Infinite Graphs in Systematic Biology, with an Application to the Species Problem

We argue that C. Darwin and more recently W. Hennig worked at times under the simplifying assumption of an eternal biosphere. So motivated, we explicitly consider the consequences which follow mathematically from this assumption, and the infinite graphs it leads to. This assumption admits certain clusters of organisms which have some ideal theoretical properties of species, shining some light onto the species problem. We prove a dualization of a law of T. A. Knight and C. Darwin, and sketch a decomposition result involving the internodons of D. Kornet, J. Metz and H. Schellinx. A further goal of this paper is to respond to B. Sturmfels’ question, “Can biology lead to new theorems?”     

量子点在生命科学中的应用

近年来 ,量子点 (半导体纳米微晶体 )的研究引起国内外研究者的广泛兴趣 ,其研究内容涉及物理、化学、材料等多学科 ,已成为一门新兴的交叉学科。虽然量子点在生物学中的应用才刚刚起步 ,但是已经取得了有意义的进展 ,成为人们极为注意的一个热点。现就量子点的光学特性、制备方法以及在生物学中的研究进展和应用前景作一简要综述     

Statistical Identifiability and the Surrogate Endpoint Problem,with Application to Vaccine Trials

Summary Given a randomized treatment Z, a clinical outcome Y, and a biomarker S measured some fixed time after Z is administered, we may be interested in addressing the surrogate endpoint problem by evaluating whether S can be used to reliably predict the effect of Z on Y. Several recent proposals for the statistical evaluation of surrogate value have been based on the framework of principal stratification. In this article, we consider two principal stratification estimands: joint risks and marginal risks. Joint risks measure causal associations (CAs) of treatment effects on S and Y, providing insight into the surrogate value of the biomarker, but are not statistically identifiable from vaccine trial data. Although marginal risks do not measure CAs of treatment effects, they nevertheless provide guidance for future research, and we describe a data collection scheme and assumptions under which the marginal risks are statistically identifiable. We show how different sets of assumptions affect the identifiability of these estimands; in particular, we depart from previous work by considering the consequences of relaxing the assumption of no individual treatment effects on Y before S is measured. Based on algebraic relationships between joint and marginal risks, we propose a sensitivity analysis approach for assessment of surrogate value, and show that in many cases the surrogate value of a biomarker may be hard to establish, even when the sample size is large.     

基于问题教学法在骨科实习医生教学中的应用

摘要目的：通过基于问题教学方法（problem based learning,PBL）对骨科临床实习医师教学培训,探索提高实习医师临床实践的能力。方法：在骨科临床实习过程中,我们根据学生实习前平均成绩将实习医生分为2组,对18名实习医生采用传统教学模式,而对另18名实习医生采用基于问题教学模式,在临床实习过程进行问诊、初步诊断和分析、治疗处理、写病历、查房,骨科实习结束进行临床基本技能考核比较。结果：在体格检查、辅助检查、问题回答和患者评价项目考核比较,实验组实习医生出科成绩优于对照组;病历书写和病史采集两组没有区别。结论：通过对两组实习医师的临床实践成绩比较,在临床教学实践中,采用基于问题教学方法能够更好地提高实习医师掌握临床知识和技能的能力。     

Application of Change-Point Problem to the Detection of Plant Patches

In ecology, if the considered area or space is large, the spatial distribution of individuals of a given plant species is never homogeneous; plants form different patches. The homogeneity change in space or in time (in particular, the related change-point problem) is an important research subject in mathematical statistics. In the paper, for a given data system along a straight line, two areas are considered, where the data of each area come from different discrete distributions, with unknown parameters. In the paper a method is presented for the estimation of the distribution change-point between both areas and an estimate is given for the distributions separated by the obtained change-point. The solution of this problem will be based on the maximum likelihood method. Furthermore, based on an adaptation of the well-known bootstrap resampling, a method for the estimation of the so-called change-interval is also given. The latter approach is very general, since it not only applies in the case of the maximum-likelihood estimation of the change-point, but it can be also used starting from any other change-point estimation known in the ecological literature. The proposed model is validated against typical ecological situations, providing at the same time a verification of the applied algorithms.     

Robust Selection of the Most Discriminative Variables in the Dichotomous Problem with Application to Some Respiratory Disease Data

A robust method for selection of variables with the greatest discriminatory power is presented in the paper. The method deals with the two groups of data problem. An application of the method to some respiratory disease data and comparisons with classical procedures are given, also.     

Halting ErbB-2 isoforms retrograde transport to the nucleus as a new theragnostic approach for triple-negative breast cancer

Triple-negative breast cancer (TNBC) is clinically defined by the absence of estrogen and progesterone receptors and the lack of membrane overexpression or gene amplification of receptor tyrosine kinase ErbB-2/HER2. Due to TNBC heterogeneity, clinical biomarkers and targeted therapies for this disease remain elusive. We demonstrated that ErbB-2 is localized in the nucleus (NErbB-2) of TNBC cells and primary tumors, from where it drives growth. We also discovered that TNBC expresses both wild-type ErbB-2 (WTErbB-2) and alternative ErbB-2 isoform c (ErbB-2c). Here, we revealed that the inhibitors of the retrograde transport Retro-2 and its cyclic derivative Retro-2.1 evict both WTErbB-2 and ErbB-2c from the nucleus of BC cells and tumors. Using BC cells from several molecular subtypes, as well as normal breast cells, we demonstrated that Retro-2 specifically blocks proliferation of BC cells expressing NErbB-2. Importantly, Retro-2 eviction of both ErbB-2 isoforms from the nucleus resulted in a striking growth abrogation in multiple TNBC preclinical models, including tumor explants and xenografts. Our mechanistic studies in TNBC cells revealed that Retro-2 induces a differential accumulation of WTErbB-2 at the early endosomes and the plasma membrane, and of ErbB-2c at the Golgi, shedding new light both on Retro-2 action on endogenous protein cargoes undergoing retrograde transport, and on the biology of ErbB-2 splicing variants. In addition, we revealed that the presence of a functional signal peptide and a nuclear export signal (NES), both located at the N-terminus of WTErbB-2, and absent in ErbB-2c, accounts for the differential subcellular distribution of ErbB-2 isoforms upon Retro-2 treatment. Our present discoveries provide evidence for the rational repurposing of Retro-2 as a novel therapeutic agent for TNBC.Subject terms: Breast cancer, Protein translocation, Oncogenes, Nuclear transport, Targeted therapies     

Orthogonal Components in MANOVA with Application to an Anesthesiology Experiment

We describe orthogonal components in multivariate analysis of variance, and illustrate their value when assessing restricted alternatives.     

High-Dimensional Heteroscedastic Regression with an Application to eQTL Data Analysis

We consider the problem of high-dimensional regression under non-constant error variances. Despite being a common phenomenon in biological applications, heteroscedasticity has, so far, been largely ignored in high-dimensional analysis of genomic data sets. We propose a new methodology that allows non-constant error variances for high-dimensional estimation and model selection. Our method incorporates heteroscedasticity by simultaneously modeling both the mean and variance components via a novel doubly regularized approach. Extensive Monte Carlo simulations indicate that our proposed procedure can result in better estimation and variable selection than existing methods when heteroscedasticity arises from the presence of predictors explaining error variances and outliers. Further, we demonstrate the presence of heteroscedasticity in and apply our method to an expression quantitative trait loci (eQTLs) study of 112 yeast segregants. The new procedure can automatically account for heteroscedasticity in identifying the eQTLs that are associated with gene expression variations and lead to smaller prediction errors. These results demonstrate the importance of considering heteroscedasticity in eQTL data analysis.     

A General Approach to the Optimization of the Conformation of Ring Molecules with an Application to Valinomycin

Abstract

A general and efficient methodology is presented which allows molecules containing one or many rings of any size to be manipulated within energy minimization procedures. Variables describing the conformation of the molecules concerned are limited to dihedral and ring valence angles and the ring closure conditions are treated as equality constraints. An application is made to the ion transporter valinomycin and its complexes with K⁺ and Na⁺ which illustrates the possibilities of the approach and leads to results which allow a better understanding of the conformational mechanics of this important ionophore.     

Quantum dots go with the flow

RNA interference (RNAi) and automated high-throughput screening is a promising combination. But the first systematic large-scale mapping of genetic interactions in an animal shows that manual methods still have advantages over sophisticated automated screens.     

The Application of Dyes in the Cancer Problem

Three fundamental requirements for the problem of developing a differential stain for cancer are discussed: I. the choice of a technic for the microscopic preparation of tissues; II. an analysis of the biological properties peculiar to cancer; and III. various groups of dyes adaptable to such peculiar properties of cancer tissue. Under I the disadvantages of intravitam staining are pointed out and the use of cell suspensions, frozen sections, and fixed material favored. Under II three characteristics of cancer tissue offering possibilities for differential staining are discussed, the cytological structure known as the “plastin reaction”, the histogenic cycle of cancer tissue, and the viability of cancer tissue under anaerobic conditions. Under III modifications of the Giemsa stain are suggested for application to the plastin reaction, specific tissue stains advocated for the use of indicating end points in histogenic cycles, and the vital dyes, congo red and trypan blue, suggested as indicators for the survival of malignant tissues because of the failure of these dyes to permeate living cancer cells.

The angle of approach thruout has been an attempt to avoid unconscious pitfalls inherent in certain microscopic technics, and to substitute analytical methods for the blind trial and error method of routinely applying dye after dye in endless succession.     

Lead Poisoning: Using Transdisciplinary Approaches to Solve an Ancient Problem

Conservation medicine examines the linkages among the health of people, animals, and the environment. Few issues illustrate this approach better than an examination of lead (Pb) toxicity. Lead is cheap and there is a long tradition of its use. But the toxic effects of Pb have also been recognized for many years. As a result, western societies have eliminated or greatly reduced many traditional uses of Pb, including many paints, gasoline, and solders because of threats to the health of humans and the environment. Legislation in several countries has eliminated the use of lead shot for hunting waterfowl. Despite these advances, a great many Pb products continue to be readily available. For example, wildlife agencies recognize that angling and shooting sports deposit thousands of tons of Pb into the environment each year. In recent years, our knowledge of the lethal and sublethal effects of Pb has grown dramatically. This discussion reviews the effects of lead on wildlife, humans, and domestic animals. It also discusses the importance of bringing together all interest groups to find safe alternatives, to develop new educational and policy initiatives, to eliminate many current uses of Pb, and to clean up existing problems.     

The Application of the Maize-Derived Gene Competition Model to the Problem of Dosage Compensation in Drosophila

The gene competition model, originally formulated from studies on the regulation of alcohol dehydrogenase activity in maize, is also applicable to the phenomenon of dosage compensation in Drosophila. The model accounts for the absence of dosage compensation in sex determination.     

Application of an airlift bioreactor to the nystatin biosynthesis

Pilot plant studies were performed using a concentric-tube airlift bioreactor of 2.5 m³ fermentation volume. The results have proven the relative merits of such a system in the biosynthesis of nystatin, produced by Streptomyces noursei, in submerged aerobic cultivation and batch operation mode. The results were compared to those obtained in a pilot-scale stirred tank bioreactor of 3.5 m³ fermentation volume. The fermentation processes in the two fermentation devices were similar with respect to substrate utilization, biomass production and nystatin biosynthesis. In the riser section, the dissolved oxygen concentration was higher than that in the downcomer. The volumetric oxygen mass transfer coefficient was dependent on the rheological behaviour of the biosynthesis liquids, which was not constant during the fermentation process. The total energy consumption for nystatin production in the airlift bioreactor was 56% of that in the stirred tank, while the operating costs represented 78% of those in the stirred tank bioreactor.     

Refractometric Sensing with Silicon Quantum Dots Coupled to a Microsphere

Quantum dots (QDs) coupled to an optical microsphere can be used as fluorescent refractometric sensors. The QD emission couples to the whispering gallery resonances of the microsphere, leading to sharp, periodic maxima in the fluorescence spectrum. Silicon QDs (Si-QDs) are especially attractive fluorophores because of their low toxicity and ease of handling. In this work, a thin layer of Si-QDs was coated onto the surface of a microsphere made by melting the end of a tapered optical fiber. Refractometric sensing experiments were conducted using two methods. First, the sphere was immersed directly into a cuvette containing methanol–water mixtures. Second, the sphere was inserted into a silica capillary and the solutions were pumped through the capillary channel. The latter method enables microfluidic operation, which is otherwise difficult to achieve with a microsphere. In both geometries, high-visibility (V?=?0.83) modes were observed with Q factors up to 1,700. Using standard signal processing methods applied to the whispering gallery mode (WGM) spectrum, sensorgram-type measurements were conducted using single Si-QD-coated microspheres. The WGM resonances shifted as a function of the refractive index of the analyte solution, giving sensitivities ranging from ~30 to 100 nm/refractive index unit (RIU) for different microspheres and a detection limit on the order of 10^?4 RIU.