Comparing and predicting between several methods of measurement

In studies designed to compare different methods of measurement where more than two methods are compared or replicate measurements by each method are available, standard statistical approaches such as computation of limits of agreement are not directly applicable. A model is presented for comparing several methods of measurement in the situation where replicate measurements by each method are available. Measurements are viewed as classified by method, subject and replicate. Models assuming exchangeable as well as non-exchangeable replicates are considered. A fitting algorithm is presented that allows the estimation of linear relationships between methods as well as relevant variance components. The algorithm only uses methods already implemented in most statistical software.     

A model for incorporating historical controls into a meta-analysis.

A method is presented for estimating the treatment effect in a meta-analysis when some of the studies are comparative studies, and the rest are noncomparative, historical control studies. A random-effects model is used in which the baseline effect in each study is random, but the treatment effect is constant. With this model the appropriate contribution of the historical studies can be determined. Extensions of the model are developed to accommodate preliminary tests for bias, and for the possibility that the treatment effect is heterogeneous.     

Heart rate and blood pressure biofeedback: II. A review and integration of recent theoretical models.

The theoretical models put forth separately by Bremer, Lang, and Schwartz to account for the data on biofeedback and cardiovascular responses are summarized and evaluated in light of recent empirical studies. Although each model makes some use of the idea that learning to control heart rate, particularly heart rate acceleration, is like motor skills learning, each model also emphasizes different sets of factors or variable. An attempted integration of these three models is presented.     

Testing for Validity and Reliability in Cross-Cultural Research

A set of procedures is offered for assessing interraler reliability and certain aspects of validity of codes in cross-cultural studies. The method assumes that at least two independent raters have coded more than one trait. Each trait coded by one rater is correlated with each trait coded by a second, and all the codings by a single rater are intercorrelated with each other. The results are presented in a multitrait-multi-rater matrix. From this matrix it is possible to determine the interrater reliability and discriminant validity of trails in addition to a higher order concept based on pairs of traits.     

Dermatoglyphics in endogamic populations of Sardinia

Several dermatoglyphic characteristics (palmar and plantar) of different populations in Sardinian communities are reported. Graphs illustrating the dermatoglyphic behaviour of the single communities examined are presented.It can be seen that each community behaves differently from the others, even when they are geographically close together. Sexual differences appear quite accentuated in some communities while in others they are negligible. From the present study, as well as from other studies on the hereditary characteristics of Sardinians, it emerges that Sardinia is in reality subdivided into many different populations, or endogamic stocks, each presenting a particular behaviour of its own, sometimes quite different from that presented by the other populations.     

Cembranoid and long-chain alkanol sites on the nicotinic acetylcholine receptor and their allosteric interaction

Long-chain alkanols are general anesthetics which can also act as uncharged noncompetitive inhibitors of the peripheral nicotinic acetylcholine receptor (AChR) by binding to one or more specific sites on the AChR. Cembranoids are naturally occurring, uncharged noncompetitive inhibitors of peripheral and neuronal AChRs, which have no demonstrable general anesthetic activity in vivo. In this study, [3H]tenocyclidine ([3H]TCP), an analogue of the cationic noncompetitive inhibitor phencyclidine (PCP), was used to characterize the cembranoid and long-chain alkanol sites on the desensitized Torpedo californica AChR and to investigate if these sites interact. These studies confirm that there is a single cembranoid site which sterically overlaps the [3H]TCP channel site. This cembranoid site probably also overlaps the sites for the cationic noncompetitive inhibitors, procaine and quinacrine. Evidence is also presented for one or more allosteric cembranoid sites which negatively modulate cembranoid affinity for the inhibitory site. In contrast, long-chain alkanols inhibit [3H]TCP binding through an allosteric mechanism involving two or more alkanol sites which display positive cooperativity toward each other. Double inhibitor studies show that the cembranoid inhibitory site and the alkanol sites are not independent of each other but interfere allosterically with each other's inhibition of [3H]TCP binding. The simplest models consistent with the observed data are presented and discussed.     

Membrane-mimetic systems for biophysical studies of the amyloid-β peptide

The interplay between the amyloid-β (Aβ) peptide and cellular membranes have been proposed as an important mechanism for toxicity in Alzheimer's disease (AD). Membrane environments appear to influence Aβ aggregation and may stabilize intermediate Aβ oligomeric states that are considered to be neurotoxic. One important role for molecular biophysics within the field of Aβ studies is to characterize the structure and dynamics of the Aβ peptide in various states, as well as the kinetics of transfer between these states. Because biological cell membranes are very complex, simplified membrane models are needed to facilitate studies of Aβ and other amyloid proteins in lipid environments. In this review, we examine different membrane-mimetic systems available for molecular studies of Aβ. An introduction to each system is given, and examples of important findings are presented for each system. The benefits and drawbacks of each system are discussed from methodical and biological perspectives.     

Metabolic regulation of neuron functions

A short analytical review of Soviet and foreign studies devoted to metabolic regulation of neuron functioning is presented. It is shown that the electrical activity of neuron is accompanied by structural changes and an increase in RNA content. It is assumed that these changes are initiated by calcium ions, coming to the neuron during its excitation. The principles of metabolic regulation of functioning of electro- and chemoexcitable neuronal membranes are considered. It is shown that the metabolic reactions can be an intermediate between the activated chemoreceptor and the electrical response of the cell. Evidence is presented that the electroexcitable and chemosensitive structures in the membrane modulate each other. The role of intracellular messengers in regulating the activity of receptors and channels is considered. Possible mechanisms for their modifications under the influence of cellular factors are discussed. It is shown that the work of neuron is controlled by several metabolic regulatory systems simultaneously.     

An empirical Bayes' approach to joint analysis of multiple microarray gene expression studies

With the prevalence of gene expression studies and the relatively low reproducibility caused by insufficient sample sizes, it is natural to consider joint analysis that could combine data from different experiments effectively to achieve improved accuracy. We present in this article a model-based approach for better identification of differentially expressed genes by incorporating data from different studies. The model can accommodate in a seamless fashion a wide range of studies including those performed at different platforms by fitting each data with different set of parameters, and/or under different but overlapping biological conditions. Model-based inferences can be done in an empirical Bayes' fashion. Because of the information sharing among studies, the joint analysis dramatically improves inferences based on individual analysis. Simulation studies and real data examples are presented to demonstrate the effectiveness of the proposed approach under a variety of complications that often arise in practice.     

Application of repeated measures designs in environmental impact and monitoring studies

Abstract Traditional environmental studies have employed sampling at different times, but based on re-randomized ‘replicate’ samples taken at each time. For example, in a 4 year monitoring study of near-shore marine benthic communities there might be three box cores collected annually at each of three depths along each of three transects. Repeated measures designs, long used in medicine and the social sciences, are based on resampling replicates (e.g. sites) at a series of times. In such designs spatial sampling variability is not used for tests of environmental impact. Error for such tests is based on variability of time trends among similar sites (similar with respect to impact). For example in a tropical oil spill study five oiled and five unoiled coral reefs were studied over 5 years. Error for tests of oil impact was based on variability among reefs (within degree-of-oiling category) in the year-to-year trends of biological response variables. It was not based on variability among field samples within reefs at given times. The two approaches (univariate and multivariate) to repeated measures analysis of variance are described. The pros and cons of each are discussed, as are the assumptions and consequences of their violations. Emphasis is especially placed on the adequacy of error degrees of freedom in the two approaches, and some exploration of power to detect impact is presented. Examples of application of repeated measures designs to various impact and monitoring studies are presented and discussed, including (i) interpretation of significant effects; (ii) decomposition of effects by contrasts (e.g. before vs after impact); and (iii) modelling time trends by polynomial and cosine functions.     

Isolation and Partial Characterization of Temperature-Sensitive Mutants in Ten Loci That Affect Cell Membrane Synthesis in Escherichia coli: Isolation and Genetic Sorting

Four hundred temperature-sensitive (ts) mutants were isolated by the (3)H-glycerol-3-phosphate membrane suicide procedure of Cronan, Ray, and Vagelos and were sorted into 13 groups by the rapid mapping procedures of Low. Recombination and complementation studies on representative members of each group suggested that the ts mutations of all 13 groups are present in genetically different complementation groups. Biochemical studies suggested that 10 of these ts mutations affected cell membrane synthesis. In this paper, the genetic data are presented in detail so that the limits of the Low rapid mapping procedures can be assessed, and in an accompanying paper the partial biochemical characterization of the ts mutations is described.     

Structuring evidence for invasional meltdown: broad support but with biases and gaps

Negative interactions have been suggested as a major barrier for species arriving in a new habitat. More recently, positive interactions drew attention from community assembly theory and invasion science. The invasional meltdown hypothesis (IMH) introduced the idea that positive interactions among non-native species could facilitate one another’s invasion, even increasing their impact upon the native community. Many studies have addressed IMH, but with contrasting results, reflecting various types of evidence on a multitude of scales. Here we use the hierarchy-of-hypotheses (HoH) approach to differentiate key aspects of IMH, organizing and linking empirical studies to sub-hypotheses of IMH. We also assess the level of empirical support for each sub-hypothesis based on the evidence reported in the studies. We identified 150 studies addressing IMH. The majority of studies support IMH, but the evidence comes from studies with different aims and questions. Supporting studies at the community or ecosystem level are currently rare. Evidence is scarce for marine habitats and vertebrates. Few sub-hypotheses are questioned by more than 50% of the evaluated studies, indicating that non-native species do not affect each other’s survival, growth, reproduction, abundance, density or biomass in reciprocal A ? B interactions. With the HoH for IMH presented here, we can monitor progress in empirical tests and evidences of IMH. For instance, more tests at the community and ecosystem level are needed, as these are necessary to address the core of this hypothesis.     

Synthesis of an alpha-aminophosphonate nucleoside as an inhibitor of S-adenosyl-L-homocysteine hydrolase

A phosphonic acid analogue of S-adenosyl-L-homocysteine was prepared by a novel method and the epimeric mixture separated. Preliminary studies indicate that each epimer causes time-dependent inactivation of S-adenosyl-L-homocysteine hydrolase, however each presented distinct kinetic characteristics.     

Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration

Much medical research is observational. The reporting of observational studies is often of insufficient quality. Poor reporting hampers the assessment of the strengths and weaknesses of a study and the generalisability of its results. Taking into account empirical evidence and theoretical considerations, a group of methodologists, researchers, and editors developed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) recommendations to improve the quality of reporting of observational studies. The STROBE Statement consists of a checklist of 22 items, which relate to the title, abstract, introduction, methods, results and discussion sections of articles. Eighteen items are common to cohort studies, case-control studies and cross-sectional studies and four are specific to each of the three study designs. The STROBE Statement provides guidance to authors about how to improve the reporting of observational studies and facilitates critical appraisal and interpretation of studies by reviewers, journal editors and readers. This explanatory and elaboration document is intended to enhance the use, understanding, and dissemination of the STROBE Statement. The meaning and rationale for each checklist item are presented. For each item, one or several published examples and, where possible, references to relevant empirical studies and methodological literature are provided. Examples of useful flow diagrams are also included. The STROBE Statement, this document, and the associated Web site (http://www.strobe-statement.org/) should be helpful resources to improve reporting of observational research.     

A molecular approach to the identification and individualization of human and animal cells in culture: Isozyme and allozyme genetic signatures

Summary The electrophoretic resolution of a group of geneticallymonomorphic gene-enzyme systems that are developmentally and biologically ubiquitous has been used to provide a species-specific and type-specific biochemical characterization of various cultured cells. The relative mobilities of gene-enzyme systems representing nine distinct gene products from cell cultures of 25 species fromDrosophils to man are presented. These isoenzymes effectively discriminate interspecies cell-to-cell contamination and almost invariably serve to identify the contaminating species. The resolution of eightpolymorphic gene-enzyme systems in human cell cultures provides a virtually unique allozyme genetic signature as a monitor of intraspecies cellular contamination. The genetic signatures of 47 commonly used human cells are presented. Included in the test were seven putative HeLa (human cervical carcinoma) contaminants each of which expressed a signature identical with that of HeLa. The probability that an unrelated human cell line will have a signature identical to a typed cell is computed for each line from the genotypic frequencies at each locus in a population of cultured human cells. The gene frequencies of this cell population are comparable to the same frequencies in natural human populations. The most common human signature has a frequency (and therefore a probability) of 0.02. The majority of the 17,010 possible signatures are far less probable. A calculation of the theoretical incidence of chance matching of signatures within test groups of two or more individuals is presented. The probability of a chance match between any two randomly selected individuals is 0.004 and among five randomly selected individuals is 0.034. The allozyme genetic signature represents a definitive monitor of cell identity and is presented as a standard of cell and tissue identification for a variety of biological studies. This work was supported in part by the Virus Cancer Program of the National Cancer Institute.     

The Case of Watson vs. James: Effect-Priming Studies Do Not Support Ideomotor Theory

In this paper we show that response facilitation in choice reaction tasks achieved by priming the (previously perceived) effect is based on stimulus-response associations rather than on response-effect associations. The reduced key-press response time is not accounted for by earlier established couplings between the key-press movement and its subsequent effect, but instead results from couplings between this effect and the contingent key-release movement. This key-release movement is an intrinsic part of the entire performed response action in each trial of a reaction-time task, and always spontaneously follows the key-press movement. Eliminating the key-release movement from the task leads to the disappearance of the response facilitation, which raises the question whether response-effect associations actually play a role in studies that use the effect-priming paradigm. Together the three experiments presented in the paper cast serious doubts on the claim that action-effect couplings are acquired and utilized by the cognitive system in the service of action selection, and that the priming paradigm by itself can provide convincing evidence for this claim. As a corollary, we question whether the related two-step model for the ideomotor principle holds a satisfying explanation for how anticipation of future states guides action planning. The results presented here may have profound implications for priming studies in other disciplines of psychology as well.     

Factors Affecting the Algicidal and Algistatic Properties of Copper

Data from laboratory studies are presented to show that, whereas five different sources of copper appear to be equally effective as toxic agents for algae, the medium in which toxicity tests are carried out has a great influence on the toxicity of copper. A technique of subculture is described for determining whether a concentration of a chemical is algicidal, algistatic, or nontoxic in action against a specific alga, and demonstrations are given of tests with algae illustrating each class of action.     

Where do all the proteins go?

The subcellular localization of a protein can be very informative in identifying its function and in understanding the regulatory mechanisms by which it is controlled. Past efforts to define protein localization have typically entailed methods of immunological and fluorescence-based detection applied to a limited number of gene products. Several current studies are shifting this paradigm – utilizing traditional and novel approaches in molecular biology, proteomics, histochemistry and bioinformatics to define protein localization on a proteome-wide scale. Selected studies highlighting each of these approaches are presented here as an overview of the diverse avenues by which protein localization may be investigated for the identification of new drug targets.     

Mechanism of activation by anions of phosphoglycolate phosphatases from spinach and human red blood cells

Phosphoglycolate phosphatases from spinach and human red blood cells show a number of common features not often found in enzymes. Both enzymes are activated more than 50-fold by millimolar concentrations of Cl-. Other inorganic anions and a number of carboxylic acids also activate. Each enzyme has limited substrate specificity yet each hydrolyzes P-glycolate and ethyl-P with the same maximal velocity. L-P-lactate is only a good substrate for the red cell enzyme. With both enzymes initial rate data obtained by varying both the P-glycolate and Cl- give parallel line double reciprocal plots. Similar experiments with ethyl-P as substrate give intersecting lines with both enzymes. The likelihood that both classes of substrates are acting at the same site is strengthened by the results of inhibition studies with alternative substrates and the constancy of inhibition constants for glycolate with all substrates for a given enzyme. For each substrate the experimentally observed variation in V/Km with different activators is small, suggesting that the enzyme has an ordered mechanism with the phosphorylated substrate reacting first. A mechanism that is consistent with all of the data is presented.     

Location of proline derivatives in conformational space. II. Theoretical optical activity

The coupling of theoretical optical calculations with experimental data provides a check of the validity of the theory or provides conformational information. The theory was validated by studies in which the approximate conformation was located independently. These studies have shown that a theory restricted to the two lowest energy transitions for each chromophore gives qualitative agreement with experiment. On the other hand, for some of the proline derivatives, the theoretical treatment allows detailed conformational assignments. Both successes and failures in correlating theory with experiment are discussed. The results presented provide a basis for assessing the prospects for relating protein and polypeptide optical activity to their conformations.