium. We provide a comparison with our models introduced in a previous article, which include only the isolated from sexual contact class.     

Population dynamics in a spin-glass model of chemical evolution

Summary We introduce a simple model describing the evolution of a population of information-carrying macromolecules. We discuss the asymptotic dependence of the variability of the population on different parameters, representing the severity or the fluctuations of the environment. We show the existence of a transition separating a neutralist evolutionary regime from a trapped one. We investigate the dependence of the evolutionary behavior of the population on the correlation properties of the fitness landscape.     

Functional evolution of the yeast protein interaction network

Protein interactions are central to most biological processes. We investigated the dynamics of emergence of the protein interaction network of Saccharomyces cerevisiae by mapping origins of proteins on an evolutionary tree. We demonstrate that evolutionary periods are characterized by distinct connectivity levels of the emerging proteins. We found that the most-connected group of proteins dates to the eukaryotic radiation, and the more ancient group of pre-eukaryotic proteins is less connected. We show that functional classes have different average connectivity levels and that the time of emergence of these functional classes parallels the observed connectivity variation in evolution. We take these findings as evidence that the evolution of function might be the reason for the differences in connectivity throughout evolutionary time. We propose that the understanding of the mechanisms that generate the scale-free protein interaction network, and possibly other biological networks, requires consideration of protein function.     

Dielectric relaxation in proteins: the computational perspective

In photoexcitation and electron transfer, a new dipole or charge is introduced, and the structure is adjusted. This adjustment represents dielectric relaxation, which is the focus of this review. We concentrate on a few selected topics. We discuss linear response theory, as a unifying framework and a tool to describe non-equilibrium states. We review recent, molecular dynamics simulation studies that illustrate the calculation of dynamic and thermodynamic properties, such as Stokes shifts or reorganization free energies. We then turn to the macroscopic, continuum electrostatic view. We recall the physical definition of a dielectric constant and revisit the decomposition of the free energy into a reorganization and a static term. We review some illustrative continuum studies and discuss some difficulties that can arise with the continuum approach. In conclusion, we consider recent developments that will increase the accuracy and broaden the scope of all these methods.     

The influence of sexually active non-reproductive groups on persistent sexually transmitted diseases

We describe several population models exposed to a mild life-long sexually transmitted disease, i.e. without significant increased mortality among infected individuals and providing no immunity/recovery. We then modify these models to include non-reproductive groups consisting of those isolated from sexual contact and those who are sexually active but infertile due to choice, medical or other reasons. We analyse the potential effect on the dynamics of the population. We are interested in how the isolated class may curb the growth of the infected group while keeping the healthy population at acceptable levels. We also analyse the difference between being sexually active and abstained within the non-reproductive class and its impact on the epidemic reproductive number and the nature of the bifurcation around the disease-free equilibrium. We provide a comparison with our models introduced in a previous article, which include only the isolated from sexual contact class.     

Extraordinary Transmission Characteristics of Subwavelength Nanoholes with Rectangular Lattice

We investigate the extraordinary optical transmission (EOT) properties of nanohole arrays with a rectangular lattice for label-free refractive index sensing applications. We show that the deviation within the periodicities along the two axes at the nanohole plane leads to more advantageous spectral quality of EOT signal compared to the conventional square lattice geometries. We introduce a way to further improve the sensitivity of the aperture system by carefully choosing the periodicities. We introduce nanohole arrays with a rectangular lattice supporting EOT signals with larger figure-of-merit values as well as enabling much stronger light transmission. We also model a nanohole system covered with a thin dielectric layer, mimicking biomolecules captured on the gold surface, in order to show its biosensing capability. We also show that certain deviation amounts between periodicities create spectral splitting within the EOT signal leading to larger spectral shifts in the presence of a thin dielectric film.